Ethers of O-Desmethyl venlafaxine

Abstract

This invention provides O-&agr;-acyloxyalkyl ethers of the venlafaxine metabolite 4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, represented by Formula (I): 1

Description

FIELD OF THE INVENTION

[0001] This invention provides O-&agr;-acyloxyalkyl ethers of 4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, as well as pharmaceutical compositions and uses thereof.

BACKGROUND OF THE INVENTION

[0002] Various patents and literature references describe the biological activities of venlafaxine, and its salts and analogs. Venlafaxine hydrochloride tablets are marketed by Wyeth-Ayerst Laboratories as EFFEXOR.

[0003] The absolute configuration of the (+) enantiomer of venlafaxine was established as S by a single crystal X-ray analysis of the hydrobromide salt and the anomalous dispersion technique (Yardley et al., J. Med. Chem., 1990, 33, 2899).

[0004] (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol and its metabolites 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol and 1-[1-(4-methoxyphenyl)-2-(methylamino)ethyl]cyclohexanol are disclosed and claimed in U.S. Pat. No. 4,535,186 (Husbands et al.). U.S. Pat. No. 5,530,013 (Husbands et al.) claims the use of venlafaxine in the inducement of cognition enhancement. U.S. Pat. No. 5,506,270 (Upton et al.) claims venlafaxine's use in methods of treating hypothalamic amenorrhea in non-depressed women.

[0005] U.S. Pat. Nos. 5,788,986 (Dodman) and 5,554,383 (Dodman) teaches and claims the use of serotonin reuptake inhibitors in modifying the behavior of dogs.

DETAILED DESCRIPTION OF THE INVENTION

[0006] This invention provides pharmaceutically active O-&agr;-acyloxyalkyl ethers of the venlafaxine metabolite 4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol (“O-Desmethyl venlafaxine” or “ODV”) having the structural formula I 5

[0007] wherein

[0008] the configuration at the steriogenic center (*) may be R, S, or RS (the racemate);

[0009] R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or the moiety: 6

[0010] R2 is selected from H, or C1-C6 alkyl; or,

[0011] R1 and R2 may be concatenated such that 7

[0012]  form a moiety having formula (b): 8

[0013] R3 is selected from H or C1-C6 alkyl; and

[0014] R4 and R5 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 thioalkoxy, —CN, —OH, —CF3, —OCF3, halogen, —NH2, —NO2, or —N(CH3)2, or pharmaceutically acceptable salts or hydrates thereof.

[0015] In some preferred embodiments of the present invention R1 is t-butyl, methoxy, or isobenzofuranone.

[0016] In other preferred embodiments of the invention R2 is C1-C3 alkyl and in still more preferred embodiments of the invention R2 is methyl.

[0017] Specific examples of compounds of Formula I include:

[0018] {4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methyl pivalate;

[0019] 1-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}ethyl propionate; and

[0020] 3-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}-2-benzofuran-1(3H)-one.

[0021] Particularly, this invention provides compounds and/or compositions of both the O-&agr;-acyloxyalkyl R-ether of Formula I and the O-&agr;-acyloxyalkyl S-ether of Formula I, both being substantially free of the other. In addition, the invention provides the O-&agr;-acyloxyalkyl RS-ether of 4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]-phenol of Formula I.

[0022] Substantially free, as used herein means the compound or composition is made up of significantly greater proportion of the desired isomer than of the optical antipode. In a preferred embodiment of the invention, “substantially free” means that the compound or composition is made up of at least about 90% of the desired isomer and about 10% or less of the optical antipode. In still more preferred embodiments of the present invention, the compound or composition is made up of at least about 95% of the desired isomer and about 5% or less of the optical antipode. In yet further embodiments of the present invention the compound or composition is made up of at least about 99% of the desired isomer and about 1% or less of the optical antipode. Preferably the characterized or separated enantiomer will exhibit physical properties of a fully characterized compound, i.e. a uniform melting point and a uniform rotation of plane-polarized light in a polarimeter. Most preferably, the enantiomers will be recrystallized to analytical purity.

[0023] C1-C6 alkyl as used herein, such as in the definition of R1, includes straight, branched chain alkyl groups within the specified range of carbon atoms.

[0024] Halogen, as used herein refers to chlorine, bromine, iodine and fluorine.

