HRP20040823A2 - Substituted amides active at the cannabinoid-1 receptor - Google Patents

Description

References to related applications

Not applicable.

Background of the invention

Marijuana (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes. The main active ingredient in marijuana and hashish is recognized as Δ9-tetrahydrocannabinol (Δ9-THC). Detailed research has revealed that the biological action of Δ9-THC and other members of the cannabinoid family takes place through two G-protein coupled receptors called CB1 and CB2. The CB1 receptor is primarily found in the central and peripheral nervous system and to a lesser extent in several peripheral organs. The CB2 receptor is found primarily in lymphoid tissue and cells. Three endogenous cannabinoid receptor ligands, derived from arachidonic acid, have been identified (anandamide, 2-arachidonulje glycerol, and 2-arachidonyl glycerol ether). Each is an agonist with activities similar to Δ9-THC, including sedation, hypothermia, intestinal motility, antinociception, analgesia, catalepsy, antinausea, and appetite stimulation.

The genes for the respective cannabinoid receptors have all already been cut out in mice. Mice with impaired CB1-/- receptors appeared normal and fertile. They were resistant to the action of Δ9-THC and showed a strong reduction in the reinforcing properties of morphine and the severity of the withdrawal syndrome. They also showed reduced motor activity and hypoalgesia. Excessive exposure to Δ9-THC can lead to excessive feeding, psychosis, hypothermia, memory loss, and sedation. There is currently at least one CB1 modulator characterized as an inverse agonist or antagonist, N-(1-piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A ), in clinical trials in the treatment of eating disorders. There remains a need for potent low molecular weight CB1 modulators that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.

Treatment of asthma with CB1 receptor modulators (such as CB1 inverse agonists) is supported by findings that the presynaptic cannabinoid CB1 receptor mediates inhibition of noradrenaline release (in guinea pig lung) (Europ. J. Pharmacology, 2001, 431 (2), 237-244) .

Treatment of liver cirrhosis with CB1 receptor modulators is supported by the finding that a CB1 receptor modulator reverses the low blood pressure observed in rats with carbon tetrachloride-induced liver cirrhosis and lowers elevated mesenteric blood flow and portal venous pressure (Nature Medicine, 2001, 7 (7), 827- 832).

US Patents US 5,624,941 and US 6,028,084, PCT Application No. WO98/43636 and WO98/43635, and EPO Application No. EP-658546 describes substituted pyrazoles, which are active against cannabinoid receptors.

PCT Application No. WO98/31227 and WO98/41519 also describe substituted pyrazoles, which are active against cannabinoid receptors.

PCT Applications No. WO98/37061, WO00/10967, and WO00/10968 describe diaryl ether sulfonamides, which are active against cannabinoid receptors.

PCT Applications No. WO97/29079 and WO99/02499 describe Alkoxyisoindolones and Alkoxyquinolones, which have activity against cannabinoid receptors.

US Patent US 5,532,237 describes N-benzoyl-indole derivatives that are active against cannabinoid receptors.

US Patents US 4,973,587, US 5,013,837, US 5,081,122, and US 5,112,820, US 5,292,736 describe aminoalkylindole derivatives, which have activity against cannabinoid receptors.

PCT publication WO 01/58869 describes pyrazole, pyrrole and imidazole cannabinoid receptor modulators useful in the treatment of respiratory and non-respiratory leukocyte activation disorders.

PCT publications WO 01/64632, 01/64633, and 01/64634 assigned to Aventis relate to azetidine derivatives as cannabinoid antagonists.

Schultz, E.M., and Dr. J. Med Chem. 1967, 10, 717 and Pien, S.H. and Dr. J. Med. Chem. 1967, 10, 725 describe maleamic acids, which act on plasma cholesterol and penicillin secretion.

The compounds of the present invention are cannabinoid-1 (CB1) receptor modulators and are useful in the treatment, prevention and control of cannabinoid-1 (CB1) receptor-mediated diseases. In particular, the compounds of the present invention are antagonists or inverse agonists of the CB1 receptor. The invention relates to the use of these compounds in modulating the cannabinoid-1 (CB1) receptor. As such, the compounds of the present invention are useful as centrally acting drugs in the treatment of psychoses, memory impairment, cognitive disorders, migraines, neuropathies, neuro-inflammatory disorders, including multiple sclerosis and Guillain-Barre syndrome and inflammatory sequelae of viral encephalitis, cerebral vascular accidents , and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful in the treatment of disorders caused by the abuse of drugs, especially opiates, alcohol, marijuana, and nicotine. The compounds are also useful in the treatment of eating disorders, by inhibiting excess food consumption and the resulting obesity, as well as the complications that arise as a result. The compounds are also useful in the treatment of constipation and chronic intestinal pseudo-obstruction, as well as in the treatment of asthma and cirrhosis of the liver.

Summary of the invention

The subject invention deals with new substituted amides of the general Formula I:

[image]

(AND)

and their pharmaceutically acceptable salts, which are antagonists and/or inverse agonists of cannabinoid-1 (CB1) receptors and are useful in the treatment, prevention and control of diseases mediated by cannabinoid-1 (CB1) receptors. The invention relates to the use of these novel compounds in selectively antagonizing the cannabinoid-1 (CB1) receptor. As such, the compounds of the present invention are useful as centrally acting drugs in the treatment of psychoses, memory impairment, cognitive disorders, migraines, neuropathies, neuro-inflammatory disorders, including multiple sclerosis and Guillain-Barre syndrome and inflammatory sequelae of viral encephalitis, cerebral vascular accidents , and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders and schizophrenia. The compounds are also useful in the treatment of disorders caused by the abuse of drugs, especially opiates, alcohol, marijuana, and nicotine, including smoking cessation. The compounds are also useful in the treatment of obesity or eating disorders related to overeating and related complications. The compounds are also useful in the treatment of constipation and chronic intestinal pseudo-obstruction. The compounds are also useful in the treatment of liver cirrhosis. The compounds are also useful in the treatment of asthma.

The subject invention also deals with the treatment of these conditions, and the use of the compounds of the subject invention in the production of a drug useful in the treatment of these conditions. The present invention also deals with the treatment of these conditions through the combination of compounds of formula I and other currently available pharmaceuticals.

The invention also relates to novel compounds of structural formula I.

The invention also deals with pharmaceutical formulations, which contain one of the compounds as an active ingredient.

The invention further deals with methods of preparing the compounds of this invention.

Detailed description of the invention

The compounds used in the methods of the present invention are represented by the compound of structural formula I:

[image]

(AND)

or its pharmaceutically acceptable salts, where;

R1 is selected from:

1) cycloheteroalkyl,

2) aryl,

3) heteroaryl, i

4) -NRaRc;

wherein the aryl and heteroaryl are optionally substituted with one to three substituents independently selected from Rb;

R2 is selected from:

1) C1-10 alkyl,

2) C3-10cycloalkyl-C1-4alkyl,

3) aryl-C1-4alkyl, i

4) heteroaryl-C1-4alkyl;

wherein each cycloalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb;

each Ra is independently selected from:

1) hydrogen,

2) methyl, i

3) -CF3;

each Rb is independently selected from:

1) halogen,

2) cyano,

3) trifluoromethyl,

4) trifluoromethoxy,

5) C1-3alkyloxy, and

6) C1-3 alkyl;

Rc is independently selected from:

1) hydrogen,

2) C1-6alkyl,

3) aryl,

4) heteroaryl,

5) aryl-methyl, and

6) heteroaryl-methyl,

each Rc may be unsubstituted or substituted with one to three substituents selected from Rh;

Rd is independently selected from:

1) cycloalkyl,

2) aryl, i

3) heteroaryl,

each Rd may be unsubstituted or substituted with one to three substituents selected from Rh;

each Rh is independently selected from:

1) halogen,

2) C1-3alkyl,

3) -CN, i

4) -CF3,

where when the pyridyl groups are unsubstituted on the nitrogen, they are optionally present as the N-oxide.

In one implementation of the subject invention, R1 is selected from:

1) phenyl,

2) pyridyl,

3) indolyl,

4) 7-aza-indolyl,

5) thiophenyl, i

[image] ;

wherein each aryl and heteroaryl is optionally substituted with one or two substituents independently selected from Rb, each pyridyl is optionally present as an N-oxide.

In one class of this implementation of the subject invention, R1 is selected from:

1) phenyl,

2) 3-cyanophenyl,

3) 3-methylphenyl,

4) 3,5-difluorophenyl,

5) 3-pyridyl,

6) 5-chloro-3-pyridyl,

7) 5-methyl-3-pyridyl,

8) 5-cyano-3-pyridyl,

9) 1-oxido-5-cyano-3-pyridyl,

10) 1-indolyl,

11) 7-aza-indol-N-yl,

12) 2-thiophenyl, i

[image] .

In one subclass of this class of the subject invention, R 1 is 5-cyano-3-pyridyl.

In another implementation of the subject invention, R2 is selected from:

1) C1-6 alkyl,

2) C3-6cycloalkylmethyl,

3) phenylmethyl,

4) heteroarylmethyl,

wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb.

In one class of this implementation of the subject invention, R2 is selected from:

1) C1-6 alkyl,

2) C4-6cycloalkylmethyl,

3) phenylmethyl,

4) pyridyl,

wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or two substituents independently selected from Rb.

In one subclass of this class of the subject invention, R2 is selected from:

1) 2-methylpropyl,

2) n-pentyl,

3) cyclobutylmethyl,

4) cyclopentylmethyl,

5) cyclohexylmethyl,

6) benzyl,

7) 4-chlorobenzyl,

8) 4-methylbenzyl,

9) 4-fluorobenzyl,

10) 4-methoxybenzyl, i

11) (5-chloro-2-pyridyl)methyl.

In one implementation of the subject invention, each Ra is independently selected from:

1) hydrogen,

2) methyl, i

3) -CF3.

In one class of this implementation of the subject invention, each Ra is independently selected from:

1) hydrogen, i

2) methyl.

In one implementation of the subject invention, each Rb is independently selected from:

1) halogen,

2) cyano,

3) C1-3alkyloxy i

4) C1-3 alkyl.

In one class of this implementation of the subject invention, each Rb is independently selected from:

1) fluoro,

2) chlorine,

3) bromine,

4) iodine,

5) cyano,

6) methoxy, and

7) methyl.

In one subclass of this class, each Rb is independently selected from:

1) fluoro,

2) chlorine,

3) cyano,

4) methoxy, and

5) methyl.

In one implementation of the subject invention, each Rc is independently selected from:

1) hydrogen,

2) C1-6alkyl,

3) phenyl,

4) pyridyl,

5) benzyl, te

6) pyridyl-methyl;

each Rc may be unsubstituted or substituted with a substituent selected from Rh.

In one class, Rc is phenyl.

In one implementation of the subject invention, Rd is selected from:

1) C4-6cycloalkyl,,

2) aryl, i

3) heteroaryl,

where Rd may be unsubstituted or substituted, with one or two substituents selected from Rh.

In one class of the subject invention, Rd is selected from:

1) phenyl,

2) pyridyl, te

3) pyrimidinyl,

where Rd may be unsubstituted or substituted, with one or two substituents selected from Rh.

In one subclass of the subject invention, Rd is selected from:

1) phenyl,

2) 4-chlorophenyl,

3) 3-chlorophenyl,

4) 3,5-difluorophenyl,

5) 3,5-dichlorophenyl,

6) 2-pyridyl,

7) 5-chloro-2-pyridyl,

8) 6-methyl-2-pyridyl,

9) 5-trifluoromethyl-2-pyridyl,

10) 4-trifluoromethyl-2-pyridyl,

11) 4-trifluoromethyl-2-pyrimidyl, i

12) 6-trifluoromethyl-4-pyrimidyl.

In another subclass of the present invention, Rd is 5-trifluoromethyl-2-pyridyl.

In one implementation of the subject invention, each Rh is independently selected from:

1) halogen,

2) C1-3alkyl,

3) -CN, i

4) -CF3.

In one class of this implementation, each Rh is independently selected from:

1) fluoro,

2) chlorine,

3) methyl,

4) -CN, i

5) -CF3.

Specific novel compounds that may be used in the methods, uses and compositions of the present invention include:

1) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;

2) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;

3) N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide;

4) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide;

5) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(3,5-dichlorophenyloxy)-2-methylpropanamide;

6) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide;

7) N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide;

8) N-[3-(4-chlorophenyl)-1-methyl-2-phenyl-propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;

9) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(6-methyl-pyridyloxy)-2-methylpropanamide;

10) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(phenyloxy)-2-methylpropanamide;

11) N-[(3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2-methylpropanamide;

12) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

13) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

14) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

15) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

16) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

17) N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

18) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

19) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide;

20) N-[3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;

21) N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

22) N-[3-(4-methyl-phenyl)-1-methyl-2-phenylpropyl]-2-(4-trifluoromethyl-phenyloxy)-2-methylpropanamide;

23) N-[3-(4-fluoro-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

24) N-[3-(4-chlorophenyl)-2-(1-indolyl)-1-methyl)propyl]-2-(5-trifluoromethyl-2-oxypyridin-2-yl)-2-methylpropanamide;

25) N-[3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-1-methyl)propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

26) N-[3-(4-chloro-phenyl)-2-(1-indolinyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

27) N-[3-(4-chloro-phenyl)-2-(N-methyl-anilino)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

28) N-[3-(4-methoxy-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

29) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;

30) N-[2-(3-cyanophenyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

31) N-[3-(4-chlorophenyl)-2-(1-oxido-5-cyano-3-pyridyl]-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

32) N-[2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

33) N-[2-(3-cyanophenyl)-1-methyl-heptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

34) N-[2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

35) N-[2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;

and their pharmaceutically acceptable salts.

"Alkyl", as well as other groups with the prefix "alk", such as alkoxy, alkanoyl, denotes carbon chains, which can be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

"Cycloalkyl" means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 10 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

"Aryl" means mono- or bicyclic aromatic rings containing only carbon atoms. Examples of aryl include phenyl, naphthyl, and the like.

"Heteroaryl" means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, each ring containing 5 to 6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo (2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, imidazothiazolyl, and the like. In particular, "heteroaryl" includes pyridyl, pyrimidyl, and thiophenyl, the heteroaryl ring may be substituted on one or more carbon or nitrogen atoms

"Cycloheteroalkyl" means mono- or bicyclic or bridged saturated rings, containing at least one heteroatom selected from N, S and O, where each of said rings has from 3 to 10 atoms where the point of attachment can be a carbon or nitrogen atom. The term also includes monocyclic heterocyclics attached to an aryl or heteroaryl group, where the point of attachment is at a non-aromatic moiety. Examples of “cycloheteroalkyl” include indolyl, azaindolyl, and the like. The cycloheteroalkyl ring may be substituted on the carbon and/or nitrogen atoms of the ring.

"Halogen" includes fluorines, chlorines, bromines and iodines.

When any variable (e.g., R1, Rd, etc.) occurs more than once in each constituent or formula I, its definition at each occurrence is independent of the definition at other occurrences. Also, combinations of substituents and/or variables are allowed, only if such combinations result in stable compounds.

Under the standard nomenclature used throughout this specification, the terminal portion of a particular side of the chain is described first, followed by the adjacent functional group, according to the point of attachment. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent

[image]

When choosing the compounds of the subject invention, the expert can recognize that the various substituents, i.e. R1, R2, etc. are chosen in accordance with the well-known principles of connectivity and stability of the chemical structure.

The term "substituted" is intended to include multiple degrees of substitution by the named substituent. Where multiple substituent moieties are described or claimed, the substituted compound may be independently substituted with one or more of the described or claimed substituent moieties, singly or multiply. By independently substituted, it is meant that (two or more) substituents can be the same or different.

The compounds of formula I may contain one or more asymmetric centers and may therefore occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention should cover all such isomeric forms of the compounds of formula I.

Some compounds described herein contain olefinic double bonds, and unless otherwise stated, are intended to include both E and Z geometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some compounds described herein may exist as tautomers with different hydrogen bonding points. Such an example can be a ketone and its enol form, known as keto-enol tautomers. Individual tautomers as well as their mixtures are covered by the compounds of formula I.

