WO2004050623A1 - Procedes pour l'elaboration de derives phenylalkyniques - Google Patents

Procedes pour l'elaboration de derives phenylalkyniques Download PDF

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Publication number
WO2004050623A1
WO2004050623A1 PCT/US2003/019601 US0319601W WO2004050623A1 WO 2004050623 A1 WO2004050623 A1 WO 2004050623A1 US 0319601 W US0319601 W US 0319601W WO 2004050623 A1 WO2004050623 A1 WO 2004050623A1
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WIPO (PCT)
Prior art keywords
phenyl
membered heterocyclyl
alkylene
alkyl
heterocyclyl
Prior art date
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PCT/US2003/019601
Other languages
English (en)
Inventor
Richard Apodaca
Xiaohu Deng
Jill A. Jablobnowski
Neelakandha Mani
Chennagiri R. Pandit
Wei Xiao
Original Assignee
Ortho-Mcneil Pharmaceutical, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2002/038480 external-priority patent/WO2003050099A1/fr
Application filed by Ortho-Mcneil Pharmaceutical, Inc. filed Critical Ortho-Mcneil Pharmaceutical, Inc.
Priority to CA002507875A priority Critical patent/CA2507875A1/fr
Priority to BR0316971-5A priority patent/BR0316971A/pt
Priority to JP2004557098A priority patent/JP2006514939A/ja
Priority to EP03739242A priority patent/EP1567494A1/fr
Priority to MXPA05005830A priority patent/MXPA05005830A/es
Priority to AU2003245613A priority patent/AU2003245613A1/en
Publication of WO2004050623A1 publication Critical patent/WO2004050623A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/42—One nitrogen atom
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    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • 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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    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
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    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to phenylalkynes, their synthesis and their use, for example, for the treatment of disorders and conditions mediated by the histamine receptor.
  • Histamine [2-(imidazol-4-yl)ethylamine] is a transmitter substance. Histamine exerts a physiological effect via multiple distinct G-protein coupled receptors. It plays a role in immediate hypersensitivity reactions and is released from mast cells following antigen IgE antibody interaction. The actions of released histamine on the vasculature and smooth muscle system account for the symptoms of the allergic response. These actions occur at the Hi receptor (Ash, A.S.F. and Schild, H.O., Br. J. Pharmac. Chemother. 1966, 27:427-439) and are blocked by the classical antihistamines (e.g. diphenhydramine).
  • Histamine is also an important regulator of gastric acid secretion through its action on parietal cells. These effects of histamine are mediated via the H 2 receptor (Black, J.W. et al., Nature 1972, 236:385-390) and are blocked by H 2 receptor antagonists (e.g. cimetidine).
  • H 2 receptor antagonists e.g. cimetidine
  • the third histamine receptor — H 3 — was first described as a presynaptic autoreceptor in the central nervous system (CNS) (Arrang, J.-M. et al., Nature 1983, 302:832- 837) controlling the synthesis and release of histamine.
  • H 3 receptors are also located presynaptically as heteroreceptors on serotonergic, noradrenergic, dopaminergic, cholinergic, and GABAergic (gamma-aminobutyric acid containing) neurons. These H 3 receptors have also recently been identified in peripheral tissues such as vascular smooth muscle. Consequently there are many potential therapeutic applications for histamine H 3 agonists, antagonists, and inverse agonists. (See: "The Histamine H 3 Receptor-A Target for New Drugs" , Leurs, R., and Timmerman, H., (Eds.), Elsevier, 1998; Morisset, S.
  • histamine H 3 agonists in sleep/wake and arousal/vigilance disorders is suggested based on animal studies (Lin, J.-S. et al., Brain Res. 1990, 523:325-330; Monti, J.M. et al., Eur. J. Pharmacol. 1991 , 205:283-287). Their use in the treatment of migraine has also been suggested (McLeod, R.L. et al., Soc. Neurosci. Abstr. 1996, 22:2010) based on their ability to inhibit neurogenic inflammation. Other applications could be a protective role in myocardial ischemia and hypertension where blockade of norepinephrine release is beneficial (Imamura, M.
  • histamine H 3 agonists may be beneficial in asthma due to their ability to reduce non- adrenergic non-cholinergic (NANC) neurotransmission in airways and to reduce microvascular leakage (lchinose, M. and Barnes, P.J., Eur. J. Pharmacol. 1989, 174:49-55).
  • NANC non- adrenergic non-cholinergic
  • histamine H 3 antagonists and inverse agonists have similarly been proposed based on animal pharmacology experiments with known histamine H 3 antagonists (e.g. thioperamide).
  • histamine H 3 antagonists e.g. thioperamide.
  • these include dementia, Alzheimer's disease (Panula, P. et al., Soc. Neurosci. Abstr. 1995, 21 :1977), epilepsy (Yokoyama, H. et al., Eur. J. Pharmacol. 1993, 234:129-133), narcolepsy, eating disorders (Machidori, H. et al., Brain Res. 1992, 590:180- 186), motion sickness, vertigo, attention deficit hyperactivity disorders (ADHD), learning and memory (Barnes, J.C.
  • ADHD attention deficit hyperactivity disorders
  • Histamine H 3 antagonists alone or in combination with a histamine Hi antagonist, are reported to be useful for the treatment of upper airway allergic response (U.S. Patent Nos.
  • histamine H 3 Receptor-A Target for New Drugs Leurs, R., and Timmerman, H., (Eds.), Elsevier, 1998.
  • histamine H 3 agonists and antagonists were reviewed (see: Krause, M. et al., and Phillips, J.G. and Ali, S.M., respectively).
  • the importance of an imidazole moiety containing only a single substitution in the 4 position was noted together with the deleterious effects of additional substitution on activity. Particularly, methylation of the imidazole ring at any of the remaining unsubstituted positions was reported to strongly decrease activity.
  • imidazole-containing drugs via their interaction with the cytochrome P450 monooxygenase system, can result in unfavorable biotransformations due to enzyme induction or enzyme inhibition (see: Kapetanovic, I.M. and Kupferberg, H.J., Drug Metab. Dispos. 1984, 12(5):560-564; Sheets, J.J. and Mason, J.I., Drug Metab. Dispos. 1984, 12(5):603-606; Back, D.J. and Tjia, J.F., Br. J. Pharmacol. 1985, 85:121-126; Lavrijsen, K. et al., Biochem. Pharmacol. 1986, 35(11 ): 1867-1878; Albengres, E.
  • the compounds of the present invention do not contain the imidazole moiety, and its inherent liabilities, and yet maintain potency at the human H 3 receptor as determined by receptor binding to the human histamine H 3 receptor (see: Lovenberg, T.W. et al., Mol. Pharmacol. 1999, 55:1101-1107). Screening using the human receptor is particularly important for the identification of new therapies for the treatment of human disease. Conventional binding assays, for example, are determined using rat synaptosomes (Garbarg, M. et al., J. Pharmacol. Exp. Ther. 1992, 263(1 ):304- 310), rat cortical membranes (West, R.E. et al., Mol. Pharmacol.
  • the present invention is directed to pharmaceutically active phenylalkynes, methods of making them, and methods of using them.
  • the invention features a compound of formula (I)
  • n is an integer from 0 to 1 ;
  • R 1 and R 2 are independently selected from C ⁇ - 3 alkyl, allyl, and C 3 . 8 cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non- aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N;
  • R 3 , R 4 , and R 5 is G, one of the remaining two is hydrogen, and the other is selected from hydrogen, fluoro, and chloro;
  • G is L 2 Q
  • L is methylene
  • Q is NR 8 R 9 wherein R 8 is independently selected from hydrogen, C 1 - 6 alkyl, C 3 - 6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (5-9-membered heterocyclyl)C ⁇ - 6 alkylene, and (phenyl) d- ⁇ alkylene; and R 9 is independently selected from C ⁇ _ 6 alkyl, C 3 .
  • Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N;
  • each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of Formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C ⁇ . 3 alkyl;
  • substituents of Q can be further independently selected (in addition to the preceding paragraph) from terf-butyloxycarbonyl, carboxamide, C-i- 6 alkyl, 5-9-membered heterocyclyl, N(C ⁇ - ⁇ alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), 0(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C-
  • substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy;
  • the present invention also features methods of making a compound of formula (I), a pharmaceutically acceptable salt, ester, or amide thereof, comprising at least one of the following steps: Reacting a compound of formula (VI) with a compound of formula (V),
  • the present invention also features methods of making a compound of formula (I), a pharmaceutically acceptable salt, ester, or amide thereof, wherein more specifically one of R 3 and R 5 is G, one of the remaining and R 4 is H, and the other is selected from hydrogen, fluoro, and chloro, comprising: reacting at least one of the compounds of formulae (XXIIIw) and (XXIIIow) with a compound of formula (V);
  • W is C(O)H (denoting ⁇ x ⁇ ) or G
  • X 2 is a suitable leaving group in a coupling reaction with an alkyne.
  • the present invention also features methods of making a compound of formula (I), a pharmaceutically acceptable salt, ester, or amide thereof, wherein more specifically R 4 is G, one of the remaining R 3 and R 5 is hydrogen, and the other is selected from hydrogen, fluoro, and chloro G is a m-substituent with respect to the alkyne chain substituent, comprising: reacting a compound of formula (XXIIImw) with a compound of formula (V).
  • the present invention also features methods of making a compound of formula (I), a pharmaceutically acceptable salt, ester, or amide thereof, comprising reacting a compound of formula (VII) with an organic base R 1 R 2 NH in the presence of a trialkylphosphonium halide and a base.