[0025] Pharmaceutically acceptable salts refer to salts prepared from pharmaceutically acceptable acids, including inorganic acids and organic acids, such as, but not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, mitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like.

[0026] Compounds of the invention are readily prepared by methods known in the art, for instance, as described by Bodor, et al., J. Org. Chem.(48) 5280-5284 (1983).

[0027] The appropriate R-, S-, or (R/S)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol is reacted with the appropriate O-&agr;-acyloxyalkyl halide (examples: pivaloyloxymethyl chloride, 3-bromophthalide, iodomethyl pivalate) (Scheme Ia) or (acyloxy)benzyl &agr;-halide (Scheme Ib) in an inert solvent (acetonitrile, tetrahydrofuran, dimethylformamide) in the presence of an alkali metal carbonate (sodium or potassium carbonate) or transition metal carbonate (silver carbonate) in accordance with Schemes Ia and Ib. 9 10

[0028] wherein R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or the moiety: 11

[0029] R2 is selected from H, or C1-C6 alkyl;

[0030] or R2 and R3 are concatenated to form a moiety having formula (b);

[0031] R3 is selected from H or C1-C6 alkyl; and

[0032] R4 and R5 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 thioalkoxy, —CN, —OH, —CF3, —OCF3, halogen, —NH2, —NO2, or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms.

[0033] In some preferred embodiments of the invention increased yield may be obtained by reacting the appropriate R-, S-, or (R/S)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol with the appropriate O-&agr;-acyloxyalkyliodide in an inert solvent (acetonitrile, tetrahydrofuran, dimethylformamide) in the presence of alkali metal carbonate such as potassium carbonate, or transition metal carbonate such as silver carbonate. Most preferred is the use of O-&agr;-acyloxyalkyliodide in the presence of silver carbonate at low temperatures in the range of approximately 0-5° C.

[0034] In a minor modification, compounds of formula I wherein R1 and R2 are concatenated to form 12

[0035] and one or both of R4 and R5 are NH2, can be obtained by catalytic reductions, such as with palladium catalysts, from corresponding analogs wherein R4 or R5 are NO2.

[0036] Racemic 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol can be produced as described in Example 26 of U.S. Pat. No. 4,535,186 (Husbands et al.), which is incorporated herein by reference. It will be understood that the enantiomers may be separated from each other by standard resolution techniques known in the art.

[0037] Alternatively, these R and S enantiomers may be obtained by O-demethylation of the separated enantiomers of venlafaxine using either boron tribromide or ethane thiol anion.

[0038] O-&agr;-acyloxyalkyl ethers of Formula I and their pharmaceutically useful salts and hydrates are useful for the biological and pharmacological activities for which venlafaxine and its salts are known in the art. These O-&agr;-acyloxyalkyl ethers may be used in treating or inhibiting central nervous system disorders, including depression, (including but not limited to major depressive disorder, biopolar disorder, and dysthymia), fibromyalgia, anxiety, panic disorder, agoraphobia, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder (including trichotillomania), social anxiety disorder, generalized anxiety disorder, autism, schizophrenia, obesity, anorexia nervosa, bulimia nervosa, Gilles de la Tourette Syndrome, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction (including premature ejaculation), borderline personality disorder, chronic fatigue syndrome, urinary incontinence, pain (including but not limited to migraine, chronic back pain, phantom limb pain, central pain, neuropathic pain such as diabetic neuropathy and postherpetic neuropathy), Raynaud's syndrome, and others. These compounds are also useful in the inducement of cognition enhancement and in regimens for cessation of smoking or other tobacco uses.

[0039] This invention also includes methods of treating, preventing, inhibiting or alleviating each of the maladies listed above in a mammal, preferably in a human, the methods comprising providing a pharmaceutically effective amount of a compound of this invention to the mammal in need thereof.

[0040] “Providing” as used herein with respect to providing a compound or substance covered by the invention, means either directly administering such a compound or substance, or administering a prodrug, derivative or analog which forms an equivalent amount of the compound or substance within the body.

