AU2008200875A1 - Synthesis, methods of using, and compositions of hydroxylated cyclobutylalkylamines - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Sepracor, Inc.

Actual Inventor(s): Thomas P Jerussi, Dr Zhi-Hui Lu, Paul D Rubin, Chrisantha H Senanayake Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: SYNTHESIS, METHODS OF USING, AND COMPOSITIONS OF HYDROXYLATED

CYCLOBUTYLALKYLAMINES

Our Ref 823485 POF Code: 467260/70025 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): 1 B008Q WO (12/46138 PCT/LUSo 1/47433 00 0 SYNTHESIS, METHODS OF USING, AND COMPOSITIONS OF 0 HYDROXYLATED CYCLOBUTYLALKYLAMINES The present application is a divisional application from Australian patent application] t 5 number 2002239572, the entire disclosure of which is incorporated herein by reference.

t 1. FIELD OF THE INVENTION 0 The invention relates, in part, to processes for making, methods of using, and 10 compositions comprising certain cyclobutylalkylarnines, including, but not limited to, 00 hydroxylated sibutramine and hydroxylated metabolites of sibutramine.

2. BACKGROUND OF THE INVENTION Sibutramine, chemically named [N-1-[1-(4-chlorophenyl)cyclobutyl]-3methylbutyl]-N,N-dimethylamine, is a neuronal monoamine reuptake inhibitor which was originally disclosed in U.S. Patent Nos. 4,746,680 and 4,806,570. Sibutramine inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine. See, e.g., Buckett et al., Prog. Neuro-psychopharm. Biol. Psychiat., 12:575-584, 1988; King et al., J. Clin. Pharm., 26:607-611 (1989).

Racemic sibutramine is sold as a hydrochloride monohydrate under the tradename MERIDIA®, and is indicated for the treatment of obesity. Physician's Desk Reference® 1509-1513 5 4 t ed., 2000). The treatment of obesity using racemic sibutramine is Sdisclosed, for example, in U.S. Patent No. 5,436,272.

Sibutramine has been extensively studied, and according to such studies can be used in the treatment of a variety of disorders. Further, U.S. Patent Nos. 4,552,828, 4,746,680, 4,806,570, and 4,929,629 disclose methods of treating depression using racemic sibutramine, and U.S. Patent Nos. 4,871,774 and 4,939,175 disclose methods of treating Parkinson's disease and senile dementia, respectively, using racemic sibutramine. Other uses of sibutramine are disclosed by PCT publications WO 95/20949, WO 95/21615, WO 98/11884, and WO 98/13033. Further, the optically active enantiomers of sibutramine have been considered for development. For example, PCT publications WO 94/00047 and 94/00114 disclose methods of treating depression and related disorders using the (+)-and (-)-enantiomers of sibutramine, respectively.

-IA-

WO (12/46138 PCT/US 1/47433 In humans, sibutramine is rapidly absorbed from the gastrointestinal tract following oral administration and- undergoes an extensive first-pass metabolism. See Jeffrey et al. J.

Chem. Soc., Perlin Trans. 1, 1996, 2583-2589. This metabolism yields the primary metabolites desmethylsibutramine (DMS) and didesmethylsibutramine (DDMS) shown below.

Scheme 1 The sibutramine metabolites desmethylsibutramine and didesmethylsibutramine can each exist as an epimeric pair of R and S enantiomers as shown below: WO 02/46438 W 0 (1/46138PCI/U SII1/47433 00 dzc-IH2 C1 H 3 CN c R-Desmethylsibutrarnine R-Didesmethylsibutrarnine 00 NH N) NH2 CI H 3

C/

00 S.Desmethylsibutramne S-D idesmethylsibutrarnine Scheme 2 It has been reported that the primiary metabolites of sibutrarnine, desmethylsibutramine and didesmethylsibutrarnine, are more potent in vitro noradrenaline and hydroxytryptamiine (5HT; serotonin) reuptake inhibitors than sibutrarnine. Stock, Int'l J Obesity, 21(Supp. 1:S25-S29 (1997); See also Luscorube et al. ANeuropharmacology Vol. 2S, No. 2, 1989, pp. 129-134. It has further been reported, however, that sibutramine and its primary metabolites have negligible affinities for a wide range of neurotransmitter receptors, including serotonergic (5-HT 1 5-FITA, 5-11T, 5-HT, 0 adrenergic, dopaminergic, muscarinic, histaminergic, glutamate, and benzodiazepine receptors. Id.

W The existence of other sibutrarnine metabolites has been. reported in mice. See Jeffrey et al. J Chemi. Soc., Perkin Tr-ans. 1, 1996, 2583-2589. For example, oxidative metabolism reportedly yields two hydroxylated amines; the synthesis of the racernic 7hyciroxyl-amine below has been described. Id.

00

OH

S NH 2 in ct 7-Hydroxyl-didesmethylsibutramine 00 Scheme 3

O

00 Sibutramine has been reported to exhibit a variety of adverse effects. See, e.g., SPhysician's Desk Reference® 1509-1513 5 4 th ed., 2000). Coupled with the reported benefits and therapeutic insufficiencies of sibutramine, this face has encourage the discovery of compounds and compositions that can be used in the treatment or prevention of disorders such as, but not limited to, obesity, depressions, and related disorders. In particular, compounds and compositions are desired that can be used for the treatment and prevention of such and other disorders and conditions while incurring fewer or avoiding adverse side-effects associated with sibutramine administration.

Throughout the description and the claims of this specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps.

The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

3. SUMMARY OF THE INVENTION This invention encompasses novel compounds (including stereomerically pure isomers) and pharmaceutical compositions for the treatment and prevent of diseases and/or disorders that are ameliorated by the inhibition of neuronal monoamine uptake in mammals.

Examples of such diseases and/or disorders include, but are not limited to, eating disorders, weight gain, or obesity; irritable bowel syndrome; obsessive-compulsive disorders; platelet adhesion; apnea; affective disorders ADHD), depression, or anxiety; male or female sexual function disorders, such a erectile dysfunction; restless leg syndrome; osteoarthritis; -4- 00 substance abuse including, nicotine addition from cigarette smoking or chewing tobacco, and 0 Scocaine addiction; narcolepsy; pain, neuropathic pain, diabetic neuropathy, chronic pain; migraines; cerebral function disorders; chronic disorders; premenstrual syndrome; and Sincontinence. The invention also encompasses method of treating and precenting diseases and V) 5 conditions, which comprise administering to a patient tn 00 00

(N

-4A- WO (12/46138 PCT/USo 1/47433 in need of such treatment or prevention a therapeutically or prophylactically effective 00 amount of a sibutramine-based compound.