  • the invention also features a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier; and methods of preparing or formulating such compositions.
  • a composition of the invention may further include more than one compound of the invention, or a combination therapy (combination formulation or combination of differently formulated active agents).
  • the invention also provides methods of treating certain conditions and diseases, each of which methods includes administering a therapeutically effective (or jointly effective) amount of a compound or composition of the invention to a subject in need of such treatment.
  • the disclosed compounds are useful in methods for treating or preventing neurologic disorders including sleep/wake and arousal/vigilance disorders (e.g.
  • insomnia and jet lag attention deficit hyperactivity disorders
  • ADHD attention deficit hyperactivity disorders
  • learning and memory disorders cognitive dysfunction, migraine, neurogenic inflammation, dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, manic disorders and depression, as well as other histamine H 3 receptor mediated disorders such as upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis in a subject in need thereof.
  • the invention features methods for preventing, inhibiting the progression of, or treating upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis.
  • the disclosed compounds may be used in a combination therapy method including administering a jointly effective dose of an H 3 antagonist and administering a jointly effective dose of a histamine Hi antagonist, such as loratidine (CLARITINTM), desloratidine (CLARINEXTM), fexofenadine (ALLEGRATM) and cetihzine (ZYRTECTM), for the treatment of allergic rhinitis, nasal congestion, and allergic congestion.
  • a histamine Hi antagonist such as loratidine (CLARITINTM), desloratidine (CLARINEXTM), fexofenadine (ALLEGRATM) and cetihzine (ZYRTECTM
  • the disclosed compounds may be used in a combination therapy method, including administering a jointly effective dose of an H 3 antagonist and administering a jointly effective dose of a neurotransmitter re-uptake blocker, such as a selective serotonin re-uptake inhibitor (SSRI) or a non-selective serotonin, dopamine or norepinephrine re- uptake inhibitor, including fluoxetine (PROZACTM), sertraline (ZOLOFTTM), paroxetine (PAXILTM) and amitryptyline, for the treatment of depression, mood disorders or schizophrenia.
  • SSRI selective serotonin re-uptake inhibitor
  • PAXILTM paroxetine
  • amitryptyline amitryptyline
  • the present invention provides phenylalkyne compounds useful for the treatment of disorders and conditions modulated by a histamine receptor.
  • alkyl shall include straight and branched carbon chains.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.
  • lower when used with alkyl means a carbon chain composition of 1-4 carbon atoms.
  • Alkylene refers to a bivalent hydrocarbyl group, such as methylene (CH 2 ), ethylene (-CH 2 -CH 2 -) or propylene (-CH 2 CH 2 CH 2 -), and so on.
  • alkenyl shall mean a straight or branched hydrocarbon group with at least two hydrogen atoms replaced with a pi bond to form a carbon-carbon double bond, such as propenyl, butenyl, pentenyl, and so on.
  • the alkenyl group is R 8 or R 9
  • the open radical point of attachment to the rest of the molecule
  • the double bond or bonds is therefore at least alpha (if not beta, gamma, etc.) to the open radical.
  • alkoxy shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
  • cycloalkyl shall denote a three- to eight-membered, saturated monocyclic carbocyclic ring structure. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkenyl shall denote a three- to eight-membered, partially unsaturated, monocyclic, carbocyclic ring structure, wherein the ring structure contains at least one double bond. Suitable examples include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexa-1 ,3-dienyl and the like.
  • aryl shall refer to carbocyclic aromatic groups such as phenyl, naphthyl, and the like.
  • Divalent radicals include phenylene (-CeH 4 -) which is preferably phen-1 ,4-diyl, but may also be phen-1 ,3- diyl.
  • aralkyl shall mean any alkyl group substituted with an aryl group such as phenyl, naphthyl and the like. Examples of aralkyls include benzyl, phenethyl, and phenylpropyl.
  • carbocyclyl shall mean any cyclic group consisting of 3-13 carbon atoms, and preferably 6-9 carbon atoms, in the skeleton ring or rings, if the carbocycle is a fused or spiro bicyclic or tricyclic group.
  • a carbocycle may be saturated, unsaturated, partially unsaturated, or aromatic. Examples include cycloalkyl, cycloalkenyl, cycloalkynyl; specific examples include phenyl, benzyl, indanyl, and biphenyl.
  • a carbocycle may have substituents that are not carbon or hydrogen, such as hydroxy, halo, halomethyl, and so on as provided elsewhere herein.
  • the heterocyclyl contains between 1 and 3 or between 1 and 2 additional heteroatoms.
  • a heterocyclyl may be saturated, partially unsaturated, aromatic or partially aromatic.
  • the heterocyclyl group may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure.
  • Exemplary monocyclic heterocyclic groups can include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, hexahydroazepinyl, 4-piperidinyl, pyridyl
  • Q is a saturated 3-13 membered N-linked heterocyclyl
  • Q necessarily contains at least one nitrogen, and the carbon atoms are sp 3 hybridized.
  • exemplary bicyclic heterocyclyls include benzthiazolyl, benzoxazolyl, benzoxazinyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N- oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1- bjpyridinyl), or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl)
  • Exemplary tricyclic heterocyclic groups include acridinyl, phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl, phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the like.
  • Preferred heterocyclyl groups include morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, acridinyl, azepinyl, hexahydroazepinyl, azetidinyl, indolyl, isoindolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, 1,3,4-trihydroisoquinolinyl,
  • heterocyclyl-alkyl or “heterocyclyl-alkylene” shall denote any alkyl group substituted with a heterocyclyl group, wherein the heterocycly-alkyl group is bound through the alkyl portion to the central part of the molecule.
  • Suitable examples of heterocyclyl-alkyl groups include, but are not limited to piperidinylmethyl, pyrrolidinylmethyl, pipehdinylethyl, piperazinylmethyl, pyrrolyl butyl, pipehdinylisobutyl, pyridylmethyl, pyrimidylethyl, and the like.
  • substituents e.g., alkyl, alkylene, cycloalkyl, aryl, heterocyclyl, heteroaryl
  • that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
  • phenyl(alkyl)amido(alkyl) refers to a group of the formula
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes prevention, inhibition of onset, or alleviation of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • NR 1 R 2 taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino;
  • Q is a saturated N-linked nitrogen-containing heterocyclyl
  • Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl;
  • (j) substituted Q is selected from N-(C ⁇ - ⁇ alkyl) piperazinyl, N-phenyl- piperazinyl, 1 ,3,8-triaza-spiro[4.5]decyl, and 1 ,4-dioxa-8-aza-spiro[4.5]decyl;
  • Q is a monovalent radical of an amine selected from aziridine, 1 ,4,7- trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1 ,3,8-triaza- spiro[4.5]decan-4-one, piperidine-3-carboxylic acid diethylamide, 1 ,2,3,4,5,6- hexahydro-[2,3']bipyridinyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin- 1-yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)- amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thiomorpholinyl, allyl- cyclopentyl-amine, [2-(1 H-indol-3-yl)-ethyl]-methyl-amine
  • Q is selected from ⁇ /-morpholinyl and /V-piperidinyl, optionally substituted with between 1 and 3 substituents independently selected from hydroxyl, carboxamide, C- ⁇ - 6 alkyl, 5-9 membered or 6-9 membered heterocyclyl, N(C ⁇ - 6 alkyl)( 5-9 membered or 6-9 membered heterocyclyl), NH(5-9 membered or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C ⁇ - 3 alkylene, 5-9 membered or 6-9 membered heterocyclyl-O-, C-i- ⁇ alkoxy, (C 3 .
