Azetidinyl diamines useful as ligands of the nociceptin receptor ORL-1

BACKGROUND OF THE INVENTION

[0001] The G protein coupled nociceptin receptor known as ORL1 has been shown to be involved in the modulation of pain in animal models. It bears high homology to the classic opioid receptors (μ, k, δ), but has little cross reactivity with their native ligands. Current opioid analgesics target these classic opioid receptors, but have limiting side effect profiles (e.g. tolerance, physical dependence, respiratory depression and decrease of gastrointestinal function). ORL1 receptors are colocalized in regions of the CNS similar to the opiod receptors, as well as in the periphery.

[0002] Nociceptin, the endogenous ligand to ORL1, was discovered in 1995 and shown to be a peptide ligand that activates the ORL1 receptor, but not the classic opioid receptors. Initial reports have suggested that nociceptin and the ORL1 receptor are involved in a newly discovered pathway involved in the perception of pain. Further reports have shown nociceptin to be analgesic when administered intrathecally to rodents. The in vivo efficacy of nociceptin in animal models of pain is similar to that of the endogenous opioids. Nociceptin is also reported to act as an anxiolytic agent when administered into the brains of rodents. The in vivo efficacy in rodent anxiety models is similar to classic benzodiazepine anxiolytics. In addition, nociceptin has been recently reported to inhibit capsaicin induced bronchoconstriction in isolated guinea pig lung tissue, suggesting a role for ORL1 agonists in the treatment of cough. Together, these data suggest that nociceptin receptor agonists may have significant analgesic, anxiolytic, or antitussive properties.

SUMMARY OF THE INVENTION

[0003] Compounds of the invention are represented by formula I:

[0004] or a pharmaceutically acceptable salt or solvate thereof, or a diastereomer or enantiomer thereof, wherein:

[0005] (a) R1 is —(CH2)nCHR4R5, fluorenyl, pyrimidinyl or

[0006] n is 0, 1, 2 or 3;

[0007] R2 is H; and R3 is —C(H)(R)—NR7R8;

[0008] R is H, aryl, R6-aryl, aryl(CH2)1-2, R6-aryl(CH2)1-2 or heteroaryl;

[0009] R4 is H, aryl, R6-aryl, heteroaryl, C1-6 alkyl, C3-6 cycloalkyl or C2-6 alkenyl;

[0010] R5 is aryl, R6-aryl, heteroaryl, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl or fluorenyl, provided that when R4 and R5 are each phenyl, R is not phenyl or R6-phenyl;

[0011] or R4 is H and R5 is tetrahydronaphthyl or tetrahydronaphthyl substituted with 1 or 2 substituents selected from the group consisting of halogen, C1-6 alkoxy, hydroxy, C1-6alkyl and trihalo(C1-6)alkyl;

[0012] R6 is 1 or 2 substituents independently selected from the group consisting of halogen, C1-6alkoxy, hydroxy, phenyl, phenoxy, C1-6alkyl, trihalo(C1-6)alkyl, amino, amido, —NO2, naphthyl, benzoyl and benzyloxy, or 2 adjacent ring carbon atoms can be substituted by methylenedioxy;

[0013] R7 is —(CH2)xR9, tetrahydronaphthyl, tetrahydronaphthyl substituted with 1 or 2 R10 groups, or C5-C7 cycloalkyl; and R8 is H;

[0014] or R7 and R8 together form a ring of the formula

[0015] x is 0 to 10;

[0016] R9 is H, C1-C6 alkoxy, phenyl, phenyl substituted with 1 or 2 R10 groups, naphthyl, pyridyl, imidazolyl, furanyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, N—(C1-C6 alkyl)-piperidinyl, N-aryl(C1-C6 alkyl)piperidinyl or diphenylmethyl;

[0017] R10 is independently selected from the group consisting of halogen, C1-C6 alkoxy, C1-C6 alkyl, —OCF3 and methylenedioxy;

[0018] R11 is aryl(C1-C6)alkyl, di-aryl(C1-C6)alkyl or piperidinyl; and

[0019] R17 is H, C1-C6 alkyl or benzyl;

[0020] or

[0021] (b) R2 is —NHR7 or

[0022] and R3 is H; and

[0023] R1 and R7 are as defined in (a).

[0024] In another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of formula I and a pharmaceutically acceptable carrier.

[0025] The compounds of the present invention are agonists of the ORL-1 receptor, and therefore, in another aspect, the invention relates to a method of treating cough, pain, anxiety, asthma, alcohol abuse or depression, comprising administering to a mammal in need of such treatment an effective amount of at least one compound of formula I.

[0026] In another aspect, the invention relates to a method of treating cough, comprising administering to a mammal in need of such treatment: (a) an effective amount of at least one compound of formula I; and (b) an effective amount of one or more additional agents for treating cough, allergy or asthma symptoms selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists.

[0027] In still another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of formula I and one or more additional agents selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK22 and NK33 tachykinin receptor antagonists, and GABAB agonists.

DETAILED DESCRIPTION

[0028] Referring to formula I above, preferred are compounds of (a) or (b) wherein R1 is —(CH2)nCHR4R5 and n is 0 or 1, more preferably 0. R4 is preferably aryl, R6-aryl or heteroaryl, more preferably phenyl, R6-phenyl or pyridyl. R5 is preferably aryl or C1-C6 alkyl, more preferably phenyl, R6-phenyl or C2-C5 alkyl, provided both R4 and R5 are not phenyl when R is optionally substituted phenyl. When R6 is a substituent on R4 or R5, it is preferably halogen, especially fluoro.

[0029] Preferred are compounds of formula I (a), i.e., those wherein R2 is H and R3 is —C(H)(R)—NR7R8. R is preferably R6-phenyl, benzyl or R6-benzyl. When R6 is a substituent on R, it is preferably 1 or 2 substituents independently selected from the group consisting of —CF3, halogen, benzyloxy and —CH3, wherein halogen is preferably chloro or fluoro. R7 and R8 are preferably each H.

[0030] As used herein, the following terms are used as defined below unless otherwise indicated:

[0031] alkyl represents straight and branched carbon chains containing from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like;

[0032] alkenyl represents an alkyl chain of 2 to 6 carbon atoms comprising one or two double bonds in the chain, e.g., vinyl, propenyl or butenyl;

[0033] alkoxy represents an alkyl moiety covalently bonded to an adjacent structural element through an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like;

[0034] aryl represents a monoaromatic ring or a bicyclic fused carbocyclic ring system of 6- to 10 carbon atoms, for example phenyl and naphthyl;

[0035] cycloalkyl represents saturated carbocyclic rings of from 3 to 7 carbon atoms, as specified in the definitions;

[0036] halo represents fluoro, chloro, bromo and iodo;

[0037] heteroaryl means a single ring heteroaromatic group of 5 to 6 atoms comprised of 2 to 5 carbon atoms and 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. N-Oxides are also contemplated, e.g. pyridyl N-oxide.

[0038] Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures.

[0039] Certain compounds will be acidic in nature, e.g. those compounds which possess a phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

[0040] Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.

[0041] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

[0042] Compounds of formula I can be prepared using procedures known in the art. For example, compounds of formula I wherein R3 is —C(H)(R)—NR7R8, wherein R7 and R8 are each H and R is R6-phenyl can be prepared according to the following overall synthetic scheme:

[0043] When R6 is an amino or hydroxy group, it must be protected by a suitable protecting group by a method well known in the art.

[0044] Following are details of the steps (A-K) in the above procedure. The procedures are exemplified for specific compounds, but those skilled in the art will recognize that other compounds of formula I can be made by similar procedures.

[0045] The following abbreviations are used in this application: RT (room temperature); Et2O (ether), EtOAc (ethyl acetate); Ph (phenyl); Et (ethyl); and TFA (trifluoroacetic acid).