Compounds of Formula I can be separated into diastereoisomeric pairs of enantiomers, for example, by fractional crystallization in a suitable solvent, for example MeOH or EtOAc or mixtures thereof. The pair of enantiomers thus obtained can be separated into individual stereoisomers by conventional means, for example using an optically active amine as a solubilizing agent or on a chiral HPLC column.

Alternatively, each enantiomer of a compound of general Formula I may be obtained by stereospecific synthesis, using optically pure starting material or reagents of known configuration.

It is generally preferred to administer the compounds of the present invention as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by various conventional methods. These include chiral chromatography, chiral derivatization followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

Furthermore, some of the crystalline forms of the compounds of the present invention may exist as polymorphs, and as such are included in the present invention. Additionally, some compounds of the present invention can form solutions with water or common organic solvents. Such solutions are included within the scope of this invention.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, zinc salts and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including natural substituted amines, cyclic amines, and base ion exchange resins, such as arginine, betaine, caffeine, choline, N,N '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins , procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The term "pharmaceutically acceptable salts" further includes all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methyl bromide, bromide, methyl nitrate, calcium edetate, methyl sulfate, camsylate , mucates, carbonates, napsilates, chlorides, nitrates, clavulanates, N-methylglucamines, citrates, ammonium salts, dihydrochlorides, oleates, edetates, oxalates, edissilates, pamoates (embonates), estolates, palmitates, esylates, pantothenates, fumarates, phosphates/diphosphates , gluceptates, polygalacturonates, gluconates, salicylates, glutamates, stearates, glycolylarsanilates, sulfates, hexylresorcinates, subacetate, hydrabamines, succinates, hydrobromide, tannates, hydrochlorides, tartrates, hydroxynaphthoates, theoclates, iodides, tosylates, isothionates, triethiodides, lactates, panoates, valerates and the like, which may be used as dosage forms to alter solubility or hydrolysis characteristics, or may be used for sustained release or prodrug formulations.

It is to be understood that, as used herein, references to compounds of formula I also include pharmaceutically acceptable salts.

The compounds of the present invention are CB1 receptor modulators. In particular, the compounds of structural formula I are antagonists or inverse agonists of the CB1 receptor.

An "agonist" is a compound (hormone, neurotransmitter, or synthetic compound) that binds to a receptor, inducing conformational changes in the receptor that, in turn, result in responses such as contractions, relaxations, secretions, changes in enzyme activity, etc., similar to this excites the physiologically relevant agonist ligand(s) for that receptor. An "antagonist" is a compound that reduces the action of an agonist. An "inverse agonist" is a compound that acts on a receptor but results in the opposite effect of a specific receptor agonist.

The compounds of this invention are CB1 receptor modulators and as such are useful as centrally acting drugs in the treatment of psychoses, memory impairment, cognitive disorders, migraines, neuropathies, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and inflammatory sequelae of viral encephalitis, cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful in the treatment of disorders caused by the abuse of drugs, especially opiates, alcohol, marijuana, and nicotine. The compounds are also useful in the treatment of obesity or eating disorders related to overeating and the resulting complications. The compounds are also useful in the treatment of constipation and chronic intestinal pseudo-obstruction. The compounds are also useful in the treatment of liver cirrhosis. The compounds are also useful in the treatment of asthma.

The term "administering" a composition should be understood to mean providing compounds of the invention or prodrug-compounds of the invention to an individual in need of treatment.

Administration of a compound of structural formula I to apply the subject methods of therapy is performed by administering an effective amount of a compound of structural formula I to a patient in need of such treatment or prophylaxis. The need for prophylactic administration of the subject invention was determined using well-known risk factors. The effective amount of a particular compound is determined, in the final analysis, by the doctor responsible for each case, but depends on factors, such as the exact disease being treated, the severity of the disease and other diseases or conditions the patient suffers from, the chosen route of administration of other drugs , and the treatment that the patient may need at the same time, as well as other factors at the doctor's discretion.

The benefit of the subject compound in these diseases or disorders can be demonstrated in animal disease models, which are described in the literature. The following are examples of such disease models in animals: a) suppression of food consumption and resulting weight loss in rats (Life Sciences 1998, 63, 113-117); b) reduction of consumption of sweet food in marmosets (Behavioural Pharm. 1998, 9, 179-181); c) reduction of sucrose and ethanol intake in mice (Psychopharm. 1997, 132, 104-106); d) increased motor activity and conditioning in rats (Psychopharm. 1998, 135, 324-332; Psychofarmacol. 2000, 151: 25-30); e) spontaneous locomotor activity in mice (J. Pharm. Exp. Ther. 1996, 277, 586-594); f) reduction of opiate administration in mice (Sci. 1999, 283, 401-404); g) bronchial hyperresponsiveness in sheep and guinea pigs as models for various stages of asthma (for example, see W. M. Abraham et al., "α4-Integrins mediate antigene-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep." J. Clin. Invest. 93, 776 (1993) and A. A. Y. Milne and P. P. Piper, “Role of VLA-4 integrin in leucocyte recruitment and bronchial hyperresponsiveness in guinea-pigs.” Eur. J. Pharmacol., 282, 243 (1995)); h) promotion of the vasodilated state in advanced cirrhosis of the liver induced by carbon tetrachloride (Nature Medicine, 2001, 7 (7), 827-832); i) amitriptyline-induced constipation in cynomolgus monkeys is suitable for laxative evaluation (Biol. Pharm. Bulletin (Japan), 2000, 23(5), 657-9); j) neuropathology of pediatric chronic intestinal pseudo-obstruction and animal models related to the neuropathology of pediatric chronic intestinal pseudo-obstruction (Journal Pathology (England), 2001, 194 (3), 277-88).

The amount of prophylactic or therapeutic doses of compounds of formula I will, of course, vary with the nature and severity of the condition being treated with both the specific compound of formula I and the route of administration. It also varies according to the age, weight and response of the individual patient. Generally, the daily dosage range is in the range of about 0.001 mg to about 100 mg per kg of body weight of the mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. It may also be necessary to use doses outside these limits in some cases.

For use of the compound for intravenous administration, a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of the compound of formula I per kg of body weight per day, for preventive use from about 0.1 mg to about 100 mg ( preferably from about 1 mg to about 100 mg and even more preferably from about 1 mg to about 10 mg) of the compound of formula I per kg of body weight per day.

In the case where oral administration of the compound is used, a suitable dosage range is, for example, from about 0.01 mg to about 1000 mg of the compound of formula I per day, preferably from about 0.1 mg to about 10 mg per day. For oral administration, the compounds are preferably administered in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 milligrams of the active ingredient for symptomatic dose adjustment of the patient being treated.

Another aspect of the present invention provides pharmaceutical compositions comprising compounds of formula I and pharmaceutically acceptable carriers. The term "preparation", in a pharmaceutical preparation, includes a product that contains active ingredient(s), and inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product that results, directly or indirectly, in combination, complexation or aggregation two or more ingredients, or by dissociation of one or more ingredients, or from other types of reaction or interaction of one or more ingredients. Accordingly, the pharmaceutical preparations of the present invention include any preparation prepared by mixing the compound of formula I, additional active ingredients, and pharmaceutically acceptable excipients.

Any suitable route of administration may be used to provide an effective dose of a compound of the present invention to a mammal, particularly a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be used. Dosage forms include tablets, pills, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like.

The pharmaceutical preparations of the present invention contain the compound of formula I as an active ingredient or its pharmaceutically acceptable salts, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and must not be harmful to the recipient. In particular, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.

Formulations include formulations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol by inhalation), or nasal administration, although the most convenient route in any given case depends on the nature and severity of the condition which is treated and about the nature of the active ingredient. They may conveniently be present in unit dosage forms and prepared by methods well known in pharmacy.

For administration by inhalation, the compounds of the present invention are conveniently administered in the form of aerosol sprays, pressurized packs or nebulizers. The compounds may also be administered as powders which may be formulated and the powder composition may be inhaled using an insufflation inhaler. The preferred route of administration by inhalation is aerosol metered dose inhalation (MDI), which may be formulated as a suspension or solution of a compound of formula I in a suitable propellant, such as fluorocarbons or hydrocarbons, and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder compound of formula I, with or without additional excipients.

Suitable topical formulation of a compound of formula I includes transdermal devices, aerosols, creams, solutions, spreads, gels, lotions, powders and the like. Topical pharmaceutical preparations containing compounds of the present invention typically include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable carrier. Transdermal skin patches useful for administering the compounds of the present invention include those well known to those skilled in the art. When administered in the form of a transdermal system, the dose administered is, of course, continuous throughout the dosing regimen.

In practice, compounds of formula I can be combined as an active ingredient in close admixture with a pharmaceutical carrier according to conventional pharmaceutical preparation techniques. The carrier may take various forms, depending on the desired form of administration of the preparation, eg, orally or parenterally (including intravenously). In the preparation of the compound for oral dosage forms, any of the usual pharmaceutical media can be used, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as are, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, in the case of oral solid preparations such as, for example, powders, capsules and tablets, provided that a solid oral preparation is preferable to a liquid preparation. Due to ease of administration, tablets and capsules represent the most preferred oral unit dose form, where solid pharmaceutical carriers are obviously used. If desired, the tablet can be coated using standard aqueous or waterless techniques.

Pharmaceutical preparations of the present invention suitable for oral administration may be present as discrete units, such as capsules (including time-release as well as delayed-release formulations), pills, sachets, powders, granules or tablets, containing a predetermined amount of active ingredient, as a powder or granules or as a solution or suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion, including elixirs, tinctures, solutions, suspensions, syrups and emulsions. Such compounds may be prepared by any of the pharmaceutical techniques, but all methods involve the step of contacting the active ingredient with a carrier, which constitutes one or more of the necessary ingredients. In general, the preparations are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or in molds, optionally with one or more excipients. A compressed tablet may be prepared by compression in a suitable machine, the active ingredient in free form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. A molded tablet may be prepared in molds in a suitable machine, the powder compound mixture moistened with an inert liquid diluent. Preferably, each tablet contains from 0.01 to 1,000 mg, especially 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 milligrams of the active ingredient for symptomatic dose adjustment of the patient being treated, and each bag or capsule contains from about 0.01 to 1,000 mg, especially 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3, 5 , 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 milligrams of active ingredient for symptomatic dose adjustment of the patient being treated.

Additional convenient routes of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneally, subcutaneously, intramuscularly, and topically, with or without occlusion.

An example of the invention is a pharmaceutical preparation containing all the compounds described above and a pharmaceutically acceptable carrier. Also an example of the invention is a pharmaceutical preparation prepared by combining all the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for the preparation of pharmaceutical compositions comprising combining all the compounds described above and a pharmaceutically acceptable carrier.

The dose may be given in single daily doses or the total daily dose may be given in divided doses of two, three or four times a day. Furthermore, based on the properties of the particular compound selected for administration, the dose can be administered less frequently, eg weekly, twice a week, monthly, etc. The unit dose is of course higher with less frequent administration.

When administration is by intranasal, transdermal routes, rectal or vaginal suppositories, or through a continuous intravenous solution, the dose of administration is, of course, continuous throughout the dosing regimen.

The following examples represent pharmaceutical dosage forms for compounds of formula I:

Injectable suspension (I.M.) mg/mL

Compound of formula I 10

methylcellulose 5.0

Tween 80 0.5

benzyl alcohol 9.0

Benzalkonium chloride 1.0

Water for injection up to a total volume of 1 mL

Tablet mg/tablets

Compound of formula I 25

Microcrystalline cellulose 415

Povidone 14.0

Pregelatinized starch 43.5

Magnesium stearate 2.5

500

Capsule mg/capsule

Compound of formula I 25

Lactose powder 573.5

Magnesium stearate 1.5

600

Aerosol Per canister

Compound of formula I 24 mg

Lecithin, NF Liquid. conc. 1.2 mg

Trichlorofluoromethane, NF 4.025 g

dichlorodifluoromethane, NF 12.15 g

The compounds of formula I may be used in combination with other drugs that have been used in the treatment/prevention/control or amelioration of diseases or conditions for which the compounds of formula I are useful. Such other drugs may be administered, by the route and in the amount usually used for this purpose, simultaneously or sequentially with the compounds of formula I. When the compounds of formula I are used simultaneously with one or more other drugs, the pharmaceutical composition containing such other drugs in addition to the compound of formula And it is desirable. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to the compound of formula I. Examples of other active ingredients that may be combined with the compounds of formula I include, but are not limited to: antipsychotic agents, cognitive enhancement agents abilities, anti-migraine agents, anti-asthma agents, anti-inflammatory agents, anxiolytics, anti-Parkinson's disease agents, anti-epileptics, anorectic agents and serotonin reuptake inhibitors, and other anti-obesity agents, which may be administered separately or in the same pharmaceutical preparations.

It should be understood that in the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, the compounds of the present invention may be used in conjunction with other anorectic agents.

The subject invention also provides a method in the treatment or prevention of eating disorders, which consists of administering to a patient in need of such treatment, an amount of a compound of the subject invention and an amount of an anorectic agent, such that together they provide an effective result.

"Obesity" is a condition where there is an excess of body fat. The operational definition of obesity is based on the body weight index (Body Mass Index - BMI), which is calculated as body weight per height in meters squared (kg/m2). "Obesity" refers to a condition where an otherwise healthy subject has a BMI greater than or equal to 30 kg/m2, or a condition where a subject with at least one co-morbidity has a BMI greater than or equal to 27 kg/m2. An "obese subject" is an otherwise healthy subject with a BMI greater than or equal to 30 kg/m2 or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m2. A "subject at risk of obesity" is an otherwise healthy subject with a BMI of 25 kg/m2 to 30 kg/m2 or a subject with at least one co-morbidity and a BMI of 25 kg/m2 to less than 27 kg/m2.

Increased obesity-related risks occur at lower BMIs in Asians. In Asian countries, including Japan, "obesity" refers to a condition where a subject with at least one obesity-induced disease or obesity-related co-morbidity, which requires weight reduction, or which would be facilitated by weight reduction, has a BMI greater than or equal to 25 kg/m2. In Asian countries, including Japan, “obese subject” refers to a subject with at least one obesity-induced or obesity-related co-morbidity, which requires weight reduction, or which would be facilitated by weight reduction, with a BMI greater than or equal to 25 kg/ m2. In Asian countries, a "subject at risk of obesity" is a subject with a BMI greater than 23 kg/m2 to less than 25 kg/m2.

As used herein, the term “obesity” encompasses all of the above definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are not limited to, diabetes, non-insulin diabetes mellitus - type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuracidinemia, gout, coronary arterial diseases, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwick's syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritic deformities, lumbodynia, emeniopathy, and infertility. In particular, co-morbidities include: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, diabetes mellitus, and other conditions caused by obesity.

"Treatment" (of obesity and obesity-related disorders) refers to the administration of compounds or compounds of the subject invention that reduce or maintain body weight in an obese subject. One outcome of the treatment may be a reduction in the body weight of the obese subject relative to the body weight immediately prior to administration of the compounds or compounds of the present invention. Another treatment outcome may be the prevention of regaining body weight previously lost, as a result of diet, exercise, or pharmacotherapy. Another outcome of treatment may be a reduction in the occurrence and/or severity of obesity-related diseases. Treatment may conveniently result in a reduction in food or calorie intake, including a reduction in total food intake, or a reduction in the intake of specific components of the diet, such as carbohydrates or fats; and/or inhibition of nutrient adsorption; and/or inhibition of metabolic rate reduction; weight reduction in patients who need it. Treatment may also result in acceleration of metabolism, such as an increase in metabolic rate, rather than additional inhibition of metabolic rate reduction; and/or in minimizing the metabolic resistance that normally results in weight loss.