  • Q is substituted with a substituent comprising a 5-9 membered or 6- 9 membered heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C- ⁇ -6 alkylene, oxazolyl, thiazolyl, 2,3-dihydro- indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C ⁇ - 6 alkylene, tetrazolyl, (triazolyl)C ⁇ -6 alkylene, triazolyl, (pyrrolyl)C ⁇ -6 alkylene, and pyrrolyl;
  • a substituent comprising a 5-9 membered or 6- 9 membered heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C- ⁇ -6 al
  • Q is a substituted or unsubstituted ⁇ /-morpholinyl
  • R 8 is hydrogen
  • R 9 is selected from phenyl or 5-9 membered aromatic heterocyclyl, wherein said phenyl or aromatic heterocyclyl is optionally substituted with 1-3 substituents selected from halo, nitro, cyano, and C 1 - 3 alkyl;
  • R 9 is selected from substituted or unsubstituted phenyl, pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C ⁇ - 6 alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl )C ⁇ - 6 alkylene, tetrazolyl, (triazolyl)C ⁇ -6 alkylene, triazolyl, (pyrrolyl)C ⁇ . 6 alkylene, and pyrrolyl;
  • R 9 is substituted or unsubstituted phenyl
  • R 9 is substituted or unsubstituted pyridyl
  • R 1 and R 2 are independently selected from C 2 alkyl, or taken together with the nitrogen to which they are attached, they form a non- aromatic 5-6 membered heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N; one of R 3 , R 4 , and R 5 is G and the two remaining are H; G is L 2 Q; L 2 is methylene; Q is NR 8 R 9 wherein R 8 is independently selected from hydrogen, C ⁇ - 2 alkyl, C 3 alkenyl, 6-9 membered carbocycle, 3-12 membered heterocyclyl (preferably 5-9 or 6-9), phenyl, (5-9-membered heterocyclyl)C ⁇ -6 alkylene, and (phenyl) C-
  • R 9 is independently selected from C- ⁇ . 2 alkyl, C 3 alkenyl, 5-9 membered carbocyclyl, 3-12 membered heterocyclyl (for example, 5-9 membered or 6-9 membered heterocyclyl, and in some cases preferably 6-membered), phenyl, (5-9-membered heterocyclyl)C ⁇ -6 alkylene, and (phenyl) d- ⁇ alkylene; or Q is a saturated 3-13 membered N-linked heterocyclyl (preferably 5-9 or 6-9), wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo
  • substituents of Q can be further independently selected from terf-butyloxycarbonyl, carboxamide, 6-9-membered heterocyclyl, NH(6- membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C 2 - hydroxyalkylene, hydroxy, and benzyl, and.where each of above heterocyclyl, phenyl, and alkyl substituent groups of Q may be optionally substituted with trifluoromethyl; or a pharmaceutically acceptable salt, ester, or amide thereof;
  • NR 1 R 2 taken together form piperidinyl, pyrrolidinyl, or diethylamino, and (2) Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl;
  • NR 1 R 2 taken together form piperidinyl, pyrrolidinyl, or diethylamino, n is 1 , and wherein Q is NR 8 R 9 and R 8 is H and R 9 is selected from phenyl or aromatic 5-9 membered heterocyclyl, wherein said phenyl or heterocyclyl is optionally substituted with 1-3 substituents selected from halo, nitro, cyano, and C-
  • Examples of compounds of the invention include: 1 -[4-(4-piperidin-1 - ylmethyl-phenyl)-but-3-ynyl]-pipehdine; 1 -[3-(4-piperidin-1 -yl-but-1 -ynyl)- benzylj-piperidine; 4-[3-(4-piperidin-1 -yl-but-1 -ynyl)-benzyl]-morpholine; 4-[3-(4- pipehdin-1 -yl-but-1 -ynyl)-benzyl]-morpholine dihydrochloride; 1 -[4-(4-pyrrolidin- 1 -yl-but-1 -ynyl)-benzyl]-piperidine; diethyl-[4-(4-piperidin-1-ylmethyl-phenyl)- but-3-ynyl]-amine; 4-[4-(4-piperidin-1-ylmethyl-phenyl
  • Additional compounds include: 1-[4-(4-piperidin-1-ylmethyl-phenyl)-but- 3-ynyl]-piperidine; 1 -[3-(4-pipehdin-1 -yl-but-1 -ynyl)-benzyl]-piperidine; 4-[3-(4- piperidin-1 -yl-but-1 -ynyl)-benzyl]-morpholine; 4-[3-(4-piperidin-1 -yl-but-1 -ynyl)- benzylj-morpholine dihydrochloride; 1-[4-(4-pyrrolidin-1 -yl-but-1 -ynyl)-benzyl]- piperidine; 1 -[4-(4-pyrrolidin-1 -ylmethyl-phenyl)-but-3-ynyl]-piperidine; diethyl- [4-(4-piperid in- 1 -yl-but-1 -ynyl
  • More preferred compounds include: 4-[3-(4-piperidin-1 -yl-but-1 -ynyl)- benzylj-morpholine and 4-[4-(4-piperidin-1 -yl-but-1 -ynyl)-benzyl]-morpholine; and particularly the former.
  • Additional examples of compounds include: 1-[3-(4-piperidin-1 -yl-but-1 - ynyl)-benzyl]-piperidine; 4-[3-(4-piperidin-1 -yl-but-1 -ynyl)-benzyl]-morpholine; 4- [3-(4-pipehdin-1 -yl-but-1 -ynyl)-benzyl]-morpholine dihydrochloride; 1 -phenyl-8- [3-(4-piperidin-1 -yl-but-1 -ynyl)-benzyl]-1 ,3,8-thaza-spiro[4.5]decan-4-one; 1 -[3- (4-piperidin-1 -yl-but-1 -ynyl)-benzyl]-piperidine-3-carboxylic acid diethylamide; 1 -[3-(4-piperidin-1 -yl-but-1 -ynyl)-benzyl
  • Further examples include: dimethyl-[4-(4-piperidin-1-ylmethyl-phenyl)- but-3-ynyl]-amine; dimethyl-[4-(4-piperidin-1 -yl-but-1 -ynyl)-benzyl]-amine; phenyl-[4-(4-piperidin-1 -yl-but-1 -ynyl)-benzyl]-amine; 1 -[4-(3-aziridin-1 -ylmethyl- phenyl)-but-3-ynyl]-pipehdine; 2- ⁇ 1 -[3-(4-piperidin-1 -yl-but-1 -ynyl)-benzyl]- piperidin-4-yloxy ⁇ -pyhmidine; ⁇ 1-[3-(4-piperidin-1 -yl-but-1 -ynyl)-benzyl]- piperidin-4-yl ⁇ -pyridin-2-yl-amine;
  • the invention also provides compounds that are useful as synthetic intermediates of the compounds of the invention.
  • Such compounds which themselves may or may not have pharmaceutical activity, include those provided in the schemes and synthetic examples.
  • the invention also contemplates compounds isotopically-labelled to be detectable by positron emission tomography (PET) or single-photon emission computed tomography (SPECT) useful for studying H 3 -mediated disorders.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • compounds of the invention may be modified by using protecting groups; such compounds, precursors, or prodrugs are also within the scope of the invention. This may be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry", ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, "Protective Groups in Organic Synthesis", 3 rd ed., John Wiley & Sons, 1999.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • Protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substitute benzyl ethers, and silyl ethers.
  • substituted methyl ethers include methyoxymethyl, methylthiomethyl, f-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl. p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, f-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2- methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 1- [(2-chloro-4-
  • substituted ethyl ethers include 1-ethoxyethyl, 1-(2- chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1- methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl)ethyl, f-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitrophenyl, and benzyl.
  • substituted benzyl ethers include p-methoxybenzyl, 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, ⁇ - naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, difp- methoxyphenyl)phenylmethyl, th(p-methoxyphenyl)methyl, 4-(4'- bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-tris(4,5- dichlorophthalimi
  • silyl ethers examples include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, f-butyldiphenylsilyl, thbenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and f-butylmethoxyphenylsilyl.
  • esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P- phenylacetate, 3-phenylpropionate, 4-oxopentanoate(levulinate), 4,4- (ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate(mesitoate)
  • carbonates include methyl, 9-fluorenylmethyl, ethyl, 2,2,2- trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2- (triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p- methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1 -naphthyl, and methyl dithiocarbonate.
  • assisted cleavage examples include 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate, 4- (methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.
  • miscellaneous esters examples include 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(1 ,1 ,3,3- tetramethylbutyl)phenoxyacetate, 2,4-bis(1 ,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2- butenoate(tigloate), o-(methoxycarbonyl)benzoate, p-P-benzoate, ⁇ - naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, N- phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4- dinitrophenylsulfenate
  • sulfonates include sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
  • cyclic acetals and ketals examples include methylene, ethylidene, 1-f- butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene, 2,2,2- trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4- dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.
  • Cyclic Ortho Esters examples include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1- ethoxyethylidine, 1 ,2-dimethoxyethylidene, ⁇ -methoxybenzylidene, 1-(N,N- dimethylamino)ethylidene derivative, ⁇ -(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.
  • silyl derivatives include di- f-butylsilylene group, and 1 ,3- (1 ,1 ,3,3-tetraisopropyldisiloxanylidene) derivative.
  • Protection for the amino group includes carbamates, amides, and special -NH protective groups.
  • carbamates examples include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, photolytic cleavage carbamates, urea-type derivatives, and miscellaneous carbamates.
  • methyl and ethyl carbamates include methyl and ethyl, 9- fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7- di-f-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, and 4- methoxyphenacyl.
  • substituted ethyl carbamates examples include 2,2,2-trichloroethyl, 2- trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1 ,1-dimethyl-2- haloethyl, 1 ,1-dimethyl-2,2-dibromoethyl, 1 ,1-dimethyl-2,2,2-trichloroethyl, 1- methyl-1-(4-biphenylyl)ethyl, 1-(3,5-d -butylphenyl)-1-methylethyl, 2-(2'- and 4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, f-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quino
  • assisted cleavage examples include 2-methylthioethyl, 2- methylsulfonylethyl, 2-(p-toIuenesulfonyl)ethyl, [2-(1 ,3-dithianyl)]methyl, 4- methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2- triphenylphosphonioisopropyl, 1 ,1-dimethyl-2-cyanoethyl, m-chloro-p- acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2- (trifluoromethyl)-6-chromonylmethyl.
  • photolytic cleavage examples include m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o- nitrophenyl)methyl.
  • urea-type derivatives include phenothiazinyl-(10)-carbonyl derivative, N'-p-toluenesulfonylaminocarbonyl, and N'- phenylaminothiocarbonyl.
  • miscellaneous carbamates include f-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl methyl, p-decyloxybenzyl, diisopropylmethyl, 2,2- dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl, 1 ,1-dimethyl-3- (N,N-dimethylcarboxamido)propyl, 1 ,1-dimethylpropynyl, di(2-pyridyl)methyl, 2- furanyl methyl, 2-iodoethyl, isobomyl, isobutyl, isonicotinyl, p-(p'- methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-
  • N-formyl N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N- phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N- benzoylphenylalanyl derivative, N-benzoyl, N-p-phenylbenzoyl.
  • N-o-nitrophenylacetyl N-o-nitrophenoxyacetyl, N-acetoacetyl, (N'- dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o- nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-methyl-2-(o- phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o- nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobenzoyl, N-o- (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.