[0041] A pharmaceutically effective dose will include those doses which provide the relief or prevention sought for the malady in question. The compounds of this invention may be provided in the dosages and pharmaceutical formulations known in the art as useful for venlafaxine hydrochloride (such as those doses known for the venlafaxine hydrochloride products marketed by Wyeth-Ayerst Laboratories under the Effexor® trademark). It will be understood that the initial dose, increases therefrom and final daily administration will be determined by a medical professional considering the needs and conditions for each recipient. For instance, a daily dose for an adult human may be from about 75 mg to about 450 mg per day, preferably between about 75 and about 225 mg per day. An initial dose of 75 mg per day may be administered, with increases as determined by a medical professional.

[0042] This invention also includes pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of this invention and one or more pharmaceutically acceptable carriers or excipients. A preferred method of administration includes the use of the present compounds in extended release formulations of the type described in published PCT application WO 99/22724 (Sherman et al.), which is incorporated herein by reference.

[0043] The present invention is exemplified, but not limited by, the following specific examples.

EXAMPLE 1

{4-[2-(Dimethylamino)-1-(1-hydroxy cyclohexyl)ethyl]phenoxy}methyl pivalate

[0044] 13

[0045] 4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol (1 g, 3.79 mmol), chloromethyl pivalate (0.75 g, 5 mmol), anhydrous K2CO3 (0.7 g, 5 mmol) and KI (75 mg, 0.5 mmol) were stirred in acetonitrile (50 mL) and refluxed overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate was dried (MgSO4) and evaporated to give the title compound as a minor component.

[0046] IR (KBr) 1758 cm−1.

[0047] MS(+)FAB[M+H]+378.3 calcd. For C22H35NO4 377.

EXAMPLE 2

{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methyl pivalate

[0048] 14

[0049] To a solution of ODV (2.0 g, 7.6 mmol) and silver carbonate (8.4 g, 30.4 mmol) in acetonitrile (60 mL) at 0° C. was added a solution of iodomethyl pivalate (prepared as described by Bodor, et al., J. Org. Chem. 1983, 48, 5280-5284.) (3.4 g, 14.0 mmol) in acetonitrile (100 mL) dropwise over 4 hr. The reaction mixture was filtered through diatomaceous earth (CELITE, Celite Corporation, Lompoc, Calif.), then absorbed onto a activated magnesium silicate (60-100 mesh) (FLORISIL, U.S. Silica Company), and purified by column chromatography (FLORISIL, ethyl acetate:acetonitrile 9:1) to afford the title compound (0.87 g, 45%, based on 68% conversion) as a yellow tinted semi-solid: 1H NMR (CD3CN) &dgr;0.78-1.0 (m, 2H), 1.19 (s, 9H), 1.15-1.35 (m, 4H), 1.4-1.7 (m, 4H), 2.2 (s, 6H), 2.25 (dd, J=11.2, 4.5 Hz, 1H), 2.94 (dd, J=11.2, 4.5 Hz, 1H), 3.22 (t, J=11.2 Hz, 1H), 5.7 (s, 2H), 6.95 (d, J=8.7 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H); 13C-NMR (CD3CN) &dgr;22.22, 22.44, 26.91, 27.10 (t), 32.83, 38.78 (t), 39.55 (s), 45.71 (q), 52.58, 61.74, 74.45 (d), 86.78 (t), 116.54, 131.48 (d), 136.68, 156.44, 178.05 (s); MS (ESI) m/z 378 (M+H)+; further characterized as the maleate salt. Anal. (C26H39NO8−0.25H2O) Calc: C, 62.69; H, 7.99; N, 2.81; Found: C, 62.68; H, 7.68; N, 2.65.

[0050] The celite cake was taken up in brine and extracted with ethyl acetate. Evaporation of the solvent affords 0.65 g (33%) recovered ODV.