CThe sibutramine-based compounds of the invention include, but are not limited to, racemates, other mixtures, and stereomerically pure compounds. The invention is also directed to pharmaceutical compositions and dosage forms that comprise therapeutically or prophylactically effective amounts of the compounds, optionally in combination with an additional phannacologically active compound. Further, the invention includes pharmaceutically acceptable solvates, including hydrates; anhydrous compounds; and 00 Oclathrates. Yet further, the invention includes pharmaceutically acceptable salts of these C 10 solvates, hydrates, anhydrous compounds and the like. Finally, the invention includes esters 00 Sand prodrugs of compounds of the invention. The universe of compounds encompassed by Sthe invention may be referred to herein as "compounds of the invention." The invention further encompasses methods of synthesizing hydroxylated sibutramine-based compounds, as well as, intermediates and isomers and mixtures thereof, including racemates and stereomerically pure compounds.

In a preferred embodiment, the pharmaceutical compositions of the invention comprise a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound, including mixtures thereof, and pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, and prodrugs thereof. In another embodiment, the pharmaceutical compositions of the invention can further comprise other drug substances including, but not limited to, 5-HT 3 antagonists, lipase inhibitors for obesity or weight management, apomorphine, or a phosphodiesterase W inhibitor.

The invention encompasses the use of a racemic or stereomerically pure sibutramine-based compounds, enantiomeric or diastereomeric mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, and prodrugs thereof as effective dopamine, serotonin, and norepinephrine reuptake inhibitors.

More specifically, in one embodiment the invention encompasses novel racemic and stereomerically pure cyclobutylalkylamines as shown below: WO (12/46138 PCT/USO 1/47433 00 R4 R3 C RNR2 tC1 00 wherein R, and R, are indpendendently a hydrogen or an alkyl group and R 3

R

4 and R, are 00 independently a hydrogen, a hydroxyl group, or an alkoxyl group and at least one of R 3

R,

and R, is a hydroxyl group or a alkoxyl group with maximum of three hydroxyl or alkoxyl groups.

As used herein and unless otherwise indicated, bonds drawn as wavy lines or single lines may represent stereochemistry in a structure or a portion of a structure and if not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

Specific examplesof novel cyclobutylalkylamine compounds encompassed by the invention include, but are not limited to, racemic and stereomerically pure 1-hydroxylated sibutramine, racemic and stereomerically pure 1-hydroxylated desmethylsibutramine, stereomerically pure 1-hydroxylated didesmethylsibutramine (Scheme racemic and stereomerically pure 3-hydroxylated sibutramine, racemic and stereomerically pure 3hydroxylated desmethylsibutramine, racemic and stereomerically pure 3-hydroxylated didesmethylsibutramine (Scheme and racemic and stereomerically pure 7-hydroxylated sibutramine, racenic and stereomerically pure 7-hydroxylated desmethylsibutramine, and stereomerically pure 7-hydroxylated didesmethylsibutramine (Scheme 6).

WO 02/46138 WO (1246138PCT/US(i 1/4 7-33 /4 :3

OH

N4HR

CI

R=H

R=Me y-OH

NHR)

R=H

R=Me Cj'j "I

OH

CI

NHR

R=H

R=Me Cj,

NHR~

R=H

R=Me Scheme 4 Schemie CI CI CI 7

OH

OH

OH

4 NHR "NHR NHIR 21 R-Meor H R4Ae or H R=Me or H (S)-cs (R)-ds (S)-trans Scheme 6

CI

OH

."NHFR

R=Me or H (R)-trans WO (12/4613 PCT/US II147433 Finally, the invention encompasses novel and efficient methods, including 00 asymmetric methods, for synthesizing hydroxylated sibutramine and hydroxylated

O

0 desmethyl- and didesmethyl-sibutramine, including novel compounds.

3.1. DEFINITIONS c, As used herein the terms "sibutramine-based compounds" and "derivatives of cyclobutylalkylamine compounds" are used interchangeably and refer to compounds of the formula: 00 0 (C R1NR2 wherein each of R, and R 2 is independently lower alkyl or hydrogen, and each of R 3

R

4 and

R

5 is independently a hydrogen, hydroxyl, or alkoxy, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, ester, or prodrug thereof. Preferably, at least one of R 3 R4, and R, is not hydrogen. It is also preferred that if Ri, R 2

R

4 and R, are each hydrogen and R 3 is hydroxyl, the compound is not racemic, and if R 2

R

3 and R 4 are each hydrogen and R, is hydroxyl, the compound is not racemic.

q 15 It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. Furthermore, a chemical structure drawn with a wavy line as a bond indicates that the structure shown encompasses all possible stereochemistries at that bond.

As used herein, the term "hydroxylated sibutramine metabolite" refers to a hydroxylated sibutramine-based compounds. Hydroxylated sibutramine metabolites include, but are not limited to, hydroxylated sibutramine-based compounds, wherein the WO (12/46138 PCT/US(I1/47433 hydroxyl is in a position to form a primary, secondary or tertiary hydroxylated sibutraminebased compound. In a particular embodiment, the hydroxylated sibutramine metabolite is a ,1 1 -hydroxyl, 3-hydroxyl, or 7-hydroxyl sibutramine metabolite or a polyhydroxylated sibutramine metabolite as shown herein or mixture thereof. As used herein, the term "hydroxylated sibutramine" refers to sibutramine that is hydroxylated in any position to c onrm a primary, secondary or tertiary hydroxylated sibutramine or polyhydroxylated sibutramine. In a particular embodiment, the hydroxylated sibutramine is 1-hydroxyl, 3hydroxyl, or 7-hydroxyl sibutramine as shown herein.

As used herein and unless otherwise indicated, the term "alkyl" or "alkyl group" 10 includes saturated monovalent linear, branched, substituted, and cyclic hydrocarbon 00 Sradicals, including aryl groups. An alkyl group can include one or more double or triple

C

1 bonds. It is understood that cyclic alkyl groups comprise at least three carbon atoms.

