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WO2002076925A2 - Composes d'aryl alkylamines non imidazole comme antagonistes des recepteurs h3 de l'histamine, preparation et applications therapeutiques - Google Patents

Composes d'aryl alkylamines non imidazole comme antagonistes des recepteurs h3 de l'histamine, preparation et applications therapeutiques Download PDF

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Publication number
WO2002076925A2
WO2002076925A2 PCT/US2002/006644 US0206644W WO02076925A2 WO 2002076925 A2 WO2002076925 A2 WO 2002076925A2 US 0206644 W US0206644 W US 0206644W WO 02076925 A2 WO02076925 A2 WO 02076925A2
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WIPO (PCT)
Prior art keywords
compound
chr
mmol
histamine
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2002/006644
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WO2002076925A3 (fr
Inventor
Lisa Selsam Beavers
Robert Alan Gadski
Philip Arthur Hipskind
Craig William Lindsley
Karen Lynn Lobb
James Arthur Nixon
Richard Todd Pickard
John Mehnert Schaus
Takako Takakuwa
Brian Morgan Watson
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Eli Lilly and Co
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Eli Lilly and Co
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Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Priority to JP2002576188A priority Critical patent/JP2004532834A/ja
Priority to AU2002254114A priority patent/AU2002254114A1/en
Priority to EP02723329A priority patent/EP1379493A2/fr
Priority to CA002441080A priority patent/CA2441080A1/fr
Priority to US10/472,675 priority patent/US7314937B2/en
Publication of WO2002076925A2 publication Critical patent/WO2002076925A2/fr
Publication of WO2002076925A3 publication Critical patent/WO2002076925A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
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    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • 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
    • C07C237/08—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 atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
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Definitions

  • the present invention relates to histamine H3 receptor antagonists, and as such are useful in the treatment of disorders responsive to the inactivation of histamine H3 receptors, such as obesity, cognitive disorders, attention deficient disorders and the like.
  • the histamine H3 receptor (H3R) is a presynaptic autoreceptor and hetero- receptor found in the peripheral and central nervous system and regulates the release of histamine and other neurotransmitters, such as serotonin and acetylcholine.
  • the histamine H3 receptor is relatively neuron specific and inhibits the release of a number of monamines, including histamine. Selective antagonism of the histamine H3 receptor raises brain histamine levels and inhibits such activities as food consumption while minimizing non-specific peripheral consequences.
  • Antagonists of the histamine H3 receptor increase synthesis and release of cerebral histamine and other monoamines. By this mechanism, they induce a prolonged wakefulness, improved cognitive function, reduction in food intake and normalization of vestibular reflexes. Accordingly, the histamine H3 receptor is an important target for new therapeutics in Alzheimer disease, mood and attention adjustments, cognitive deficiencies, obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy and motion sickness.
  • EP 978512 published March 1 2000 discloses non-imidazole aryloxy alkylamines discloses histamine H3 receptor antagonists but does not disclose the affinity, if any, of these antagonists for recently identified histamine receptor GPRv53, described below.
  • EP 0982300 A2 (pub.
  • March 1, 2000 discloses non-imidazole alkyamines as histamine HS receptor ligand which are similar to the subject invention by having a phenoxy core structure although the subject invention is unique in the dissimilar substitutions at the ortho, meta or para positions of the central benzene ring, the exact substitutions of the non-oxygen benzene ring substituent, and in some cases the presence of a saturated, fused heterocyclic ring appended to the central benzene core. Furthermore the compounds of this invention are highly selective for the H3 receptor (vs. other histamine receptors), and possess remarkable drug disposition properties (pharmacokinetics).
  • H1R, H2R, H3R and a newly identified receptor designated GPRv53 [(Oda T., et al., J.Biol.Chem. 275 (47): 36781-6 (2000)].
  • GPRv53 is a widely distributed receptor found at high levels in human leukocytes. Activation or inhibition of this receptor could result in undesirable side effects when targeting antagonism of the H3R receptor.
  • the identification of this new receptor has fundamentally changed histamine biology and must be considered in the development of histamine H3 receptor antagonists.
  • the present invention provides compounds that are useful as histamine H3 receptor antagonists.
  • the present invention provides compounds that are useful as selective antagonists of the histamine H3 receptor but have little or no binding affinity of GPRv53.
  • the present invention provides pharmaceutical compositions comprising antagonists of the histamine H3 receptor.
  • the present invention provides compounds, pharmaceutical compositions, and methods useful in the treatment of obesity, cognitive disorders, attention deficient disorders and other disorders associated with histamine H3 receptor.
  • the present invention is a compound structurally represented by Formula I
  • X is O, NR 7 or S
  • Rl is hydrogen
  • R2 is independently R 1 , or
  • R3 is independently C 3 -C 7 cycloalkylene, or C.- C 4 alkylene optionally substituted;
  • R4 is hydrogen, halogen, C1 -C4 alkyl,
  • R5 is hydrogen , or C1-C4 alkyl
  • R6 is hydrogen, halo or cyclized with the attached carbon atom at the R ⁇ position to form a 5 to 6 member carbon ring, cyclized with the attached carbon atom at the R ⁇ position to form a 5 to 6 member heterocyclic ring or
  • R7 is hydrogen
  • R8 is hydrogen, a bond, Ci -Cg alkyl
  • R 9 is hydrogen, halogen, Cj-Cg alkyl optionally substituted with 1 to 4 halogens,
  • the core phenoxy ring is an o, m, or p- disubstituted benzene, more preferably a p-di substituted benzene.
  • R 6 forms a bicyclic carbon ring at the R 5 position.
  • R 6 may form a bicyclic heterocyclic ring at the R 7 position.