  • N-phthalimide N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5- dimethylpyrrolyl, N-1 ,1 ,4,4-tetramethyldisilylazacyclopentane adduct, 5- substituted 1 ,3-dimethyl-1 ,3,5-triazacyclohexan-2-one, 5-substituted 1 ,3- dibenzyl-1 ,3,5-triazacyclohexan-2-one, and 1 -substituted 3,5-dinitro-4- pyridonyl.
  • Examples of acyclic acetals and ketals include dimethyl, bis(2,2,2- trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.
  • Examples of cyclic acetals and ketals include 1 ,3-dioxanes, 5- methylene-1 ,3-dioxane, 5,5-dibromo-1 ,3-dioxane, 5-(2-pyridyl)-1 ,3-dioxane, 1 ,3-dioxolanes, 4-bromomethyl-1 ,3-dioxolane, 4-(3-butenyl)-1 ,3-dioxolane, 4- phenyl-1 ,3-dioxolane, 4-(2-nitrophenyl)-1 ,3-dioxolane, 4,5-dimethoxymethyl- 1 ,3-dioxolane, O,O'-phenylenedioxy and 1 ,5-dihydro-3H-2,4-benzodioxepin.
  • Examples of acyclic dithio acetals and ketals include S,S'-dimethyl, S,S'-diethyl, S.S'-dipropyl, S,S'-dibutyl, S.S'-dipentyl, S,S'-diphenyl, S,S'- dibenzyl and S,S'-diacetyl.
  • cyclic dithio acetals and ketals examples include 1 ,3-dithiane, 1 ,3- dithiolane and 1 ,5-dihydro-3H-2,4-benzodithiepin.
  • Examples of acyclic monothio acetals and ketals include O-trimethylsilyl- S-alkyl, O-methyl-S-alkyl or -S-phenyl and O-methyl-S-2-(methylthio)ethyl.
  • Cyclic Monothio Acetals and Ketals Examples of cyclic monothio acetals and ketals include 1 ,3- oxathiolanes.
  • O-substituted cyanohydrins examples include O-acetyl, O- trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
  • substituted hydrazones include N,N-dimethyl and 2,4- dinitrophenyl.
  • oxime derivatives include O-methyl, O-benzyl and O- phenylthiomethyl.
  • substituted methylene and cyclic derivatives include oxazolidines, 1-methyl-2-(1'-hydroxyalkyl)imidazoles, N,N'- dimethylimidazolidines, 2,3-dihydro-1 ,3-benzothiazoles, diethylamine adducts, and methylaluminum bis(2,6-di-f-butyl-4-methylphenoxide)(MAD)complex.
  • ⁇ -and ⁇ -Diketones examples include enamines, enol acetates, enol ethers, methyl, ethyl, /-butyl, piperidinyl, morpholinyl, 4-methyl-1 ,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, and trimethylsilyl.
  • Cyclic Ketals, Monothio and Dithio Ketals Examples of cyclic ketals, monothio and dithio ketals include bismethylenedioxy derivatives and tetramethylbismethylenedioxy derivatives.
  • substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, ⁇ -methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl.
  • 2-substituted ethyl esters examples include 2,2,2-trichloroethyl,
  • substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthryl methyl, 2-(9,10- dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6- chromylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p- nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4- sulfobenzyl, piperonyl, 4-picolyl and p-P-benzyl.
  • silyl esters examples include trimethylsilyl, triethylsilyl, t- butyldimethylsilyl, /-propyldimethylsilyl, phenyldimethylsilyl and d -t- butylmethylsilyl.
  • activated esters include thiols.
  • miscellaneous derivatives include oxazoles, 2-alkyl-1 ,3- oxazolines, 4-alkyl-5-oxo-1 ,3-oxazolidines, 5-alkyl-4-oxo-1 ,3-dioxolanes, ortho esters, phenyl group and pentaaminocobalt(lll) complex.
  • stannyl esters examples include triethylstannyl and tri-n-butylstannyl.
  • amides include N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6- dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-Nitro-1 , 2,3,4- tetrahydroquinolyl, and p-P-benzenesulfonamides.
  • hydrazides examples include N-phenyl and N,N'-diisopropyl.
  • the compounds of the invention can be prepared according to the methods described in the next section.
  • the compounds of the invention can be prepared according to traditional synthetic organic methods and matrix or combinatorial chemistry methods, as shown in Schemes 1 - 5 below and in Examples 1 - 76.
  • a person of ordinary skill will be aware of variations and adaptations of the schemes and examples provided to achieve the compounds of the invention.
  • R 5 is illustrative only and that the reacting functionality could also be located at R 3 and/or R 4 .
  • a compound of formula (V) is prepared as outlined in Scheme 1 from a compound of formula (II).
  • a compound of formula (II) is reacted with a reagent capable of converting a hydroxyl function into a leaving group X 1 under hydroxyl activation conditions.
  • Leaving group X 1 is a suitable leaving group in a nucleophilic substitution reaction with an amine, such as amine R 1 R 2 NH.
  • leaving group X 1 is a sulfonate ester, obtained by reacting a compound of formula (III) with an alkyl or arylsulfonyl chloride in a non-acoholic solvent in the presence of an organic or inorganic base at temperature from - 78°C to 50°C
  • organic bases are pyridine, TEA, and mixtures thereof.
  • inorganic bases are, KOH, NaOH, Na 2 CO 3 , K 2 CO 3 or mixtures thereof.
  • a compound of formula (II) is reacted with p-toluenesulfonyl chloride or methanesulfonyl chloride in DCM in the presence of TEA at a temperature between 0°C and room temperature.
  • a compound of formula (V) is obtained from a compound of formula (III) by reacting a compound of formula (IV) with a compound of formula (III) under nucleophilic displacement conditions, either neat or in a solvent in the presence or absence of a base at a temperature from 0°C to 100°C
  • a solvent examples include methanol, ethanol, propanol, n-butanol, DMF, DMSO, DME, and compatible mixtures thereof.
  • Examples of such base when present, are sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, tetramethylguanidine, and compatible mixtures thereof.
  • a high polarity solvent may increase the rate and reduce byproduct formation in these reactions.
  • Such high polarity solvent is provided in some embodiments as a mixture of a first solvent with a cosolvent that increases the dielectric constant of the mixture with respect to the dielectric constant of such first solvent.
  • a cosolvent that increases the dielectric constant of the mixture with respect to the dielectric constant of such first solvent.
  • water is water, ethanol, or a mixture of water and ethanol and/or propanol
  • the base is sodium or potassium carbonate or absent
  • the temperature is room temperature to 80°C.
  • the solvent is ethanol, no exogenous base is used, and the temperature is 0°C to room temperature.
  • a compound of formula (V) may also be obtained from a compound of formula (II) by reaction of a compound of formula (IV) in the presence of a trialkylphosphonium halide, such as (cyanomethyl)trimethylphosphonium iodide and a base such as DIPEA in a solvent such as propionitrile at 90°C
  • a trialkylphosphonium halide such as (cyanomethyl)trimethylphosphonium iodide
  • DIPEA a base such as DIPEA
  • a compound of formula (I) is prepared from a compound of formula (VI) as shown in Scheme 2.
  • Group X 2 such as group X 2 in compound (VI), denotes a suitable leaving group for a coupling reaction with an alkyne, wherein "alkyne” in this definition refers to a chain, whether substituted or unsubstituted, that has a triple carbon-carbon bond.
  • alkyne in this definition refers to a chain, whether substituted or unsubstituted, that has a triple carbon-carbon bond.
  • Examples of such leaving group include halo, such as iodo, bromo, and chloro, and sulfonate, such as trifluoromethanesulfonate.
  • a compound of formula (VI) is reacted with a compound of formula (II) under Sonogashira conditions in the presence of a palladium-containing catalyst, such as palladium on carbon, Pd(PPh 3 ) 2 CI 2 , Pd 2 (dba) 3 , Pd 2 (dba) 3 «CHCI 3 , Pd(P'Bu 3 ) 2 , Pd 2 (dba) 3 .CHCl3/ Pd(P f Bu 3 ) 2 , Pd(OAc) 2 , Pd(PhCN) 2 CI 2 , and PdCI 2 , and a base, such as triethylamine, DIEA, di-/so-propylamine, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof in a solvent such as THF, DME, dioxane, DCE, DCM, toluene, acetonitrile, and mixtures thereof at a temperature from 0°C
  • a copper compound is used as a catalyst in this reaction, such as Cu(l) compound.
  • Such Cu(l) catalyst is preferably incorporated in the reaction medium as substoichiometric quantities of a copper salt, such as Cul or CuBrMe 2 S.
  • phosphine ligands such as PPh 3 or P( l Bu) 3 , ispart fo the methodology of some embodiments of the present invention.
  • a high polarity solvent may increase the rate and reduce by-product formation in these reactions.
  • Such high polarity solvent is provided in some embodiments as a mixture of a first solvent with a cosolvent that increases the dielectric constant of the mixture with respect to the dielectric constant of such first solvent.
  • a cosolvent that increases the dielectric constant of the mixture with respect to the dielectric constant of such first solvent.
  • water as such cosolvent may increase the rate and reduce by-product formation in these reactions.
  • the palladium source is Pd 2 (dba) 3 »CHCI 3 / Pd(P f Bu 3 ) 2 , Pd(PPh 3 ) 2 CI 2 , or palladium on carbon
  • the base is triethylamine or potassium carbonate
  • the solvent is THF, or a mixture of DME and water
  • the temperature is between room temperature and 80°C
  • the palladium source is Pd(PPh 3 ) 2 CI 2
  • the base is triethylamine
  • the solvent is THF
  • a catalytic quantity of Cul or CuBrMe 2 S is used
  • the reaction temperature is room temperature to reflux temperature.