Preferred alkyl groups include, but are not limited to, branched or linear alkyl having from 1 to 6, more preferably from 1 to 4 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, and tertiary butyl.

As used herein and unless otherwise indicated, the term "substituted" as used to describe a compound or chemical moiety means that at least one hydrogen atom of that compound or chemical moiety is replaced with a second chemical moiety. Examples of second chemical moieties include, but are not limited to: halogen atoms chlorine, bromine, and iodine); C 1

-C

6 linear, branched, or cyclic alkyl methyl, ethyl, butyl, tertbutyl, and cyclobutyl); hydroxyl; thiols; carboxylic acids; esters, amides, silanes, nitriles, thioethers, stannanes, and primary, secondary, and tertiary amines -NH 2 -NH(CH3),

S-N(CH

3 2 and cyclic amines). Preferred second chemical moieties are chlorine, hydroxyl, methoxy, amine, thiol, and carboxylic acid.

As used herein and unless otherwise indicated, the term "aryl" includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.

As used herein and unless otherwise indicated, the term "alkoxyl" or "alkoxyl group" refers to the group -OR, wherein O is oxygen and R is an alkyl as described above.

Preferred alkoxyl groups include, but are not limited to, branched or linear alkoxyl groups having from 1 to 6, more preferably from 1 to 4 carbon atoms. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, and tertiary butoxy.

00 0 As used herein and unless otherwise indicated, a composition that is "substantially C free" of a compound means that the composition contains less than about 20% by weight, such compositions will more preferably contain less than about 10% by weight, even more Spreferably less than about 5% by weight, and most preferably less than about 3% by 5 weight of the compound.

As used herein and unless otherwise indicated, the terms "stereomerically pure," and "optically pure" are used interchangeably to mean a composition that comprises one Sstereoisomer of a compound and is substantially free of other stereoisomers of that Scompound. For example, a stereomerically pure composition of a compound having one 00 10 chiral center will be substantially free of the opposition enantiomer of the compound. A Sstereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound. More preferably such a compound will comprise greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and more preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.

For example, in one embodiment the invention encompasses stereomerically pure S-cis-7-hydroxylated desmethylsibutramine, which is substantially free of R-cis-7hydroxylated desmethylsibutramine, S-trans-7-hydroxylated desmethylsibutramine, and Rtrans-7-hydroxylated desmethylsibutramine. Another example of an embodiment the invention encompasses (2R,4R)-1-hydroxylated desmethylsibutramine substantially free from (2S,4R)-1-hydroxylated desmethylsibutramine, (2S,4S)-1-hydroxylated desmethylsibutramine, and (2R,4S)-1-hydroxylated desmethylsibutramine. Still another example of an embodiment the invention encompasses (3R,4R)-3-hydroxylated desmethylsibutramine substantially free from (3S,4R)-3-hydroxylated desmethylsibutramine, (3S,4S)-3-hydroxylated desmethylsibutramine, and (3R,4S)-3hydroxylated desmethylsibutramine. Typical stereomerically pure compounds of the invention are optically active.

\VO (12/46138 PCT/UIS( 1/47433 As used herein and unless otherwise indicated, the term "enantiomerically pure" 00 means a stereomerically pure composition of a compound having one chiral center.

C As used herein, the term "prodrug" means a derivative of an active compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the active compound. Examples of prodrugs include, but are not limited to,

C

r derivatives of hydroxylated didesmethylsibutramine having biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, r- biohydrolyzable carbonates, and biohydrolyzable ureides. As used herein, prodrugs of 00 0 hydroxylated didesmethylsibutramine, for example, do not include hydroxylated N 10 sibutramine or metabolites of sibutramine and do not include sibutramine, 00 Sdesmethylsibutramine, or didesmethylsibutramine.

As used herein, the terms "biohydrolyzable carbamate," "biohydrolyzable carbonate," and "biohydrolyzable ureide" mean a carbamate, carbonate, or ureide, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

As used herein, the term "biohydrolyzable ester" means an ester of a compound that either: 1) does not interfere with the biological activity of the compound but can confer Supon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.

As used herein, the term "biohydrolyzable amide" means an amide of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, 11 WO 02/46138 PCT/USi 1/47433 lower alkyl amides, a-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl OO amides.

As used herein, the tenr "pharmaceutically acceptable salt" refers to a salt prepared Sfrom a phanraceutically acceptable non-toxic inorganic or organic acid. Inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric. Organic acids include, but are not limited to, aliphatic, aromatic, carboxylic, and sulfonic organic acids including, but not limited to, formic, acetic, propionic, succinic, benzoic camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, 00 para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, C 10 salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 00 O pantothenic, benzenesulfonic, stearic, sulfanilic, alginic, and galacturonic acid.

(C

4. DETAILED DESCRIPTION OF THE INVENTION 4.1. COMPOUNDS The invention encompasses sibutramine-based compounds, methods of their synthesis, and methods of their use. A first embodiment of the invention encompasses racemic or stereomerically pure mono, di, and tri-hydroxylated sibutramine compounds as shown below: R4 S RiNR2 wherein each of R, and R 2 is independently lower alkyl or hydrogen, and each of R 3

R

4 and R, is independently hydrogen, hydroxyl, or alkoxy provided that at least one of R 3 R4, and Rs is not hydrogen, and pharmaceutically acceptable salts, solvates, hydrates, clathrate, prodrug thereof. In a specific embodiment, if R2, R4, and R, are each hydrogen and R3 is hydroxyl, the compound is not racemic. In another specific embodiment, ifR R, and

R

4 are each hydrogen and R, is hydroxyl, the compound is not racemic.