EXAMPLE 3

4-[(1R)-2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenyl pivalate

[0051] 15

[0052] To a solution of ODV (3.0 g, 11.4 mmol) and silver carbonate (12.6 g, 45.6 mmol) in acetonitrile (300 mL) at 0° C. was added a solution of iodomethyl pivalate (prepared as described by Bodor, et al., J. Org. Chem. 1983, 48, 5280-5284.) (6.9 g, 28.5 mmol) in acetonitrile (40 mL) in eight equal portions over 16 hr. The reaction mixture was filtered through diatomaceous earth (CELITE, Celite Corporation, Lompoc, Calif.), then absorbed onto activated magnesium silicate (60-100 mesh) (FLORISIL, U.S. Silica Company) and purified by column chromatography (FLORISIL, ethyl acetate:acetonitrile 9:1) to afford the title compound (1.15 g, 39%, based on 60% conversion) as a white foam: 1H NMR (CD3CN) &dgr;0.78-1.0 (m, 2H), 1.19 (s, 9H), 1.15-1.35 (m, 4H), 1.4-1.7 (m, 4H), 2.2 (s, 6H), 2.25 (dd, J=11.2, 4.5 Hz, 1H), 2.94 (dd, J=11.2, 4.5 Hz, 1H), 3.22 (t, J=11.2 Hz, 1H), 5.7 (s, 2H), 6.95 (d, J=8.7 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H); 13C-NMR (CD3CN) &dgr;22.22, 22.44, 26.91, 27.10 (t), 32.83, 38.78 (t), 39.55 (s), 45.71 (q), 52.58, 61.74, 74.45 (d), 86.78 (t), 116.54, 131.48 (d), 136.68, 156.44, 178.05 (s); [&agr;]20D −5.95° (c 1.00, MeOH); MS (ESI) m/z 378 (M+H)+.

[0053] The CELITE cake was taken up in brine and extracted with ethyl acetate. Evaporation of the solvent affords 1.2 g (40%) recovered ODV.

EXAMPLE 4

4-[(1S)-2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenyl pivalate

[0054] 16

[0055] To a solution of ODV (4.0 g, 15.2 mmol) and silver carbonate (16.8 g, 60.8 mmol) in acetonitrile (400 mL) at 0° C. was added a solution of iodomethyl pivalate (prepared as described by Bodor, et al., J. Org. Chem. 1983, 48, 5280-5284.) (8.3 g, 34.3 mmol) in acetonitrile (150 mL) over a 9 hr period. The reaction mixture was filtered through diatomaceous earth (CELITE, Celite Corporation, Lompoc, Calif.), then absorbed onto activated magnesium silicate (60-100 mesh) (FLORISIL, U.S. Silica Company), and purified by column chromatography (FLORISIL, ethyl acetate:acetonitrile 9:1) to afford the title compound (1.58 g, 48%, based on 57% conversion) as a clear viscous oil: 1H NMR (CD3CN) &dgr;0.78-1.0 (m, 2H), 1.19 (s, 9H), 1.15-1.35 (m, 4H), 1.4-1.7 (m, 4H), 2.2 (s, 6H), 2.25 (dd, J=11.2, 4.5 Hz, 1H), 2.94 (dd, J=11.2, 4.5 Hz, 1H), 3.22 (t, J=11.2 Hz, 1H), 5.7 (s, 2H), 6.95 (d, J=8.7 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H); 13C-NMR (CD3CN) &dgr;22.22, 22.44, 26.91, 27.10 (t), 32.83, 38.78 (t), 39.55 (s), 45.71 (q), 52.58, 61.74, 74.45 (d), 86.78 (t), 116.54, 131.48 (d), 136.68, 156.44, 178.05 (s); [&agr;]20D +7.23° (c 1.00, MeOH); MS (ESI) m/z 378 (M+H)+.

[0056] The CELITE cake was taken up in brine and extracted with ethyl acetate. Evaporation of the solvent affords 1.7 g (43%) recovered ODV.

EXAMPLE 5

{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methyl pivalate Maleate salt

[0057] 17

[0058] To a solution of {4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methyl pivalate (0.032 g, 0.085 mmol) prepared as described in Example 1, in THF (1.0 mL) at RT was added a solution of maleic acid (0.007 g, 0.06 mmol) in THF (1.0 mL). The mixture was warmed and diluted with hexane. The solution was cooled and the resulting crystals filtered off giving the desired maleate salt as a white solid: mp 112-113° C., 1H NMR (DMSO-d6) &dgr;0.9-1.6 (m, 10H), 1.13 (s, 9H), 2.7 (br.s, 6H), 2.97 (m, 1H), 3.55 (m, 2H), 4.59 (br.s, 1H), 5.78 (s, 2H), 6.02 (s, 2H), 7.03 (d, J=8.6 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 8.4 (br.s, 1H); MS (ESI) m/z 378 (M+H)+; (C26H39NO8−0.25H2O) Calc: C, 62.69; H, 7.99; N, 2.81, Found: C, 62.68; H, 7.68; N, 2.65.