  • a compound of formula (I) is obtained from a compound of formula (VII) in analogy with Scheme 1 , steps A and B, or by analogy with Scheme 1 step C.
  • a compound of formula (I) may also be obtained directly from a compound of formula (VI) by reaction with a compound of formula (V) under Sonogashira conditions.
  • a compound of formula (XII) is prepared as outlined in Scheme 3 from a compound of formula (IX).
  • One skilled in the art will be capable of selecting a suitable protecting group P 1 for the compound of formula (IX).
  • a compound of formula (IX) is reacted with a compound of formula (X) under reductive amination conditions in the presence of a reducing agent such as NaBH(OAc) 3 in a solvent such as DCE, THF, and mixtures thereof at a temperature from 0 °C to 80 °C Amine (X) reacts in this reductive amination with aldehyde (IX) to form an iminium ion.
  • an acid such as acetic acid
  • the iminium ion thus formed is subsequently reduced by NaBH(OAc) 3 to the desired product.
  • a compound of formula (IX) is reacted with a compound of formula (X) in the presence of NaBH(OAc) 3 and acetic acid in DCE at room temperature.
  • a compound of formula (XII) is obtained from a compound of formula (XI) by removal of the protecting P 1 under conditions familiar to one skilled in the art. Selection and removal of protecting group P 1 is within the ordinary skill in the art in light of, for example, reference material cited herein (for example, works by Greene, et al., and McOmie), and description of protecing groups provided herein.
  • a compound of formula (XVI) is prepared as outlined in Scheme 4 from a compound of formula (XIII). As noted above, one skilled in the art will be capable of selecting a suitable protecting group P 2 for the compound of formula (XIII).
  • a compound of formula (XIII) is reacted with a compound of formula (XIV), where X 3 is a leaving group such a halogen or an activated ester, in the presence of a base, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, DBU, triethylamine, and butyllithium in a solvent such as DMF, THF, toluene, DMAC, acetonitrile, and mixtures thereof, at a temperature from room temperature to 140 °C
  • a base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, DBU, triethylamine, and butyllithium
  • a solvent such as DMF, THF, toluene, DMAC, acetonitrile, and mixtures thereof, at a temperature from room temperature to 140 °C
  • a compound of formula (XVI) is obtained from a ccoommppoouunndd ooff ffoorrmmuullaa ((XXVV)) bbyy rreemoval of the protecting P 2 under conditions familiar to one skilled in the art.
  • a compound of formula (XXVI) is prepared from a compound of formula (XXIII) as outlined in Scheme 5.
  • the group X 2 in the compound of formula (XXIII) denotes a leaving group, as defined in Scheme 2.
  • a compound of formula (XXVIII) is obtained by reacting a compound of formula (XXIII) with a compound of formula (II) under Sonogashira conditions, as outlined in Scheme 2, step A.
  • a compound of formula (XXIX) is obtained by reacting a compound of formula (XXVIII) with a compound of formula (XXIV) under reductive amination conditions as outlined in Scheme 3, step A.
  • a substituted or unsubstituted nonaromatic heterocycle containing secondary amine functionality for example piperidine derivatives, such as compounds (XII) and (XVI), may be used in place of the compound of formula (XXIV).
  • a compound of formula (XXVI) is obtained by reacting a compound of formula (XXIX) under the conditions described in Scheme 1 , step C, or Scheme 1 , steps A and B.
  • compound of formula (XXVI) is obtained by reacting a compound of formula (XXV) with a compound of formula (V) under Sonogashira conditions, as described in Scheme 2, step A.
  • Compound of formula (XXV) is obtained by reacting a compound of formula (XXIII) under reductive amination conditions, as described in Scheme 3, step A.
  • compound of formula (XXVI) is obtained by reacting a compound of formula (XXVII) with a compound of formula (XXIV) under reductive amination conditions, as described in Scheme 3, step A.
  • Compound of formula (XXVII) is obtained by reacting a compound of formula (XXMI) with a compound of formula (V) under Sonogashira conditions, as described in Scheme 2, step A.
  • Substituent X 2 and the aldehyde group are shown in a p-arrangement with respect to each other in compound (XXMI).
  • Other schemes similar to Scheme 5 with substituent X 2 and the aldehyde group in arrangements o- and m- with respect to each other are not shown explicitly in the form of additional schemes. It is understood in light of the description provided herein that embodiments of this invention include schemes in which compound (XXMI) is analogous to that shown in Scheme 5 with substituent X 2 and the aldehyde group in o-arrangement with respect to each other.
  • embodiments of this invention include schemes in which compound (XXIII) is analogous to that shown in Scheme 5 with substituent X 2 and the aldehyde group in m-arrangement with respect to each other. Specific examples with such m-arrangement are provided herein because of the different reactivity under m-substitution conditions as compared with those under o- and p-substitution conditions.
  • Some embodiments include methods of making compounds of formula (I), a pharmaceutically acceptable salt, ester, or amide thereof, comprising at least one of the steps : reacting a compound of formula (VI) with a compound of formula (V)
  • additional embodiments include those methods wherein NR 1 R 2 taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino, more specifically, wherein NR 1 R 2 taken together form piperidinyl, pyrrolidinyl, or diethylamino, and still more specifically, wherein NR 1 R 2 taken together form piperidinyl or pyrrolidinyl. Additional embodiments include methods wherein one of R 4 and R 5 is G, more specifically, wherein R 4 is G, or wherein R 5 is G. Additional embodiments include methods wherein n is 1.
  • Additional embodiments include methods wherein Q is a saturated N-linked nitrogen-containing heterocyclyl, more specifically, wherein Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl; or wherein substituted Q is selected from N-(C ⁇ alkyl) piperazinyl, N-phenyl-piperazinyl, 1 ,3,8-triaza-spiro[4.5]decyl, and 1 ,4-dioxa-8- aza-spiro[4.5]decyl; or wherein Q is a monovalent radical of an amine selected from aziridine, 1 ,4,7-trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1 ,3,8- triaza-spiro[4.5]decan-4-one, piperidine-3-
  • Q is substituted with a substituent comprising a C- ⁇ -6 heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C ⁇ - 6 alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C- ⁇ -6 alkylene, tetrazolyl, (triazolyl)C ⁇ .6 alkylene, triazolyl, (pyrrolyl)C ⁇ -6 alkylene, and pyrrolyl, or more specifically wherein Q is a substituted or unsubstituted ⁇ /-morpholinyl. Further embodiments include methods wherein n is 1 ;
  • R 1 and R 2 are independently selected from C 2 alkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 5-6 membered heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N; one of R 3 , R 4 , and R 5 is G and the two remaining are H; G is L 2 Q; L 2 is methylene;
  • Q is NR 8 R 9 wherein R 8 is independently selected from hydrogen, C ⁇ - 2 alkyl, C 3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 2 alkylene, and (phenyl) C 2 alkylene; and R 9 is independently selected from C ⁇ - 2 alkyl, C 3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 2 alkylene, and (phenyl) C 2 alkylene; or
  • Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, and carbocyclyl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from methoxy, halo, amino, nitro, hydroxyl, and C ⁇ - 3 alkyl; and wherein substituents of Q can be further selected from tert- butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl, NH(6- membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C 2 - hydroxyalkylene, hydroxy, benzyl and, where each of above heterocyclyl, phenyl, and alkyl substituent groups
  • Still other embodiments include methods wherein NR 1 R 2 taken together form piperidinyl, pyrrolidinyl, or diethylamino, and Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl; or wherein said organic base R 1 R 2 NH is piperidine and said nucleophilic substitution is performed at room temperature; or wherein said nucleophilic substitution is performed at room temperature with 10 equivalents of piperidine in the presence of ethanol; or wherein said nucleophilic substitution is performed at room temperature with 10 equivalents of piperidine in the presence of ethanol and X 1 is mesylate, to yield a mixture of a substituted base and an elimination product; with or without further comprising exposing said mixture to HCl to yield a saline solution, selectively precipitating and crystallizing form said saline solution a phenylalkyn
  • NR 1 R 2 taken together form piperidinyl or pyrrolidinyl, n is 1 , and Q is selected from morpholinyl and piperidinyl;
  • nucleophilic substitution is performed in the presence of ethanol at room temperature and said organic base is R 1 R 2 NH is piperidine, further comprise converting an alcohol of formula (VII) to said compound of formula (VIII), which more specifically can further comprise the reductive amination of a compound of formula (Vila) with an amine R 8 R 9 NH, wherein one of R 3 , R 4 , and R 5 is C(O)H and the other two are selected from H, chloro and bromo, to give a compound of formula (VII), wherein one of R 3 , R 4 , and R 5 is NR 8 R 9 and the other two are selected from H, chloro and bromo,
  • said amine is morpholine; and further comprising the coupling in the presence of a palladium-containing catalyst and a copper salt of a compound of formula (II) with a disubstituted benzene, wherein one of said benzene substitutents is C(O)H and the other of said benzene substitutents is selected from chloro and bromo, to yield a compound of formula (Vila).