  • X is nitrogen
  • R 4 and R 5 are independently H or CH 3
  • Rl and R2 are independently a C]-C 8 alkyl
  • R9 is a di-Ci to C 2 alkyl-amino.
  • the present invention is a pharmaceutical composition which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • Pharmaceutical formulations of Formula I can provide a method of selectively increasing histamine levels in cells by contacting the cells with an antagonist of the histamine H3 receptor, the antagonists being a compound of Formula I.
  • the present invention further provides an antagonist of Formula I which is characterized by having little or no binding affinity for the histamine receptor GPRv53.
  • a pharmaceutical preparation of Formula I can be useful in the treatment or prevention of obesity, cognitive disorders, attention deficient disorders and the like, which comprises administering to a subject in need of such treatment or prevention an effective amount of a compound of Formula I.
  • a pharmaceutical preparation of Formula I can be useful in the treatment or prevention of a disorder or disease in which inhibition of the histamine H3 receptor has a beneficial effect or the treatment or prevention of eating disorders which comprises administering to a subject in need of such treatment or prevention an effective amount of a compound of Formula I.
  • GPRv53 means a recently identified novel histamine receptor as described in Oda, et al, supra. Alternative names for this receptor are PORT3 or H4R.
  • H3R means to the histamine H3 receptor that inhibits the release of a number of monoamines, including histamine.
  • H1R means to the histamine HI receptor subtype.
  • H2R means to the histamine H2 receptor subtype.
  • selective H3R antagonists is defined as the ability of a compound of the present invention to block forskolin-stimulated cAMP production in response to agonist R (-) ⁇ methylhistamine.
  • Alkylene are a saturated hydrocarbyl diyl radical of straight or branched configuration made up of from 1 to 4 carbon atoms. Included within the scope of this term are methylene, 1,2 -ethane-diyl, 1,1-ethane-diyl, 1,3-propane diyl, 1,2-propane diyl, 1,3 butane-diyl, 1,4 -butane diyl, and the like.
  • C 3 -C 7 cycloalkylene are a saturated hydrocarbyldiyl radical of cyclic configuration, optionally branched, made up of from 3 to 7 carbon atoms. Included within the scope of this term are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the like.
  • Alkyl are one to four or one to eight carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric forms thereof.
  • Aryl are six to twelve carbon atoms such as phenyl, alpha -naphthyl, beta - naphthyl, m-methylphenyl, p-trifluoromethylphenyl and the like.
  • the aryl groups can also be substituted with one to 3 hydroxy, fluoro, chloro, or bromo groups.
  • Cycloalkyl are three to seven carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Heteroaryl are six to twelve carbon atoms aryls, as described above, containing the heteroatoms nitrogen, sulfur or oxygen. Heteroaryls are pyridine, thiophene, furan, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pryidazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3- isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4- pyrazolyl, 5-pyrazolyl, 2-oxazolyl
  • Heterocycle are three to twelve carbon atom cyclic aliphatic rings, wherein one or more carbon atoms is replaced by a hetero-atom which is nitrogen, sulfur or oxygen.
  • Halogen or “halo” means fluoro, chloro, bromo and iodo.
  • Composition means a pharmaceutical composition and is intended to encompass a pharmaceutical product comprising the active ingredient(s), Formula I, and the inert ingredient(s) that make up the carrier. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • unit dosage form means physically discrete units suitable as unitary dosages for human subjects and other non-human animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
  • treating and “treat”, as used herein, include their generally accepted meanings, i.e., preventing, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, or reversing the progression or severity of a pathological condition, described herein.
  • the present invention provides compounds of Formula I as described in detail above.
  • Another embodiments are where the phenoxy core structure is an o, m, or p- disubstituted aryl.
  • Another embodiment is a compound wherein R 6 is cyclized with the attached carbon atom at R 7 to form, including the fused benzene ring, a substituted tetrahydroisoquinoline ring.
  • Another embodiment is a compound wherein X is nitrogen, and wherein R 7 and R 8 are cyclized to form, together with X, a pyrrolidine ring, and wherein R 9 is -CH2-N-pyrrolidinyl.
  • a preferred moiety for X is independently O or N.
  • a preferred moiety for R 9 is C]-C 8 dialkylamino.
  • a more preferred embodiment is where the dialkylamino is dimethylamine
  • references to the compounds of Formula I are meant to also include the pharmaceutical salts, its enantiomers and racemic mixtures thereof. Because certain compounds of the invention contain a basic moiety (e.g., amino), the compound of Formula I can exist as a pharmaceutical acid addition salt.
  • Such salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono- hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-l,4 dioate, 3-hexyne-2, 5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, beta-hydroxybutyrate, glycollate, maleate, tart
  • the invention includes tautomers, enantiomers and other stereoisomers of the compounds also.
  • certain aryls may exist in tautomeric forms. Such variations are contemplated to be within the scope of the invention.
  • the compounds of Formula I may be prepared by several processes well known in the art.
  • the compounds of the present invention are prepared by standard alkylation or Mitsunobu chemistries and reductive animations known to one skilled in the art, or by the methods provided herein, supplemented by methods known in the art.
  • this reaction is conducted in an organic solvent such as, for example, halogenated hydrocarbons, toluene, acetonitrile and the like, preferably in the absence of moisture, at temperatures in the range about O-lOOo C, by bringing together the ingredients in contact in the solvent medium and stirring for about 10 minutes to about 48 hours at such temperatures.
  • the compounds of Formula I when existing as a diastereomeric mixture, may be separated into diastereomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate 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 acid as a resolving agent.
  • any enantiomer of a compound of the formula may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration or through enantioselective synthesis.
  • Table 1 are being provided to further illustrate the present invention. They are for illustrative purposes only; the scope of the invention is not to be considered limited in any way thereby.
  • the preparation of compounds of Formula I are depicted in the schemes and procedures below.