"Prevention" (of obesity and obesity-related disorders) refers to the administration of compounds or compounds of the subject invention in order to reduce or maintain the body weight of a subject at risk of obesity. One outcome of the prevention may be a reduction in the body weight of a subject at risk of obesity, compared to the body weight prior to the administration of the compounds or compounds of the subject invention. Another outcome of prevention may be the prevention of regaining body weight, previously lost as a result of diet, exercise, or pharmacotherapy. Another prevention outcome can be the prevention of obesity if treatment is undertaken before the onset of obesity in a subject at risk for obesity. Another outcome of prevention may be a reduction in the occurrence and/or severity of obesity-related disorders, if treatment is undertaken before the onset of obesity in a subject at risk for obesity. Moreover, if treatment is initiated in already obese subjects, such treatment may prevent the onset, progression, or severity of obesity-related disorders such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.

Obesity-related disorders are related to, caused by, or result from obesity. Examples of obesity-related disorders include binge eating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemia, hyperlipidemia, endometriosis, breast, prostate, and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones. , heart disease, abnormal heart rhythm and arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniopharyngioma, Prader-Willi Syndrome, Frohlich Syndrome, GH-deficient subjects, short stature of the normal type, Turner's syndrome, and other pathological conditions that show reduced metabolic activity or a decrease in energy consumption as a percentage of total lean mass, for example, children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as gastro-oesophageal reflux related to obesity, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of blood vessels, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallstone disease, gout, and kidney cancer. The compounds of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.

The term "diabetes," as used herein, includes both insulin-dependent diabetes mellitus (ie, IDDM, also known as Type I diabetes) and non-insulin-dependent diabetes mellitus (ie, NIDDM, also known as Type II diabetes Type I diabetes, or insulin-dependent diabetes, is the result of an absolute disorder of insulin, the hormone that regulates the use of glucose. Type II diabetes, or insulin-independent diabetes (ie, non-insulin-dependent diabetes mellitus), often occurs with normal, or even elevated insulin levels, and appears to result in an inability of tissues to respond appropriately to insulin. Most Type II diabetics are also obese. The compounds and compositions of the present invention are useful in the treatment of both Type I and Type II diabetes. The compounds and compositions are particularly effective in the treatment of Type II diabetes The compounds and compositions of the present invention are also useful in the treatment and/or prevention of gestational diabetes mellitus.

As used herein, the term “drug abuse disorders” includes substance dependence or abuse with or without physiological dependence. Substances related to these disorders are: alcohol, amphetamine (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opiates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepine and others (or unknown) substances and combinations of all the above.

In particular, the term “drug abuse disorders” includes substance withdrawal disorders, such as alcohol withdrawal crisis with or without perceptual disturbances; alcohol withdrawal crisis delirium; amphetamine withdrawal crisis; cocaine withdrawal crisis; nicotine withdrawal crisis; opiate withdrawal crisis; sedative, hypnotic or anxiolytic withdrawal crisis with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal crisis delirium; and withdrawal crisis symptoms caused by other substances. It should be understood that references to the treatment of a nicotine withdrawal crisis include the treatment of symptoms related to smoking cessation.

Other “drug abuse disorders” include substance-induced anxiety disorder with onset during a withdrawal crisis; substance-induced mood disorder with onset during a withdrawal crisis; and substance-induced sleep disturbance with onset during a withdrawal crisis.

It should be understood that the combination of a conventional antipsychotic drug with a CB1 receptor modulator may provide improved efficacy in the treatment of mania. Such a combination would be expected to provide a rapid onset of action in the treatment of a manic episode, allowing the prescription of the drug "as needed". Furthermore, such combinations may allow a lower dose of the antipsychotic agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side effects. A further advantage of such a combination is that, due to the action of the CB1 receptor modulator, adverse side effects caused by the antipsychotic agent, such as acute dystonias, dyskinesias, akathesias and tremors can be reduced or prevented.

The subject invention also provides a method for treating or preventing mania, and the method comprises administering to a patient in need of such treatment, or at risk of developing mania, an amount of a CB1 receptor modulator and an amount of an antipsychotic agent, such that together they provide the expected effect.

It should be understood that the CB1 receptor modulator and antipsychotic agent may be present as a combination ready for simultaneous, separate or sequential use in the treatment or prevention of mania.

It should be understood that when using the combination of the present invention, the CB1 receptor modulator and the antipsychotic agent may be in the same pharmaceutically acceptable carrier, and therefore administered simultaneously. They may be in separate pharmaceutical carriers, such as conventional oral dosage forms, which are taken simultaneously. The term "combination" also refers to the case where the compounds are administered in separate dosage forms and sequentially. Thus, for example, the antipsychotic agent may be administered as a tablet and then, within a reasonable period of time, the CB1 receptor modulator may be administered as an oral dosage form, such as a tablet or fast-dissolving oral dosage form. By "fast-dissolving oral formulation" is meant an oral form of administration, which, when placed on the patient's tongue, dissolves within about 10 seconds.

It should be understood that the combination of a conventional antipsychotic drug with a CB1 receptor modulator can provide an improved effect in the treatment of schizophrenic disorders. Such a combination would be expected to enable a rapid onset of action in the treatment of schizophrenic symptoms, thus enabling prescription "as needed". Furthermore, such combinations may allow a lower dose of the CNS agent without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side effects. A further advantage of such a combination is that, due to the action of the CB1 receptor modulator, adverse side effects caused by the antipsychotic agent, such as acute dystonias, dyskinesias, akathesias and tremors, can be reduced or prevented.

It should be understood that the combination of a conventional anti-asthmatic drug with a CB1 receptor modulator may provide improved efficacy in the treatment of asthma.

Therefore, according to a further aspect of the present invention there is administration using a CB1 receptor modulator and an anti-asthmatic agent for the production of a drug in the treatment or prevention of asthma.

The present invention also provides a method for the treatment or prevention of asthma, the method comprising administering to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-asthmatic agent such that together they provide the expected effect.

Methods of treatment of the present invention include a method of modulating the CB1 receptor and treating CB1 receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of the present invention that selectively antagonizes the CB1 receptor over other CB or G-protein coupled receptors.

The term "therapeutically effective amount" means an amount of a compound of structural formula I that elicits a biological or medical response in a tissue, system, animal, or human sought by an investigator, veterinarian, physician, or other clinician, which includes alleviation of symptoms of the disorder being treated. The novel treatment methods of this invention relate to disorders well known to those skilled in the art. The term "mammal" includes humans.

Abbreviations used in the following Schemes and Examples:

aq.: aqueous; API-ES: ionization-electrospray under atmospheric pressure (term from mass spectrometry); DMF: dimethylformamide; DMSO: dimethylsulfoxide; EDC: 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride; EPA: ethylene polyacrylamide (plastic); EtOAc: ethyl acetate; h: hours; Hex: hexane; HOBt: 1-hydroxybenzo-triazole; HPLC: high pressure liquid chromatography; HPLC/MS: high pressure liquid chromatography/mass spectrometry; in vacuo: by rotoevaporation; IPAC: isopropyl acetate; KHMDS: potassium hexamethyldisilazide; LC: Liquid Chromatography; LC/MS, LC-MS: liquid chromatography-mass spectrum; M: molar; Me: methyl; MeOH: methanol; mmol: millimole; MS or ms: mass spectrum; N: normal; NaHMDS: sodium hexamethyldisilazide; NMR: nuclear magnetic resonance; PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; Rt: retention time; room temperature or RT: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin layer chromatography.

The compounds of the subject invention can be prepared according to the procedures shown in the accompanying schemes and examples.

Scheme 1.

[image]

In Scheme 1, an appropriately substituted amine reacts with a carboxylic acid B under a standard amide bond, forming the conditions necessary to afford the arylamide C. To illustrate the invention, the following examples are included. These examples do not limit the invention. They are only a suggestion of methods of applying the invention in practice. Those skilled in the art can find other methods for applying the invention, which are obvious to them. However, these methods are also included within the scope of this invention.

General Procedures. LC/MS analyzes were performed using a MICROMASENI ZMD mass spectrometer, coupled to an AGILENT 1100 Series HPLC using a YMC ODS-A 4.6 x 50 mm column, eluted at 2.5 mL/min with a solvent gradient of 10 to 95% B over 4.5 min, followed by 0.5 min at 95% B: solvent = 0.06% TFA in water; solvent B = 0.05% TFA in acetonitrile. 1H-NMR spectra were obtained on a 500 MHz VARIAN spectrometer in CDCl3 or CD3OD as indicated and chemical shifts are reported as � using the solvent peak as reference, coupling constants are reported in hertz (Hz).

Reference Example 1

[image]

N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride

The preparation of the two diastereomers (alpha and beta) of N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride salt has been described (Schultz, E.M, et al. J. Med Chem. 1967, 10, 717 ). diastereomer α: LC-MS: calculated for C16H17Cl2N 293, observed m/e 294 (M + H)+ (retention time 2.5 min). diastereomer β: LC-MS: calculated for C16H17Cl2N 293, observed m/e 294 (M + H)+ (retention time 2.2 min).

REFERENCE EXAMPLE 2

[image]

2-amino-4-(4-chlorophenyl)-3-phenylbutane hydrochloride salt

The title compound was prepared by the procedure described in Reference Example 1.

diastereomer α:

LC-MS: calcd for C16H18ClN 259, observed m/e 260 (M + H)+ (2.3 min).

diastereomer β:

LC-MS: calcd for C16H18ClN 259, observed m/e 260 (M + H)+ (2.2 min).

Reference Example 3

[image]

N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-amine hydrochloride

(diastereomer α)

Step A 3-(4-Chlorophenyl)-2-phenylpropanoic acid, methyl ester.

To a solution of methyl phenylacetate (12 g, 80 mmol) and 4-chlorobenzyl bromide (16 g, 80 mmol) in 250 mL of anhydrous THF at –78ºC was added sodium hexamethyldisilazide (1 M in THF, 80 mL, 80 mmol) (potassium hexamethyldisilazide in toluene can be used with a similar result). The reaction was allowed to warm to room temperature overnight. Volatile materials were removed on a rotary evaporator, the resulting mixture was partitioned between saturated ammonium chloride (200 mL) and EtOAc (200 mL). The organic layers were separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound.

1H NMR (500 MHz, CD3OD): δ 7.36-7.10 (m, 9H), 3.81 (dd, 1H), 3.52 (s, 3H), 3.36 (dd, 1H), 3.02 (dd, 1H).

Step B 3-(4-chlorophenyl)-2-phenylpropanoic acid.

Lithium hydroxide monohydrate (8.8 g, 0.21 mol) was added to a mixture of methyl 3-(4-chlorophenyl)-2-phenylpropionate (Step A, 20 g, 74 mmol) in acetonitrile (100 mL) and water (100 mL). After stirring at room temperature for 3 days, unstable materials were removed by concentration on a rotary evaporator, the residue was partitioned between water (300 mL) and hexane/ether (1:1, 200 mL). The aqueous layers were separated, acidified to pH = 2-3, and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.34-7.10 (m, 9H), 3.82 (dd, 1H), 3.36 (dd, 1H), 2.98 (dd, 1H).

Step C N-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide.

Dimethyl formamide (50 μL) and oxalyl chloride (14 g, 0.11 mol) were added to a solution of 3-(4-chlorophenyl)-2-phenylpropionic acid (Step B, 14 g, 55 mmol) in CH2Cl2 (125 mL) at 0ºC. in drops. The reaction was allowed to warm to room temperature overnight and concentrated to dryness to give the crude acyl chloride, which was used without further purification. N-methoxy-N-methylamine hydrochloride (11 g, 0.11 mol) and triethylamine (dried by flow through activated molecular sieves, 30 mL, 0.22 mol) were then added to a solution of acyl chloride in CH2Cl2 (250 mL) at 0ºC. After stirring at room temperature for 4 h, the reaction mixture was diluted with ether (500 mL) and then washed with water, diluted with aqueous sodium hydrogen sulfate and brine, dried over anhydrous MgSO4, filtered and concentrated to dryness to give the crude product, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.4-7.1 (m, 9H), 4.38 (br, 1H), 3.48 (s, 3H), 3.35 (dd, 1H), 3.10 (s, 3H), 2.92 (dd , 1H); LC-MS: m/e 304 (3.6 min).

Step D 4-(4-chlorophenyl)-3-phenyl-2-butanone

To a solution of N-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide (Step C, 16 g, 53 mmol, dried by azeotroping with toluene) in anhydrous THF (200 mL) at 0ºC was added methylmagnesium bromide ( 3 M in ether, 35 mL, 0.11 mol). After stirring at 0ºC for 2 h, the reaction was quenched with MeOH (5 mL) and 2 M hydrochloric acid (50 mL) was added. Unstable materials were removed by concentration on a rotary evaporator and the residue partitioned between saturated ammonium chloride (200 mL) and ether (200 mL). The organic layers were separated, the aqueous layer was extracted with ether (2 x 200 mL). The combined organic extracts were dried over anhydrous MgSO 4 , filtered and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.45-7.02 (m, 9H), 4.08 (dd, 1H), 3.34 (dd, 1H), 2.90 (dd, 1H), 2.03 (s, 3H).

Step E 4-(4-chlorophenyl)-3-phenyl-2-butanol.

To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanone (Step D, 13 g, 50 mmol) in MeOH (100 mL) at 0°C was added sodium borohydride (3.8 g, 100 mmol). After stirring at 0ºC for 30 min, the reaction was quenched by the addition of 2 M hydrochloric acid (50 mL). Unstable materials were removed by concentration on a rotary evaporator and the residue partitioned between water (100 mL) and EtOAc (200 mL). The organic layers were separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was purified by flash column chromatography on silica gel, eluted with 10% EtOAc in hexane, to give pure flash eluted isomer and a mixture containing both rapidly eluted isomers and a slower eluted isomer.

Fast eluted isomer: 1H NMR (500 MHz, CD3OD): δ 7.25-7.00 (m, 9H), 4.00 (m, 1H), 3.15 (m, 1H), 2.97 (m, 1H), 2.85 (m, 1H) , 1.10 (d, 3H).

Step F 4-(4-chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane.

To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanol (Step E, rapidly eluting isomer, 9.0 g, 34 mmol) in EtOAc (100 mL) at 0ºC was added triethylamine (dried by flow through activated molecular sieves , 5.8 mL, 42 mmol) and methanesulfonyl chloride (3.0 mL, 38 mmol). After stirring at 0ºC for 30 min, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (100 mL). After stirring at room temperature for 1 h, the organic layers were separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.3-7.0 (m, 9H), 5.05 (m, 1H), 3.2-3.0 (m, 3H), 2.80 (s, 3H), 1.40 (d, 3H).

Step G 2-azido-4-(4-chlorophenyl)-3-phenylbutane.

To a solution of 4-(4-chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane (Step F, 12 g, 34 mmol) in DMF (50 mL) was added sodium azide (11 g, 0.17 mol). After stirring at 120ºC for 1 h, the reaction mixture was poured into water (200 mL), and the product was extracted with ether (2 x 100 mL). The combined organic extracts were washed with water, dried with a stream of MgSO4, filtered and concentrated to dryness, the residue was purified on a silica gel column, eluted with hexane, to give the title compound.

Step H 2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-phenylbutane

To a solution of 2-azido-4-(4-chlorophenyl)-3-phenylbutane (Step G, 7.0 g, 24 mmol) in EtOAc (150 mL) was added di(tert-butyl) dicarbonate (8.0 g, 37 mmol) and platinum dioxide (0.50 g, 2.2 mmol). The mixture is degassed and filled with hydrogen with a balloon. After stirring for 1 day, the reaction mixture was filtered through Celite diatomaceous earth, the filtrate was concentrated to give the crude product, which was contaminated with some unreacted di(tert-butyl) dicarbonate. 1H NMR (500 MHz, CD3OD): δ 7.25-6.88 (m, 9H), 3.89 (m, 1H), 3.20 (m, 1H), 2.86-2.77 (m, 2H), 1.54 (s, 9H), 0.92 (d, 3H).

Step I N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-amine hydrochloride (diastereomer α).