-12- WO (12/46 138 PCT/USOI/4 7433 For example, the invention encompasses racemic or stereomerically pure 1, 3, and 7 hydroxylated sibutramine compounds as shown below: 1, 3, AND 7 HfYDROXYrLATED SIBUTRAMINE 00 00 A preferred embodiment of the invention encompasses stereomnerically pure sibutramine-based compounds that are hydroxylated in the I -position as shown below: _4 3 K/ NHRIOH /I N HR OH R=H R=H R=Me9 R=Me9 K NHR K- NHR CI" k OH- C1 OH R=H R=-H R=Me R=Me Scheme 7: 1-Hydr-oxy DDMS and DMS Another embodiment encompasses racermic and stereomnerically pure 3-hydroxylated sibutramine-based compounds as shown below: 13 W1O (12/46138 PCT/US 11/47433 00 C OH 1 4 3

RNR

2

CI

wherein each of R, and R, is independently hydrogen or alkyl or enantiomeric and diastereomeric mixtures of 3-hydroxyl desmethylsibutramine and enantiomeric and 00 O diastereomeric mixtures of 3-hydroxy didesmethylsibutramine, respectively.

0 In a particular embodiment, the invention encompasses stereomerically pure 3- 00 hydroxyl desmethylsibutramine isomers and 3-hydroxyl didesmethylsibutramine isomers as shown below: OH OH OH OH 1 4 -3 "I I

SR

1 NR 2 R 1

NR

2 RNR R 1

NR

2 Cl CI CI C1 Scheme 8: 3-Hydroxy DDMS and DMS wherein each of R, and R 2 is independently hydrogen or alkyl or. enantiomeric and diastereomeric mixtures thereof.

When R, is Me methyl) and R, is hydrogen the compounds include a hydroxylated secondary amine metabolite of sibutramine, 3-hydroxydesmethylsibutramine. When R, and R 2 are both H the compounds include a hydroxylated primary amine metabolite of sibutramine, 3-hydroxy-didesmethylsibutramine.

In another embodiment, the invention relates to racemic and stereomerically pure 7hydroxylated desmethylsibutramine as shown below: -14- WO (12/46138 WO (124613XPCTIUSU 1147433

OH

7 4 kRI 00 00 wherein each of RI and R, is independently hydrogen or alkyl or eniantiomeric and diastereomeric mixtures thereof.

in a particular embodiment, the invention encompasses stereomnerically pure 7hydroxylated sibutram-ine metabolites as shown below: C1 C1 C1

CI

OH

OH

OH

NR

1

R

2 "NRjfR 2 NRjR 2 2 1 (S)-cis (R)-cis (S)-trans(R-rn (R)-trans Scheme 9: 7-Hydroxy DDMS and DMS wherein each of R, and R.

2 is independently hydrogen or alkyl or enantiomeric, and diastereomeric mixtures thereof, whiich includes its cis and trans isomers and imixtures thereof.

The invention also encompasses mixtures of stereoisomers, which include mixtures of diastereomers and mixtures of enantiomers. For example, each mono-hydroxylated compound of the invention 1 -hydroxyl-desmethylsibutrainine) can exist as one of four possible stereoisomers, 1-hydroxyl-desmethylsibutrai-nine can exist as hydroxyl-desmethylsibutramine, -hydroxyl-desmethylsibutramine, 1-hydroxylt5 WO (1246138 PCT/USI01/47433 desmethylsibutramine, (S,R)-l-hydroxyl-desmethylsibutramine, or mixtures thereof. As Ssuch, the invention encompasses stereomerically pure compounds, as defined herein, as well as, any stereomeric mixtures including mixtures of enantiomers or diastereoisomers. For Sexample, mixtures include, but are not limited to, varying amounts of(S,S), orientations and the like. Preferred mixtures are not racemic.

4.2. PHARMACEUTICAL COMPOSITIONS The invention encompasses pharmaceutical compositions and unit dosage forms 00 0 comprising a racemic or stereomerically pure sibutramine-based compound, preferably C1 10 hydroxylated in the 1-position, the 3-position, or the 7-position as described herein, or a 00 Spharmaceutically acceptable salt, solvate, hydrate, ester clathrate, or prodrug thereof.

Stereomerically pure sibutramine-based compounds are most preferred.

The invention also encompasses pharmaceutical compositions and dosage forms which comprise diastereomeric and enantiomeric nixtures of a sibutramine-based compound, and diastereomeric or enantiomeric mixtures of 1-hydroxylated, 3-hydroxylated, and 7-hydroxylated sibutramine-based compounds, respectively.

These pharmaceutical compositions and dosage fonns are particularly useful in the methods described herein. For example, the pharmaceutical compositions and dosage forms of the invention are suitable for oral, mucosal nasal, sublingual, buccal, rectal, and vaginal), parenteral intravenous, intramuscular or subcutaneous), or transdermal administration. In a preferred embodiment, the pharmaceutical compositions and dosage forms comprise a racemic or stereomerically pure sibutramine-based compound, in an Samount from about 0.01 mg to about 500 mg, preferably from about 0.1 mg to about 250 mg, more preferably from about, and even more preferably from about 1 mg to about 100 mg.

Pharmaceutical compositions and dosage fonns of the invention comprise one or more of the sibutramine-based compounds disclosed herein 1-hydroxyl desmethylsibutramine, or a pharmaceutically acceptable prodrug, ester, salt, solvate, hydrate, or clathrate thereof). Pharmaceutical compositions and dosage forms of the F invention typically also comprise one or more pharmaceutically acceptable excipients or diluents. Specific compounds and pharmaceutical compositions can further comprise a -16- WO 0(12/46138 PCT/USOI/47433 second therapeutically or prophylactically active compound as set forth herein in 0 Section 4.4).

Single unit dosage forms of the invention are suitable for oral, mucosal nasal, Ssublingual, vaginal, buccal, or rectal), parenteral subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient.

rC Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; 00 Spatches; aerosols nasal sprays or inhalers); gels; liquid dosage forms suitable for oral CN 10 or mucosal administration to a patient, including suspensions aqueous or non-aqueous 00 0 liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, ,N and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention will typically vary depending on their use. For example, a dosage form used in the acute treatment of disorder may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disorder. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder.

These and other ways in which specific dosage forms encompassed by this invention will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients, such as, 17 WO 02/46138 PCT/US11/47433 hydroxylated desmethyl and didesmethyl-sibutramine and its stereomerically pure 00 enantiomers and diastereomers in particular, can be accelerated by some excipients such as C lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines 1-hydroxyl desmethylsibutramine and its stereomerically pure enantiomers and diastereomers) are particularly susceptible to such accelerated decomposition.

Consequently, this invention encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose or mono- or di-saccharides. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to 00 0 substantially increase the degradation rate of an active ingredient.