  • Example 2 To a 100 mL round-bottom flask was placed NaH (60% dispersion, 38.4 mg, 1.0 mmol) and anhydrous THF (10 mL, 0.1 M) under an atmosphere of nitrogen. Then, a DMF solution of p-hydroxyacetophenone ( 62 mg, 0.5 mmol) was added at 0 C. After 15 minutes, a DMF solution of 3-chloro-N,N-diethyl-N-proplyamine (150 mg, 1.0 mmol) was added, and the reaction was allowed to slowly reach room temperature over 3 hours. The reaction was then quenched with water, diluted with ether and washed with water (3 x 20 mL) and brine (2x 20 mL).
  • Example 228 7-(3-Piperidin-l-yl-propoxy-3,4-dihydro-l-H-isoquinoline-2-carboxylic acid tert-butyl ester;
  • Procedure A A 100 mL dioxane solution of 7-hydroxy-3,4-dihydro-l-H-isoquinoline-2- carboxylic acid tert-butyl ester (5.0 g, 20 mmol) is stirred under N 2 as Cs 2 CO 3 (13.3 g, 43 mmol), KI (0.1 g, 0.6 mmol), then N-(3-chloropropyl)piperidine (3.9 g, 24 mmol) are added in succession. The reaction mixture is heated at 90°C for 10 hours, cooled, filtered, and concentrated to give the crude product. Purification by chromatography (SiO 2 ; 0- 10% MeOH/CH ⁇ h/ ⁇ NH-OH gradient) gives the product as an amber oil (7.5 g, 100% yield). MS(ES+)375.3(M+H) + .
  • Example 238 7-(3-Piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride; Procedure B: A 50 mL CH 2 C1 2 solution of 7-(3-Piperidin-l-yl-propoxy-3,4-dihydro-l-H- isoquinoline-2-carboxylic acid tert-butyl ester (5.1 g, 13.8 mmol) is stirred under N 2 at 0- 10°C as 4N HCl/dioxane (11.5 mL, 46 mmol) is added dropwise. After the addition is complete, reaction mixture is stirred at this temperature for 30-60 min, then allowed to warm to room temperature.
  • Procedure B A 50 mL CH 2 C1 2 solution of 7-(3-Piperidin-l-yl-propoxy-3,4-dihydro-l-H- isoquinoline-2-carboxylic acid tert-butyl ester
  • Example 245 2-Methyl-7-(3-Piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline: A 10 mL THF suspension of LAH (150 mg,4 mmol) is stirred under N 2 at 0-10°C as a 10 mL THF solution of 7-(3-piperidin-l-yl-propoxy-3,4-dihydro-l-H-isoquinoline-2-carboxylic acid tert-butyl ester (200 mg, 0.53 mmol) is added dropwise.
  • reaction mixture is allowed to warm to room temperature, then reaction mixture is concentrated, dissolved in dry MeOH, concentrated, triturated in Et 2 O, filtered, and dried in vacuo to give the di-HCl salt (4.5 g, 94% yld) as a white solid.
  • 2-Isopropyl-7-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline 2-Isopropyl-7- (3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3- piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride (520 mg, 1.5 mmol), MP-CNBH 3 (3.2 g, 7.5 mmol), and acetone (1.1 mL, 15 mmol) via a procedure substantially analogous to Procedure C except that the SCX column is not used in purification. The product (210 mg, 44% yld) is isolated as a clear oil. MS(ES+)317.2(M+H) + .
  • Example 275 l-[7-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinolin-2-yl]-ethanone: A 5 mL CH 2 C1 2 solution of 7-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol) and NEt 3 (0.25 mL, 1J mmol) is stirred under N 2 , a 1 mL CH 2 C1 2 solution of acetyl chloride (0.043 mL, 0.6 mmol) is added, and reaction is stirred at room temp, for 5-6 hours.
  • Procedure E A 7 mL CHCl 3 /t-BuOH/MeCN (5:1:1) mixture of 7-(3-piperidin-l-yl- propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride (256 mg, 0.74 mmol), resin bound DCC (1.1 g, 0.9 mmol), hydroxybenzotriazole (HOBt, 150 mg, 1.1 mmol), and thiophene-2-carboxylic acid (118 mg, 0.9 mmol) is shaken in a capped vial at room temperature for 48 hours. The reaction mixture is filtered and the resin beads washed twice alternately with MeOH, then CH 2 C1 2 .
  • 2-Dimethylamino-l-[7-(3-piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinolin-2-yl]- ethanone 2-Dimethylamino-l-[7-(3-piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinolin- 2-yl]-ethanone is prepared from 7-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro- isoquinoline dihydrochloride (175 mg, 0.5 mmol), PS-DCC (800 mg, 1.1 mmol), HOBt (80 mg, 0.77 mmol), NEt 3 (0.21 mL, 1.5 mmol)and N,N-dimethylglycine (1.1 mL, 15 mmol) via a procedure substantially analogous to Procedure E except that PS-trisamine resin beads (700 mg, 2.6 mmol
  • Example 266 7-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinoline-2-carboxylic acid isopropylamide: A 10 mL CH 2 C1 2 solution of 7-(3-piperidin-l-yl-propoxy)-l,2,3,4- tetrahydro-isoquinoline dihydrochloride (254 mg, 0.73 mmol), NEt 3 (0.20 mL, 1.4 mmol), isopropyl isocyanate (192 mg, 2.2 mmol), and 4-dimethylaminopyridine (12 mg, 0.1 mmol) is stirred under N 2 , at room temperature for 18 hours.