Claims

1. A compound of the Formula (I):

18

wherein

the configuration at the steriogenic center (*) may be R, S, or RS (the racemate);

R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or the moiety:

19

R2 is selected from H, or C1-C6 alkyl; or

R1 and R2 may be concatenated such that

20

 form a moiety having formula (b):

21

R3 is selected from H or C1-C6 alkyl; and

R4 and R5 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 thioalkoxy, —CN, —OH, —CF3, —OCF3, halogen, —NH2, —NO2, or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or pharmaceutically acceptable salts or hydrates thereof.

2. A compound of claim 1 wherein R1 is C1-C6 alkyl or C1-C6 alkoxy.

3. A compound of claim 1 wherein R2 is C1-C6 alkyl.

4. A compound of claim 1 wherein R1 and R2 are concatenated such that

22

form a moiety having formula (b):

23

and R4 and R5 are hydrogen.

5. A compound of claim 1 which is {4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methyl pivalate, or a pharmaceutically acceptable salt or hydrate thereof.

6. A compound of claim 1 which is 1-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}ethyl propionate, or a pharmaceutically acceptable salt or hydrate thereof.

24

7. A compound of claim 1 which is 3-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}-2-benzofuran-1(3H)-one, or a pharmaceutically acceptable salt or hydrate thereof.

8. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula I

25

wherein:

the configuration at the steriogenic center (*) may be R, S, or RS;

R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or the moiety:

26

R2 is selected from H, or C1-C6 alkyl; or,

R1 and R2 may be concatenated such that

27

 form a moiety having formula (b):

28

R3 is selected from H or C1-C6 alkyl; and

R4 and R5 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 thioalkoxy, —CN, —OH, —CF3, —OCF3, halogen, —NH2, —NO2, or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or pharmaceutically acceptable salts or hydrates thereof; and a pharmaceutically acceptable carrier or excipient.

9. A method of treating disorders of the central nervous system in a mammal, the method comprising providing to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula I

29

wherein:

the configuration at the steriogenic center (*) may be R, S, or RS;

R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or the moiety:

30

R2 is selected from H, or C1-C6 alkyl; or,

R1 and R2 may be concatenated such that

31

 form a moiety having formula (b):

32

R3 is selected from H or C1-C6 alkyl; and

R4 and R5 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 thioalkoxy, —CN, —OH, —CF3, —OCF3, halogen, —NH2, —NO2, or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or a pharmaceutically acceptable salt or hydrate thereof.

10. The method of claim 9 wherein the central nervous system disorder is depression.

11. The method of claim 9 wherein the central nervous system disorder is generalized anxiety disorder.

12. The method of claim 9 wherein the central nervous system disorder is panic disorder.

13. The method of claim 9 wherein the central nervous system disorder is post traumatic stress disorder.

14. The method of claim 9 wherein the central nervous system disorder is attention deficit disorder, with and without hyperactivity.

15. The method of claim 9 wherein the central nervous system disorder is anxiety.

16. The method of claim 9 wherein the central nervous system disorder is schizophrenia.

17. The method of claim 9 wherein the central nervous system disorder is cocaine and alcohol addiction.

18. The method of claim 9 wherein the central nervous system disorder is premenstrual dysphoric disorder.

19. The method of claim 9 wherein the central nervous system disorder is autism.

20. The method of claim 9 wherein the central nervous system disorder is anorexia nervosa, bulimia nervosa, vasomotor flushing, and chronic fatigue syndrome.

21. The method of claim 9 wherein the central nervous system disorder is urinary incontinence.

22. The method of claim 9 wherein the central nervous system disorder is pain.

23. The method of claim 9 wherein the central nervous system disorder is sexual dysfunction.

24. A method of enhancing cognition in a mammal, the method comprising providing to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula I

33

wherein:

the configuration at the steriogenic center (*) may be R, S, or RS;

R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or the moiety:

34

R2 is selected from H, or C1-C6 alkyl; or,

R1 and R2 may be concatenated such that

35

 form a moiety having formula (b):

36

R3 is selected from H or C1-C6 alkyl; and

R4 and R5 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 thioalkoxy, —CN, —OH, —CF3, —OCF3, halogen, —NH2, —NO2, or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or a pharmaceutically acceptable salt or hydrate thereof.