  • Some embodiments include methods of making compounds of formula (I), a pharmaceutically acceptable salt, ester, or amide thereof, wherein more specifically one of R 3 and R 5 is G, one of the remaining and R 4 is H, and the other is selected from hydrogen, fluoro, and chloro, these embodiments comprising reacting at least one of the compounds of formulae (XXIIIw) and (XXIIIow) with a compound of formula (V)
  • additional embodiments include methods wherein any one of the following is additionally satisfied: said W is C(O)H, further comprising performing a reductive amination of said W with an organic base R 9 R 8 NH; NR 1 R 2 taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino, including the more specific conditions wherein NR 1 R 2 taken together form piperidinyl, pyrrolidinyl, or diethylamino, or wherein NR 1 R 2 taken together form piperidinyl or pyrrolidinyl; R 5 is G; R 3 is G; n is 1 ; Q is a saturated
  • Q is substituted with a substituent comprising a Ci- 6 heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C ⁇ - 6 alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2- oxobenzimidazolyl, (tetrazolyl)C ⁇ -6 alkylene, tetrazolyl, (triazolyl)C ⁇ - 6 alkylene, triazolyl, (pyrrolyl)C ⁇ -6 alkylene, and pyrrolyl; Q is a substituted or unsubstituted ⁇ /-morpholinyl; NR 1 R 2 taken together form piperidinyl, pyrrolidinyl, or diethylamino, and Q is selected from substituted or unsubstituted piperidinyl, piperazinyl
  • NR 1 R 2 taken together form piperidinyl or pyrrolidinyl, n is 1 , and Q is morpholinyl or substituted morpholinyl; n is 1 , R 4 is H, one of R 3 and R 5 is H, the other one of R 3 and R 5 is L 2 Q, with Q being morpholinyl, and L 2 as defined above, and NR 1 R 2 taken together form piperidinyl; n is 1 , R 4 is H, R 3 is H, R 5 is C(O)H, NR 1 R 2 taken together form a piperidinyl, wherein said reacting is performed at room temperature; n is 1 , R 4 is H, R 3 is H, R 5 is C(O)H, NR 1 R 2 taken together form a piperidinyl, wherein said reacting is performed at room temperature; n is 1 , R 4 is H, R 3 is H, R 5 is C(O)H, NR 1 R 2 taken together form a piperidiny
  • R 1 and R 2 are independently selected from C 2 alkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 5-6 membered heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N; one of R 3 and R 5 is G, and the remaining and R 4 are H;
  • G is L 2 Q
  • L 2 is methylene
  • Q is NR 8 R 9 wherein R 8 is independently selected from hydrogen, C 1 . 2 alkyl, C 3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 2 alkylene, and
  • Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, and carbocyclyl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from methoxy, halo, amino, nitro, hydroxyl, and C 1 - 3 alkyl; and wherein substituents of Q can be further selected from tert- butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl, NH(6- membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C 2 - hydroxyalkylene, hydroxy, benzyl and, where each of above heterocyclyl, phenyl, and alkyl substituent groups
  • Some embodiments include methods of making compounds of formula (I), a pharmaceutically acceptable salt, ester, or amide thereof, comprising reacting a compound of formula (VII) with an organic base R 1 R 2 NH in the presence of a trialkylphosphonium halide and a base. More specifically, additional embodiments include methods wherein any one of the following is satisfied: said trialkylphosphonium halide is (cyanomethyl)trimethylphosphonium iodide, and said base is DIPEA;
  • NR 1 R 2 taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino;
  • NR 1 R 2 taken together form piperidinyl, pyrrolidinyl, or diethylamino;
  • NR 1 R 2 taken together form piperidinyl or pyrrolidinyl; one of R 4 and R 5 is G;
  • R 4 is G
  • R 5 is G; n is 1 ;
  • Q is a saturated N-linked nitrogen-containing heterocyclyl
  • Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl;
  • NR 1 R 2 taken together form piperidinyl, pyrrolidinyl, or diethylamino, and
  • Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl;
  • NR 1 R 2 taken together form piperidinyl or pyrrolidinyl, n is 1 , and Q is selected from morpholinyl and piperidinyl;
  • Some embodiments include methods of making compounds of formula (I), a pharmaceutically acceptable salt, ester, or amide thereof, wherein more specifically R 4 is G, one of the remaining R 3 and R 5 is hydrogen, and the other is selected from hydrogen, fluoro, and chloro, these embodiments comprising reacting a compound of formula (XXIIImw) with a compound of formula (V).
  • W is C(O)H or G
  • X 2 is a suitable leaving group in a coupling reaction with an alkyne. More specifically, additional embodiments include methods wherein any one of the following is satisfied: said W is C(O)H, further comprising performing a reductive amination of said
  • NR 1 R 2 taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino;
  • NR 1 R 2 taken together form piperidinyl, pyrrolidinyl, or diethylamino;
  • NR 1 R 2 taken together form piperidinyl or pyrrolidinyl; n is 1 ;
  • Q is a saturated N-linked nitrogen-containing heterocyclyl
  • Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl; substituted Q is selected from N-(C 1 - 6 alkyl) piperazinyl, N-phenyl-piperazinyl,
  • Q is a monovalent radical of an amine selected from aziridine, 1 ,4,7-trioxa-10- aza-cyclododecane, thiazolidine, 1-phenyl-1 ,3,8-triaza-spiro[4.5]decan-4-one, piperidine-3-carboxylic acid diethylamide, 1 ,2,3,4,5,6-hexahydro-
  • Q is selected from A/-morpholinyl and ⁇ /-piperidinyl, optionally substituted with between 1 and 3 substituents selected from hydroxyl, carboxamide, C- ⁇ - 6 alkyl,
  • Q is substituted with a substituent comprising a Ci- 6 heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C ⁇ - 6 alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2- oxobenzimidazolyl, (tetrazolyl )C ⁇ - 6 alkylene, tetrazolyl, (triazolyl)C ⁇ - 6 alkylene, triazolyl, (pyrrolyl)C ⁇ -6 alkylene, and pyrrolyl;
  • a substituent comprising a Ci- 6 heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C ⁇ - 6 alkylene, oxazolyl, thi
  • Q is a substituted or unsubstituted A/-morpholinyl
  • NR 1 R 2 taken together form piperidinyl, pyrrolidinyl, or diethylamino, and
  • Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl; and n is 1 , R 5 is H, R 3 is H, and R 4 is L 2 Q, with Q being morpholinyl, and L 2 as defined above, and NR 1 R 2 taken together form piperidinyl.
  • n 1 ;
  • R 1 and R 2 are independently selected from C 2 alkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic
  • heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N;
  • R 3 and R 5 are H
  • G is L 2 Q
  • L 2 is methylene
  • Q is NR 8 R 9 wherein R 8 is independently selected from hydrogen, C ⁇ - 2 alkyl, C 3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl )C 2 alkylene, and (phenyl) C 2 alkylene; and R 9 is independently selected from C ⁇ . 2 alkyl, C 3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C 2 alkylene, and (phenyl) C 2 alkylene; or
  • Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, and carbocyclyl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from methoxy, halo, amino, nitro, hydroxyl, and C 1 - 3 alkyl; and wherein substituents of Q can be further selected from tert- butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl, NH(6- membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C 2 - hydroxyalkylene, hydroxy, benzyl and, where each of above heterocyclyl, phenyl, and alkyl substituent groups
  • Still additional embodiments satisfy NR 1 R 2 taken together form piperidinyl or pyrrolidinyl, n is 1 , and Q is selected from morpholinyl and piperidinyl, of which some embodiments more specifically satisfy NR 1 R 2 taken together form piperidinyl or pyrrolidinyl, n is 1 , and Q is morpholinyl or substituted morpholinyl.
  • n is 1
  • R 3 is H
  • R 5 is H
  • W is C(O)H
  • X 2 is choloro or bromo
  • compound of formula (V) is 1-but-3- ynyl-piperidine, to form a phenylalkyne, of which some embodiments more specifically satisfy at least one of: said reacting is performed in the presence of pyrrolidine and at a temperature of about 50°C to form a phenylalkayne, with still some embodiments further satisfying wherein said reacting is performed in the presence of a palladium- containing catalyst and a copper salt;
  • X 2 is bromo, and said reacting is performed under conditions such that the yield of said phenylalkyne is at least 80%; further comprising a reductive amination with R 8 R 9 NH of said phenylalkyne to yield a base, with some more specific embodiments additionally satisfying at least one of: wherein said R 8 R 9 NH is morpholine and said base is 4-[3-(4- piperidin-1 -yl-but-1 -ynyl)-benzyl]-morpholine, and further comprising forming a saline solution with HCl, of which embodiments some also further comprise obtaining a dihydrochloride salt of said base by crystallization, and some even more specifically satisfy said base being 4-[3-(4-piperidin-1 -yl-but-1 -ynyl)-benzyl]- morpholine.
  • linear synthetic paths such as those illustrated by embodiments of steps B, C, and D in Scheme 2, and by embodiments of steps B and E in Scheme 2. Additional illustrations of linear processes are provided by embodiments of steps C, D, and E in Scheme 5, and the combination of steps C and D in Scheme 5 and steps C and D in Scheme 2.
  • convergent synthetic paths such as those illustrated by embodiments of step A in Scheme 2. Additional illustrations of convergent processes are provided by embodiments of steps A and B in Scheme 5, and also by embodiments of steps F and G in Scheme 5.
  • Embodiments of processes according to this invention are particularly suited for the scale-up synthesis of compounds described herein and compounds related thereto that can be obtained on the basis of the teachings provided herein and the ordinary skill in the art.
  • These related compounds include pharmaceutically acceptable salts, esters, and amides of compounds according to the present invention.
  • Conventional methodologies for nucleophilic substitutions yield unpractical low yields of the substitution product of interest, with yields of such product of about 50%, the remaining by-product being mainly a corresponding elimination product.