  • Example 249 2-Benzenesulfonyl-7-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline; Procedure F: A 5 L CH 2 C1 solution of 7-(3-piperidin-l-yl-propoxy)-l,2,3,4- tetrahydro-isoquinoline dihydrochloride (185 mg, 0.53 mmol) and NEt 3 (0.22 mL,1.8 mmol) is stirred under N 2 , benzenesulfonyl chloride (0.08 mL, 0.62 mmol) is added, and reaction is stirred at room temperature for 5-6 hours.
  • Procedure F A 5 L CH 2 C1 solution of 7-(3-piperidin-l-yl-propoxy)-l,2,3,4- tetrahydro-isoquinoline dihydrochloride (185 mg, 0.53 mmol) and NEt 3 (0.22 mL,1.8 m
  • Example 268 7-(3-Piperidin-l-yl-propoxy)-2-(thiophene-2-sulfonyl)-l,2,3,4-tetrahydro-isoquinoline: 7-(3-Piperidin-l-yl-propoxy)-2-(thiophene-2-sulfonyl)-l,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-l-yl-propoxy)-l ,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol), NEt 3 (0.25 mL, 1.8 mmol), and thiophene-2- sulfonyl chloride (114 mg, 0.63 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product (160 mg, 76% yld). MS(ES+)421.1(M+H) +
  • Example 284 2-Methanesulfonyl-7-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline hydrochloride: 2-Methanesulfonyl-7-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro- isoquinoline hydrochloride is prepared from 7-(3-piperidin-l-yl-propoxy)-l,2,3,4- tetrahydro-i soquinoline dihydrochloride (183 mg, 0.52 mmol), NEt 3 (0.25 mL, 1.8 mmol), and methanelsulfonyl chloride (0.05 mL, 0.66 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the free base product.
  • Example 286 2-(4-Methoxy-benzenesulfonyl-7-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro- isoquinoline hydrochloride: 2-(4-Methoxy-benzenesulfonyl-7-(3-piperidin-l-yl-propoxy)- 1,2,3,4-tetrahydro-isoquinoline hydrochloride is prepared from 7-(3-piperidin-l-yl- propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride (150 mg, 0.43 mmol), NEt 3 (0.21 mL, 1.5 mmol), and 4-methoxybenzenesulfonyl chloride (115 mg, 0.57 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the free base product.
  • Example 277 l- ⁇ 4-[7-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinoline-2-sulfonyl]-phenyl ⁇ - ethanone: l- ⁇ 4-[7-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinoline-2-sulfonyl]- phenylj-ethanone is prepared from 7-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro- isoquinoline dihydrochloride (175 mg, 0.5 mmol), NEt 3 (0.25 mL, 1.8 mmol), and 4- acetylbenzenelsulfonyl chloride (131 mg, 0.60 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product (85 mg, 37% y
  • Example 278 2-(4-Cyanobenzenesulfonyl)-7-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro- isoquinoline: 2-(4-Cyanobenzenesulfonyl)-7-(3-piperidin-l-yl-propoxy)-l, 2,3,4- tetrahydro-isoquinoline is prepared from 7-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro- isoquinoline dihydrochloride (175 mg, 0.5 mmol), NEt 3 (0.25 mL, 1.8 mmol), and 4- cyanobenzenesulfonyl chloride (121 mg, 0.60 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product (157 mg, 71% yld). MS(ES+) 440.1(M+H) +
  • 6-hydroxy-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester is prepared by the procedures similar to those described in Selnick, H.G.; Smith, G. R.; Tebben, A. J.; Synth. Commun. 1995, 25, 3255-3262.
  • Example 127 6-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester: To a round-bottom flask, equipped with stir bar and septum, is placed 6-hydroxy- 3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester (1 g, 4.01 mmol), KI (599 mg, 4.01 mmol) and NaH (162 mg, 95%dry, 6.42 mmol).
  • 6-(3-Piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride To a round-bottom flask, equipped with stir bar and septum, is placed 6-(3-piperidin-l-yl- propoxy)-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester (1 g, 2.6 mmol), DCM (20 L) and 4M HCl/dioxane (5 L). The reaction is allowed to stir at room temperature for 3 h.
  • Example 40 Dimethyl-[3-(l,2,3,4-tetrahydro-isoquinolin-6-yloxy)-propyl]-amine dihydrochloride; M+l 235.
  • Example 140 6-[3-(2-Methyl-piperidin-l-yl)-propoxy]-l,2,3,4-tetrahydro-isoquinoline dihydrochloride; M+l 289.
  • Example 129 2-Ethyl-6-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline: To a 25 mL round- bottom flask is placed 6-(3-Piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride (700 mg, 2.01 mol), MP-CNBH 3 (2.5 g, 6.05 mmol, 2.42 mmol/g) and DCM/MeOH (9mL/lmL). Then, acetaldehyde is added (0.7 mL, 12 mmol) and the reaction is allowed to stir overnight.
  • 6-(3-Piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride 700 mg, 2.01 mol
  • MP-CNBH 3 2.5 g, 6.05 mmol, 2.42 mmol/g
  • Example 250 2-Ethyl-6-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride: 2-Ethyl-6- (3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline (5.12g, 16.9 mmol) is dissolved in MeOH (50 mL), and IM HCl in ether is added dropwise (37.2 mL, 37.2 mmol) and the mixture is stirred for 10 minutes and concentrated to give the dihydrochloride salt as a white solid (6.0 g, 93%).