2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-phenylbutane (Step H, 7.0 g, 24 mmol) was treated with a saturated solution of hydrogen chloride in EtOAc (100 mL) at room temperature for 30 min. (4 M hydrogen chloride in dioxane can be used with similar results). The mixture was concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.35-6.98 (m, 9H), 3.62 (m, 1H), 3.20 (dd, 1H), 3.05 (m, 1H), 2.98 (dd, 1H), 1.19 (d , 3H). LC-MS: m/e 260 (M + H) + (2.3 min).

Reference Example 4

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N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine hydrochloride

Step A 4-(4-chlorophenyl)-3(S)-phenyl-2(R)-butanol.

A magnesium sample (20 g, 0.82 mol) was activated by stirring under nitrogen for 12 h, and anhydrous ether (100 mL) was added to the solid material. The mixture was cooled to 0ºC, and 4-chlorobenzyl chloride (40 g, 0.25 mmol) in 400 mL of anhydrous ether was added dropwise. After stirring at room temperature for 1 h, a sample of the above solution (32 mL) was added to (1R,2R)-1-phenylpropylene oxide (1.0 g, 7.5 mmol) in 100 mL ether at 0ºC via syringe. After stirring at 0ºC for 2 h, the reaction was quenched by the addition of saturated aqueous ammonium chloride (100 mL). The organic layers were separated and the aqueous layer extracted with ether (2 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness, and the residue purified by flash column chromatography on silica gel, eluting with hexane to 15% EtOAc in hexane, to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.28-7.02 (m, 9H), 4.01 (m, 1H), 3.14 (dd, 1H), 2.97 (dd, 1H), 2.85 (m, 1H), 1.12 (d , 3H).

Step B N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine, hydrochloride

The product from Step A (4-(4-chlorophenyl)-3(S)-phenyl-2(R)-butanol, 1.8 g, 7.0 mmol) was converted to the title compound, following the steps described in Reference Example 3, Steps F-I, except that hydrogen chloride in dioxane (4 M) was used instead of hydrogen chloride in EtOAc. 1H NMR (500 MHz, CD3OD): δ 7.35-6.98 (m, 9H), 3.62 (m, 1H), 3.20 (dd, 1H), 3.05 (m, 1H), 2.98 (dd, 1H), 1.19 (d , 3H). LC-MS: m/e 260 (M + H) + (2.3 min).

Reference Example 5

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N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-amine, hydrochloride (a mixture of diastereomers α�β 10:1)

Step A 4-(4-Chlorophenyl)-3-pyridyl-2-butanone

In a solution of 3-pyridylacetone hydrochloride (Wibaud, van der V. Recl. Trav. Chim. Pays-Bas. 1952, 71, 798) (10 g, 58 mmol) and 4-chlorobenzyl chloride (9.1 g, 58 mmol) in 100 mL of CH2Cl2 at –78ºC, cesium hydroxide monohydrate (39 g, 0.23 mol) and tetrabutyl ammonium iodide (1 g) were added. The reaction was allowed to warm to room temperature overnight, and the resulting mixture was partitioned between brine (100 mL) and EtOAc (100 mL). The organic layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.42 (d, 1H), 8.34 (d, 1H), 7.72 (d, 1H), 7.40 (dd, 1H), 7.18 (d, 2H), 7.06 (d, 1H) ), 4.23 (dd, 1H), 3.38 (dd, 1H), 2.95 (dd, 1H), 2.10 (s, 3H). LC-MS: m/e 260 (M + H)+ (1.9 min).

Step B N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-amine, hydrochloride (a mixture of diastereomers α�β 10:1).

Product Step (4-(4-chlorophenyl)-3-pyridyl-2-butanone) (14 g, 57 mmol) was converted to the title compound according to the procedure described in Reference Example 3, Steps E-I. LC-MS: m/e 261 (M + H)+ (1.2 min).

Reference Example 6

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2-(2-fluorophenyloxy)-2-methylpropionic acid

Step A 2-(2-fluorophenyloxy)-2-methylpropionic acid

To a solution of 2-fluorophenol (2.0 g, 18 mmol) and 1,1,1-trichloro-2-methyl-2-propanol (7.9 g, 45 mmol) in acetone (100 mL) was added sodium hydroxide (7.1 g, 0.18 mol), and an ice water bath is periodically used to maintain a gentle reflux. After the reflux ceased, the reaction was stirred for an additional hour. Unstable materials were removed on a rotary evaporator, and the residue partitioned between ether (100 mL), hexane (100 mL), and water (200 mL). The aqueous layers were separated and acidified with concentrated hydrochloric acid (pH = 2), and extracted with ether (3 x 100 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.15-7.05 (m, 4H), 1.56 (s, 6H). LC-MS: m/e 199 (M + 1) + (2.3 min).

The acids in Reference Examples 7 and 8 were prepared according to the procedures described for Reference Example 6, replacing the 2-fluorophenol with suitably substituted phenols.

Reference Example 7

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2-(3-Chlorophenyloxy)-2-methylpropionic acid

1H NMR (500 MHz, CD3OD): δ 7.23 (t, 1H), 7.00 (dd, 1H), 6.93 (t, 1H), 6.84 (dd, 1H), 1.59 (s, 6H).

LC-MS: m/e 215 (M + 1)+, (2.7 min).

REFERENCE EXAMPLE 8

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2-(3,5-dichlorophenyloxy)-2-methylpropionic acid

1H NMR (500 MHz, CD3OD): δ 7.05 (t, 1H), 6.84 (d, 2H), 1.60 (s, 6H).

Reference Example 9

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2-(2-Pyridyloxy)-2-methylbutanoic acid.

Step A Benzyl 2-(2-pyridyloxy)propionate

Diethyl azodicarboxylate (7.8 mL, 45 mmol) was added to a mixture of 2-hydroxypyridine (2.9 g, 30 mmol), benzyl lactate (5.0 g, 21 mmol) and triphenylphosphine (12 g, 47 mmol) in 100 mL of CH2Cl2 at 0ºC. The reaction was allowed to warm to room temperature over 4 h. The resulting mixture was diluted with hexane (100 mL) and concentrated with 20 g of silica gel. The material was applied to a silica gel column, eluted with 10% EtOAc in hexane, to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.00 (dd, 1H), 7.68 (ddd, 1H), 7.36-7.28 (m, 5H), 6.94 (dd, 1H), 6.84 (dd, 1H), 5.30 ( q, 1H), 5.18 (s, 2H), 1.59 (d, 3H). LC-MS: m/e 258 (M + H)+ (3.3 min).

Step B Benzyl 2-(2-pyridyloxy)-2-methylbutanoate.

To a solution of benzyl 2-(2-pyridyloxy)propionate (1.6 g, 6.2 mmol) and ethyl iodide (1.5 mL, 25 mmol) in 10 mL of anhydrous THF at –78ºC was added sodium hexamethyldisilazide (1 M in THF, 9.3 mL, 9.3 mmol) (potassium hexamethyldisilazide in toluene can be used with similar results). The reaction was allowed to warm to room temperature over 2 h and was partitioned between saturated ammonium chloride (100 mL) and EtOAc (100 mL). The organic layers were separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried with a stream of anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel, eluted with 10% EtOAc in hexane, to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.87 (dd, 1H), 7.63 (ddd, 1H), 7.27 (m, 3H), 7.18. (m, 2H), 6.85 (dd, 1H), 6.74 (dd, 1H), 5.08 (ABq, 2H), 2.13 (m, 1H), 1.94 (m, 1H), 1.65 (s, 3H), 0.95 ( t, 3H). LC-MS: m/e 286 (M + H) + (3.8 min).

Step C 2-(2-Pyridyloxy)-2-methylbutanoic acid

A mixture of benzyl 2-(2-pyridyloxy)-2-methylbutanoate (1.6 g, 5.5 mmol) and 10% palladium on carbon (50 mg) in 50 mL MeOH was degassed and filled with hydrogen using a balloon. After stirring at room temperature overnight, the reaction mixture was filtered through CELITE diatomaceous earth and washed with MeOH (20 mL), and the filtrate was concentrated to dryness to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.03 (dd, 1H), 7.64 (ddd, 1H), 6.89 (dd, 1H), 6.76 (dd, 1H), 2.14 (m, 1H), 1.94 (m, 1H ), 1.64 (s, 3H), 0.99 (t, 3H). LC-MS: m/e 196 (M + H)+ (1.8 min).

Reference Example 10

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2-(2-Pyridyloxy)-2-methylpropionic acid

The title compound was prepared according to the procedures described in Reference Example 9, replacing ethyl iodide and sodium hexamethyldisilazide with methyl iodide and potassium hexamethyldisilazide, respectively, in Step B.

1H NMR (500 MHz, CD3OD): δ 8.04 (dd, 1H), 7.64 (ddd, 1H), 6.89 (dd, 1H), 6.76 (dd, 1H), 1.66 (s, 6H). LC-MS: m/e 182 (M + H)+ (1.5 min).

Reference Example 11

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N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

The title compound was prepared according to the procedures described in Reference Example 3 by replacing methyl phenylacetate with methyl 3,5-difluorophenylacetate (prepared from 3,5-difluorophenylacetic acid and trimethylsilyldiazomethane) in Step A and sodium borohydride in MeOH with lithium tri(sec-butylborohydride in THF in Step E. LC-MS: m/e 296 (M + H)+ (2.39 min).

Reference Example 12

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N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

Step A 2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3-cyanophenyl)butane

Zinc was added to a solution of 2-(N-tert-butoxycarbonyl)amino-3-bromophenyl-4-(4-chlorophenyl)butane (prepared according to the procedure from Reference Example 3, Step H, 1.0 g, 2.3 mmol) in 5 mL of DMF cyanide (0.16 g, 1.4 mmol), tris(dibenzylidene-acetone)dipalladium chloroform complex (3.0 mg, 2.8 μmol), 1,1'-bis(diphenylp-phosphino)ferrocene (5.0 mg, 9.0 μmol) and water (0.1 mL ). After heating at 120ºC for 6 h under nitrogen, a second batch of zinc cyanide (0.16 g, 1.4 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (5.0 mg, 4.8 μmol), 1,1'-bis(diphenylphosphino)ferrocene (5.0 mg , 9.0 μmol) and water (0.05 mL) was added, and heating was continued for 18 h. After cooling to room temperature, the resulting mixture was partitioned between water (50 mL) and ether (50 mL). The organic layers were separated and the aqueous layer extracted with ether (2 x 50 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated, and the residue was purified by flash column chromatography on silica gel, eluting with 20% EtOAc in hexane, to afford the title compound. 1H NMR (400 MHz, CD3OD): δ 7.6-7.3 (m, 4H), 7.10 (d, 2H), 6.92 (d, 2H), 3.88 (m, 1H), 3.20 (m, 1H), 2.97 (m , 1H), 1.82 (m, 1H), 1.45 (s, 9H), 0.94 (d, 3H). LC-MS: m/e 385 (M + H) + (3.9 min).

Step B N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

The title compound was prepared according to the procedure described for Reference Example 3, Step I. LC-MS: m/e 285 (M + H)+ (2.2 min).

Reference Example 13

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2-methyl-2-(5-chloro-2-pyridyloxy)propionic acid

Step A ethyl 2-methyl-2-(5-chloro-2-pyridyloxy)propionate

A mixture of 5-chloro-2-hydroxypyridine (5.0 g, 39 mmol), ethyl 2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77 mmol) in 50 mL acetonitrile was heated at 50ºC overnight. Unstable materials were removed by concentration on a rotary evaporator, and the residue was partitioned between water (100 mL) and EtOAc (100 mL). The organic layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel, eluted with 5% EtOAc in hexane, to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.99 (d, 1H), 7.67 (dd, 1H), 6.68 (d, 1H), 4.13 (q, 2H), 1.64 (s, 6H), 1.14 (t, 3H ). LC-MS: m/e 244 (M + H) + (3.41 min).

Step B 2-methyl-2-(5-chloro-2-pyridyloxy)propionic acid

A mixture of ethyl 2-methyl-2-(5-chloro-2-pyridyloxy)propionate and sodium hydroxide (0.85 g, 21 mmol) in 15 mL of acetonitrile and 15 mL of water was heated at 50°C overnight. Unstable materials were removed by concentration on a rotary evaporator, and the residue was partitioned between 2 M hydrochloric acid (100 mL) and ether (100 mL). The organic layers were separated and washed with water (2 x 50 mL), dried over anhydrous MgSO 4 , filtered and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.02 (d, 1H), 7.65 (dd, 1H), 6.77 (d, 1H), 1.62 (s, 6H). LC-MS: m/e 216 (M + H)+ (2.33 min).

Reference Example 14

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2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic acid

The title compound was prepared according to the procedures described for Reference Example 13 replacing 5-chloro-2-hydroxypyridine with 5-trifluoromethyl-2-hydroxypyridine in Step A. 1H NMR (500 MHz, CD3OD): δ 8.38 (br s, 1H), 7.93 (dd, 1H), 7.13 (d, 1H), 1.70 (s, 6H). LC-MS: m/e 250 (M + H)+ (2.6 min).

Reference Example 15

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2-methyl-2-(6-methyl-2-pyridyloxy)propionic acid

The title compound was prepared according to the procedures described for Reference Example 13 replacing 5-chloro-2-hydroxypyridine with 6-methyl-2-hydroxypyridine in Step A. 1H NMR (500 MHz, CD3OD): δ 7.51 (t, 1H), 6.74 ( d, 1H), 6.53 (d, 1H), 2.34 (s, 3H), 1.64 (s, 6H). LC-MS: m/e 196 (M + H)+ (1.3 min).

REFERENCE EXAMPLE 16

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2-amino-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane:

Step A Benzyl 2-(1-(1,2,3-triazolyl))acetate:

A mixture of 1,2,3-triazole (2.07 g, 30 mmol), phenyl bromoacetate (6.9 g, 30 mmol), and diisopropylethylamine (5.1 mL, 30 mmol) in 40 mL of CH2Cl2 was stirred overnight at room temperature. This mixture was diluted with ether until the precipitate disappeared. The solid was filtered and washed with ether. The filtrate was concentrated and the residue was purified on silica gel, using 10% hexane in CH2Cl2, to give the isomer of the title compound, benzyl 2-(2-(1,2,3-triazolyl)acetate) as an amorphous solid. Further elution with a mixt. solvents containing equal amounts of ether and CH2Cl2 gave the title compound as an amorphous solid. 7.785(s, 1H)

Step B 2-(1-(1,2,3-triazolyl))acetic acid:

Palladium hydroxide (20% on carbon, 800 mg) was added to a solution of benzyl 2-(1-(1,2,3-triazolyl))acetate (Step A, 8.68 g, 39.9 mmol) in 150 mL MeOH and the mixture was hydrogenated overnight on a Parr shaker under a hydrogen atmosphere at room temperature and 45 psi. The catalyst was filtered through a pad of CELITE diatomaceous earth and washed with MeOH. The filtrate was concentrated to give a solid, which was dried in vacuo at 50°C for 36 h to give the title compound. 1H NMR (400 MHz, CD3OD): δ�5.3 (s, 2H), 7.75 (s, 1H0, 8.016 (s, 1H).

Step C N-methoxy-N-methyl-2-(1-(1,2,3-triazolyl))acetamide:

Oxalyl chloride (0.95 mL, 11 mmol) was added dropwise to a suspension of 2-(1-1,2,3-triazolyl))acetic acid (Step B, 1.27 g, 10 mmol) in 10 mL CH2Cl2 containing 0.05 mL DMF. . A strong effervescence was observed. The mixture was stirred at room temperature for 4 h and cooled to -78oC. A solution of N.O-dimethylhydroxylamine hydrochloride (1.2 g, 13 mmol) and diisopropylethyl amine (6.0 mL, 35 mmol) in 10 mL of CH 2 Cl 2 was added slowly over 3 min. The mixture was left to warm to room temperature and stirred overnight. The reaction mixture was diluted with ether until there was no more precipitate. The solid was filtered and washed with ether. The filtrate was concentrated and the residue was purified on silica gel using EtOAc as the solvent to give the title compound as an amorphous solid. 1H NMR (400 MHz, CDCl3): δ�3.252 (s, 3H0, 3.812 (s, 3H), 5.379 (s, 2H), 7.753 & 7.761 (s's, 2H).