[0046] Step A:

[0047] To a solution of ethyl 2,4-dibromobutyrate (36.31 g, 0.132 mol) in CH3CN (140 ml) was added aminodiphenylmethane (73.59 g, 0.402 mol). The solution was stirred at RTfor 1 h, then heated to 55° C. for 20 h. The suspension was cooled to RT and the precipitated salt was collected by filtration and washed with Et2O. The combined filtrate and Et2O washings were concentrated in vacuo and the residue dissolved in Et2O (400 ml). The solution was washed with saturated NaHCO3 (100 ml) and the wash was extracted with Et2O (2×100 ml). The combined ethereal solutions were washed with saturated NaCl (100 ml), dried over MgSO4, and concentrated in vacuo to give 49.99 g of an oil which slowly solidified. This material was purified by SiO2 chromatography eluting with 2% EtOAc in hexanes progressing to 10% EtOAc in hexanes. Concentration of the appropriate fractions gave 25.67 g (66%) of the desired product as a white solid. MS: calcd for C19H21NO2oH+ m/z=296.16, observed m/z=296.1 (M+1)+.

[0048] The following compounds were prepared by an analogous procedure:

Prep.R1Analytical Data1bPhCH2MS calcd for C13H17NO2oH+ m/z = 220.1observed m/z = 220 (M + 1)+1cCH2═CHCH2MS calcd for C9H15NO2oH+ m/z = 170.1observed m/z = 170 (M + 1)+Step B:

[0049] To a stirred solution of 1a (7.00 g, 23.7 mmol) in dry THF (50 ml) at −75° C. under Ar was added a cooled (−78° C.) 1 M solution of DiBAL-H in toluene (28.4 ml, 28.4 mmol) dropwise via a cannula over ˜1 h. The reaction was stirred for 1 h at −70° C. It was quenched by the careful addition of several small portions of Na2SO4o(H2O)10. The reaction was stirred at RT, then diluted with EtOAc (200 ml). It was filtered through Celite and concentrated in vacuo to give 5.98 g of a white solid. This material was triturated with 10% EtOAc in hexanes to give the desired aldehyde 2a as a white solid (3.09 g, 52%). MS: calc'd for C17H17NOoH+ m/z=252.14, observed m/z=252.20 (M+1)+.

[0050] The following compounds were prepared by an analogous procedure:

Prep.R1Analytical Data2bPhCH21H NMR (400MHz, CDCl3) δ 9.47 (d, J= 3.9Hz,1H, CHO), 7.25-7.40 (m, 5H, Ph), 3.60-3.90 (m,3H), 2.95-3.30 (m, 2H), 2.00-2.40 (m, 2H)2cCH2═CHCH21H NMR (400MHz, CDCl3) δ 9.73 (d, J=2.6Hz,1H, CHO), 5.75-5.90 (m, 1H), 5.10-5.30 (m,2H), 2.90-3.80 (m, 5H), 2.00-2.40 (m, 2H)Step C:

[0051] A solution of 2a (15.00 g, 59.7 mmol) in dry THF(75 ml) was cooled to −40° C. underN2. To this solution was added a 0.5M solution of 3-chlorophenylmagnesium-bromide (155.2 ml, 77.6 mmol) in THF dropwise over 1.25 h. The reaction was stirred with gradual warming to 0° C. over 2.5 h. The reaction was quenched by the dropwise addition of water (20 ml) while maintaining the 0° C. temperature. The reaction was warmed to RT and additional water (150 ml) was added. The solution was extracted with EtOAc (2×700 ml). The combined EtOAc layers were washed with brine (200 ml) and dried over Na2SO4. The solvent was removed in vacuo to give 20.78 g of a semisolid residue. This residue was recrystallized from EtOH to give 8.76 g of the erythro isomer 3a as a white solid. The mother liquor was concentrated to give an orange oil. The resulting oil was purified by flash chromatography over 500 g of SiO2, eluting with a gradient of 3% EtOAc in hexanes, progressing slowly to 18% EtOAc in hexanes. The less polar erythro isomer 3a eluted first to give another 3.61 g, followed by 4.20 g of the more polar threo isomer 4a.

[0052] Analytical data for 3a: MS calcd for C23H22ClNOoH+ m/z=364.15, observed m/z=364.1 (M+1)+. Analytical data for 4a: MS calcd for C23H22ClNOoH+ m/z=364.15, observed m/z=364.35 (M+1)+

[0053] The following compounds were prepared by an analogous procedure:

[0054] wherein

[0055] R1 and R6 are as defined in the table:

3Prep.R1R6Analytical Data3bPhCH23-CF3MS calcd for C18H18F3NOoH+ m/z=322.14observed m/z=322 (M+1)+3cCH2═3-CF3MS calcd for C14H16F3NOoH+ m/z=272.13CHCH2observed m/z=272 (M+1)+3dCH2═3-ClMS calcd for C13H16ClNOoH+ m/z=238.10CHCH2observed m/z=238 (M+1)+3ePh2CH3-CF3MS calcd for C24H22F3NOoH+ m/z=398.17observed m/z=398.2 (M+1)+3fPh2CH3-OCH3MS calcd for C24H25NO2oH+ m/z=360.20observed m/z=360.3 (M+1)+3gPh2CH3-CH3MS calcd for C24H25NOoH+ m/z=344.20observed m/z=344 (M+1)+3hPh2CH4-OCH3MS calcd for C24H25NO2oH+ m/z=360.20observed m/z=360 (M+1)+3iPh2CH3-NH2MS calcd for C23H24N2OoH+ m/z=345.20observed m/z=345 (M+1)+3jPh2CH3-FMS calcd for C23H22FNOoH+ m/z=348.18observed m/z=348 (M+1)+3kPh2CH3-F-4-MS calcd for C24H24FNOoH+ m/z=362.19CH3observed m/z=362.1 (M+1)+3lPh2CH3,5-F2MS calcd for C23H21F2NOoH+ m/z=366.17observed m/z=366 (M+1)+3mPh2CH4-CH31H NMR (400 MHz, CDCl3) δ 7.51 (d, 2H,J=10), 7.47 (d, 2H, J=9), 7.34-7.42 (m, 4H),7.25-7.41 (m, 2H), 7.08 (d, 2H, J=9), 7.00(d, 2H, J=9), 4.60 (s, 1H, CHPh2), 3.87 (s,1H), 3.51 (m, 1H), 3.37-3.44 (m, 2H), 2.77-2.84 (m, 1H), 2.32 (s, 3H, Me), 2.20-2.31(m, 1H), 1.04-1.12 (m, 1H)3nPh2CH4-Cl1H NMR (400 MHz, CDCl3) δ 7.51 (d, 2H,J=8), 7.47 (d, 2H, J=8), 7.34-7.40 (m, 4H),7.28-7.31 (m, 2H), 7.25 (d, 2H, J=8), 7.07(d, 2H, J=8), 4.61 (s, 1H, CHPh2), 3.96 (brs, 1H), 3.58 (dt, 1H, J=3, 8), 3.40-3.43 (m,2H), 2.82 (q, 1H, J=9), 2.09-2.21 (m, 1H),1.52 (dq, 1H, J=3, 8)3oPhCH24-PhO1H NMR (400 MHz, CDCl3) δ 7.52 (d, 2H,J=8), 7.50 (d, 2H, J=8), 7.28-7.42 (m, 9H),7.09-7.16 (m, 2H), 7.01 (d, 2H, J=8), 6.94(d, 2H, J=8), 4.65 (s, 1H, CHPh2), 3.92 (s,1H), 3.62 (dt, 1H, J=4, 8), 3.43-3.47 (m, 2H),2.85 (q, 1H, J=4), 2.28-2.34 (m, 1H)3pPh2CH2-CH31H NMR (400 MHz, CDCl3) δ 7.50-7.53 (m,4H), 7.30-7.42 (m, 4H), 7.10-7.20 (m, 4H),7.02 (d, 2H, J=8), 4.61 (s, 1H, CHPh2), 4.00(s, 1H), 3.76 (d, 1H, J= 3), 3.63 (m, 1H),3.45 (m, 1H), 2.81 (m, 1H), 2.36 (m, 1H),1.85 (s, 3H), 1.52-1.57 (m, 1H)4bPhCH23-CF3MS calcd for C18H18F3NOoH+ m/z=322.14observed m/z=322 (M+1)+4cCH2═3-CF3MS calcd for C14H16F3NOoH+ m/z=272.13CHCH2observed m/z=272 (M+1)+4dCH2═3-ClMS calcd for C13H16ClNOoH+ m/z=238.10CHCH2observed m/z=238 (M+1)+4ePh2CH3-CF3MS calcd for C24H22F3NOoH+ m/z=398.17observed m/z=398.2 (M+1)+4fPh2CH3-OCH31H NMR (400 MHz, CDCl3) δ 7.45 (d, 2H,J=9 Hz, ArH) 7.20-7.38 (m, 9H, ArH) 6.86(d, 1H, J=9 Hz, ArH) 6.78-6.82 (m, 2H,ArH) 4.56 (br s, 1H) 4.51 (d, 1H, J=4 Hz)3.82 (s, 3H, OCH3) 3.65 (q, 1H, J=7 Hz)3.30-3.38 (m, 1H) 2.84 (q, 1H, J=7 Hz)2.34 (Br s, 1H) 2.00 (qu, 1H, J=7 Hz) 1.78-1.88 (m, 1H)4gPh2CH3-CH31H NMR (400 MHz, CDCl3) δ 7.45 (d, 2H,J=9 Hz, ArH) 7.18-7.38 (m, 9H, ArH) 7.15(d, 1H, J=9 Hz, ArH) 6.98-7.03 (m, 2H,ArH) 4.98 (br s, 1H) 4.45 (d, 1H, J=5 Hz)3.56 (q, 1H, 5 Hz) 3.28 (m, 1H) 2.78 (q, 1H,6 Hz) 2.30 (s, 3H, CH3) 1.86-1.97 (m, 1H)1.68-1.78 (m, 1H)4hPh2CH4-OCH3—4jPh2CH3-F1H NMR (400 MHz, CDCl3) δ 7.38 (d, 2H,J=9 Hz, ArH) 7.15-7.32 (m, 9H, ArH) 6.95(d, 1H, J=9 Hz, ArH) 6.82-6.89 (m, 2H,ArH) 4.48 (br s, 1H) 4.42-4.46 (m, 1H) 3.58(q, 1H, J=5 Hz) 3.30-3.35 (m, 1H) 2.80 (q,1H, J=7 Hz) 2.58 (br s, 1H) 1.92-2.05 (m,1H 1.78-1.86 (m,1H)4kPh2CH3-F-4-—CH34lPh2CH3,5-F21H NMR (400 MHz, CDCl3) δ 7.12-7.35 (m,10H, ArH) 6.53-6.66 (m, 3H, ArH) 4.48 (brs, 1H) 4.35 (br s, 1H) 3.60-3.67 (m, 1H)3.30-3.40 (m, 1H) 2.80-2.89 (m, 1H) 2.65(br s, 1H) 1.90-2.08 (m, 2H)4mPh2CH4-CH31H NMR (400MHz, CDCl3) δ 7.50 (d, 2H,J=10, ArH), 7.23-7.38 (m, 8H), 7.14 (d, 2H,J=9, ArH), 7.10 (d, 2H, J=9, ArH), 4.47-4.62(br m, 2H), 3.52-3.63 (br m, 1H), 3.23-3.37(br m, 1H), 2.73-2.86 (br m, 1H), 2.33 (s,3H, Me), 1.89-2.00 (m, 2H), 1.71-1.82 (m,1H)4oPhCH24-PhO1H NMR (400 MHz, CDCl3) δ 7.54 (d, 2H,J=8), 7.28-7.36 (m, 9H), 7.18 (d, 2H, J=8),7.04-7.10 (m, 2H), 6.96 (d, 2H, J=8), 6.88(d, 2H, J=8), 4.52 (s, 1H, CHPh2), 4.45(d, 1H, J=8), 3.55 (q, 1H, J=4), 3.24-3.34(m, 1H), 2.78 (q, 1h, J=4), 1.85-1.97 (m,1H, 1.71-1.79 (m, 1H)