  • Example 143 2-Isopropyl-6-[3-(2-methyl-piperidin-l-yl)-propoxy]-l,2,3,4-tetrahydro-isoquinoline: To a flask equipped with a stir bar is placed 6-[3-(2-Methyl-piperidin-l-yl)-propoxy]-l,2,3,4- tetrahydro-isoquinoline dihydrochloride (300 mg, 0.83 mmol), acetone (excess), NaCNBH 3 (155 mg, 2.5 mmol) in MeOH (8 mL) and the mixture stirred at room temperature for 2h. The reaction mixture is diluted with water, and extracted with CH 2 C1 2 . The organic phase is dried over Na 2 SO 4 and concentrated. M+l 331, LCMS
  • Example 138 is prepared:
  • Example 178 6-(2-Piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinoline-2-carboxylic acid isopropylamide: To a 4 mL vial is placed 6-(3-piperidin-l-yl-propoxy)-l,2,3,4- tetrahydro-isoquinoline dihydrochloride (25.0 mg, 0.07 mmol), resin-bound Hunigs base (81 mg, 0.29 mmol, 3.54 mmol/g), resin bound DMAP (catalytic), and dry CH 2 C1 2 and isopropyl isocyanate (16 DL, 0.18 mmol). The vial is agitated by means of a lab quake shaker overnight.
  • Example 79 [3-(2-Methanesulfonyl-l,2,3,4-tetrahydro-isoquinolin-6-yloxy)-propyl]-dimethyl-amine: To a 4 mL vial is placed Dimethyl-[3-(l,2,3,4-tetrahydro-isoquinolin-6-yloxy)-propyl]- amine (24.0 mg, 0.1 mmol), resin-bound DIEA (58 mg, 0.2 mmol, 3.54 mmol/g), MsCl (12 DL, 0.15 mmol) and dry CH 2 C1 2 (2 mL). The vial is allowed to rotate overnight.
  • PS-trisamine (136 mg, 0.41 mmol, 3.0 mmol/g) is added and the reaction again allowed to rotate for 4 hours to scavenge excess MsCl. Filtration, washing with CH 2 C1 2 and concentration affords the desired urea LCMS >99% @ 230 nm and ELSD, M+l 360.
  • Example 302 2-Benzenesulfonyl-6-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline: 2- Benzenesulfonyl-6-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline is prepared from 6-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride (330 mg, 0.95 mmol), NEt 3 (0.48 mL, 3.5 mmol), and benzenesulfonyl chloride (0.15 mL, 1.17 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product as a white solid (250 mg, 63% yld). MS(ES+) 415.3(M+H) + .
  • 5-Hydroxy-3,4-dihydro-l-H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared by the procedures similar to those described in Durand S.; Lusinchi, X.; Moreau, R. C. Bull. Soc. Chim. France 1961, 207, 270; and Georgian, V.; Harrison, R. J.; Skaletzky, L. L.; / Org Chem 1962, 27, 4571.
  • Example 290 5-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester is prepared from 5-Hydroxy-3,4-dihydro-l-H-isoquinoline-2-carboxylic acid tert- butyl ester (5.69 g, 22.8 mmol) in a manner substantially analogous to Procedure A except DMF is used in place of dioxane.
  • Example 309 [5-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinolin-2-yl]-thiophen-2-yl- methanone is prepared from 5-(3-Piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride salt (0.256 g, 0.74 mmol) in a manner substantially analogous to Procedure E to give the title compound as an off-white solid (0.109 g, 38%). MS (ES+) 415.2
  • 8-Methoxy-l,2,3,4-tetrahydro-isoquinoline is prepared according to Shanker, P. S.; Subba Rao, G. S. R. Indian I. of Chemistry section B 1993, 32B, 1209-1213.
  • 8-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester is prepared from 8-hydroxy-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert- butyl ester (0.84 g, 3.4 mmol) in a manner substantially analogous to Procedure A except DMF is used in place of dioxane.
  • Example 310 2-Ethyl-8-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline is prepared from 8- (3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride salt (0.375 g, 1.1 mmol) in a manner substantially analogous to Procedure C to give the title compound as a yellow oil (0.124 g, 37%). MS (ES+) 303.3.
  • Example 312 [8-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-lH-isoquinolin-2-yl]-thiophen-2-yl- methanone: To a mixture of 8-(3-piperidin-l-yl-propoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride salt (300 mg, 0.86 mmol) and NEt 3 (0.36 mL, 2.6 mmol) in CH 2 C1 2 (10 mL) is added 2-thiophene carbonyl chloride (0.10 mL, 0.95 mmol). After stirring at room temperature overnight, the mixture is partitioned between EtOAc and water.
  • Example 206 6-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-2H-isoquinolin-l-one is prepared from 6- hydroxy-3,4-dihydro-2H-isoquinolin-l-one (CAS Registry Number 22245-98-3) (0.5 g, 2.9 mmol) in a manner substantially analogous to Procedure A except DMF is used in place of dioxane. Following aqueous workup, the crude material is purified by flash chromatography (Biotage 40M SiO 2 , elute 90/10/1 CH 2 Cl 2 /MeOH/NH 4 OH) to give the title compound as a white solid (0.516 g, 61%). MS (ES+) 289.1
  • Example 207 7-(3-Piperidin-l-yl-propoxy)-3,4-dihydro-2H-isoquinolin-l-one is prepared from 7- hydroxy-3,4-dihydro-2H-isoquinolin-l-one (CAS Registry Number 22246-05-5) (1.43 g, 8.76 mmol) in a manner substantially analogous to Procedure A except DMF is used in place of dioxane. Following aqueous workup, the crude material is purified by flash chromatography (Biotage 40M SiO 2 , elute 90/10/1 to give the title compound as a white solid (1.11 g, 44%). MS (ES+) 289.1
  • Example 205 7-(3-Pyrrolidin-l-yl-propoxy)-3,4-dihydro-2H-isoquinolin-l-one is prepared from 7- hydroxy-3,4-dihydro-2H-isoquinolin-l-one (0.48 g, 2.94 mmol) in a manner substantially analogous to Procedure A except DMF is used in place of dioxane and l-(3-Chloro- propyl)-pyrrolidine is used instead of N-(3-chloropropyl)pi peri dine.