Step D N-methoxy-N-methyl-3-(4-chlorophenyl)-2-(1-(1,2,3-triazolyl)) propionamide

Lithium hexamethyldisilazide (1molar in THF, 8.4 mL, 8.4 mmol) was added dropwise to a solution of N-methoxy-N-methyl-2-(1-(1,2,3-triazolyl))acetamide (Step C, 1.19 g, 7 mmol) in 15 mL THF at -78oC. After stirring for an additional 30 min, a solution of 4-chlorobenzyl bromide (1.65 g, 8 mmol) in 5 mL of THF was added dropwise. The mixture was allowed to warm to room temperature and stirred for 5.5 h. This mixture was purified on silica gel, using 40% EtOAc in hexane, to afford the title compound. 1H NMR (400 MHz, CDCl3.): δ�3.186 (s, 3H), 3.234-3.267 (m, 1H), 3.453-3.506 (m, 1H), 3.582 (s, 3H), 6.145-6.188 (m, 1H), 7.048-7.279 (m, 4H), 7.726 (s, 1H), 7.954 (s, 1H).

Step E 2-azido-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane:

The product from Step D, N-methoxy-N-methyl-3-(4-chlorophenyl)-2-(1-(1,2,3-triazolyl)propionamide was converted to the title compound, following the procedures described in Reference Example 3, Steps D-G. 1H NMR (400 MHz, CDCl3): δ�1.219-1.246 (d's 3H), 3.253-4.754 (m, 4H0, 6.866-7.299 (d's, 4H), 7.313, 7.618, 7.63, & 7.706 (s's, 2H).

Step F 2-amino-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane:

Platinum oxide (14 mg) was added to a solution of 2-azido-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane (Step E, 138 mg, 0.5 mmol) in 4 mL of MeOH. This mixture was hydrogenated under a hydrogen atmosphere using a hydrogen-filled balloon for 3 h at room temperature. The catalyst was filtered through a pad of CELITE diatomaceous earth and washed with MeOH. The filtrate was concentrated to give the title compound as an oil. 1H NMR (400 MHz, CDCl3):δ�1.085-1.174 (d's 3H), 3.220-3.361 (m, 2H), 3.517-3.563 (m, 1H), 4.379-4.431 (m, 1H), 6.679-7.179 ( d's, 4H), 7.297, 7.40, 7.592 & 7.607 (s's, 2H).

Reference Example 17

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N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

Step A 2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3-methylphenyl)butane

A mixture of 2-(N-tert-butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)butane (Reference Example 3, Step H, 0.50 g, 1.1 mmol), tetramethyltin (0.41 g, 2.3 mmol ), triphenylphosphine (0.12 g, 0.46 mmol), lithium chloride (0.38 g, 9.1 mmol) and dichlorobis(triphenylphosphine)palladium (0.12 g, 0.17 mmol) in 20 mL of anhydrous DMF was heated at 100ºC, under nitrogen, for 18 h. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and ether (100 mL). The organic layers were separated and the aqueous layer was extracted with ether (100 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel, eluted with 10% EtOAc in hexane, to afford the title compound. 1H NMR (400 MHz, CD3OD): δ 7.2-6.8 (m, 8H), 3.84 (m, 1H), 3.16 (m, 1H), 2.80-2.68 (m, 2H), 2.24 (s, 3H), 1.45 (s, 9H), 0.86 (d, 3H). LC-MS: m/e 396 (M + Na)+ (4.4 min).

Step B N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

The title compound was prepared according to the procedure described for Reference Example 3, Step I. LC-MS: m/e 274 (M + H)+ (2.5 min).

Reference Example 18

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N-[3-(5-chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]amine hydrochloride (diastereomer α)

Step A 5-chloro-2-methylpyridine

A mixture of 2,5-dichloropyridine (15 g, 0.10 mol), tetramethyltin (15 mL, 0.11 mol), and dichlorobis(triphenylphosphine)palladium (2.0 g, 2.8 mmol) in 200 mL of anhydrous DMF was heated to 110ºC under nitrogen, 72 h. The reaction mixture was cooled to room temperature and poured into a saturated solution of potassium fluoride (200 mL). The resulting mixture was partitioned between water (500 mL) and ether (500 mL). The organic layers were separated and the aqueous layer was extracted with ether (200 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel, eluting with 2 to 10% ether in hexane, to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.41 (d, 1H), 7.75 (dd, 1H), 7.30 (d, 1H), 2.53 (s, 3H).

Step B 4-(5-Chloro-2-pyridyl)-3(S)-phenyl-2(R)-butanol.

Phenyllithium (1.8 M in cyclohexane/ether, 7.2 mL, 13 mmol) was added to a solution of 5-chloro-2-methylpyridine (Step A, 1.1 g, 8.7 mmol) in 15 mL of anhydrous ether at 0ºC, and the reaction was stirred at at room temperature for 30 min. The resulting mixture was cooled to 0ºC, and (1R,2R)-1-phenylpropylene oxide (2.3 g, 17 mmol) was added, and the reaction was allowed to warm to room temperature overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel, eluted with 10 to 40% EtOAc in hexane, to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.28 (d, 1H), 7.59 (dd, 1H), 7.25-7.12 (m, 5H), 7.05 (d, 1H), 4.03 (m, 1H), 3.29 (dd , 1H), 3.19 (dd, 1H), 3.12 (m, 1H), 1.12 (d, 3H).

Step C 2(S)-azido-4-(5-chloro-2-pyridyl)-3(S)-phenylbutane

To a mixture of 4-(5-chloro-2-pyridyl)-3-phenyl-2-butanol (Step B, 0.24 g, 0.92 mmol), triphenylphosphine (1.5 g, 1.4 mmol) and diphenylphosphoryl azide (0.30 mL, 1.4 mmol) diethyl azodicarboxylate (0.24 mL, 1.4 mmol) was added to 5 mL of anhydrous THF. After stirring at room temperature overnight, the resulting mixture was concentrated with silica gel (10 g) and the residue was applied to a silica gel column. Elution with 5 to 15% EtOAc in hexane gave the title compound. 1H NMR (500 MHz, CD3OD): δ 8.35 (d, 1H), 7.52 (dd, 1H), 7.25-7.05 (m, 5H), 6.95 (d, 1H), 3.81 (m, 1H), 3.48 (m , 1H), 3.15-3.05 (m, 2H), 1.14 (d, 3H).

Step D N-[3-(5-chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]amine, hydrochloride

The product from Step C (0.20 g, 0.70 mmol) was converted to the title compound, according to the procedure described in Reference Example 3, Steps H-I, except that hydrogen chloride in dioxane (4 M) was used instead of hydrogen chloride in EtOAc. 1H NMR (500 MHz, CD3OD): δ 8.75 (d, 1H), 8.19 (dd, 1H), 7.55 (d, 1H), 7.4-7.2 (m, 5H), 3.78 (m, 1H), 3.62 (dd , 1H), 3.48 (m, 1H), 3.43 (dd, 1H), 1.22 (d, 3H). LC-MS: m/e 261 (M + H)+ (2.2 min).

Reference Example 19

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N-[2-(3-bromophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

Step A 3-bromophenylacetone

To a solution of N-methoxy-N-methylacetamide (10 g, 100 mmol) in 100 mL of anhydrous ether at 0ºC was added 3-bromobenzylmagnesium bromide (0.25 M in ether, 200 mL, 50 mmol). The reaction was allowed to warm to room temperature overnight and quenched by addition of saturated ammonium chloride (100 mL). The organic layers were separated and the aqueous layer was extracted with hexane (100 mL). The combined extracts were dried over anhydrous MgSO 4 , filtered and concentrated to dryness to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.45-7.40 (m, 2H), 7.26 (t, 1H), 7.19 (d, 1H), 2.20 (s, 3H).

Step B 3-(3-Bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone

A suspension of 5-chloro-2-methylpyridine (Reference Example 18, Step A, 6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mL of carbon tetrachloride was heated to gentle reflux (bath temperature 90ºC), and 2,2'-azobisisobutyronitrile (0.74 g) was added in several batches over 30 min. After stirring at this temperature for 5 h, the reaction mixture was concentrated. The resulting mixture was diluted with EtOAc (100 mL) and washed with water (100 mL), saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate, and brine. The organic solution was dried with a stream of anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel, eluted with 2 to 15% ether/CH2Cl2 (1:1) in hexane, to obtain 2-bromomethyl -5-chloropyridine (6.0 g, 60%), which was used immediately for the next reaction. Cesium was then added to a highly stirred solution of 2-bromomethyl-5-chloropyridine (6.0 g, 29 mmol) and 3-bromophenyl acetone (Step A, 6.0 g, 28 mmol) and tetrabutylammonium iodide (20 mg) in 30 mL of CH2Cl2 at -78ºC. hydroxide monohydrate (10 g, 60 mmol), and the reaction was allowed to slowly warm to room temperature overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried with a stream of anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel, eluted with 5 to 40% EtOAc in hexane, to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.44 (d, 1H), 7.66 (dd, 1H), 7.46-7.41 (m, 2H), 7.24 (t, 1H), 7.22 (d, 1H), 7.15 (d , 1h), 4.42 (dd, 1H), 3.54 (dd, 1H), 3.07 (dd, 1H), 2.12 (s, 3H). LC-MS: m/e 338 (M + H) + (3.0 min).

Step C 3-(3-Bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanol

Lithium tri(sec- butyl)borohydride (1.0 M in THF, 30 mL, 30 mmol), and the reaction was allowed to warm to room temperature overnight. The reaction was cooled to 0ºC, 2 M hydrochloric acid (50 mL) was carefully added, and the resulting mixture was partitioned between hexane (200 mL) and water (200 mL). The aqueous layers were separated and the organic layer was extracted with 2 M hydrochloric acid (2 x 100 mL). The combined aqueous extracts were neutralized with 5 N aqueous sodium hydroxide (pH > 12), and extracted with EtOAc (2x200 mL). The combined extracts were dried with a stream of anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound.

Step D N-[2-(3-bromophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]amine, hydrochloride

The product from Step C (5.9 g, 17 mmol) was converted to the title compound, according to the procedure described in Reference Example 18, Steps C-D. LC-MS: m/e 338 (M + H) + (2.3 min).

Reference Example 20

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N-[2-(5-bromo-2-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

Step A 5-Bromo-3-pyridylacetone

A mixture of 3,5-dibromopyridine (50 g, 0.21 mol), isopropenyl acetate (26 mL, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (1.0 g, 1.1 mmol) and 2-(diphenylphosphino)-2'(N,N- dimethylamino)biphenyl (1.6 g, 4.2 mmol) in 400 mL toluene was heated at 100ºC under nitrogen for 2 h. The reaction mixture was cooled to room temperature and concentrated to about 100 mL. The resulting mixture was applied to a silica gel column and eluted with 0 to 60% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.54 (br s, 1H), 8.33 (br s, 1H), 7.88 (br s, 1H), 3.90 (s, 2H), 2.25 (s, 3H).

Step B 3-(5-Bromo-3-pyridyl)-4-(4-chlorophenyl)-2-butanol

The title compound was prepared according to the procedure described in Reference Example 19, Steps B-C, replacing 2-bromomethyl-5-chloropyridine with 4-chlorobenzyl chloride and 3-bromophenylacetone with 5-bromo-3-pyridylacetone (Step A). 1H NMR (500 MHz, CD3OD): δ 8.43 (d, 1H), 8.24 (d, 1H), 7.98 (dd, 1H), 7.17 (d, 2H), 7.07 (d, 2H), 4.04 (m, 1H ), 3.16 (dd, 1H), 3.0-2.9 (m, 2H), 1.04 (d, 3H).

Step C N-[2-(5-bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

The title compound was prepared according to the procedure described for Reference Example 4, Step B. LC-MS: m/e 339 (M + H)+ (2.5 min).

Reference Example 21

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N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

Step A 5-cyano-3-pyridylacetone

The title compound was prepared according to the procedure described for Reference Example 20 replacing 3,5-dibromopyridine with 5-bromonicotinonitrile (5-bromo-3-cyanopyridine) in Step A. 1H NMR (400 MHz, CD3OD): δ 8.89 (d, 1H) , 8.60 (d, 1H), 8.02 (t, 1H), 3.98 (s, 2H), 2.24 (s, 3H).

Step B N-[3-(4-chlorophenyl)-2-(5-cyano-2-pyridyl)-1-methylpropyl]amine hydrochloride (diastereomer α�β�5:1)

The title compound was prepared according to the procedure described for Reference Example 5 replacing 3-pyridylacetone with 5-cyano-3-pyridylacetone (Step A). LC-MS: m/e 286 (M + H) + (1.9 min).

Reference Example 22

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N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

Step A 5-chloro-3-pyridylacetone

The title compound was prepared according to the procedure described for Reference Example 20 replacing 3,5-dibromopyridine with 3,5-dichloropyridine and 2-(diphenylphosphino)-2'(N,N-dimethylamino)biphenyl with 2-(di-t-butylphosphino) with biphenyl in Step A. 1H NMR (500 MHz, CD3OD): δ 8.42 (d, 1H), 8.27 (d, 1H), 7.73 (dd, 1H), 3.90 (s, 2H), 2.25 (s, 3H).

Step B N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

The title compound was prepared according to the procedure described for Reference Example 20, Steps B-C, replacing 5-bromo-3-pyridylacetone with 5-chloro-3-pyridylacetone in Step B. LC-MS: m/e 295 (M + H)+ ( 1.9 min).

Reference Example 23

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N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

The title compound was prepared according to the procedure described for Reference Example 17 replacing 2-(N-tert-butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)butane with 2-(N-tert-butoxycarbonyl)amino -3-(5-bromo-3-pyridyl)-4-(4-chlorophenyl)butane (intermediate Reference Example 20, Step B) in Step A. LC-MS: m/e 275 (M + H)+ (1.3 min).

Reference Example 24

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2-methyl-2-(2-pyrimidyloxy)propionic acid

The title compound was prepared according to the procedures described for Reference Example 13, replacing 5-chloro-2-hydroxypyridine with 2-hydroxypyrimidine in Step A. 1H NMR (500 MHz, CD3OD): δ 8.53 (d, 2H), 7.09 (t, 1H ), 1.74 (s, 6H).

Reference Example 25

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2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionic acid

The title compound was prepared according to the procedures described for Reference Example 13, replacing 5-chloro-2-hydroxypyridine with 4-trifluoromethyl-2-hydroxypyridine in Step A. 1H NMR (500 MHz, CD3OD): δ 8.30 (d, 1H), 7.18 (d, 1H), 7.05 (s, 1H), 1.71 (s, 6H).

Reference Example 26

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2-Methyl-2-(6-trifluoromethyl-4-pyrimidyloxy)propionic acid

The title compound was prepared according to the procedures described for Reference Example 13, replacing 5-chloro-2-hydroxypyridine with 6-trifluoromethyl-4-hydroxypyrimidine in Step A. 1H NMR (500 MHz, CD3OD): δ 8.81 (s, 1H), 7.28 (s, 1H), 1.75 (s, 6H). LC-MS: m/e 251 (M + H) + (2.1 min).

REFERENCE EXAMPLE 27

2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propionic acid

KHMDS in THF (0.91 M, 3.52 L each, 3.205 mol, 1.5 eq) was charged to two nitrogen-purged, 12 L, three-necked, round-bottomed flasks, equipped with a thermometer and a reflux condenser. The solutions were cooled to -70oC and mixed magnetically. Ethyl-2-hydroxyisobutyrate (98%) (463 mL, 447g, 3.38 mol) was added to each flask over 30 min, maintaining the reaction temperature below -62oC. After 10 min, 2-chloro-5-trifluoromethylpyridine (388 g, 2.14 mol) was added to each flask in one portion. The cold bath was removed and the reactions were allowed to warm to 20°C overnight (ca. 16 hours). The reactions were monitored by TLC (silica, 90/10 Hex/EtOAc) and HPLC:

Sodium hydroxide (1.36 L, 5N) was added to each reaction flask and the reactions were refluxed overnight (ca. 22 hr). The reactions were concentrated together on a rotary evaporator to remove THF. Water (4L) and a solution extracted with n-heptane (2 x 4L) were added to the concentrate. The aqueous layer was added over 10 min to 2N HCl (9L, 18 mol) with stirring. The resulting suspension was left for 30 min (temperature 30oC) and then filtered. The residue was washed with water (3 x 2L) and air-dried to give a moist dark solid.