[0056] The following compounds were also prepared by an analogous procedure:

[0057] wherein

[0058] R1 and R are as defined in the table (wherein Ph is phenyl):

4Prep.R1RAnalytical Data3qPh2CHPhCH2MS calcd for C24H25NOoH+ m/z=344.2observed m/z=344 (M+1)+3rPh2CH4-BnO-1H NMR (400 MHz, CDCl3) δ 7.14-7.48 (m,PhCH217H), 6.86 (d, 2H, J=8), 4.99 (t, 2H, J=4),4.52 (s, 1H, CHPh2), 3.92 (s, 1H), 3.66 (s,1H), 3.52 (dt, 1H, J=4, 8), 3.33 (dt, 1H,J=4, 8), 2.71 (q, 1HO J=4), 2.21 (m, 1H),1.72 (s, 2H), 1.39 (q, 1H, J=4)4sPh2CH2-MS calcd for C20H20N2OSoH+ m/z=337.14thi-observed m/z=337 (M+1)+azolyl3ac+Ph2CH3,5-Cl2-—4acC6H3-(mix)CH2

[0059] Step D:

[0060] To an argon degassed solution of erythro alcohol 3a (2.00 g, 5.50 mmol) and triphenylphosphine (2.89 g, 11.0 mmol) in toluene (27 ml) was added Zn(N3)2o2Pyr complex (1.27 g, 4.13 mmol). To the resulting suspension at RT was added diiso-propylazodicarboxylate (2.20 ml, 11.0 mmol) dropwise over 25 min. A slight exotherm was noted. The reaction was stirred at RT for 1.5 h, filtered through Celite, and concentrated in vacuo to give 8.23 g of a foamy residue. The residue was purified by chromatography over 450 g SiO2. The erythro and threo azides were eluted with a gradient starting with 0.5% EtOAc in hexanes and progressing to 6% EtOAc in hexanes to give two main fractions. Fraction 1 contained 0.96 g of a mixture of the erythro and threo azides, 6a and 5a respectively. Fraction 2 contained 0.51 g of the more polar threo azide, 5a.

[0061] Analytical data for 5a: MS calcd for C23H21ClN4oH+ m/z=389.15, observed m/z=389.15 (M+1)+

[0062] The following compounds were prepared by an analogous procedure:

Prep.R1R6Analytical Data5bPhCH23-CF3MS calcd for C18H17F3N4oH+m/z = 347.15observed m/z = 347 (M + 1)+5cCH2═CHCH23-CF3MS calcd for C14H15F3N4oH+m/z = 297.13observed m/z = 297 (M + 1)+5dCH2═CHCH23-ClMS calcd for C13H15ClN4oH+m/z = 263.11observed m/z = 263 (M + 1)+5ePh2CH3-CF31H NMR (400MHz, CDCl3) δ7.20-7.63 (m, 14H), 4.62 (s, 1H),3.73 (m, 2H), 3.09 (m, 1H), 2.70 (q,1H), 1.82 (m, 1H), 1.53 (m, 1H)5fPh2CH3-OCH3MS calcd for C24H24N4OoH+m/z = 385.20observed m/z = 385.1 (M + 1)+5gPh2CH3-CH31H NMR (400MHZ, CDCl3) δ7.08-7.46 (m, 14H), 4.88 (s, 1H),3.87 (m, 1H), 3.54 (d, 1H), 3.17 (m,1H), 2.59 (q, 1H), 2.38 (s, 3H) 2.33(m, 1H), 1.81 (m, 1H)5hPh2CH4-OCH31H NMR (400MHz, CDCl3) δ7.14-7.50 (m, 12H), 6.88 (d, 2H),4.18 (s, 1H), 3.89 (d, 1H), 3.83 (s,3H), 3.58 (m, 1H), 3.13 (m, 1H),2.68 (m, 1H), 1.66 (m, 2H)5jPh2CH3-F1H NMR (400MHz, CDCl3) δ7.19-7.48 (m, 11H), 7.12 (m, 3H),4.63 (s, 1H), 3.78 (d, 1H), 3.64 (m,1H), 3.13 (m, 1H), 2.69 (q, 1H), 1.77(m, 1H), 1.60 (m, 1H)5kPh2CH3-F-4-CH31H NMR (400MHz, CDCl3) δ7.12-7.53 (m, 11H), 6.95 (d, 2H),4.64 (s, 1H), 3.78 (d, 1H), 3.60 (m,1H), 3.14 (m, 1H), 2.69 (q, 1H), 2.28(s, 3H), 1.75 (m, 1H), 1.63 (m, 1H)51Ph2CH3,5-F21H NMR (400MHz, CDCl3) δ7.20-7.48 (m, 10H), 6.88 (d, 2H),6.76 (t, 1H), 4.60 (s, 1H), 3.65 (m,2H), 3.15 (m, 1H), 2.70 (q, 1H), 1.83(m, 1H), 1.57 (m, 1H)5mPh2CH4-CH3MS calcd for C24H24N4oH+m/z = 369.21observed m/z = 369.2 (M + 1)+5nPh2CH4-ClMS calcd for C23H21ClN4oH+m/z = 389.15observed m/z = 389 (M + 1 )+5oPh2CH4-PhO1H NMR (400MHz, CDCl3) δ7.20-7.44 (m, 4H), 7.19-7.35 (m,9H), 7.11 (t, 2H, J=8), 7.01 (d, 2H,J=8), 6.98 (d, 2H, J=8), 4.65 (s, 1H,CHPh2), 3.87 (d, 1H, J=8), 3.62 (q,1H, J=4), 3.12-3.20 (m, 1H), 3.07 (q,1H, J=4), 1.62-1.80 (m, 2H)5pPh2CH2-CH31H NMR (400MHz, CDCl3) δ7.53 (d, 2H, J=7), 7.36-7.40 (m, 6H),7.25-7.31 (m, 2H), 7.18-7.23 (m,4H), 4.84 (s, 1H, CHPh2), 4.66 (d,1H, J=7), 3.70 (q, 1H, J=8), 3.26 (m,1H), 2.78 (q, 1H, J=7), 2.46 (s, 3H),1.72 (m, 2H)6bPhCH23-CF3MS calcd for C18H17F3N4oH+m/z = 347.15observed m/z = 347 (M + 1)+6cCH2═CHCH23-CF3MS calcd for C14H15F3N4oH+m/z = 297.13observed m/z = 297 (M + 1)+61Ph2CH3-NH21H NMR (400MHz, CDCl3) δ7.11-7.46 (m, 11H), 6.86 (d, 1H),6.76 (s, 1H), 6.65 (d, 1H), 4.96 (s,1H), 3.86 (m, 1H), 3.72 (br s, 2H),3.48 (d, 1H), 3.17 (m, 1H), 2.51 (m,1H), 2.34 (m, 1H), 1.79 (m, 1H)6kPh2CH3-F-4-CH3MS calcd for C24H23FN4oH+m/z = 387.20observed m/z = 387 (M + 1)+6mPh2CH4-CH3MS calcd for C24H24N4oH+m/z = 369.21observed m/z = 369.2 (M + 1)+