  • Example 240 ⁇ l-[4-(3-Piperidin-l-yl-propoxy)-phenyl]-cyclopropyl ⁇ -carbamic acid benzyl ester is prepared from [l-(4-Hydroxy-phenyl)-cyclopropyl]-carbamic acid benzyl ester (1.21 g, 4.28 mmol), Cs 2 CO 3 (2.78 g, 8.55 mmol), KI (71 mg, 0.43 mmol), and N-(3- chloropropyl)piperidine (0.86 g, 5.34 mmol) in dioxane (50 mL) in a manner substantially analogous to Procedure A to give the product( (1.16 g, 66%). MS (ES+) 409.3.
  • 2-Morpholin-4-yl-N- ⁇ l-[4-(3-piperidin-l-yl-propoxy)-phenyl]-cyclopropyl ⁇ -acetamide l-[4-(3-Piperidin-l-yl-propoxy)-phenyl]-cyclopropylamine (0.195 g, 0.72 mmol) and morpholin-4-yl-acetic acid (0.125 g, 0.86 mmol) are dissolved in DMF, and diisopropylethylamine added (0.15 mL), followed by EDC (0.165 g, 0.86 mmol) and HOBt (0.116 g, 0.86 mmol). The reaction mixture was stirred overnight at room temperature.
  • Example 314 7-(4-Piperidin-l-yl-butoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride: 7-(4- Piperidin-l-yl-butoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride is prepared from
  • 2-Ethyl-7-(4-piperidin-l-yl-butoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride 2- Ethyl-7-(4-piperidin-l-yl-butoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride is prepared from 7-(4-piperidin-l-yl-butoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride (252 mg, OJ mmol), and acetaldehyde (0.40 mL, 7 mmol) in a manner substantially analogous to Procedure C to give the dihydrochloride product as an off white solid(125 mg, 70% yld). MS(ES+)317.2(M+H) + free base.
  • 2-Cyclohexylmethyl-7-(4-piperidin-l-yl-butoxy)-l,2,3,4-tetrahydro-isoquinoline dihydrochloride 2-Cyclohexylmethyl-7-(4-piperidin-l-yl-butoxy)-l,2,3,4-tetrahydro- isoquinoline dihydrochloride is prepared from 7-(4-piperidin-l-yl-butoxy)-l, 2,3,4- tetrahydro-i soquinoline dihydrochloride (175 mg, 0.48 mmol), and cyclohexanecarboxaldehyde (0.35 mL, 2.9 mmol) in a manner substantially analogous to
  • Example 208 [3-(3-Piperidin-l -yl-propox y)-benzyl]-(3-pyrrolidin-l-yl-propyl)-amine: The reductive amination is run with 3-(3-piperidin-l-yl-propoxy)-benzaldehyde (1 g, 4 mmol) and ), 3- pyrrolridin-1-yl propylamine (1 mL, 8 mmol), and MP-CNBH 3 resin(4.5g, 10.4 mmol)via a procedure substantially analogous to [2-(3-piperidin-l-yl-propoxy)-benzyl]-(3- pyrrolidin-l-yl-propyl)-amine to give the product as a yellow oil(818 mg, 58 % yld). MS(ES+)360.3(M+H) + free base.
  • Example 202 [4-(4-Piperidin-l-yl-butoxy)-benzyl]-(2-pyrrolidin-l-yl-ethyl)-amine: An 8 mL DMF solution of [4-(4-bromo-butoxy)-benzyl]-(2-pyrrolidin-l-yl-ethyl)-amine (307 mg, 0.86 mmol) and piperidine (0.22 mL, 2.2 mmol) is stirred at 90 °C for six hours under N 2 . The reaction mixture is cooled, diluted with CH 2 C1 2 , filtered, washed with brine, dried (Na 2 SO 4 ), and concentrated.
  • Example 237 2-Fluoro-N-(2-piperidin-l-yl-ethyl)-4-(3-piperidin-l-yl-propoxy)-benzamide: To a mixture of 2-Fluoro-4-(3-piperidin-l-yl-propoxy)-benzoic acid (70 mg, 0.25 mmol) and l-(2-aminoethyl)piperidine (45 DL, 0.3 mmol) in DMF (5 mL) was added EDC (58 mg, 0.3 mmol), HOBT (40 mg, 0.3 mmol), and diisopropylethyl amine (52 Dl, 0.3 mmol). The mixture was stirred at room temperature overnight.
  • EDC 58 mg, 0.3 mmol
  • HOBT 40 mg, 0.3 mmol
  • diisopropylethyl amine 52 Dl, 0.3 mmol
  • This compound was synthesized according to the method described in the preparation of (5).
  • Example 209 This compound was synthesized according to the method described in the preparation of Example 261.
  • Example 131 Trisamine To a 4 mL vial was placed 101 (28.5 mg, 0.1 mmol), resin-bound DCC (170 mg, 0.16 mmol, 0.94 mmol/g), HOBt (16 mg, 0.12 mmol), amine (13 uL, 0.08 mmol) and a 5:1:1 mixture of CHCl 3 :CH 3 CN:tBuOH. The vial was agitated by means of a lab quake shaker overnight. In the morning, PS-trisamine (134 mg, 0.4 mmol, 3.0 mmol/g) was added and the reaction again allowed to rotate overnight to scavenge excess carboxylic acid and
  • keto-phenol 500 mg, 3 mmol
  • CsCO 3 1.99 g, 6 mmol
  • KI KI
  • Example 94 Example 94, and 192.