10 Lactose-free compositions of the invention can comprise excipients that are well 00 0 known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.

Preferred lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, Jens T.

Carstensen, Drug Stability: Principles Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds.

Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.

18

I

\\WO (12/46138 PCT/US 1/47433 An anhydrous pharmaceutical composition should be prepared and stored such that 0 its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included Sin suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers vials), blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosage forms r- that comprise one or more compounds that reduce the rate by which an active ingredient 00 0 will decompose. Such compounds, which are referred to herein as "stabilizers," include, C 10 but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

00 O Like the amounts and types of excipients, the amounts and specific types of active c ingredients in a dosage forn may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. However, typical dosage forms of the invention comprise a racemic or optically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof in an amount of from about 0.01 mg to about 500 mg, preferably in an amount of from about 0.1 mg to about 250 mg, and more preferably in an amount of from about 1 mg to about 100 mg.

4.2.1. ORAL DOSAGE FORMS Pharmaceutical compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets chewable tablets), caplets, capsules, and liquids flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

Typical oral dosage forms of the invention are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms powders, tablets, capsules, and -19- \WO (2/46138 PICT/USO1/47433 caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, 0 granulating agents, lubricants, binders, fillers, and disintegrating agents.

SBecause of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If S 5 desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage 'I forms can be prepared by any of the methods of pharmacy. In general, phannaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then 00 O shaping the product into the desired presentation if necessary.

N 10 For example, a tablet can be prepared by compression or molding. Compressed 00 Stablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH- 105.

(available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook PA), and mixtures thereof. An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 T and Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, cicium carbonate granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or WO (12/46138 PCT/IS011/47433 filler in pharmaceutical compositions of the invention is typically present in from about O to about 99 weight percent of the pharmaceutical composition or dosage form.

O

SDisintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous enviromnent. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the 0 active ingredients should be used to form solid oral dosage forms of the invention. The O amount of disintegrant used varies based upon the type of formulation, and is readily 00 10 discernible to those of ordinary skill in the art. Typical pharmaceutical compositions Scomprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, guns, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

The magnitude of a prophylactic or therapeutic dose of an active ingredient in the acute or chronic management of a disorder or condition will vary with the severity of the disorder or condition to be treated and the route of administration. The dose, and perhaps -21- ~~iz e WO 02/46138 PCT/US(I1/47433 the dose frequency, will also vary according to age, body weight, response, and the past medical history of the patient. Suitable dosing regimens can be readily selected by those skilled in the art with due consideration of such factors.

The dosage amounts and frequencies provided above are encompassed by the terms "therapeutically effective," "prophylactically effective," and "therapeutically or Sprophylactically effective" as used herein. When used in connection with an amount of a racemic or optically pure sibutramine metabolite, these terms further encompass an amount of racemic or optically pure sibutramine metabolite that induces fewer or less sever adverse 00 Seffects than are associated with the administration of racemic sibutramine. Adverse effects I 10 associated with racemic sibutramine include, but are not limited to, significant increases in 00 Ssupine and standing heart rate, including tachycardia, increased blood pressure S(hypertension), increased psychomotor activity, dry mouth, dental caries, constipation, hypohidrosis, blurred or blurry vision, tension, mydriasis, seizures, formation of gallstones, renal/hepatic dysfunction, fevers, arthritis, agitation, leg cramps, hypertonia, abnormal thinking, bronchitis, dyspnea, pruritus, amblyopia, menstrual disorder, ecchymosis/bleeding disorders, interstitial nephritis, and nervousness. See, Physician's Desk Reference® 1494-1498 (53r d ed., 1999).

4.2.2. DELAYED RELEASE DOSAGE FORMS Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile inm.

varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage 22 WO 02146138 PCT/USO 1/47433 forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, 00 0 and caplets that are adapted for controlled-release.

C1 All controlled-release pharmaceutical products have a common goal of improving Sdrug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a N minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release fonnulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, 00 0 controlled-release formulations can be used to affect the time of onset of action or other 00 10 characteristics, such as blood levels of the drug, and can thus affect the occurrence of side adverse) effects.

C

Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlledrelease of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

4.2.3. PARENTERAL DOSAGE FORMS Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited -23 WO (12/46138 PCT/US 1/47433 to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride SInjection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, C, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl C myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients S- disclosed herein can also be incorporated into the parenteral dosage forms of the invention.

00 N 10 4.2.4. TRANSDERMAL, TOPICAL, 00 AND MUCOSAL DOSAGE FORMS Transdennal, topical, and mucosal dosage forms of the invention include, but are not limited to, ophthahnic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include "reservoir type" or "matrix type" patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.

Suitable excipients carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired.

Examples of such additional ingredients are well known in the art.' See, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 1990).

-24- WO 02/46138 PCT/US 1/47433 Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the Sinvention. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and 00 SSpan 60 (sorbitan monostearate).

00 10 The pH of a pharmaceutical composition or dosage form, or of the tissue to which Sthe pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the fornulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.

4.2.5. KITS Typically, active ingredients of the invention are preferably not administered to a patient at the same time or by the same route of administration. This invention therefore encompasses kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.

A typical kit of the invention comprises a unit dosage form of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof, and a unit dosage form of a second active ingredient. Examples of second active ingredients include, but are not limited to,

HT

3 antagonists, apomorphine, phosphodiesterase inhibitors, and lipase inhibitors for obesity and weight management.

WO (12/46138 PCT/US( 1/47433 Kits of the invention can further comprise devices that are used to administer the 00 0 active ingredients. Examples of such devices include, but are not limited to, syringes, drip CN bags, patches, and inhalers.

Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active c 1 ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable 00 Sfor parenteral administration. Examples of pharmaceutically acceptable vehicles include, C 10 but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited 00 Sto, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

4.3. METHODS OF USE The invention is based, in part, on the discovery that sibutramine-based compounds and racemic and stereomerically pure isomers thereof, can be used for the treatment and prevention of disorders that are ameliorated by the inhibition of neuronal monoamine uptake.