[0063] The following compounds were also prepared by an analogous procedure:

Ex.R1RAnalytical Data5qPh2CHPhCH21H NMR (400MHz, CDCl3) δ 7.04-7.52(m, 15H), 4.78 (s, 1H), 4.60 (d, 1H,J=10), 3.64 (q, 1H, J=9), 3.21 (m, 1H),2.73 (q, 1H, J=8), 2.20 (s, 2H),1.66 (m, 2H)5rPh2CH4-BnOPhCH2MS calcd for C31H30N4OoH+m/z = 475.25observed m/z = 475 (M + 1)+5sPh2CH2-thiazolyl1H NMR (400MHz, CDCl3) δ 7.15-7.70(m, 12H), 4.54 (s, 1H), 4.10 (m, 1H),3.75 (d, 1H, J=3), 3.48 (m, 1H), 2.78 (q,1H, J=8), 2.28 (m, 1H), 1.78 (m, 1H)

[0064] Step E:

[0065] To a solution of the threo azide 5a (0.50 g, 1.29 mmol) in CH3OH (10 ml) at 0° C. was added NiCl2o6H2O (1.47 g, 6.19 mmol). To this solution was added NaBH4 (0.39 g, 10.3 mmol) in portions. The reaction was stirred at 0° C. for 1.5 h, then quenched with the dropwise addition of ˜3.4 ml water. It was partitioned between water (40 ml) and EtOAc (100 ml). The aqueous layer was extracted with EtOAc (2×100 ml). The combined EtOAc layers were washed with brine (50 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to give 0.473 g of an oil. The oil was purified by column chromatography over 100 g SiO2, eluting with a solvent gradient starting with 0.5% CH3OH in CH2Cl2 and progressing to 3% CH3OH in CH2Cl2. Concentration of the appropriate fractions gave 0.31 g of the desired racemic threo amine 7a as an oil. The enantiomers were separated by preparative HPLC on a Chiracel OJ column eluting with 5% EtOH in hexanes containing 0.2% Et2NH.

[0066] Analytical data for racemic 7a :

[0067] MS calcd for C23H23ClN2oH+ m/z=363.16, observed m/z=363.10 (M+1)+

[0068] Analytical data for the first eluted enantiomer 7a-E1:

[0069] MS calcd for C23H23ClN2oH+ m/z =363.16, observed m/z=363.30 (M+1)+

[0070] Analytical data for the second eluted enantiomer 7a-E2:

[0071] MS calcd for C23H23ClN2oH+ m/z =363.16, observed m/z=363.30 (M+1)+

[0072] The following compounds were prepared by an analogous procedure:

[0073] wherein

[0074] R1 and R6 are defined in the table:

7Prep.R1R6Analytical Data7bPhCH23-CF3MS calcd for C18H19F3N2oH+ m/z=321.16observed m/z=321 (M+1)+7cCH2═3-CF3MS calcd for C14H17F3N2oH+ m/z=271.14CHCH2observed m/z=271 (M+1)+7dCH2═3-ClMS calcd for C13H17ClN2oH+ m/z=237.12CHCH2observed m/z=237.1 (M+1)+7ePh2CH3-CF3MS calcd for C24H23F3N2oH+ m/z=397.19observed m/z=397.4 (M+1)+7e-E1Ph2CH3-CF3MS calcd for C24H23F3N2oH+ m/z=397.19observed m/z=397.4 (M+1)+7e-E2Ph2CH3-CF3MS calcd for C24H23F3N2oH+ m/z=397.19observed m/z=397.4 (M+1)+7fPh2CH3-OCH3MS calcd for C24H26N2OoH+ m/z=359.21observed m/z=359.1 (M+1)+7gPh2CH3-CH3MS calcd for C24H26N2oH+ m/z=343.22observed m/z=343 (M+1)+7hPh2CH4-OCH3MS calcd for C24H26N2OoH+ m/z=359.21observed m/z=359.1 (M+1)+7jPh2CH3-FMS calcd for C23H23FN2oH+ m/z=347.19observed m/z=347 (M+1)+7kPh2CH3-F-4-CH3MS calcd for C24H25FN2oH+ m/z=361.21observed m/z=361.1 (M+1)+7lPh2CH3,5-F2MS calcd for C23H22F2N2oH+ m/z=365.19observed m/z 365.1 (M+1)+7mPh2CH4-CH3MS calcd for C24H26N2oH+ m/z=343.22observed m/z=343.4 (M+1)+7nPh2CH4-ClMS calcd for C23H23ClN2oH+ m/z=363.16observed m/z=363 (M+1)+7n-E1Ph2CH4-ClMS calcd for C23H23ClN2oH+ m/z=363.16observed m/z=363 (M+1)+7n-E2Ph2CH4-ClMS calcd for C23H23ClN2oH+ m/z=363.16observed m/z=363 (M+1)+7oPh2CH4-PhOMS calcd for C29H28N2OoH+ m/z=421.23observed m/z=421 (M+1)+7pPh2CH2-CH3MS calcd for C24H26N2oH+ m/z=343.22observed m/z=343 (M+1)+8bPhCH23-CF3MS calcd for C18H19F3N2oH+ m/z=321.16observed m/z=321 (M+1)+8cCH2═3-CF3MS calcd for C14H17F3N2oH+ m/z=271.14CHCH2observed m/z 271 (M+1)+8iPh2CH3-NH2MS calcd for C23H25N3oH+ m/z=344.21observed m/z=344.1 (M+1)+8kPh2CH3-F-4-CH3MS calcd for C24H25FN2oH+ m/z=361.21observed m/z=361.1 (M+1)+

[0075] The following compounds were also prepared by an analogous procedure:

Ex.R1RAnalytical Data7qPh2CHPhCH2MS calcd for C24H26N2oH+m/z = 343.22observed m/z = 343 (M + 1)+7q-E1Ph2CHPhCH2MS calcd for C24H26N2oH+m/z = 343.22observed m/z = 343.4 (M + 1)+7q-E2Ph2CHPhCH2MS calcd for C24H26N2oH+m/z = 343.22observed m/z = 343.4 (M + 1)+7rPh2CH4-BnOPhCH2MS calcd for C31H32N2OoH+m/z = 449.26observed m/z = 449.3 (M + 1)+7sPh2CH2-thiazolylMS calcd for C20H21N3SoH+m/z = 336.15observed m/z = 336.1 (M + 1)+

[0076] Step F:

[0077] To a stirred solution of compound 7d (3.41 g, 14.4 mmol) and Et3N (1.6 g, 16 mmol) in THF (40 ml) was added a solution of di-tert-butyl dicarbonate (3.52 g, 16 mmol) in THF (20 ml) over 1 h. The mixture was stirred at RT for another 2 h and then concentrated. The residue was chromatographed over silica gel, eluting with a solvent gradient starting with 5% EtOAc in hexanes progressing to 20% EtOAc in hexanes to give 3.69 g (76%) of product 9a as a colorless oil. MS calcd for C18H25ClN2O2oH+ m/z=337.17, observed m/z=337 (M+1)+.