  • Example 192 can be made by a substantially analogous procedure, Observed mass 360. The following examples are made by a substantially analogous procedure:
  • Example 142 To a round-bottom flask, equipped with stir bar and septum, was placed (103) (300 mg, 1.03 mmol), KI (230 mg, 1.54 mmol) and NaH (78 mg, 95%dry, 3.09 mmol). Then, dry DMF (20 mL, 0.5 M) was added via syringe followed by chloroethylpiperidine (285 mg, 1.54 mmol). The reaction was allowed to stir at 50 degrees overnight. In the morning, the reaction was quenched with water, extracted into EtOAc (3 x 20 mL) and dried over brine. Column chromatography in 9:1 DCM:MeOH afforded 631934 an yellow oil (300 mg, 79%). Mass sec hit M+l, 404; LCMS >95% @ 230 nm and ELSD.
  • Example 15 The solution of diisopropylazodicarboxylate(3.93 ml, 20 mmoles) in 20 ml anhydrous THF was added dropwise with stirring to the cold solution of 4- hydroxyacetophenone(2.18 g, 16 mmoles), 3-diethylaminopropanol(2.23 ml, 15 mmoles) and triphenylphosphine(4.98 g, 19 mmoles) in 50 ml anhydrous THF over 45 minutes. The reaction was stirred in an ice bath for one hour and at room temperature for 18 hours. The solvent was evaporated and ether was added. This solution was extracted with dilute HC1(1.0 N) four times.
  • the compound of Formula I is preferably formulated in a unit dosage form prior to administration. Therefore, yet another embodiment of the present invention is a pharmaceutical composition comprising a compound of Formula I and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the active ingredient (Formula I compound) will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
  • a carrier When the carrier serves as a diluent, it may be a solid, semisolid or liquid material that acts as a vehicle, excipient, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
  • the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e., antihistaminic activity and the like.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions and emulsions.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as a re conventional in the art for this purpose.
  • the compound is administered orally.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • the quantity of the inventive active composition in a unit dose of preparation may be generally varied or adjusted from about 0.01 milligrams to about 1,000 milligrams, preferably from about 0.01 to about 950 milligrams, more preferably from about 0.01 to about 500 milligrams, and typically from about 1 to about 250 milligrams, according to the particular application.
  • the actual dosage employed may be varied depending upon the patient's age, sex, weight and severity of the condition being treated. Such techniques are well known to those skilled in the art.
  • the human oral dosage form containing the active ingredients can be administered 1 or 2 times per day. Utility
  • Compounds of Formula I are effective as histamine H3 receptor antagonists. More particularly, these compounds are selective histamine H3 receptor antagonists that have little or no affinity for histamine receptor GPRv53(H4R). As selective antagonists, the compounds of Formula I are useful in the treatment of diseases, disorders, or conditions responsive to the inactivation of the histamine H3 receptor, including but not limited to obesity and other eating-related disorders. It is postulated that selective antagonists of H3R will raise brain histamine levels and possibly that of other monoamines resulting in inhibition of food consumption while minimizing peripheral consequences. Although a number of H3R antagonists are known in the art, none have proven to be satisfactory obesity drugs. There is increasing evidence that histamine plays an important role in energy homeostasis.
  • Histamine acting as a neurotransmitter in the hypothalamus, suppressed appetite. Histamine is an almost ubiquitous amine found in many cell types and it binds to a family of G protein-coupled receptors (GPCRs). This family provides a mechanism by which histamine can elicit distinct cellular responses based on receptor distribution. Both the H1R and H2R are widely distributed. H3R is primarily expressed in the brain, notably in the thalamus and caudate nucleus. High density of expression of H3R was found in feeding center of the brain. A novel histamine receptor GPRv53 has been recently identified.
  • GPCRs G protein-coupled receptors
  • GPRv53 is found in high levels in peripheral white blood cells; only low levels have been identified in the brain by some investigators while others cannot detect it in the brain. However, any drug discovery effort initiated around H3R must consider GPRv53 as well as the other subtypes.
  • inventive compounds can readily be evaluated by using a competitive inhibition Scintillation Proximity Assay (SPA) based on a H3R binding assay using [3H] methylhistamine as ligand.
  • Stable cell lines including but not limited to HEK can be transfected with cDNA coding for H3R to prepare membranes used for the binding assay. The technique is illustrated below (Example 3) for the histamine receptor subtypes.
  • Membranes isolated as described in Example 3 were used in a [35S]GTP ⁇ S functional assay. Binding of [35S]GTP ⁇ S to membranes indicates agonist activity.
  • Compounds of the invention of Formula I were tested for their ability to inhibit binding in the presence of agonists. Alternately, the same transfected cell lines were used for a cAMP assay wherein H3R agonists inhibited forskolin-activated synthesis of cAMP.
  • Compounds of Formula I were tested for their ability to permit forskolin -stimulated cAMP synthesis in the presence of agonist. Preparation of Histamine Receptor Subtype Membranes A.
  • H1R membranes cDNA for the human histamine 1 receptor was cloned into a mammalian expression vector containing the CMV promoter (pcDNA3.1(+), Invitogen) and transfected into HEK293 cells using the FuGENE Tranfection Reagent (Roche Diagnostics Corporation). Transfected cells were selected using G418 (500 ⁇ /ml). Colonies that survived selection were grown and tested for histamine binding to cells grown in 96-well dishes using a scintillation proximity assay (SPA) based radioligand binding assay.
  • SPA scintillation proximity assay
  • Astemizole (lO ⁇ M, Sigma #A6424) was added to appropriate wells to determine nonspecific binding. Plates were covered with FasCal and incubated at room temperature for 120 minutes. Following incubation, plates were centrifuged at l,000rpm ( ⁇ 800g) for 10 minutes at room temperature. Plates were counted in a Wallac Trilux 1450 Microbeta scintillation counter. Several clones were selected as positive for binding, and a single clone (H1R40) was used to prepare membranes for binding studies. Cell pellets, representing -10 grams, were resuspended in 30ml assay buffer, mixed by vortexing, and centrifuged (40,000g at 4°C) for 10 minutes.