The material was dissolved in n-heptane (4 L) at 65oC. IPAc (1 L) and DARCO KB (40 g, 100 mesh) were added. The mixture was stirred for 15 min, filtered through CELITE diatomaceous earth, and the residue washed with 4:1 heptane/IPAc (3 x 500 mL). The filtrate is concentrated to approx. 2 L, giving a white suspension. The mixture was washed with heptane (2 x 3L) and concentrated to ca. 3L. The resulting white suspension was cooled to 0°C and left for 1 hour. The product was filtered and the residue washed with cold heptane (1 L) to give the title compound as a white crystalline material. HPLC Column: YMC Combiscreen Pro C18, 50 x 4.6mm; Mobile phase: 0.1% TFA in H2O; B CH3CN. Gradient: 90/10 A/B to 10/90 A/B in 4 min. Flow rate: 4 mL/min. Detection: 254 nm. Retention time 2-chloro-5-trifluoromethylpyridine 2.1 min. Retention time 2-ethoxy-5-trifluoromethylpyridine 2.9 min. Retention time product ester 3.1 min. final acid retention time 2.05 min.

REFERENCE EXAMPLE 28

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2-amino-3-indolin-N-yl-4(4-chloro)phenylbutane

Step A. Ethyl 3-(4-chlorophenyl)-2-indolin-N-ylpropanoate. To an oven-dried flask, under a nitrogen atmosphere, 1.1 g of LiOH⋅H2O (26.25 mmol) in DMF (20 mL) was added with stirring to a suspension of 4Å molecular sieves. After 30 minutes of stirring at room temperature, 2.8 mL (25 mmol) of indoline was added dropwise. After one hour at room temperature, 2.9 mL (26.25 mmol) of ethyl bromoacetate was added dropwise. After 1.5 h the solid material was filtered and the residue was washed with copious amounts of EtOAc. The organic layers were washed 3 times with water and the organic material was dried with a flow of MgSO4. Solvents were evaporated under reduced pressure. The crude material was dissolved in 75 mL of anhydrous THF, filled into a round-bottomed flask, dried in an oven under a nitrogen atmosphere, cooled to -78oC, and treated with 26.25 mL of 1M NaHMDS solution. The solution was allowed to stir for 30 minutes at –78oC, after which the enolate was alkylated with 5.4 g (26.25 mmol) of parachlorobenzyl bromide (solution in 25 mL of anhydrous THF). The reaction was allowed to warm to room temperature overnight. The next day, the reaction was quenched with water. The aqueous layer was extracted with 3 large portions of EtOAc. The combined organic layers were dried with a flow of MgSO4. The solvents were removed under reduced pressure and the residue was purified by flash chromatography, which gave the title compound as a yellow oil. LC/MS m/e=331 (M+1). TLC Rf=0.22 (20:1 hexanes : EtOAc). 1H NMR (500 MHz, CDCl3): δ 1.11 (t, J=3.55 Hz, 3H), 2.96 (m, 2H), 3.06 (m, 1H), 3.25 (m, 1H), 3.60 (t, 2H), 4.07 (m, 2H), 4.36 (t, J=3.75 Hz, 1H).

Step B. N,O-dimethyl-3-(4-chlorophenyl)-2-indolin-N-ylpropanamide. In an oven-dried flask under a nitrogen atmosphere, 11.75 mL of a 1-M solution of (CH3)2AlCl in CH2Cl2 was added via a funnel to a stirred suspension of 1.15 g (11.75 mmol) of N,O-dimethylhydroxylamine hydrochloride at 0oC. After warming to room temperature, a solution of 970 mg (2.94 mmol) of ethyl 3-(4-chlorophenyl)-2-indolinylpropanoate (obtained in Step A) in 10 mL was added via funnel. After stirring at room temperature for 5 h, 35 mL of pH 8 phosphate buffer solution was added and the resulting mixture was vigorously stirred for 30 min. The phases were separated and the aqueous layer was extracted twice with chloroform. The combined organic extracts were washed with water and then dried with a flow of MgSO4. A brown oil was collected. The raw material was transferred to the next step. TLC Rf=0.12 (10:1 hexanes : EtOAc). 1H NMR (500 MHz, CDCl3): δ 2.83 (m, 1H), 2.97(m, 2H), 3.13 (s, 3H), 3.34 (m, 1H), 3.45 (s, 3H), 3.61 (m, 2H ), 4.87 (b, 1H), 6.54 (d, 1H), 6.66 (t, J=7.1 Hz, 1H), 7.07 ( t, J=7.1 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H ), 7.24 (d, J=8.5 Hz, 2H)

Step C. 4-(4-Chlorophenyl)-3-indolin-N-ylbutan-2-one.

In an oven-dried flask under nitrogen, 2.8 mL of a 1-M solution of CH3MgBr in THF was added dropwise to a stirred solution of N,O-dimethyl-3-(4-chlorophenyl)-2-indolinylpropanamide (from Step B, 965 mg). in 25 mL of anhydrous THF. The solution was stirred for 4 h and allowed to warm to room temperature. Then approximately 20 mL of water was added. The mixture was extracted three times with 50 mL of ether. The combined extracts were dried with a flow of MgSO4. the solvents were removed under reduced pressure to give a brown oil, which was carried to the next step without purification. LC/MS m/e=301 (M+1). TLC Rf=0.5 (4:1 hexanes:EtOAc). 1H NMR (500 MHz, CDCl3): δ 2.14 (s, 3H), 2.81 (dd, J=14.6, 6.6 Hz, 1H), 2.97 (t, J=8.5 Hz, 2H), 3.26 (m, 2H), 3.5 (m, 1H), 4.21 (dd, J=6.6, 6.6 Hz), 6.39 (d, J=8 Hz, 1H), 6.66 (dd, J=7, 7 Hz, 1H), 7.07 (m, 2H ), 7.13 (d, J=8.5 Hz), 7.22 (d, J=8.3 Hz).

Step D. 4-(4-Chlorophenyl)-3-indolin-N-ylbutan-2-one methoxy.

A solution of 472 mg (1,573 mmol) of the product from Step C and 263 mg (3,147 mmol) of methoxylamine hydrochloride in anhydrous ethanol was treated with 255 μL (3,147 mmol) of pyridine. The solution was stirred for 2 h at room temperature. The solvent was removed under reduced pressure, the residue was partitioned between water and ether. The water was extracted with ether again. The extracts were then combined and dried with a stream of MgSO4, filtered and concentrated to give the crude material. Both E and Z isomers were carried over to the next step. LC/MS m/e=330 (M+1). TLC Rf=.77 and .65 (4:1 hexanes:EtOAc). 1H NMR (500 MHz, CDCl3): δ 1.78 (2s, 1H), 2.88 (dd, J=6.2, 13.8 Hz, 1H), 2.95 (m, 2H), 3.30 (m, 2H), 3.45 (m, 1H ), 3.75 and 3.89 (2s, 3H), 4.21 (dd, J=6.9, 7.8 Hz, 1H), 6.28 and 6.47 (2d, J=8.1, 1H), 6.61 (m, 1H), 7.02 (m, 2H ), 7.22 (m, 4H).

Step E. 2-Amino-3-indolin-N-yl-4(4-chloro)phenylbutane

In an oven-dried flask equipped with a water condenser, under a nitrogen atmosphere, a solution of 301 mg (0.914 mmol) of 4-(4-chlorophenyl)-3-indolinylbutan-2-one methoxyme (obtained from Step D) in 1.5 mL of anhydrous THF was treated with 3.7 mL (3.7 mmol) of 1M BH3⋅THF at room temperature. The solution was heated to 75oC for 2 days. The solution was cooled to 0oC and treated with pieces of ice, until the formation of bubbles stopped. 500 μL of 20% KOH was then added and the solution was heated at 45oC for 2h. The solution was cooled to room temperature and extracted with ether 3x. The combined extracts were dried with a stream of MgSO4, filtered, and concentrated to give the crude amine, which was used in the next experiment without further purification. LC/MS m/e=302 (M+1). 1H NMR (500 MHz, CDCl3): δ 1.13, 1.14 (2d, J=6.5 Hz, 1H), 1.55-1.60 (m, 2H), 2.80-3.10 (m, 4H), 3.30-3.60 (m, 2H) , 6.348 and 6.38 (2d, J=7.9 Hz, 1H), 6.50-6.78 (m, 2H), 6.95-7.24 (m, 5H)

REFERENCE EXAMPLE 29

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2-amino-3-indole-N-yl-4(4-chloro)phenylbutane

This compound was prepared in an analogous manner to Reference Example 28, except that during Step A, sodium hydride was used as the base, instead of the lithium hydroxide monohydrate/molecular sieve combination. LC/MS: calcd for C18H19CIN2299, observed m/e 300 (M + H)+ (2.4 min).

Reference Example 30

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2-amino-3-(N-methyl, N-phenyl)amino-4(4-chloro)phenylbutane

This compound was prepared in an analogous manner to Reference Example 28. LC/MS: calculated for C17H21ClN2289, observed m/e 290 (M + H)+ (2.4 min).

Reference Example 31

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2-amino-3-(7-azaindol-N-yl)-4(4-chloro)phenylbutane

This compound was prepared in an analogous manner to Reference Example 28. LC/MS: calcd for C17H18ClN3 300, observed m/e 301 (M + H)+ (2.7 min).

REFERENCE EXAMPLE 32

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4-(4-methylphenyl)-3-phenylbutan-2-amine (mixture of 4 isomers)

Step A 1-phenylacetone

Benzylmagnesium chloride (97 mL of 1M solution in ether) was added to a solution of N-methyl-N-methoxyacetamide (9.9 mL, 97 mmol) in ether (300 mL) at 0°C. The off-white reaction mixture was warmed to room temperature for 2 h, then quenched by the careful addition of 1N hydrochloric acid (100 mL). The organic phases were separated, washed with brine, dried with a flow of MgSO4 and concentrated. The crude material was purified by column chromatography on silica gel, eluting with 0-10% EtOAc/hexane, to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 7.36 (t, J = 7.1Hz, 2H), 7.30 (t, J = 7.3Hz, 1H), 7.24 (d, J = 7.3Hz, 2H), 3.72 (s, 2H), 2.18 (s, 3H). LC-MS: m/e 135 (M + H)+ (1.95 min).

Step B 4-(4-methylphenyl)-3-phenylbutan-2-one

1-Phenylacetone (200 mg, 1.49 mmol) was mixed with potassium hydroxide powder (167 mg, 2.98 mmol) and tetra-n-butylammonium bromide (1 mol %, 5 mg) in a solvent-free flask. This mixture was stirred at room temperature for 90 min. before adding 1-(chloromethyl)-4-methylbenzene (198 μl, 1.49 mmol). The reaction mixture was stirred overnight before dilution with water and CH2Cl2. The aqueous layers were separated and neutralized to pH 7 with 2N hydrochloric acid, and extracted again in CH2Cl2. The combined organic washes were dried with MgSO4 and concentrated. The crude material was purified by column chromatography on silica gel, eluting with 0-10% EtOAc/hexane, to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 7.35 (t, J = 7.0 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 7.1 Hz, 2H), 7.05 (d, 7.8 Hz, 2H), 6.98 (d, J = 7.8 Hz, 2H), 3.94 (t, J = 7.3 Hz, 1H), 3.43 (dd, J = 13.9, 7.5 Hz, 1H), 2.91 (dd, J = 14, 7.1 Hz, 1H), 2.32 (s, 3H), 2.08 (s, 3H). LC-MS: m/e 239 (M + H) + (3.61 min).

Step C 4-(4-methylphenyl)-3-phenylbutan-2-amine

To a solution of 4-(4-methylphenyl)-3-phenylbutan-2-one (308 mg, 1.29 mmol) in 7M ammonia in MeOH (5 mL) and acetic acid (3 mL) was added sodium cyanoborohydride (130 mg, 2.06 mmol). ) and the reaction stirred at room temperature overnight. The reaction was quenched by pouring into 2M sodium carbonate solution and extracted into EtOAc. The aqueous layer was desalted and re-extracted. The combined organic extracts were dried with a stream of MgSO4 and concentrated to give the title compound as a mixture of 4 isomers, which was used without further purification. LC-MS: m/e 240 (M + H)+ (2.22 min).

REFERENCE EXAMPLE 33

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3-[2-amino-1-(4-fluorobenzyl)propyl]benzonitrile

Prepared using the procedures described in Example 5, Steps B and C, using 3-(2-oxopropyl)benzonitrile and 1-(chloromethyl)-4-fluorobenzene as reactants in Step B. LC-MS: m/e 269 (M + H )+ (2.87 min).

REFERENCE Example 34

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2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methylpropylamine

Step A 2-(1H-1,2,3-benzotriazol-1-yl)-N-methoxy-N-methylacetamide

A mixture of 1.77 g (10 mmol) 2-(1H-1,2,3-benzotriazol-1-yl)acetic acid, 1.07 g (11 mmoles) N,O-dimethylhydroxylamine hydrochloride, 5.8 g (11 mmol) PyBOP, and 3.4 mL (24.2 mmol) of diisopropylethylamine in 50 mL of CH2Cl2 was stirred overnight at room temperature. This mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous MgSO4. Removal of the solvent gave the crude product, which was purified on silica gel using 60% EtOAC in hexane as the solvent to give 2.01 g of the desired amide as a solid. 1H NMR: (CDCl3): δ 3.26 (s, 3H), 3.84 (s, 3H), 5.63 (s, 2H), 7.35-8.2 (m, 4H).

Step B 2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-N-methoxy-N-methyl-propanamide.

In a solution of 2.0 g (9 mmol) of 2-(1H-1,2,3-benzotriazol-1-yl)-N-methoxy-N-methylacetamide in 15 mL of anhydrous THF at –78 oC, 10 mL (10 mmol) of 1M of lithium bis(trimethylsilyl)amide was added dropwise. After stirring for 25 min, a solution of 2.06 g (10 mmol) of 4-chlorobenzyl bromide in 2 mL of anhydrous THF was added. The resulting reaction mixture was allowed to warm to room temperature and stirred for 6 h. This reaction was quenched, diluted with 75 mL EtOAc and washed 3 times with 10 mL brine each. After drying the organic phases, removal of the solvent gave the crude product, which was purified on silica gel, using 40% EtOAc in hexane as solvent, to obtains the desired product as a solid. 1H NMR: (CDCl3): δ 3.2 (s, 3H), 3.34 (s, 3H), 3.52 (m, 1H), 3.7 (m, 1H), 6.32 (t, 1H), 6.9-8.2 (m, 8H ).

Step C 2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-butan-2-one.

In a solution of 1.73 g (5 mmol) of 2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-N-methoxy-N-methyl-propanamide in 10 mL of anhydrous THF at 0 oC, 4 mL (10 mmol) of 2.5 M methyl magnesium bromide in ether was added. The reaction mixture was stirred for 4 h and warmed to room temperature. The reaction was quenched by the addition of 10 mL of 1N HCl and the resulting mixture was partitioned between EtOAc and water. The organic phase was washed with brine and dried over anhydrous MgSO4. Removal of the solvent gave the crude ketone, which was purified on silica gel using 40% EtOAc in hexane to afford the desired ketone.

Step D 2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methyl propylamine

In a solution of 1.18 g (4 mmol) of 2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-butan-2-one in 8.5 mL (60 mmol) of 7N ammonia in MeOH at 0 oC, 4 mL (964 mmol) of glacial acetic acid was added, followed by 410 mg (6.5 mmol) of sodium cyanoborohydride. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was partitioned between EtOAc and saturated NaHCO3 solution. The organic phase was dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified on silica gel using a mixture of 5% 2N methanolic ammonia and 95% CH 2 Cl 2 to give the desired amine as a mixture of diastereomers. LC-MS, retention time = 2.0 min, m/e = 301.