  • An example of a substitution product of interest is the title compound in Example 16.
  • An example of an elimination by-product is the following compound:
  • This elimination byproduct can be generated according to conventional methodology with a yield of as much as 50%.
  • the following references provide background material on related conventional methodologies: Abdel-Magid, A.F., et al., J. Org. Chem. 1996, 61 :3849-3862; Furst, A., Helvetica Chemica Ada 1947, 30:1454; and Kawai, S.H., et al., J. Org. Chem. 1994, 59:2620- 2622.
  • methods according to the present invention permit the reduction in the formation of such elimination byproduct, so that its yield does not exceed 20%, and it was in some embodiments as low as 15%.
  • palladium-containing catalysts and/or copper salts typically employ palladium-containing catalyst in amounts that range from about 1% to about 5% (both percentages given in terms of molar ratios).
  • the following reference provides background material on related conventional methodologies: Sonogashera, K., et al., Tetrahedron Letters 1975, 50:4467-4470.
  • methods according to the present invention permit the reduction in the amount of palladium catalyst, so that its effective use was in some embodiments as low as 0.1 % (also molar). This reduction in the amount of catalyst leads to a reduction in the production cost, an important consideration in scale-up processes.
  • the less catalyst is used the less likely it is that catalyst contamination will significantly propagate along the synthetic process. Purification along the process and/or purification of the final product is/are necessary when this contamination is significant.
  • Embodiments of convergent processes according to the present invention remove the production of elimination byproduct. High yields of final product were obtained in just a reduced number of synthetic steps. Embodiments of the present invention are illustrated by convergent methods that have at most three linear steps. Such reduction in the number of synthetic steps leads to an increase in efficiency.
  • methods according to the present invention increased such reactions yields to at least 80%, with actual yields ranging from about 86% (m-, or meta, substitution, in contrast with conventional yields of 25%-30% for the same substitution) to about 92% (o-, or orto, and p-, or para, substitution).
  • a strong base such as pyrrolidine and temperature conditions, such as those described herein, facilitated high yields in the context of the present methods.
  • Preferred temperature conditions include about room temperature (RT) when there is o- or p- substitution, and about 50°C when there is m- substitution.
  • the disclosed compounds are useful for treating or preventing neurologic disorders including sleep/wake and arousal/vigilance disorders (e.g. insomnia and jet lag), attention deficit hyperactivity disorders (ADHD), learning and memory disorders, cognitive dysfunction, migraine, neurogenic inflammation, dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, manic disorders and depression, as well as other histamine H 3 receptor mediated disorders such as upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis in a subject in need thereof.
  • sleep/wake and arousal/vigilance disorders e.g. insomnia and jet lag
  • ADHD attention deficit hyperactivity disorders
  • learning and memory disorders e.g. insomnia and memory disorders
  • cognitive dysfunction migraine, neurogenic inflammation, dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eating disorders, obesity,
  • the compounds or compositions of the invention may be formulated and administered to a subject by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral administration.
  • the quantity of the compound which is effective for treating each condition may vary, and can be determined by one of ordinary skill in the art.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate,
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention provides the esters, amides, and other protected or derivatized forms of the described compounds.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier and optionally additional pharmaceutical agents such as Hi antagonists or SSRIs.
  • these compositions are in unit dosage forms such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), powders, granules, sterile parenteral solutions or suspensions (including syrups and emulsions), metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once- weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • an insoluble salt of the active compound such as the decanoate salt
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphat
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 5 to about 1000 mg of the active ingredient of the present invention. Examples include 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, 35 mg, 50 mg, 75 mg, 100 mg, 120 mg, 150 mg, and so on.
  • the tablets or pills of the disclosed compositions can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be septed by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • compounds of the present invention 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.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of ADHD is required.
  • the daily dosage of the products may be varied over a wide range from 1 to 1 ,000 mg per adult human per day.
  • the compositions are preferably provided in the form of tablets containing 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 20 mg/kg of body weight per day.
  • the range is from about 0.02 mg/kg to about 10 mg/kg of body weight per day, and especially from about 0.05 mg/kg to about 10 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • the disclosed compounds are useful in combination with other therapeutic agents, including Hi receptor antagonists, H 2 receptor antagonists, and neurotransmitter modulators such as SSRIs and non-selective serotonin re-uptake inhibitors (NSSRIs).
  • Hi receptor antagonists H 2 receptor antagonists
  • neurotransmitter modulators such as SSRIs and non-selective serotonin re-uptake inhibitors (NSSRIs).
  • compositions or the disclosed drug combinations are known in the art for determining effective doses for therapeutic and prophylactic purposes for the disclosed pharmaceutical compositions or the disclosed drug combinations, whether or not formulated in the same composition.
  • joint effective amount means that amount of each active compound or pharmaceutical agent, alone or in combination, that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the term "jointly effective amount” refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that inhibits in a subject the onset or progression of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician, the delaying of which disorder is mediated, at least in part, by the modulation of one or more histamine receptors.
  • the present invention provides combinations of two or more drugs wherein, for example, (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (b) at least one drug in the combination is administered in an amount that is sub-therapeutic or sub- prophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second or additional drugs according to the invention; or (c) both drugs are administered in an amount that is sub- therapeutic or sub-prophylactic if administered alone, but are therapeutic or prophylactic when administered together. Combinations of three or more drugs are analogously possible. Methods of combination therapy include co- administration of a single formulation containing all active agents; essentially contemporaneous administration of more than one formulation; and administration of two or more active agents separately formulated.
  • a 1-L, 3-necked round-bottom flask was equipped with a magnetic stirring bar, a condenser with a nitrogen inlet, and two stoppers. The vessel was charged with 3-bromobenzaldehyde (18.5 g, 0.1 mol), 3-butyn-1-ol (10.5 g, 0.15 mol), triethylamine (100 mL), and THF (100 mL).
  • a 1-L, 3-necked round-bottom flask was equipped with a mechanical stirrer, a rubber septum with a nitrogen inlet and a stopper. The flask was charged with the product of Example 5 (14.6 g, 0.0838 mol) and dichloromethane (250 mL). Morpholine (8.85 mL, 0.1 mol) was added, and then to this well-stirred reaction mixture was added sodium triacetoxyborohydride (32 g, 0.15 mol) in 4 equal portions. After the addition, the reaction mixture was stirred at room temperature overnight.
  • Aqueous NaOH (10% w/v, 75 mL) was added, and the reaction mixture was transferred to a 1-L separatory funnel, to which water (100 mL) was then added. After separation of the layers, the aqueous phase was extracted once with dichloromethane (100 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO , and filtered. After filtration, the solvents were removed from the filtrate by evaporation under reduced pressure to yield the product as yellow oil (19 g with a 90% yield). Purity at this stage did not exceed 90% as determined by HPLC.
  • the aqueous phase was extracted with ethyl acetate (2x400 mL), and the combined organic phases were washed with water (100 mL) and brine (100 mL), dried (magnesium sulfate), and concentrated under reduced pressure. The residue was azeotroped with toluene (2x100 mL) to give a brown solid (2.1 g). To a solution of this solid and triethylamine (7.1 mL) in DCM (100 mL) was added p-toluene sulfonyl chloride at 0 °C.
  • Method B To a mixture of Pd(PPh 3 ) 2 CI 2 (0.57 g, 0.81 mmol, 0.01 equiv) and Cul (0.31 g, 1.6 mmol, 0.02 equiv), THF (180 mL) and Et 3 N (90 mL, 0.64 mol, 8.0 equiv) were added under N 2 . A stream of N 2 was bubbled through the solution for 15 min, and then 1-but-3-ynyl-piperidine (11.7 g, 85 mmol, 1.05 equiv) was added. The reaction mixture was stirred at room temperature for 16 h. A white precipitate (Et 3 N ⁇ Br) was collected by filtration and washed with EtOAc.
  • Example 1 A mixture of the product of Example 1 (254 mg), potassium carbonate (346 mg), copper(l) iodide (7.6 mg), triphenylphosphine (21 mg), 10% palladium on carbon (43 mg) in water (2 mL) and DME (1 mL) was stirred at room temperature for 30 min, and treated with a solution of the product of Example 2 (343 mg) in DME (1 mL). The resulting mixture was heated at 80 °C for 16 h, cooled to room temperature, and filtered through a pad of Celite. The pad was washed with DCM (3x3 mL), and the filtrate was diluted with water (3 mL).
  • Method B A 500-mL, 3-necked round-bottom flask was equipped with a magnetic stirring bar, an addition funnel, a thermometer, and a rubber septum with a nitrogen inlet.
  • the vessel was charged with piperidine (54 mL, 46 g, 0.54 mol) and anhydrous ethanol (25 mL).
  • the solution was cooled to 0 °C in an ice bath, and a solution of the product of Example 7 (17.5 g, 0.054 mol) in anhydrous ethanol (30 mL) was added.
  • the ice bath was removed, and the reaction mixture was allowed to warm to room temperature. Room temperature is a preferred temperature condition.
  • the amount of 10 mol equivalent piperidine in ethanol given here is a preferred amount.
  • Example of selective precipitation of compounds such as the title compound A 3-L, 3-necked round-bottom flask was charged with the product of Example 16, Method B (77.0 g, 0.25 mol). To this was added absolute EtOH (385 mL). The reaction mixture was stirred and cooled to ⁇ 0 °C in an ice bath. HCl in dioxane (4 N, 126.5 mL) was added drop-wise over 0.5 h. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 h.