  • H2R10 a single clone (H2R10) was used to prepare membranes for binding studies. Five micrograms of protein was used per well in the SPA receptor-binding assay.
  • H3R membranes cDNA for the human histamine 3 receptor was cloned and expressed as described in Example 1, above.
  • Transfected cells were selected using G418 (500 ⁇ /ml), grown, and tested for histamine binding by the SPA described above.
  • Thioperimide was added to determine non-specific binding.
  • Several clones were selected as positive for binding, and a single clone (H3R8) was used to prepare membranes for binding studies described above. Five micrograms of protein was used per well in the SPA receptor-binding assay.
  • Example 1 Transfected cells were selected, tested for histamine binding, and selected.
  • HEK293 GPRv53 50 cells were grown to confluency in DMEM F12 (Gibco) supplemented with 5 % FBS and 500 ug/ml G418 and washed with Delbecco's PBS (Gibco) and harvested by scraping.
  • Whole cells were homogenized with a Polytron tissuemizer in binding buffer, 50 mM Tris pH 7.5. Cell lysates, 50 ug, were incubated in 96 well dishes with 3 nM (3H) Histamine and compounds in binding buffer for 2 hours at room temperature.
  • Lysates were filtered through glass fiber filters (Perkin Elmer) with a Tomtec cell harverster. Filters were counted with melt-on scintillator sheets (Perkin Elmer) in a Wallac Trilux 1450 Microbeta Scintillation counter for 5 minutes.
  • HEK293 H3R8 cells prepared as described above were seeded at a density of 50,000 cells/well and grown overnight in DMEM/F12 (Gibco) supplemented with 5 % FBS and 500 ug/ml G418. The next day tissue culture medium was removed and replaced with 50 ⁇ l cell culture medium containing 4 mM 3-isobutyl-l-methylxanthine (Sigma) and incubated for 20 minutes at room temperature. Antagonist were added in 50 ⁇ l cell culture medium and incubated for 20 minutes at room temperature.
  • Agonist R (-) ⁇ methylhistamine (RBI) at a dose response from lxlO "10 to lxlO "5 M was then added to the wells in 50 ⁇ l cell culture medium and incubated for 5 minutes at room temperature. Then 50 ⁇ l of cell culture medium containing 20 ⁇ M Forskolin (Sigma) was added to each well and incubated for 20 minutes at room temperature. Tissue culture medium was removed and cells were lysed in 0.1M HCl and cAMP was measured by ELISA (Assay Designs, Inc.).
  • [35S] GTP ⁇ [S] Binding Assay Antagonist activity of selected compounds was tested for inhibition of [35S] GTP ⁇ [S] binding to H3R membranes in the presence of agonists. Assays were run at room temperature in 20 mM HEPES, 100 mM NaCl ,5 mM MgCl 2 and 10 uM GDP at pH 7.4 in a final volume of 200 ul in 96-well Costar plates. Membranes isolated from H3R8- expressing HEK293 cell line (20 ug/well) and GDP were added to each well in a volume of 50 ⁇ l assay buffer.
  • Antagonist was then added to the wells in a volume of 50 ⁇ l assay buffer and incubated for 15 minutes at room temperature.
  • Agonist R(-)alpha methylhistamine (RBI) at either a dose response from lxlO "10 to lxlO "5 M or fixed concentration of 100 nM were then added to the wells in a volume of 50 ⁇ l assay buffer and incubated for 5 minutes at room temperature.
  • GTP ⁇ [35S] was added to each well in a volume of 50 ⁇ l assay buffer at a final concentration of 200 pM, followed by the addition of 50 ⁇ l of 20 mg/ml WGA coated SPA beads (Amersham).
  • Non-imidazole containing histamine H3 receptor antagonists disclosed in the literature generally have very poor pharmacokinetic properties (see J. Apelt, et al, J. Med. Chem. 2002, 45, 1128-1141). Compounds of this invention have markedly and unexpectedly improved pharmacokinetic properties.
  • Examples 131 and 271 were analyzed using LC/MS/MS.
  • compound example 131 was found to have an oral bioavailability of 58% (AUC 0-24hr; po/iv ratio) and an oral half-life of 10.4 + 4.2 hours (+SEM).
  • Compound example 271 was found to have an oral bioavailability of 69% (AUC 0-24hr; po/iv ratio) and an oral half-life of 71.9 ⁇ 3.3 hours ( ⁇ SEM).

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Abstract

L'invention concerne de nouveaux composés d'aryl alkylamine substitués représentés par la formule (I), ou des sels pharmaceutiquement acceptables de ceux-ci, qui possèdent une activité sélective d'antagoniste des récepteurs H3 de l'histamine, ainsi que des procédés de préparation de ces composés. Dans une autre forme de réalisation, l'invention concerne des compositions pharmaceutiques contenant de telles amines cycliques, ainsi que des procédés d'utilisation de celles-ci pour traiter l'obésité et d'autres maladies associées aux récepteurs H3 de l'histamine.
PCT/US2002/006644 2001-03-23 2002-03-21 Composes d'aryl alkylamines non imidazole comme antagonistes des recepteurs h3 de l'histamine, preparation et applications therapeutiques Ceased WO2002076925A2 (fr)

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AU2002254114A AU2002254114A1 (en) 2001-03-23 2002-03-21 Non-imidazole aryl alkylamines compounds as histamine h3 receptor antagonists, preparation and therapeutic uses
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CA002441080A CA2441080A1 (fr) 2001-03-23 2002-03-21 Composes d'aryl alkylamines non imidazole comme antagonistes des recepteurs h3 de l'histamine, preparation et applications therapeutiques
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