REFERENCE Example 35

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3-(4-Chlorophenyl)-2-(thiophen-3-yl)-1-methylpropylamine

The title amine was prepared according to the method described in Reference Example 34, replacing thiophene-3-acetic acid with 2-(1H-1,2,3-benzotriazol-1-yl)acetic acid in Step A. LC-MS, retention time = 2.19 min, m/e = 266.

REFERENCE Example 36

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2-(3-Cyanophenyl)-3-cyclobutyl-1-methylpropylamine

Step A 1-(3-Cyanophenyl)acetone

The title compound was prepared from 3-bromobenzonitrile and isopropenyl acetate by the procedure of Reference Example 20, Step A.

Step B 3-(3-Cyanophenyl)-4-cyclobutyl-butan-2-one

To a solution of 1.45 g (9.07 mmol) of 1-(3-cyanophenyl)acetone in 18 mL of acetonitrile, 1.1 mL (9.5 mmol) of cyclobutyl bromide and 5.91 g (18.1 mmol) of cesium carbonate were added. After heating the solution in a 60 oC bath overnight, it was cooled and filtered. The filtrate was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified on a flash column, using a gradient of 5-10% EtOAc/hexane to isolate the title compound. 1H NMR: (500 MHz, CDCl3): δ 1.5-2.2 (m, 9H), 2.13 (s, 3H), 3.64 (m, 1H), 7.4-7.7 (m, 4H).

Step C 2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropylamine

This amine was prepared according to the method of Reference Example 3, Steps E-I. LC-MS, retention time = 2.48 min, m/e = 229.

The compounds from Reference Examples 37 and 38 were obtained by the procedures described in Reference Example 36.

REFERENCE Example 37

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2-(3-Cyanophenyl)-3-cyclopentyl-1-methylpropylamine

LC-MS, retention time = 2.7 min, m/e = 243.

REFERENCE Example 38

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2-(3-Cyanophenyl)-3-cyclohexyl-1-methylpropylamine

LC-MS, retention time = 2.8 min, m/e = 257.

EXAMPLE 1

Automated synthesis of a one-dimensional amide library

The following synthesis of a 1-dimensional, single, pure compound library was performed on the MYRIAD CORE System. All reaction vessels were dried under nitrogen flow at 120°C for 12 h, before use. All solvents were dried over a sieve for at least 12 h before use. A suitable standard solution of N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (alpha isomer) was prepared immediately before use in pyridine with 0.05 equivalents (relative to N-[2,3-bis (4-Chlorophenyl)-1-methylpropyl]-amine hydrochloride (alpha isomer)) was added with dimethylaminopyridine; various commercially available carboxylic acids were dissolved in DMSO immediately before use. The relative amounts of reactants and coupling reagents are shown in Table 1.

Table 1.

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Procedure: An appropriate different acid subunit (1.0 mL, 0.2 mmol, 0.2 M in DMSO) was added to vessel one of a total of 192 dry, 10 mL MYRIAD reaction vessels under nitrogen; this was repeated for the remaining 191 reactions, while the different acids were numbered in all 192 reaction vessels. EDC/HOBt cocktail (0.8 mL, 0.2 mmol, 0.25 M each in deuterated chloroform) was added to each of the 192 reaction vessels under nitrogen. Finally, N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (alpha isomer) (0.6 mL, 0.12 mmoles, 0.2M in pyridine) was added to each of the 192 reaction vessels. The reactions were then allowed to stand for 4 h at room temperature (20-25°C), then for 16 h at 65°C with nitrogen jet agitation (1s nitrogen pulse every 30 minutes). The crude reaction mixture was analyzed by HPLC-MS method 1.

Analytical LC method 1:

Column: MetaChem Polaris C-18A, 30 mm X 4.6 mm, 5.0 μm

Eluent A: 0.1% TFA in water

Eluent B: 0.1 % TFA in acetonitrile

Gradient: 5% B to 95 % B in 3.3 minutes, return ramp to 5% B in 0.3 min

Flow: 2.5 mL/min.

Column Temp.: 50° C

Injected amount: 5 uL undiluted crude reaction mixture.

Detection: UV at 220 and 254 nm.

MS: API-ES ionization mode, mass scan range (100-700)

ELSD: Light Scattering Detector

The crude reaction was purified by preparative HPLC, using UV-based detection (Preparative Method 2). The collected fractions were then analyzed for purity by LC-MS (Analytical Method 3); fractions that are more than 90% pure were collected in 40 mL EPA tubes and lyophilized.

Preparative LC method 2:

Column: MetaChem Polaris C-18A, 100 mm X 21.2 mm, 10 μm

Eluent A: 0.1% TFA in water

Eluent B: 0.1% TFA in acetonitrile

Pre-injection Equilibration: 1.0 min

Post-Inject Hold: 0.0 min

Gradient: 10% B to 100 % B in 6.0 minutes, hold at 100% B for additional 2.0 minutes, return ramp from 100% B to 10% B in 1.5 minutes.

Flow rate: 25 mL/min.

Column temp.: room temperature

Inject. amount: 1.5 mL undiluted crude reaction mixture.

Detection: UV at 220 and 254 nm.

Analytical LC method 3:

Column: MetaChem Polaris C-18A, 30 mm X 2.0 mm, 3.0 μm

Eluent A: 0.1% TFA in water

Eluent B: 0.1% TFA in acetonitrile

Gradient: 5% B to 95 % B in 2.0 minutes, recovery ramp to 5% B in 0.1 min

Flow rate: 1.75 mL/min.

Column Temp.: 60°C

Inject. amount: 5 uL undiluted fraction.

Detection: UV at 220 and 254 nm.

MS: API-ES ionization mode, mass scan range (100-700)

ELSD: Light Scattering Detector

Lyophilization parameters

Initial freezing point: 1 h at –70°C

Condensation point of the drying phase: -50°C

Drying phase table:

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Examples 2 and 3

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N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide (diastereomers α�and β).

DMF and oxalyl chloride (0.27 mL, 3.0 mmol) were added dropwise to a solution of 2-(4-chlorophenyloxy)-2-methylpropionic acid (Aldrich, 0.22 g, 1.0 mmol) in CH2Cl2 (2 mL) at 0ºC. After stirring at room temperature for 1 h, the reaction mixture was concentrated on a rotary evaporator and dried under vacuum, and the resulting crude acyl chloride was used without further purification. Therefore, the crude acyl chloride was dissolved in 1 mL of CH2Cl2 and added to a suspension of 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (Reference Example 1) (diastereomer α contaminated with some diastereomer β, 0.20 g, 0.60 mmol ) and N-methylmorpholine (0.27 mL, 2.4 mmol) in 4 mL of CH2Cl2. After stirring at room temperature for 6 h, the reaction mixture was placed on a silica gel column and eluted with 10% EtOAc to obtain the pure rapidly eluted isomer (diastereomer α) and the slower eluted isomer (diastereomer β).

diastereomer α: 1H NMR (500 MHz, CD3OD): δ 7.24 (d, 2H), 7.20 (d, 2H), 7.05 (d, 2H), 7.01 (d, 2H), 6.94 (d, 2H), 6.76 ( d, 2H), 4.25 (m, 1H), 3.03 (dd, 1H), 2.88 (ddd, 1H), 2.67 (dd, 1H), 1.59 (s, 3H), 1.53 (s, 3H), 0.88 (d , 3H). LC-MS: m/e 490(M + H)+ (4.7 min).

diastereomer β: 1H NMR (500 MHz, CD3OD): δ 7.16 (d, 2H), 7.14 (d, 2H), 7.09 (d, 2H), 6.99 (d, 2H), 6.88 (d, 2H), 6.64 ( d, 2H), 4.33 (m, 1H), 3.12 (dd, 1H), 3.03 (ddd, 1H), 2.74 (dd, 1H), 1.36 (s, 3H), 1.30 (d, 3H), 1.30 (s , 3H). LC-MS: m/e 490(M + H)+ (4.7 min).

Examples 4-7 (Table 2) were prepared according to the procedures described in Examples 2 and 3, exchanging the 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt with the appropriate amines from Reference Examples and 2-(4-chlorophenyloxy )-2-methylpropionic acid with the appropriate acids from the Reference Examples. In some cases, commercial acids or acyl chlorides have been used, and N-diisopropyl-ethylamine can be used instead of N-methylmorpholine, with similar results. Diastereomeric designations (α or β� correspond to the initial amine designations.

Table 2. Compounds prepared according to the methods described in Examples 2-3.

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EXAMPLES 8 and 9

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N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide (diastereomer �enantiomers and B).

Preparative HPLC was performed on a Gilson HPLC system for enantiomer separation. Then a solution of N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide (diastereomer α) (Example 60, 1.0 g) in hexane (3 mL) /ethanol (7 mL) loaded onto a Chiralpak AD column (2 cm x 25 cm), eluted with 5% ethanol in hexane (flow rate 9 mL/min, 500 μL per injection), to give two pure enantiomers.

Rapidly eluted enantiomer (Enantiomer A): Analytical HPLC: retention time = 7.8 min (Chiralpak AD column, flow rate = 0.75 mL/min, 5% ethanol/hexane). LC-MS: m/e 490 (M + H)+ (4.7 min).

Slower eluted enantiomer (Enantiomer B): Analytical HPLC: retention time = 9.6 min (Chiralpak AD column, flow rate = 0.75 mL/min, 5% ethanol/hexane). LC-MS: m/e 490 (M + H)+ (4.7 min).

Examples 10-17 (Table 3) were isolated as single enantiomers, according to the procedures described in Examples 8-9 from the corresponding racemic material (Table 2) with suitable modifications (1) of the eluent compound (4-15% ethanol/hexane), ( 2) flow rates (6-9 mL/min) and (3) injection volumes (200 to 2000 μL).

Table 3. Enantiomeric compounds isolated according to the methods described in

Examples 8-9.

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Example 18 (Table 4) was prepared according to the procedures described in Examples 2-3, using N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine, hydrochloride from Reference Example 4, coupled with a suitable carboxylic acid.

Table 4. Single enantiomeric compounds prepared with N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine, hydrochloride from Reference Example 4.

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Example 19

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N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenylamino)-2-methylpropanamide.

To a mixture of 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (diastereomer α, Section I, Reference Example 1, 0.31 g, 0.94 mmol) and 2-(4-chlorophenylamino)-2-methylpropionic acid ( 0.20 g, 0.94 mmol) in 5 mL of CH2Cl2 was added N-methylmorpholine (0.41 mL, 3.5 mmol) and tris(pyrrolindinyl)phosphonium hexafluorophosphate (0.73 g, 1.4 mmol). After stirring at room temperature overnight, the reaction mixture was loaded onto a silica gel column, eluted with 30% EtOAc in hexane, to afford the title compound. 1H NMR (400 MHz, CD3OD): δ 7.18 (d, 2H), 7.04 (d, 2H), 7.02 (d, 2H), 6.97 (d, 2H), 6.70 (d, 2H), 6.56 (d, 2H ), 4.20 (m, 1H), 3.02 (dd, 1H), 2.78 (ddd, 1H), 2.64 (dd, 1H), 1.52 (s, 3H), 1.45 (s, 3H), 0.82 (d, 3H) . LC-MS: m/e 489 (M + H) + (4.3 min).

EXAMPLE 20

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N-(2,3-diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide (diastereomer β)

A solution of 2-(4-chlorophenoxy)-2-methylpropionic acid (20 mg, 0.095 mmol) in CH2Cl2 (1 mL) and DMF (10 μL) was treated with oxalyl chloride (11 μL). After 30 min, the reaction was concentrated and the residue was dissolved in 1 mL of CH2Cl2. This solution was added to a mixture of 16 mg of N-(2,3-diphenyl-1-methylpropylamine (β isomer of Reference Example 2) and 1 mL of saturated NaHCO3. The reaction was stirred overnight and the organic layer was removed by pipette. Purification of this solution with preparative TLC eluted with 30% EtOAc/hexane gave the title compound 1H NMR: (500 MHz, CDCl3): δ 1.17 (d, 3H), 1.36 (s, 3H), 1.46 (s, 3H), 2.85-3.05 ( m, 3H), 4.44(m, 1H), 6.37 (d, 1H), 6.75-7.4 (m, 14H). LC-MS: retention time = 4.4 min. m/e = 422.2 (M+1).

The following compounds in Table 5 were prepared following the procedures of Example 20, substituting the appropriate amine for N-(2,3-diphenyl-1-methylpropylamine) and the appropriate carboxylic acid for 2-(4-chlorophenoxy)-2-methyl-propionic acid.

Table 5.

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The following compounds in Table 6 were prepared following the procedures in Examples 2-3, substituting the appropriate amine for N-(2,3-diphenyl-1-methylpropylamine) and the appropriate carboxylic acid for 2-(4-chlorophenoxy)-2-methyl-propionic acid. .

Table 6. Compounds prepared according to the methods described in Examples 2-3.

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The following compounds in Table 7 were isolated according to the enantiomer separation procedures described in Examples 8-9.

Table 7. Enantiomeric compounds isolated according to the methods described in Examples 8-9.

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The following compounds in Table 8 were prepared with N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine hydrochloride from Reference Example 4 and the appropriate acid to give the single enantiomer.

Table 8. Single enantiomeric compounds prepared with N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine, hydrochloride.

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Examples 30-33 (Table 9) were prepared from N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]amine, hydrochloride (Reference Example 4) or N-[3- (5-chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]amine, hydrochloride (Reference Example 18) and the appropriate carboxylic acid, according to the procedures described in Examples 2-3 (via the acyl chloride intermediate ) or Example 19 (with coupling reagent).

Table 9.

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Examples 34-39 (Table 10) were prepared from the appropriate amine and acid of the Reference Examples, according to the procedures described in Examples 2-3 (via an acyl chloride intermediate) or Example 19 (with a coupling reagent).

Table 10.

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Examples 41-52 (Table 11) were isolated as single enantiomers from the corresponding racemic materials (Table 10) according to the procedures described in Examples 8-9, with suitable modifications (1) of the elution compound (4-15% ethanol/hexane), ( 2) flow rates (6-9 mL/min) and (3) injection volumes (200 to 2000 μL).

Table 11. Enantiomeric compounds isolated according to the methods described in Examples 8-9.

[image] [image]

Examples 53-56 (Table 12) were isolated as diastereomers, as indicated (Isomer A or B), on silica gel column chromatography. The single enantiomers that were observed were separated on a chiral AD column, as noted above.

Table 12.

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EXAMPLE 57

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2-methyl-N-[1-methyl-3-(4-methylphenyl)-2-phenylpropyl]-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide

In a solution of 2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoic acid (Reference Example 14, 250 mg, 1.04 mmol) and 4-(4-methylphenyl)-3-phenylbutan-2 -amine (Reference Example 102, 260 mg, 1.04 mmol, mixture of 4 isomers) in CH2Cl2 (5.5 mL) at room temperature was added diisopropylethylamine (272 μl, 1.56 mmol) followed by PyBOP (649 mg, 1.25 mmol) and the reaction mixture was stirred during the night. The reaction was purified by applying the reaction mixture directly to a silica gel column and eluting with 0-30% EtOAc/hexane to give the title compound as a mixture of 4 isomers. The diastereomers were separated by HPLC on a ZORBAX RxSi column, eluted with 97% hexane: 3% ethanol at 20 mL/min with a retention time of:

- less polar diastereomer eluted at 4.73 minutes; the more polar diastereomer eluted at 5.87 minutes. The more polar diastereomer was further separated into enantiomers on a ChiralPak AD column, eluted with 95% hexane : 5% ethanol at 8 mL/min with a retention time of:

Less polar enantiomer eluted at 6.84 minutes; more polar diastereomer eluted at 8.36 minutes.