As such, the invention encompasses a method of treating or preventing a disorder and/or disease ameliorated by the inhibition of neuronal monoamine uptake which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of 1-hydroxy, 3-hydroxy, or 7-hydroxy sibutramine compound hydroxylated desmethyl- or didesmethylsibutramine), or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. In a preferred embodiment, the disorder and condition ameliorated by inhibition of neuronal monoamine uptake is an eating disorder, weight gain, or obesity; platelet adhesion; apnea; obsessive-compulsive disorders; affective disorders ADHD), depression, or anxiety; male and female sexual function disorders, such as erectile dysfunction; restless leg syndrome; osteoarthritis; irritable bowel syndrome; substance abuse including, nicotine -26- d i WO 02146138 PCT/US(I1/47433 addiction from cigarette smoking or chewing tobacco, and cocaine addiction; migraines; 0 chronic pain; pain, such as neuropathic pain, such as diabetic neuropathy; cerebral function 0 N disorders; chronic disorders; and incontinence. The patients include manmmals, particularly humans and also includes dogs, cats, and feedstock.

In a preferred embodiment the hydroxyl group is selectively substituted in the 1c position, the 3-position, or the 7-position, to form a compound as illustrated below: 00 OH

OH

7 7 00 4 0 I NRR' C NRR' NRR C1 Cl N OH c1 Cl R and R' H or Me R and R' H or Me R and R' H or Me Scheme 11 The "stereomerically pure" isomers of these compounds can also be synthesized or otherwise isolated and their use in the methods or compositions of the invention is contemplated.

As used herein, the term "treating or preventing disorders ameliorated by inhibition of neuronal monoamine reuptake" means relief from symptoms of conditions associated with abnormal neuronal monoamine levels.

9 Another embodiment of the invention encompasses a method of treating or preventing male or female sexual function disorders, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound, or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. As used herein, the terms "sexual dysfunction" and "sexual function disorder" encompass sexual dysfunction in men and women caused by psychological and/or physiological factors.

Examples of sexual dysfunction include, but are not limited to, sexual arousal disorder, erectile dysfunction, vaginal dryness, lack of sexual excitement, orgasmic disorder, or inability to obtain orgasm. The term "sexual dysfunction" further encompasses psycho- -27- WO 02/46138 PCT/US(1/47433 sexual dysfunction. Examples of psycho-sexual dysfunction include, but are not limited to, 00 0 hypoactive sexual desire disorder, sexual aversion disorders, inhibited sexual desire, C inhibited sexual excitement, inhibited female orgasm, inhibited male orgasm, premature ejaculation, functional dyspareunia, functional vaginismus, and atypical psychosexual dysfunction. In a preferred method of this embodiment, the racemic or stereomerically pure ,I sibutramine-based compound, or pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof is administered orally, transdermally, or mucosally. In a particular embodiment, the sibutramine-based compound is hydroxylated in the i-position, Sthe 3-position, or the 7-position. The treatment or prevention of sexual dysfunction in S 10 elderly or postmenstrual patients is also included. The prevention of sexual dysfunction Sdisorder involves recognition by one of skill in the art of that population at risk of sexual dysfunction disorder. In particular, one of skill in the art will recognize those at risk of sexual dysfunction disorder and in need of prevention to include, but not limited to, individuals suffering from: psychological problems, for example, anxiety over sexual intercourse, guilt after a pleasurable experience, shame, fear of intimacy, depression, ignorance of sexual norms, or fr:. tration; situational factors, for example, marital discord, boredom, or negative emotions; or physical factors.

Another embodiment of the invention encompasses a method of treating or preventing an affective disorder which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound, or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. Affective disorders include, but are not limited to, depression melancholia), attention deficit disorder (including attention deficit disorder with hyperactivity and attention deficit/hyperactivity disorder), bipolar and manic conditions, dysthymic disorder, and cyclothymic disorder. As used herein, the terms "attention deficit disorder" (ADD), "attention deficit disorder with hyperactivity" (ADDH), and "attention deficit/hyperactivity disorder" (AD/HD), are used in accordance with their accepted meanings in the art. See, Diagnostic and Statistical Manual ofMental Disorders, Fourth Ed., American Psychiatric Association, 1997 (DSM-IV T M and Diagnostic and Statistical Manual ofMental Disorders, 3 d Ed., American Psychiatric Association (1981) (DSM-mr

M

28 @2 WO 02/46138 PCT/US 1/47433 A preferred method of this embodiment is a method of treating or preventing 00 0 attention deficit disorder which comprises administering to a patient in need of such N treatment or prevention a therapeutically or prophylactically effective amount of racemic or stereomerically pure sibutramine-based compound, or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. In the treatment or prevention of attention deficit disorder, the sibutramine-based compound is stereomerically pure, and more preferably the stereomerically pure sibutramine-based compound is hydroxylated in the 1-position, the 3-position, or the 7-position. In a particular embodiment, the method can 00 Salso be used to treat or prevent a condition in children ages 3-18). One of skill in the S 10 art will recognize those at risk of attention deficit disorders and in need of prevention of such include, but not limited to, individuals who, for example, fail to maintain close attention, fail to listen, fail to finish tasks, avoid sustained mental effort, are distracted by extraneous stimuli, talk excessively, or interrupts or intrudes on others.

Another preferred method of this embodiment is a method of treating or preventing depression which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. As used herein, the term "treating or preventing depression" means relief from or prevention of the symptoms of depression which include, but are not limited to, changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, and self-deprecation.

Physical changes can also be relieved or prevented by this method, and include, but are not Slimited to, insomnia, anorexia, decreased energy and libido, and abnormal hormonal circadian rhythms. One of skill in the art will recognize those at risk of depression and in need of prevention of such disorder to include, but not limited to, individuals who, for example, appear miserable, with furrowed brows, down-turned comers of the mouth, slumped posture, poor eye contact, and monosyllabic speech. These activities may be accompanied by preoccupation with guilt, self-denigrating ideas, decreased ability to concentrate, indecisiveness, diminished interest in usual activities, social withdrawal, helplessness, hopelessness, recurrent thoughts of death or suicide or combinations thereof.