  • the viscous reaction mixture was transferred to a 500 mL addition funnel and then added in a slow, steady stream to a 3-L, 3-necked round-bottom flask containing ether (500 mL), as the flask contents were stirred.
  • the addition funnel was rinsed with absolute EtOH (115 mL), which was subsequently added to the ether solution.
  • Ether (500 mL) was added via an addition funnel in a slow, steady stream. This resulted in the formation of a pale tan precipitate.
  • the suspension was stirred at room temperature for 12 h. More ether (500 mL) was added, and the suspension was cooled to 0 °C and held at that temperature while stirred for 3 h.
  • the product was collected by suction filtration using a medium porosity glass frit (filtration was slow). The filter cake was broken and washed with absolute EtOH/Et 2 O (1 :3, 2x75 mL). The product was dried under house vacuum and, subsequently, in a vacuum oven at 35 °C for 24 h.
  • the dihydrochloride salt was obtained as an off-white powder (80.7 g). HPLC and 1 H-NMR indicated the product to be >95% pure. At most, only trace amounts of the elimination product were present.
  • a 2-L, 3-necked round- bottom flask equipped with an addition funnel, a reflux condenser and a mechanical stirrer was charged with the crude dihydrochloride salt (80.0 g).
  • Example 13 A mixture of the product of Example 13 (199 mg), 1-methylpiperazine (0.067 mL) and potassium carbonate (69 mg) in 1:1 ethanol/water (6 mL) was heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature.
  • Ki 1.0 nM
  • CDCI 3 7.37(s, 1 H), 7.28-7.22(m, 3H), 3.56(s, 2H), 2.68-2.57(m, 4H), 2.51-
  • Example 61 May be prepared analogously to Example 15 using aziridine hydrochloride.
  • Example 64 May be prepared analogously to Example 15 using the product of Example 10 and morpholine.
  • Example 15 May be prepared analogously to Example 15 using the product of Example 11 and morpholine.
  • Example 67 May be prepared analogously to Example 15 using the product of Example 10 and thiomorpholine.
  • Example 15 May be prepared analogously to Example 15 using the product of Example 11 and thiomorpholine.
  • Example 15 May be prepared analogously to Example 15 using the product of Example 10 and 1-methylpiperazine.
  • Example 70 May be prepared analogously to Example 15 using the product of Example 11 and 1-methylpiperazine.
  • Example 70
  • Example 73 May be prepared analogously to Example 15 using the product of Example 10 and piperidin-4-ol.
  • Example 73
  • Example 15 May be prepared analogously to Example 15 using the product of Example 11 and piperidin-4-ol.
  • Example 76 May be prepared analogously to Example 15 using the product of Example 10 and 4-methoxypiperidine.
  • Example 76
  • Example 15 May be prepared analogously to Example 15 using the product of Example 11 and 4-methoxypiperidine.
  • a 10 cm tissue culture dish with a confluent monolayer of SK-N-MC cells was split two days prior to transfection. Using sterile technique the media were removed and the cells were detached from the dish by the addition of trypsin. One fifth of the cells were then placed onto a new 10 cm dish. Cells were grown in a 37 °C incubator with 5% CO 2 in Minimal Essential Media Eagle with 10% Fetal Bovine Serum. After two days cells were approximately 80% confluent. These were removed from the dish with trypsin and pelleted in a clinical centrifuge. The pellet was then re-suspended in 400 ⁇ L complete media and transferred to an electroporation cuvette with a 0.4 cm gap between the electrodes.
  • One microgram of supercoiled H 3 receptor cDNA was added to the cells and mixed.
  • the voltage for the electroporation was set at 0.25 kV, the capacitance was set at 960 ⁇ F.
  • the cells were diluted into 10 mL complete media and plated onto four 10 cm dishes. Because of the variability in the efficiency of electroporation, four different concentrations of cells were plated. The ratios used were; 1 :20, 1 :10, 1 :5, with the remainder of the cells being added to the fourth dish.
  • the cells were allowed to recover for 24 hours before adding the selection media (complete media with 600 ⁇ g/mL G418). After 10 days dishes were analyzed for surviving colonies of cells. Dishes with well isolated colonies were used.
  • SK-N-MC cells were used because they give efficient coupling for inhibition of adenylate cyclase.
  • the clones that gave the most robust inhibition of adenylate cyclase in response to histamine were used for further study.
  • [ 3 H]- ⁇ /-methylhistamine binding Cell pellets from histamine H 3 receptor-expressing SK-N-MC cells were homogenized in 20 mM TrisHCI/0.5 mM EDTA. Supematants from a 800 g spin were collected, recentrifuged at 30,000 g for 30 min. Pellets were re- homogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes were incubated with 0.8 nM [ 3 H]-N-methylhistamine plus/minus test compounds for 45 min at 25 °C and harvested by rapid filtration over GF/C glass fiber filters (pretreated with 0.3 % polyethylenimine) followed by four washes with ice cold buffer.
  • a rat in vivo system was used to determine the blood-brain barrier penetration profiles and kinetics of various H 3 receptor antagonists after single bolus oral administration.
  • the blood was added to 0.3 mL of 6% trichloroacetic acid, and the acidified sample was vortexed and then centrifuged (5 min at 14,000 rpm in a microcentrifuge). The clear supernatant was retained for analysis.
  • the frozen brain was weighed, homogenized in 6% trichloroacetic acid (3 mL/g wet weight of tissue), and then centrifuged. The clear supernatant was retained for analysis.
  • the supernatants from the blood and brain samples were analyzed by liquid chromatography with mass spectral detection utilizing selective reaction monitoring (LC-MS/MS).
  • the LC method used a Phenomonex Polar RP column (2 x 50 mm) and a linear solvent gradient of water and acetonitrile (both 1% in acetic acid).
  • Graphs of H 3 receptor antagonist concentration versus time for blood and brain were generated from the LC-MS/MS results.
  • the mean residency time (MRT) of the H 3 receptor antagonist, in blood or in the brain, was calculated from the ratio of the area under the first moment curve (AUMC) to the area under the concentration time curve (AUC): AUMC/AUC.
  • the Blood Brain Barrier index was calculated from the log of AUC r ain/AUCbioo d -

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Quinoline Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Indole Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des procédés permettant de faire des phénylalkynes substitués représentés par la formule générale (I).
PCT/US2003/019601 2002-12-02 2003-06-17 Procedes pour l'elaboration de derives phenylalkyniques WO2004050623A1 (fr)

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CA002507875A CA2507875A1 (fr) 2002-12-02 2003-06-17 Procedes pour l'elaboration de derives phenylalkyniques
BR0316971-5A BR0316971A (pt) 2002-12-02 2003-06-17 Fenilalquinas
JP2004557098A JP2006514939A (ja) 2002-12-02 2003-06-17 フェニルアルキン誘導体の製造方法
EP03739242A EP1567494A1 (fr) 2002-12-02 2003-06-17 Procedes pour l'elaboration de derives phenylalkyniques
MXPA05005830A MXPA05005830A (es) 2002-12-02 2003-06-17 Metodos para preparar derivados de fenilalquino.
AU2003245613A AU2003245613A1 (en) 2002-12-02 2003-06-17 Methods for preparing phenylalkyne derivatives

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PCT/US2002/038480 WO2003050099A1 (fr) 2001-12-10 2002-12-02 Phenylalkynes

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999059969A1 (fr) * 1998-05-15 1999-11-25 American Home Products Corporation Compositions comprenant des composes a base de 2-phenyl-indole et de formulations d'oestrogenes
WO2001066534A2 (fr) * 2000-03-09 2001-09-13 Abbott Laboratories Antagonistes du recepteur d'histamine-3 diamino cycliques et bicycliques
WO2002055501A2 (fr) * 2001-01-12 2002-07-18 Amgen Inc Derives d'arylamine substitues et leurs methodes d'utilisation
WO2003050099A1 (fr) * 2001-12-10 2003-06-19 Ortho-Mcneil Pharmaceutical, Inc. Phenylalkynes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999059969A1 (fr) * 1998-05-15 1999-11-25 American Home Products Corporation Compositions comprenant des composes a base de 2-phenyl-indole et de formulations d'oestrogenes
WO2001066534A2 (fr) * 2000-03-09 2001-09-13 Abbott Laboratories Antagonistes du recepteur d'histamine-3 diamino cycliques et bicycliques
WO2002055501A2 (fr) * 2001-01-12 2002-07-18 Amgen Inc Derives d'arylamine substitues et leurs methodes d'utilisation
WO2003050099A1 (fr) * 2001-12-10 2003-06-19 Ortho-Mcneil Pharmaceutical, Inc. Phenylalkynes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DELLA, E. W. ET AL.: "Synthesis of Bridgehead Nitrogen Hetrocycles via Cyclization of alpha-Ammonio 5-Hexenyl Radicals", JOURNAL OF ORGANIC CHEMISTRY, vol. 64, no. 6, 1999, pages 1798 - 1806, XP002255631 *
GLASE ET AL: "Aryl 1-But-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines as Potential Antipsychotic Agents: Synthesis and Structure-Activity Relationships", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 39, no. 16, 1 July 1996 (1996-07-01), pages 3179 - 3187, XP002092426, ISSN: 0022-2623 *
WRIGHT, J. L. ET AL: "Subtype-Selective N-Methyl-D-Aspartate Receptor Antagonists: Synthesis and Biological Evaluation of 1-(Arylalkynyl)-4-Benzylpiperidines", JOURNAL OF MEDICINAL CHEMISTRY, vol. 42, no. 13, 1999, pages 2469 - 2477, XP002255630 *

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