Less polar diastereomer: 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.86 (dd, J = 8.6, 2.5 Hz, 1H), 7.19 (t, J = 3.2 Hz, 3H), 7.00 (dd , J = 21.3, 8.0 Hz, 4H), 6.91 (m, 2H), 6.83 (d, J = 8.7 Hz, 1H), 5.70 (d, J = 9.4 Hz, 1H), 4.43 (m, 1H), 3.02 (dd, J = 13.3, 6.7 Hz, 1H), 2.84 (dt, J = 7.3, 4.3 Hz, 1H), 2.84 (dd, J = 13.2, 7.7 Hz, 1H), 2.29 (s, 3H), 1.69 ( s, 3H), 1.66 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H). LC-MS: m/e 471 (M + H)+ (4.22 min)

More polar diastereomer: 1H NMR (500 MHz, CDCl3): δ 8.40 (s, 1H), 7.83 (dd, J = 8.7, 2.6 Hz, 1H), 7.21 (m, 3H), 7.00 (dd, J = 30.4, 6.2 Hz, 4H), 6.82 (t, J = 9.2 Hz, 3H), 5.84 (d, J = 9.2 Hz, 1H), 4.36 (ddt, J = 9.1, 6.7, 6.6 Hz, 1H), 3.06 (dd, J = 12.8, 4.1 Hz, 1H), 2.88 (m, 1H), 2.26 (s, 3H), 1.78 (s, 3H), 1.73 (s, 3H), 0.92 (d, J = 6.6 Hz, 3H). LC-MS: m/e 471 (M + H)+ (4.17 min).

EXAMPLE 58

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N-[2-(3-cyanophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide

Prepared as in Example 57 only using 3-[2-amino-1-(4-fluorobenzyl)propyl]benzonitrile (Reference Example 33) as the amine component, to give the title compound as a mixture of 4 isomers. Diastereomers were separated by HPLC on a Zorbax RxSi column, eluted with 96% hexane: 4% ethanol at 20 mL/min with retention times of: less polar diastereomer eluted at 11.75 minutes;

- more polar diastereomer eluted at 15.17 minutes. The more polar diastereomer was further separated into enantiomers on a ChiralPak AD column, eluted with 92% hexane : 8% ethanol at 8 mL/min with a retention time of: less polar enantiomer eluted at 9.65 minutes; the more polar diastereomer eluted at 11.78 minutes.

Less polar diastereomer: 1H NMR (500 MHz, CD3OD): δ 8.29 (s, 1H), 7.93 (dd, J = 8.7, 2.5 Hz, 1H), 7.50 (m, 1H), 7.42 (m, 1H), 7.27 (m, 2H), 6.96-6.78 (m, 5H 5.70 (d, J = 9.6 Hz, 1H), 4.33 (m, 1H), 3.18-3.04 (m, 2H), 2.7 (dd, J = 13.5, 6.6 Hz, 1H), 1.52 (s, 3H), 1.35 (s, 3H), 1.17 (d, J = 6.6 Hz, 3H). LC-MS: m/e 500 (M + H)+ (4.33 min)

More polar diastereomer: 1H NMR (500 MHz, CD3OD): δ 8.28 (s, 1H), 7.95 (dd, J = 8.7, 2.5 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.36 (m , 3H), 7.05 (d, J = 8.9 Hz, 3H), 6.78 (m, 2H), 6.72 (m, 2H) 4.26 (dq, J = 10, 6.6 Hz, 1H), 3.04 (dd, J = 13.7 , 3.4 Hz, 1H), 2.85 (ddt J = 11.2, 3.7 Hz, 1H), 2.63 (dd, J = 13.7, 11.4 Hz, 1H), 1.77 (s, 3H), 1.74 (s, 3H), 0.81 ( d, J = 6.8 Hz, 3H). LC-MS: m/e 500 (M + H)+ (4.25 min).

The compound of Table 13 was prepared from the appropriate amine and acid of the Reference Examples, according to the procedures described in Examples 2-3 (via an acyl chloride intermediate) or Example 19 (with a coupling reagent.)

Table 13.

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The compounds in Table 14 were isolated according to the enantiomer separation procedure described in Examples 8-9.

Table 14. Enantiomeric compounds isolated according to the methods described in Examples 8-9.

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Example 64

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pyridine N-oxide N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide (enantiomer B )

A mixture of N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide (Enantiomer B, Example 50 , 0.10 g, 0.19 mmol) and m-chloroperbenzoic acid (77%, 0.15 g, 0.67 mmol) in 2 mL of methylene chloride was stirred at room temperature for 14 h. The reaction mixture was concentrated and the residue was purified by HPLC, eluting on a C18 reverse phase column, with 30 to 100% acetonitrile in water (containing 0.1% trifluoroacetic acid), to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.58 (s, 1H), 8.32 (br s, 1H), 8.17 (s, 1H), 7.99 (br d, 1H), 7.97 (dd, 1H), 7.81 (s , 1H), 7.16 (d, 2H), 7.06 (d, 1H), 6.87 (d, 2H), 4.28 (m, 1H), 3.11 (dd, 1H), 3.01 (m, 1H), 2.71 (dd, 1H), 1.75 (s, 3H), 1.74 (s, 3H), 0.94 (d, 3H). LC-MS: m/e 533 (M + H) + (4.1 min).

EXAMPLE 65

Cannabinoid receptor-1 (CB1) binding assay

Determination of binding affinity was based on recombinant human CB1 receptor, expressed in Chinese hamster egg (CHO) cells (Felder et al., Mol. Pharmacol. 48: 443-450, 1995). The total test volume is 250 μl (240 μl CB1 receptor membrane solution plus 5 μl test compound solution plus 5 μl [3H]CP-55940 solution). The final concentration of [3H]CP-55940 is 0.6 nM. The binding buffer contains 50mM Tris-HCl, pH7.4, 2.5mM EDTA, 5mM MgCl2, 0.5mg/mL fatty acid free albumin from bovine serum and a protease inhibitor (Cat#P8340, from Sigma). In order to induce the binding reaction, 5 μl of radioligand solution was added, the mixture was incubated with gentle shaking on a shaker for 1.5 h at 30oC. Binding was completed using a 96-well harvester and filtering through a GF/C filter soaked in 0.05% polyethyleneimine. Radioligand binding was quantified using a scintillation counter. Binding affinities for various compounds were calculated from IC50 values (DeBlasi et al., Trends Pharmacol. Sci 10: 227-229, 1989).

The CB2 receptor binding assay was performed similarly, with recombinant human CB2 receptor expressed in CHO cells.

EXAMPLE 66

Cannabinoid receptor-1 (CB1) functional activity assay

Functional activation of the CB1 receptor is based on the recombinant human CB1 receptor, expressed in CHO cells (Felder I dr, Mol. Pharmacol. 48: 443-450, 1995). To determine the agonist activity or inverse agonist activity of each test compound, 50 µl of CB1-CHO cell suspension was mixed with the test compound and 70 µl of assay buffer, containing 0.34 mM 3-isobutyl-1-methylxanthine and 5.1 µM forskolin in a plate with 96-well. The assay buffer contained Earle's Balanced saline, supplemented with 5 mM MgCl2, 1 mM glutamine, 10 mM HEPES, and 1 mg/mL bovine serum albumin. The mixture was incubated at room temperature for 30 minutes, and the reaction was completed by adding 30uL/well of 0.5M HCl. Total intracellular cAMP levels were quantified using the New England Nuclear Flashplate and cAMP radioimmunoassay kit.

To determine the antagonistic activity of the test compound, the reaction mixture also contained 0.5 nM of the agonist CP55940, and the reverse action of CP55940 was quantified. Alternatively, a series of dose-matching curves for CP55940 were performed with increasing concentrations of test compound, at each dose-matching curve.

A functional assay for the CB2 receptor was performed similarly, with recombinant human CB2 receptor, expressed in CHO cells.

The invention is described and shown by reference and certain specific implementations, and experts can determine various changes, modifications and substitutions, which can be made without leaving the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the Claims that follow and as such, the claims should be interpreted as broadly as is reasonable.

Claims (17)

1. Compound of structural formula I: [image] (AND) or its pharmaceutically acceptable salts, indicated that: R1 selected from: 1) cycloheteroalkyl, 2) aryl, 3) heteroaryl, i 4) -NRaRc; wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from Rb; R2 is selected from: 1) C1-10 alkyl, 2) C3-10cycloalkyl-C1-4alkyl, 3) aryl-C1-4alkyl, 4) heteroaryl-C1-4alkyl, wherein each cycloalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb; each Ra is independently selected from: 1) hydrogen, 2) methyl, i 3) -CF3; each Rb is independently selected from: 1) halogen, 2) cyano, 3) trifluoromethyl, 4) trifluoromethoxy, 5) C1-3alkyloxy, and 6) C1-3 alkyl; Rc is independently selected from: 1) hydrogen, 2) C1-6alkyl, 3) aryl, 4) heteroaryl, 5) aryl-methyl, and 6) heteroaryl-methyl, each Rc may be unsubstituted or substituted with one to three substituents selected from Rh; Rd is independently selected from: 1) cycloalkyl, 2) aryl, 3) heteroaryl, each Rd may be unsubstituted or substituted with one to three substituents selected from Rh; each Rh is independently selected from: 1) halogen, 2) C1-3alkyl, 3) -CN, i 4) -CF3; where, when the pyridyl groups are unsubstituted on nitrogen, may optionally be present as the N-oxide. 2. A compound according to Claim 1, characterized in that R1 is selected from: 1) phenyl, 2) pyridyl, 3) indolyl, 4) 7-aza-indolyl, 5) thiophenyl, i [image] ; wherein each aryl and heteroaryl is optionally substituted with one or two substituents independently selected from Rb, and each pyridyl may optionally be present as an N-oxide; and their pharmaceutically acceptable salts. 3. A compound according to Claim 2, characterized in that R1 selected from: 1) phenyl, 2) 3-cyanophenyl, 3) 3-methylphenyl, 4) 3,5-difluorophenyl, 5) 3-pyridyl, 6) 5-chloro-3-pyridyl, 7) 5-methyl-3-pyridyl, 8) 5-cyano-3-pyridyl, 9) 1-oxido-5-cyano-3-pyridyl, 10) 1-indolyl, 11) 7-aza-indol-N-yl, 12) 2-thiophenyl, i [image] ; and their pharmaceutically acceptable salts. 4. Compound according to Claim 3, characterized in that R1 is 5-cyano-3-pyridyl; and pharmaceutically acceptable salts thereof. 5. A compound according to Claim 2, characterized in that R2 is selected from: 1) C1-6 alkyl, 2) C3-6cycloalkylmethyl, 3) phenylmethyl, 4) heteroarylmethyl, wherein each cycloalkyl, aryl and heteroaryl is optionally substituted with one to three substituents, independently selected from Rb, and pharmaceutically acceptable salts thereof. 6. A compound according to Claim 5, characterized in that R2 is selected from: 1) 2-methylpropyl, 2) n-pentyl, 3) cyclobutylmethyl, 4) cyclopentylmethyl, 5) cyclohexylmethyl, 6) benzyl, 7) 4-chlorobenzyl, 8) 4-methylbenzyl, 9) 4-fluorobenzyl, 10) 4-methoxybenzyl, i 11) (5-chloro-2-pyridyl)methyl; and their pharmaceutically acceptable salts. 7. A compound according to Claim 2, characterized in that Rd is selected from: 1) C4-6cycloalkyl, 2) aryl, 3) heteroaryl, where Rd may be unsubstituted or substituted, with one or two substituents selected from Rh, and their pharmaceutically acceptable salts. 8. A compound according to Claim 7, characterized in that Rd is selected from: 1) phenyl, 2) pyridyl, te 3) pyrimidinyl, where Rd can be unsubstituted or substituted, with one or two substituents, selected from Rh; and their pharmaceutically acceptable salts. 9. A compound according to Claim 8, characterized in that Rd is selected from: 1) phenyl, 2) 4-chlorophenyl, 3) 3-chlorophenyl, 4) 3,5-difluorophenyl, 5) 3,5-dichlorophenyl, 6) 2-pyridyl, 7) 5-chloro-2-pyridyl, 8) 6-methyl-2-pyridyl, 9) 5-trifluoromethyl-2-pyridyl, 10) 4-trifluoromethyl-2-pyridyl, 11) 4-trifluoromethyl-2-pyrimidyl, i 12) 6-trifluoromethyl-4-pyrimidyl; and their pharmaceutically acceptable salts. 10. Compound according to Claim 1, characterized in that it is selected from: 1) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-chlorophenyloxy)-2-methylpropanamide; 2) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide; 3) N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenyloxy)-2-methylpropanamide; 4) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenyloxy)-2-methylpropanamide; 5) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(3,5-dichlorophenyloxy)-2-methylpropanamide; 6) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenyloxy)-2-methylpropanamide; 7) N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methylpropanamide; 8) N-[3-(4-chlorophenyl)-1-methyl-2-phenyl-propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide; 9) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(6-methyl-pyridyloxy)-2-methylpropanamide; 10) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(phenyloxy)-2-methylpropanamide; 11) N-[(3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2-methylpropanamide; 12) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 13) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 14) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 15) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 16) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 17) N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 18) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 19) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide; 20) N-[3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide; 21) N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 22) N-[3-(4-methyl-phenyl)-1-methyl-2-phenylpropyl]-2-(4-trifluoromethyl-phenyloxy)-2-methylpropanamide; 23) N-[3-(4-fluoro-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 24) N-[3-(4-chlorophenyl)-2-(1-indolyl)-1-methyl)propyl]-2-(5-trifluoromethyl-2-oxypyridin-2-yl)-2-methylpropanamide; 25) N-[3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-1-methyl)propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 26) N-[3-(4-chloro-phenyl)-2-(1-indolinyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 27) N-[3-(4-chloro-phenyl)-2-(N-methyl-anilino)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 28) N-[3-(4-methoxy-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 29) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide; 30) N-[2-(3-cyanophenyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 31) N-[3-(4-chlorophenyl)-2-(1-oxido-5-cyano-3-pyridyl]-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 32) N-[2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 33) N-[2-(3-cyanophenyl)-1-methyl-heptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 34) N-[2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 35) N-[2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; and their pharmaceutically acceptable salts. 11. Compound according to Claim 9, characterized in that Rd is 5-trifluoromethyl-2-pyridyl; and pharmaceutically acceptable salts thereof. 12. Compound according to Claim 11, characterized in that it is selected from: 1) N-[(3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2-methylpropanamide; 2) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 3) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 4) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 5) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 6) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 7) N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 8) N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 9) N-[3-(4-fluoro-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 10) N-[3-(4-chlorophenyl)-2-(1-indolyl)-1-methyl)propyl]-2-(5-trifluoromethyl-2-oxypyridin-2-yl)-2-methylpropanamide; 11) N-[3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-1-methyl)propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 12) N-[3-(4-chloro-phenyl)-2-(1-indolinyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 13) N-[3-(4-chloro-phenyl)-2-(N-methyl-anilino)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 14) N-[3-(4-methoxy-phenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 15) N-[2-(3-cyanophenyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 16) N-[3-(4-chlorophenyl)-2-(1-oxido-5-cyano-3-pyridyl]-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 17) N-[2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 18) N-[2-(3-cyanophenyl)-1-methyl-heptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; 19) N-[2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; N-[2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; and their pharmaceutically acceptable salts. 13. A compound characterized in that it contains a compound according to Claim 1 and a pharmaceutically acceptable carrier. 14. Use of the compound according to Claim 1, characterized in that it is used for the production of a drug useful in the treatment of diseases mediated by the cannabinoid-1 receptor in a human patient in need of such treatment. 15. Use according to Claim 14, characterized in that the disease mediated by the cannabinoid-1 receptor is an eating disorder related to excessive food consumption. 16. Use according to Claim 15, characterized in that the eating disorder is related to excessive food consumption, i.e. obesity. 17. Use of the compound according to Claim 1, characterized in that it is used for the production of a medicine for the prevention of obesity in persons who are at risk.