[0078] The following compound was prepared by an analogous procedure:

[0079] MS calcd for C19H25F3N2O2oH+ m/z=371.19, observed m/z=371 (M+1)+

[0080] Step G:

[0081] A suspension of Pd2(dba)3 (275 mg, 0.3 mmol) and DPPB (256 mg, 0.6 mmol) in THF (3 ml) under N2 was stirred at RT for 30 min. The above catalyst was added slowly to a stirred solution of compound 9a and thiosalicylic acid in THF (35 ml). The mixture was stirred at RT for another 2 h and then concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a solvent gradient starting with 20% EtOAc in hexanes progressing to 66% EtOAc in hexanes containing 1% CH3OH to give 1.15 g (73%) of product 10a as a pale yellow solid and 0.15 g of starting material 9a (8%). MS calcd for C15H21ClN2O2oH+ m/z=297.14, observed m/z=297 (M+1)+.

[0082] The following compound was prepared by an analogous procedure:

[0083] MS calcd for C16H21F3N2O2oH+ m/z=331.16, observed m/z=331 (M+1)+

[0084] Step H:

[0085] See Example 1.

[0086] Step I:

[0087] See Example 2.

[0088] Step J:

[0089] See Example 3.

[0090] Step K:

[0091] To 1-diphenylmethyl-3-hydroxyazetidine (2.00 g, 7.26 mmol), 16, in CH2Cl2 (35 ml) was added diisopropylethylamine (7.6 ml, 44 mmol). The solution was cooled to 0° C. and sulfurtrioxide-pyridine (3.47 g, 21.8 mmol) in DMSO (6 ml) was slowly added. The solution was stirred overnight while the cold bath expired. The solution was partitioned between Et2O (100 ml) and brine (50 ml). The aqueous layer was extracted with Et2O (2×50 ml). The combined Et2O layers were washed with half-saturated brine (100 ml), dried overNa2SO4, and concentrated in vacuo. The residue was chromatographed over 60 g SiO2, eluting with a solvent gradient starting with 2% EtOAc in hexanes, progressing to 10% EtOAc in hexanes. Concentration of the appropriate fractions yielded 1.24 g (72%) of the desired ketone, 17, as a white solid:

EXAMPLE 1

[0092]

[0093] A suspension of compound 10a (20 mg, 0.067 mmol), 4,4′-difluorobenzhydryl chloride (50 mg, 0.21 mmol), Nal (10 mg, 0.067 mmol) and Et3N (20 mg, 0.2 mmol) in CH3CN (2 ml) was stirred at 50° C. for 14 h. The solvent was removed in vacuo, the residue was suspended in TFA (2 ml) and CH2Cl2 (2 ml). The mixture was stirred at RT for 2 h and concentrated. The residue was purified by preparative TLC, eluting with 33% EtOAc in hexanes containing 1% CH3OH to give 12.4 mg (46% in two steps) of product 1a, which was treated with HCl in ether to generate the dihydrochloric acid salt. MS calcd for C23H21ClF2N2oH+ m/z=399.14, observed m/z=399 (M+1)+.

[0094] Enantiomers were resolved using chiral chromatography over either Chiralcel OD or OJ columns on either the free amine or their N-Boc derivatives and appear in the tables with the notations, E1 or E2.

[0095] The following compounds were prepared by an analogous procedure:

Ex.R1R6Analytical Data1b

3-ClMS calcd for C23H21Cl3N2oH+ m/z = 431.08 observed m/z = 431 (M + 1)+1c

3-ClMS calcd for C23H21Br2ClN2oH+ m/z = 518.98 observed m/z = 519.0, 520.9, 521.9 (M + 1)+1d

3-ClMS calcd for C25H27ClN2oH+ m/z = 391.19 observed m/z = 391 (M + 1)+1e

3-ClMS calcd for C23H21ClF2N2oH+ m/z = 399.14 observed m/z = 399 (M + 1)+1f

3-ClMS calcd for C23H21Cl3N2oH+ m/z = 431.08 observed m/z = 431 (M + 1)+1g

3-ClMS calcd for C25H21ClF6N2oH+ m/z = 499.14 observed m/z = 499 (M + 1)+1h

3-ClMS calcd for C22H22ClN3oH+ m/z = 364.16 observed m/z = 364 (M + 1)+1h diast 1-E1

3-ClMS calcd for C22H22ClN3oH+ m/z = 364.16 observed m/z = 364 (M + 1)+1h diast. 1-E2

3-ClMS calcd for C22H22ClN3oH+ m/z = 364.16 observed m/z = 364 (M + 1)+1i diast. 2

3-ClMS calcd for C22H22ClN3oH+ m/z = 364.16 observed m/z = 364 (M + 1)+1i diast. 2-E1

3-ClMS calcd for C22H22ClN3oH+ m/z = 364.16 observed m/z = 364 (M + 1)+1i diast. 2-E2

3-ClMS calcd for C22H22ClN3oH+ m/z = 364.16 observed m/z = 364 (M + 1)+1j

3-ClMS calcd for C23H21ClN2oH+ m/z = 361.15 observed m/z = 361 (M + 1)+1k

3-ClMS calcd for C26H27ClF2N2oH+ m/z = 441.19 observed m/z = 441 (M + 1)+1L

3-ClMS calcd for C18H21ClN2oH+ m/z = 301.15 observed m/z = 301 (M + 1)+1m diast. 1

3-ClMS calcd for C19H23ClN2oH+ m/z = 315.16 observed m/z = 315 (M + 1)+1n diast. 2

3-ClMS calcd for C19H23ClN2oH+ m/z = 315.16 observed m/z = 315 (M + 1)+11o diast. 1

3-ClMS calcd for C20H25ClN2oH+ m/z = 329.18 observed m/z = 329 (M + 1)+1p diast. 2

3-ClMS calcd for C20H25ClN2oH+ m/z = 329.18 observed m/z = 329 (M + 1)+1q diast. 1

3-ClMS calcd for C21H27ClN2oH+ m/z = 343.19 observed m/z = 343 (M + 1)+1r diast. 2

3-ClMS calcd for C21H27ClN2oH+ m/z = 343.19 observed m/z = 343 (M + 1)+1s diast. 1

3-ClMS calcd for C22H29ClN2oH+ m/z = 357.20 observed m/z = 357 (M + 1)+1t diast. 2

3-ClMS calcd for C22H29ClN2oH+ m/z = 357.20 observed m/z = 357 (M + 1)+1u diast. 1

3-ClMS calcd for C23H31ClN2oH+ m/z = 371.23 observed m/z = 371 (M + 1)+1v diast. 2

3-ClMS calcd for C23H31ClN2oH+ m/z = 371.23 observed m/z = 371 (M + 1)+1w diast. 1

3-ClMS calcd for C21H26ClFN2oH+ m/z = 361.18 observed m/z = 361 (M + 1)+1x diast. 2

3-ClMS calcd for C21H26ClFN2oH+ m/z = 361.18 observed m/z = 361 (M + 1)+1y diast. 1

3-ClMS calcd for C21H25ClF2N2oH+ m/z = 379.17 observed m/z = 379 (M + 1)+1z diast. 2

3-ClMS calcd for C21H25ClF2N2oH+ m/z = 379.17 observed m/z = 379 (M + 1)+1aa diast. 1