Another embodiment of the invention encompasses a method of treating or preventing weight gain or obesity which comprises administering to a patient in need of -29- WO (12/46138 PCT/US(I1/47433 such treatment or prevention a therapeutically or prophylactically effective amount of a 00 racemic or stereomerically pure sibutramine-based compound or a pharmaceutically 0 acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. As used herein, the term "treating or preventing weight gain or obesity" means reduction of weight, relief from C 5 being overweight, treating weight gain caused by the administration of other drugs, relief from gaining weight, or relief from obesity, and prevention from gaining weight, all of which are usually due to unnecessary consumption of food. The invention also encompasses methods of treating or preventing conditions incidental to obesity including, 00 0 but not limited to, hypertension, such as pulmonary hypertension; cancers, such as breast, colon, gall bladder, and endometrial; gall stones; cardiovascular disease, such as 00 Sdyslipidemia and carotid intimal medial thickening; hiatial hernia; osteoarthritis; gout; Sthyroid disease, such as diabetes; gastro-esophogeal reflux disease; menstrual dysfunction; and infertility. In a particular embodiment, the racemic or stereomerically pure sibutraminebased compound or a racemic is hydroxylated in the 1-position, the 3-position, or the 7position. In a particular method of this embodiment, the weight gain is associated with the administration of a drug that induces weight gain. In another method of this embodiment, the weight gain is associated with smoking cessation.

Another embodiment encompasses a method of treating or preventing a disorder associated with the administration of a lipase inhibitor for obesity or weight management, such as, for example, orlistat (XENICAL®), which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof As used herein, the term "treating or preventing a disorder associated with the administration of a lipase inhibitor" means alleviating or reducing adverse effects associated with administration of a lipase inhibitor, which include, but are not limited to, infectious diarrhea, oily fecal spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation, anal leakage, and fecal incontinence.

Another embodiment encompasses a method of treating or preventing cerebral function disorders which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, WO 02/46138 PCT/US01/47433 solvate, hydrate, or clathrate thereof. Cerebral function disorders include, but are not 0 limited to, senile dementia, Alzheimer's type dementia, memory loss, amnesia/anmestic C syndrome, disturbance of consciousness, coma, lowering of attention, speech disorders, Parkinson's disease, Lennox syndrome, autism, epilepsy, hyperkinetic syndrome, and schizophrenia. Cerebral function disorders can be induced by factors including, but not

C

1 limited to, cerebrovascular diseases, such as cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, and head injuries, and conditions having 00 symptoms selected from the group consisting of disturbances of consciousness, senile dementia, coma, lowering of attention, and speech disorders. As used herein, the term 00 10 "treating or preventing a cerebral function disorder" means relief from or prevention of one or more symptoms associated with cerebral function disorders. One of skill in the art will recognize those at risk of cerebral function disorders and in need of prevention of such disorders include, but are not limited to, individuals who, for example, exhibit dementia, memory loss, amnesia/amnestic syndrome, disturbance of consciousness, coma, lowering of attention, speech disorders, autism, epilepsy, hyperkinetic syndrome, and schizophrenia.

Another embodiment encompasses a method of treating or preventing restless leg syndrome, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutrarnine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. As used herein, the term "restless leg syndrome" encompasses a disorder that typically occurs during sleep or rest and is characterized by uncomfortable sensations in the legs, which include, but are not limited to, 9 pulling, drawing, crawling, wormy, boring, tingling, pins and needles, prickly and sometimes painful sensations that are usually accompanied by an overwhelming urge to move the legs. As used herein, the term "restless leg syndrome" also encompasses Ekbom Syndrome, Wittmaack-Ecbom Syndrome, Hereditary Acromelalgia, and Anxieties Tibialis.

Another embodiment encompasses a method of treating or preventing pain which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. In a particular embodiment, the pain is chronic pain, such as neuropathic pain, such as diabetic neuropathy.

WO 02/46138 PCT/US01/47433 Still another embodiment of the invention encompasses a method of treating or 00 preventing obsessive-compulsive disorder which comprises administering to a patient in Sneed of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. One of skill in the art Swill recognize those at risk of or predisposed to obsessive-compulsive disorder and in need of prevention of such disorders include, but are not limited to, individuals who, for example, feel compelled to perform repetitive, purposeful, intentional behaviors called 00 Srituals to balance their obsessions. As used herein, the terms "obsessive-compulsive N 10 disorder," "pre-menstrual syndrome," "anxiety," and "eating disorder" are used consistently 00 O with their accepted meanings in the art. See, DSM-IVTM and DSM-II

T

M. The term N "methods of treating or preventing" when used in connection with these disorders means the amelioration, prevention, or relief from symptoms and/or effects associated with these disorders.

Another embodiment encompasses a method of treating or preventing substance abuse which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. In a particular embodiment, the substance abuse is cocaine addiction or alcohol addiction. As used herein, the term "substance abuse" encompasses the abuse of, and physical and/or psychological addiction to, drugs or alcohol. The term "substance abuse" further encompasses its accepted meaning in the art. See, DSM-

IV

rM and DSM-mTM. A preferred method encompassed by this embodiment is a method of treating or preventing cocaine and/or heroin abuse. One of skill in the art will recognize those at risk of or predisposed to substance abuse and in need of prevention of such include, but are not limited to, individuals who, for example, are frequent users of drugs or alcohol.

Another embodiment encompasses a method of treating or preventing nicotine addiction which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate,-ester, clathrate, prodrug thereof. Nicotine addiction includes nicotine -32 WO (12/46138 PCT/US I/47433 addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, and addiction 00 O to chewing tobacco.

N Another embodiment encompasses a method of eliciting smoking cessation which comprises administering to a patient who smokes tobacco a therapeutically effective amount of a racemic or stereomerically pure sibutramine-based compound or a phannaceutically c acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. In a preferred method encompassed by this embodiment, the racemic or stereomerically pure sibutramine-based compound or pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug 00 8 thereof is administered orally, mucosally, or transdermally. In a more preferred method, it 00 10 is administered transdermally.

Another preferred method encompassed by this embodiment is a method of eliciting smoking cessation which comprises adjunctively administering to a patient who smokes tobacco a therapeutically or prophylactically effective amounts of a racemic or stereomerically pure sibutramine-based compound, or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof, and nicotine. Preferably, the nicotine and/or racemic or stereomerically pure sibutramine-based compound or pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof is administered orally, mucosally, or transdermally. More preferably, it is administered transdermally.

Another method encompassed by this embodiment is a method of treating or preventing weight gain associated with smoking cessation which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a 0 pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof.