3-ClMS calcd for C20H26ClN3oH+ m/z = 344.19 observed m/z = 344 (M + 1)+1ab diast. 2

3-ClMS calcd for C20H26ClN3oH+ m/z = 344.19 observed m/z = 344 (M + 1)+1ac

3-ClMS calcd for C19H31ClN2oH+ m/z = 323.23 observed m/z = 323 (M + 1)+1ad

3-ClMS calcd for C14H15ClN4oH+ m/z = 275.11 observed m/z = 275 (M + 1)+1ae

3-ClMS calcd for C16H16ClN3O2oH+ m/z = 318.10 observed m/z = 318 (M + 1)+1af

3-CF3MS calcd for C20H17F9N2oH+ m/z = 457.13 observed m/z = 457 (M + 1)+1ag

3-CF3MS calcd for C24H23F3N2oH+ m/z = 397.19 observed m/z = 397 (M + 1)+1ah

3-CF3MS calcd for C24H23F3N2oH+ m/z = 397.19 observed m/z = 397 (M + 1)+1ai

3-CF3MS calcd for C25H21Cl2F3N2OoH+ m/z = 493.11 observed m/z = 493 (M + 1)+1aj

3-CF3MS calcd for C24H23F3N2OoH+ m/z = 413.18 observed m/z = 413 (M + 1)+1ak

3-CF3MS calcd for C19H19F3N2O2oH+ m/z = 365.15 observed m/z = 365 (M + 1)+1al

3-CF3MS calcd for C24H21F3N2oH+ m/z = 395.17 observed m/z = 395 (M + 1)+1am

3-CF3MS calcd for C23H22F3N3oH+ m/z = 398.18 observed m/z = 398 (M + 1)+1an

3-CF3MS calcd for C26H27F3N2oH+ m/z = 425.22 observed m/z = 425 (M + 1)+1ao

3-CF3MS calcd for C23H22F3N3oH+ m/z = 398.18 observed m/z = 398.1 (M + 1)+Example 2

[0096] To a stirred solution of compound 10b (20 mg, 0.061 mmol), 1-naphthaldehyde (11 mg, 0.070 mmol) and acetic acid (0.06 mmol) in CH2Cl2 (1.5 ml) was added sodium triacetoxyborohydride (21 mg, 0.10 mmol). The suspension was stirred at RT for 15 h. TFA (1.5 ml) was added to the solution, and the mixture was stirred at RT for 1 h. It was concentrated and the residue was purified by preparative TLC eluting with 33% EtOAc in hexanes containing 1 % CH3OH to give 9.8 mg of product (Ex. 2a). The free amine was treated with HCl in Et2O to give the dihydrochloric acid salt. MS calcd for C22H21F3N2oH+ m/z=371.17, observed m/z=371 (M+1)+.

[0097] The following compounds were prepared by an analogous procedure:

Ex.R1R6Analytical Data2b

3-CF3MS calcd for C22H21F3N2oH+ m/z = 371.17 observed m/z = 371 (M + 1)+2c

3-CF3MS calcd for C25H23F3N2oH+ m/z = 409.19 observed m/z = 409 (M + 1)+2e

3-CF3MS calcd for C23H28F3N3oH+ m/z = 404.23 observed m/z = 404 (M + 1)+Example 3

[0098] To a vial containing 2a (50 mg, 0.20 mmol) in THF (1 ml) was added 3-chloro-benzylamine (0.22 ml, 0.2 mmol) as a 1M solution in 1,2-dichloroethane. The solution was stirred for 30 min, then sodium triacetoxyborohydride (42 mg, 0.20 mmol) was added. After ˜2 h, the reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated and the residue dissolved in Et2O. To the ethereal solution was added ˜1 ml of 1M HCl in Et2O to give the dihydrochloride salt 3a as a precipitated solid. MS calcd for C24H25ClN2oH+ m/z=377.18, observed m/z=377 (M+1)+.

[0099] The following compounds were prepared by this reductive amination route:

Ex.R7Analytical Data3b

MS calcd for C25H25F3N2oH+m/z = 411 observed m/z = 411 (M + 1)+3c

MS calcd for C27H30N2oH+m/z = 383 observed m/z = 383 (M + 1)+3d

MS calcd for C25H27ClN2oH+m/z = 391 observed m/z = 391 (M + 1 )+3e

MS calcd for C31H32N2oH+m/z = 433 observed m/z = 433 (M + 1)+3f

MS calcd for C32H34N2oH+m/z = 447 observed m/z = 447 (M + 1)+3g

MS calcd for C25H27ClN2oH+m/z = 391 observed m/z = 391 (M + 1)+3h

MS calcd for C24H24ClFN2oH+m/z = 395 observed m/z = 395 (M + 1)+3i

MS calcd for C25H28N2oH+m/z = 357 observed m/z = 357 (M + 1)+3j

MS calcd for C26H30N2OoH+m/z = 387 observed m/z = 387 (M + 1)+3k

MS calcd for C24H25ClN2oH+m/z = 377 observed m/z = 377 (M + 1)+3l

MS calcd for C25H25F3N2oH+m/z = 411 observed m/z = 411 (M + 1)+3m

MS calcd for C26H30N2OoH+m/z = 387 observed m/z = 387 (M + 1)+3n

MS calcd for C26H30N2OoH+m/z = 387 observed m/z = 387 (M + 1)+3o

MS calcd for C24H32N2oH+m/z = 349 observed m/z = 349 (M + 1)+3p

MS calcd for C25H28N2OoH+m/z = 373 observed m/z = 373 (M + 1)+3q

MS calcd for C25H27ClN2oH+m/z = 391 observed m/z = 391 (M + 1)+3r

100

MS calcd for C24H25ClN2oH+m/z = 377 observed m/z = 377 (M + 1)+3sC10H21-nMS calcd for C27H40N2oH+m/z = 393observed m/z = 393 (M + 1)+3t

101

MS calcd for C24H27N3oH+m/z = 357 observed m/z = 357 (M + 1)+3u

102

MS calcd for C24H24Cl2N2oH+m/z = 411 observed m/z = 411, 413 (M + 1)+3v

103

MS calcd for C23H28N4oH+m/z = 361 observed m/z = 361 (M + 1)+3wPhMS calcd for C23H24N2oH+m/z = 329observed m/z = 329 (M + 1)+3x

104

MS calcd for C25H27ClN2oH+m/z = 391 observed m/z = 391 (M + 1)+3y

105

MS calcd for C22H24N2OoH+m/z = 333 observed m/z = 333 (M + 1)+3zPh(CH2)4MS calcd for C27H32N2oH+m/z = 385observed m/z = 385 (M + 1)+3aa

106

MS calcd for C24H33N3oH+m/z = 364 observed m/z = 364 (M + 1)+3ab

107

MS calcd for C21H28N2OoH+m/z = 325 observed m/z = 325 (M + 1)+3ac

108

MS calcd for C23H25N3oH+m/z = 344 observed m/z = 344 (M + 1)+3ad

109

MS calcd for C23H25N3oH+m/z = 344 observed m/z = 344 (M + 1)+3ae

110

MS calcd for C30H30N2oH+m/z = 419 observed m/z = 419 (M + 1)+3af

111

MS calcd for C24H31N3OoH+m/z = 378 observed m/z = 378 (M + 1)+3ag

112

MS calcd for C29H35N3oH+m/z = 426 observed m/z = 426 (M + 1)+3ah

113

MS calcd for C25H26N2O2oH+m/z = 387 observed m/z = 387 (M + 1)+3ai

114

MS calcd for C25H25F3N2oH+m/z = 411 observed m/z = 411 (M + 1)+3aj

115

MS calcd for C25H28N2OoH+m/z = 373 observed m/z = 373 (M + 1)+3ak

116

MS calcd for C23H25N3oH+m/z = 344 observed m/z = 344 (M + 1)+

[0100] The following secondary amines were prepared by this reductive amination route:

117

Ex.—NR7R8Analytical Data3al

118

MS calcd for C29H34N2oH+m/z = 411 observed m/z = 411 (M + 1)+3am

119

MS calcd for C34H35F2N3oH+m/z = 524 observed m/z 524 (M + 1)+3an

120

MS calcd for C27H37N3oH+m/z = 404 observed m/z = 404 (M + 1)+3ao

121

MS calcd for C28H33N3oH+m/z = 412 observed m/z = 412 (M + 1)+

EXAMPLE 4

[0101] The following azetidines were prepared by the reductive amination route of Example 3, starting with 1-benzhydryl-3-azetidinone:

122

Ex.R7Analytical Data4a

123

MS calcd for C26H28N2oH+m/z = 369 observed m/z = 369 (M + 1)+4b

124

MS calcd for C24H25ClN2oH+m/z = 377 observed m/z = 377 (M + 1)+4c

125

MS calcd for C23H23ClN2oH+m/z = 363 observed m/z = 363 (M + 1)+4d

126

MS calcd for C23H24N2oH+m/z = 329 observed m/z = 329 (M + 1)+4e

127

MS calcd for C23H23ClN2oH+m/z = 363 observed m/z = 363 (M + 1)+4f

128

MS calcd for C25H28N2OoH+m/z = 373 observed m/z = 373 (M + 1)+4g

129

MS calcd for C24H26N2oH+m/z = 343 observed m/z = 343 (M + 1)+4h

130

MS calcd for C25H28N2OoH+m/z = 373 observed m/z = 373 (M + 1)+4i

131

MS calcd for C24H23F3N2oH+m/z = 397 observed m/z = 397 (M + 1)+4j

132

MS calcd for C23H23ClN2oH+m/z = 363 observed m/z = 363 (M + 1)+4k

133

MS calcd for C24H25ClN2oH+m/z = 377 observed m/z = 377 (M + 1)+4lPh(CH2)4MS calcd for C26H30N2oH+m/z = 371observed m/z = 371 (M + 1)+4m

134

MS calcd for C23H22ClFN2oH+m/z = 381 observed m/z = 381 (M + 1)+4n

135

MS calcd for C24H25ClN2oH+m/z = 377 observed m/z = 377 (M + 1)+4o

136

MS calcd for C31H32N2oH+m/z = 433 observed m/z = 433 (M + 1)+4p

137

MS calcd for C23H22Cl2N2oH+m/z = 397 observed m/z = 397 (M + 1)+4q

138

MS calcd for C23H30N2oH+m/z = 335 observed m/z = 335 (M + 1)+4rC10H21-nMS calcd for C26H38N2oH+m/z = 379observed m/z = 379 (M + 1)+4s

139

MS calcd for C24H24N2O2oH+m/z = 373 observed m/z = 373 (M + 1)+4t

140

MS calcd for C21H22N2OoH+m/z = 319 observed m/z = 319 (M + 1)+4u

141

MS calcd for C24H23F3N2oH+m/z = 397 observed m/z = 397 (M + 1)+4v

142

MS calcd for C24H25ClN2oH+m/z = 377 observed m/z = 377 (M + 1)+4w

143

MS calcd for C24H26N2OoH+m/z = 359 observed m/z = 359 (M + 1)+4x

144

MS calcd for C27H26N2oH+m/z = 379 observed m/z = 379 (M + 1)+4y

145

MS calcd for C24H26N2OoH+m/z = 359 observed m/z = 359 (M + 1)+4z

146

MS calcd for C30H30N2oH+m/z = 419 observed m/z = 419 (M + 1)+4aa

147

MS calcd for C24H23F3N2oH+m/z = 397 observed m/z = 397 (M + 1)+4ab

148

MS calcd for C29H28N2oH+m/z = 405 observed m/z = 405 (M + 1)+4ac

149

MS calcd for C22H23N3oH+m/z = 330 observed m/z = 330 (M + 1)+4ad

150

MS calcd for C20H26N2OoH+m/z = 311 observed m/z = 311 (M + 1)+4ae

151

MS calcd for C25H28N2OoH+m/z = 373 observed m/z = 373 (M + 1)+

[0102] In a similar manner, the following secondary amines were prepared:

152

Ex.—NR7R8Analytical Data4af

153

MS calcd for C26H35N3oH+ m/z = 390 observed m/z = 390 (M + 1)+4ag

154

MS calcd for C28H32N2oH+ m/z = 397 observed m/z = 397 (M + 1)+4ah

155

MS calcd for C27H31N3oH+ m/z = 398 observed m/z = 398 (M + 1)+4ai

156

MS calcd for C33H33F2N3oH+ m/z = 510 observed m/z = 510 (M + 1)+

EXAMPLE 5

[0103] The following diazetidines were prepared by the reductive amination route of Example 3:

157

Ex.R7Analytical Data5a

158

MS calcd for C42H43N3oH+ m/z = 590 observed m/z = 590 (M + 1)+5b

159

MS calcd for C38H41N5oH+ m/z = 568 observed m/z = 568 (M + 1)+5c

160

MS calcd for C43H41N3oH+ m/z = 600 observed m/z = 600 (M + 1)+5d

161

MS calcd for C40H38F3N3oH+ m/z = 618 observed m/z = 618 (M + 1)+5e

162

MS calcd for C38H38N4oH+ m/z = 551 observed m/z = 551 (M + 1)+5f

163

MS calcd for C38H38N4oH+ m/z = 551 observed m/z = 551 (M + 1)+5g

164

MS calcd for C39H44N4OoH+ m/z = 585 observed m/z = 585 (M + 1)+5h

165

MS calcd for C40H39N3O2oH+ m/z =594 observed m/z = 594 (M + 1)+5i

166

MS calcd for C36H41N3OoH+ m/z = 532 observed m/z = 532 (M + 1)+5j

167

MS calcd for C40H41N3oH+ m/z = 564 observed m/z = 564 (M + 1)+5k

168

MS calcd for C46H45N3oH+ m/z = 640 observed m/z = 640 (M + 1)+5lC10H21-nMS calcd for C42H53N3oH+ m/z = 600observed m/z = 600 (M + 1)+5m

169

MS calcd for C40H40ClN3oH+ m/z =598 observed m/z = 598 (M + 1)+5n

170

MS calcd for C40H41N3OoH+ m/z = 580 observed m/z = 580 (M + 1)+

[0104] Biological Activity of the Compounds

[0105] Nociceptin Binding Assay:

[0106] CHO cell membrane preparation expressing the ORL-1 receptor (2 mg) was incubated with varying concentrations of [I125][Tyr14]nociceptin (3-500 pM) in a buffer containing 50 mM HEPES (pH7.4), 10 mM NaCl, 1 mM MgCl2, 1 mg/ml bovine serum albumin and 0.025% bacitacin. In a number of studies, assays were carried out in buffer 50 mM tris-HCl (pH7.4), 1 mg/ml bovine serum albumin and 0.025% bacitracin. Samples were incubated for 1 h at room temperature (22° C.). Radiolabelled ligand bound to the membrane was harvested over GF/B filters presoaked with 0.1% polyethyleneimine using a Brandell cell harvester and washed five times with 5 ml cold distilled water. Nonspecific binding was determined in parallel by similar assays performed in the presence of 1 μM nociceptin. All assay points were performed in duplicates of total and nonspecific binding. Calculations of Ki were made using methods well known in the art.

[0107] For compounds of this invention, Ki values were determined to be in the range of about 0.009 to about 50 μM, with compounds having a Ki value in the range of about 0.009 to about 0.500 μM being preferred.

[0108] Agonist Activity

[0109] Using the procedures described the European Journal of Pharmacology, 336 (1997), p. 233-242, the agonist activity of compounds of the invention are determined.

[0110] Cough Studies

[0111] The effect of compounds of formula I are evaluated in capsaicin-induced cough in the guinea pig according to the methods of Bolser et al. British Journal of Pharmacology (1995) 114, 735-738. This model is a widely used method to evaluate the activity of potential antitussive drugs. Overnight fasted male Hartley guinea pigs (350-450 g, Charles River, Bloomington, Mass., USA) are placed in a 12″×14″ transparent chamber. The animals are exposed to aerosolized capsaicin (300 μM, for 4 min) produced by a jet nebulizer (Puritan Bennett, Lenexa, Kans., USA) to elicit the cough reflex. Each guinea pig is exposed only once to capsaicin. The number of coughs are detected by a microphone placed in the chamber and verified by a trained observer. The signal from the microphone is relayed to a polygraph which provides a record of the number of coughs. Either vehicle (methylcellulose 1 ml/kg, p.o.) or test compound is given 2 hours before aerosolized capsaicin. The antitussive activity of baclofen (3 mg/kg, p.o.) is also tested as a positive control.

[0112] Respiratory Measurements

[0113] Studies are performed on male Hartley guinea pigs ranging in weight from 450 to 550 g. The animals are fasted overnight but given water and libitum. The guinea pigs are placed in a whole-body, head-out plethysmograph and a rubber collar is placed over the animal's head to provide an airtight seal between the guinea pig and the plethysmograph. Airflow is measured as a differential pressure across a wire mesh screen which covered a 1-in hole in the wall of the plethysmograph. The airflow signal is integrated to a signal proportional to volume using a preamplifier circuit and a pulmonary function computer (Buxco Electronics, Sharon, Conn., model XA). A head chamber is attached to the plethysmograph and air from a compressed gas source (21% O2, balance N2) is circulated through the head chamber for the duration of study. All respiratory measurements are made while the guinea pigs breathe this circulating air.

[0114] The volume signal from each animal is fed into a data acquisition/analysis system (Buxco Electronics, model XA) that calculates tidal volume and respiratory rate on a breath-by-breath basis. These signals are visually displayed on a monitor. Tidal volume and respiratory rate are recorded as an average value every minute.

[0115] The guinea pigs are allowed to equilibrate in the plethysmograph for 30 min. Baseline measurements are obtained at the end of this 30 min period. The guinea pigs are then removed from the plethysmograph and orally dosed with test compound (e.g., 10 mg/kg, p.o.), baclofen (3 mg/kg, p.o.) or a methylcellulose vehicle placebo (2 ml/kg, p.o.). Immediately after dosing, the guinea pigs are placed into the plethysmograph, the head chamber and circulating air are reconnected and respiratory variables are measured at 30, 60, 90 and 120 min post treatment. This study is performed under ACUC protocol #960103.

[0116] Data Analysis

[0117] The data for tidal volume (VT), respiratory rate (f) and minute volume (MV=VT X f) are made for the baseline condition and at each time point after the drug or vehicle. The results are expressed as the mean ±SEM.

[0118] One to three compounds of formula I can be administered in the method of this invention, preferably one.

[0119] For mammals treated for coughing, the nociceptin receptor ORL-1 agonists of formula I may be administered along with one or more additional agents for treating cough, allergy or asthma symptoms selected from antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, R-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists. One to three additional agents can be combined with a compound of formula I, preferably one or two, more preferably one.

[0120] Non limitative examples of antihistamines include: astemizole, azatadine, azelastine, acrivastine, brompheniramine, certirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine (also known as SCH-34117), doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, equitazine, mianserin, noberastine, meclizine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

[0121] Non-limitative examples of histamine H3 receptor antagonists include: thioperamide, impromidine, burimamide, clobenpropit, impentamine, mifetidine, S-sopromidine, R-sopromidine, SKF-91486, GR-175737, GT-2016, UCL-1199 and clozapine. Other compounds can readily be evaluated to determine activity at H3 receptors by known methods, including the guinea pig brain membrane assay and the guinea pig neuronal ileum contraction assay, both of which are described in U.S. Pat. No. 5,352,707. Another useful assay utilizes rat brain membranes and is described by West et al., “Identification of Two-H3-Histamine Receptor Subtypes,” Molecular Pharmacology, Vol. 38, pages 610-613 (1990).

[0122] The term “leukotriene inhibitor” includes any agent or compound that inhibits, restrains, retards or otherwise interacts with the action or activity of leukotrienes. Non-limitative examples of leukotriene inhibitors include montelukast [R-(E)]-1[[[1-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]-methyl]cyclopropaneacetic acid and its sodium salt, described in EP 0 480 717; 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)-phenyl)thio)methylcyclopropaneacetic acid, and its sodium salt, described in WO 97/28797 and U.S. Pat. No. 5,270,324; 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1 -hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid, and its sodium salt, described in WO 97/28797 and U.S. Pat. No. 5,472,964; praniukast, N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-p-(4-phenylbutoxy)benzamide) described in WO 97/28797 and EP 173,516; zafirlukast, (cyclopentyl-3-[2-methoxy-4-[(o-tolylsulfonyl)carbamoyl]benzyl]-1-methylindole-5-carbamate) described in WO 97/28797 and EP 199,543; and [2-[[2(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid, described in U.S. Pat. No. 5,296,495 and Japanese patent JP08325265 A.

[0123] The term “5-lipoxygenase inhibitor” or “5-LO inhibitor” includes any agent or compound that inhibits, restrains, retards or otherwise interacts with the enzymatic action of 5-lipoxygenase. Non-limitative examples of 5-lipoxygenase inhibitors include zileuton, docebenone, piripost, ICI-D2318, and ABT 761.

[0124] Non-limitative examples of β-adrenergic receptor agonists include: albuterol, bitolterol, isoetharine, mataproterenol, perbuterol, salmeterol, terbutaline, isoproterenol, ephedrine and epinephrine.

[0125] A non-limitative example of a xanthine derivative is theophylline.

[0126] Non-limitative examples of α-adrenergic receptor agonists include arylalkylamines, (e.g., phenylpropanolamine and pseudephedrine), imidazoles (e.g., naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline), and cycloalkylamines (e.g., propylhexedrine).

[0127] A non-limitative example of a mast cell stabilizer is nedocromil sodium.

[0128] Non-limitative examples of anti-tussive agents include codeine, dextromethorphan, benzonatate, chlophedianol, and noscapine.

[0129] A non-limitative example of an expectorant is guaifenesin.

[0130] Non-limitative examples of NK1, NK2 and NK3 tachykinin receptor antagonists include CP-99,994 and SR 48968.

[0131] Non-limitatve examples of GABAB agonists include baclofen and 3-aminopropyl-phosphinic acid.

[0132] For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 70 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

[0133] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0134] Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.

[0135] Liquid form preparations may also include solutions for intranasal administration.

[0136] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.

[0137] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

[0138] The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

[0139] Preferably the compound is administered orally.

[0140] Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0141] The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg. to 300 mg, according to the particular application.

[0142] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0143] The amount and frequency of administration of the compounds of the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended dosage regimen is oral administration of from 10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four divided doses to provide relief from pain, anxiety, depression, asthma or alcohol abuse. The compounds are non-toxic when administered within this dosage range.

[0144] For treating cough, the amount of nociceptin receptor ORL-1 agonist in a unit dose is preferably from about 0.1 mg to 1000 mg, more preferably, from about 1 mg to 300 mg. A typical recommended dosage regimen is oral administration of from 1 mg to 2000 mg/day, preferably 1 to 1000 mg/day, in two to four divided doses. When treating coughing, the nociceptin receptor ORL-1 agonist may be administered with one or more additional agents for treating cough, allergy or asthma symptoms selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABAB agonists. The nociceptin receptor ORL-1 agonist and the additional agents are preferably administered in a combined dosage form (e.g., a single tablet), although they can be administered separately. The additional agents are administered in amounts effective to provide relief from cough, allergy or asthma symptoms, preferably from about 0.1 mg to 1000 mg, more preferably from about 1 mg to 300 mg per unit dose. A typical recommended dosage regimen of the additional agent is from 1 mg to 2000 mg/day, preferably 1 to 1000 mg/day, in two to four divided doses.

[0145] The following are examples of pharmaceutical dosage forms which contain a compound of the invention. The scope of the invention in its pharmaceutical composition aspect is not to be limited by the examples provided.

Pharmaceutical Dosage Form Examples

EXAMPLE A

Tablets

[0146]

16

No.
Ingredients
mg/tablet
mg/tablet

1.
Active compound
100
500

2.
Lactose USP
122
113

3.
Corn Starch, Food Grade, as a
30
40

10% paste in Purified Water

4.
Corn Starch, Food Grade
45
40

5.
Magnesium Stearate
3
7

Total
300
700

[0147] Method of Manufacture

[0148] Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., ¼″, 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weigh on a suitable tablet machine.

EXAMPLE B

Capsules

[0149]

17

No.
Ingredient
mg/capsule
mg/capsule

1.
Active compound
100
500

2.
Lactose USP
106
123

3.
Corn Starch, Food Grade
40
70

4.
Magnesium Stearate NF
7
7

Total
253
700

[0150] Method of Manufacture

[0151] Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.

[0152] While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Azetidinyl diamines useful as ligands of the nociceptin receptor ORL-1

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