Another embodiment encompasses a method of treating or preventing weight gain associated with the administration of other drugs that may induce weight gain, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, ester, clathrate, or prodrug thereof. One of skill in the art will recognize those at risk of or predisposed to weight gain and in need of prevention of such include, but are not limited to, individuals who, for example, are taking a drug or prescribed a drug that may induce weight gain.

-33 WO 02/46138 PCT/USI 1/47433 Another embodiment encompasses a method of treating or preventing a chronic 00 0 disorder including, but not limited to, narcolepsy, chronic fatigue syndrome, seasonal CN affective disorder, fibromyalgia, and premenstrual syndrome (or premenstrual dysphoric Sdisorder), which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. Examples of chronic disorders include, but are not limited to, narcolepsy, chronic fatigue syndrome, seasonal affective disorder, Sfibromyalgia, and premenstrual syndrome (or premenstrual dysphoric disorder), 10 perimenopause, and menopause). Prefen-ed methods are methods of treating or preventing narcolepsy, premenstrual syndrome, or chronic fatigue syndrome. One of skill in the art Swill recognize those at risk of or predisposed to chronic disorders and in need of prevention of such include, but are not limited to, individuals who, for example, have difficulty sleeping, suffer from depression, or irritability.

Another embodiment encompasses a method of treating or preventing anxiety, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. One of skill in the art will recognize those at risk of or predisposed to anxiety and in need of prevention of such include, but are not limited to, individuals who, for example, are under high stress, exhibit sleeplessness or restlessness.

Another embodiment encompasses a method of treating or preventing an eating disorder including, but not limited to, anorexia, bulimia, binging, and snacking, which U comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine or a racemic or stereomerically pure sibutramine-based compound metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof.

Another embodiment encompasses a method of treating or preventing migraines which comprises administering to a patient in need of such. treatment or prevention a therapeutically or prophylactically effective amount of a racemic or stereomerically pure sibutramine-based compound, or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. One of skill in the art will recognize those at risk of or -34- WO (2/46138 PCT/IUS0 1/47433 predisposed to migraines and in need of prevention of such include, but are not limited to, 00 0 individuals who, for example, suffer from depression, irritability, restlessness, or anorexia C1 anmd may be associated with aura transient, reversible, neurologic visual, C) somatosensory, motor, or language deficit).

Another embodiment encompasses a method of treating or preventing incontinence which comprises administering to a patient in need of such treatment or prevention a t therapeutically or prophylactically effective amount of a racemic or stereomerically pure 00 sibutramine-based compound or a pharmaceutically acceptable salt, solvate, ester, clathrate, or prodrug thereof. In particular embodiment, the racemic or stereomerically pure 00 10 sibutiamine-based compound can be used to treat fecal incontinence, stress urinary 0 incontinence urinary exertional incontinence, urge incontinence, reflex Sincontinence, passive incontinence, anal leakage, and overflow incontinence. In a particular embodiment, the method can treat or prevent incontinence in children younger than 18) or in elderly older 50) patients.

As used herein, the term "treating or preventing incontinence" means treatment, prevention of, or relief from the symptoms of incontinence including involuntary voiding of feces or urine, and dribbling or leakage or feces or urine, which may be due to one or more causes including, but not limited to, pathology altering sphincter control, loss of cognitive function, overdistention of the bladder, hyper-reflexia and/or involuntary urethral relaxation, weakness of the muscles associated with the bladder or neurologic abnormalities.

A preferred method encompassed by this embodiment is a method of treating or preventing stress urinary incontinence. In a further preferred method encompassed by this embodiment, the patient is an elder human of an age greater than 50 or a child of an age less than 13. 4.4. COMBINATION THERAPY The invention also encompasses a method of treating or preventing male and female sexual function disorders, such as erectile dysfunction, which comprises adjunctively administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amounts of a racemic and stereomerically pure sibutramine-based compound or pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, and prodrugs thereof in combination with a 5-HT 3 antagonist, a phosphodiesterase inhibitor, or a WO 02/46138 PCT/USo 1/47433 lipase inhibitor for obesity or weight management. Particularly preferred racemic and 00 stereomerically pure sibutramine-based compounds are 1-hydroxyl, 3-hydroxy, or 7-

O

Chydroxy sibutramine-based compounds.

Preferred 5-HT 3 antagonists are antiemetic agents. Examples of suitable 5-HT 3 antagonists include, but are not limited to, granisetron (KYTRL®), metoclopramide ri (REGLAN"), ondansetron (ZOFRAN®), renzapride, zacopride, tropisetron, and stereomerically pure stereoisomers, active metabolites, and pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, or prodrugs thereof.

00 SPhosphodiesterase inhibitors that can be combined with compounds of the invention r 10 are disclosed in U.S. Patent No. 5,250,534; U.S. Patent No. 5,719,283; U.S. Patent No.

6,127,363; WO 94/28902; WO 97/03675; WO 98/06722, each of which are expressly incorporated herein by reference in their entirety. Preferred phosphodiesterase inhibitors are and PDE6 inhibitors. Particular phosphodiesterase inhibitors include, but are not limited to, sildenophil (Viagra®), desmethylsildenophil, vinopocetine, milrinone, amrinone, pimobendan, cilostamide, enoximone, peroximone, vesnarinone, rolipran, R020-1724, zaprinast, and dipyridamole.

The invention also encompasses a method of treating or preventing disorders associated with the administration of a lipase inhibitor for obesity or weight management which comprises adjunctively administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amounts of a racemic and stereomerically pure sibutramine-based compound or pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, and prodrugs thereof in combination with a lipase inhibitor. A preferred lipase inhibitor for obesity or weight management includes, but is not limited to, orlistat (XENICAL). Particularly preferred racemic and stereomerically pure sibutramine-based compound are 1-hydroxyl, 3-hydroxy, or 7-hydroxy sibutramine-based compounds.

In each of the methods of the invention, the racemic or stereomerically pure sibutramine-based compound, or a pharmaceutically acceptable salt, solvate, hydrate, ester'- clathrate, or prodrug thereof, can adjunctively administered with one or more additional pharmacologically active compounds, the sibutramine-based compound and at least one additional pharmacologically active compound are administered as a combination, -36- WO 02/46138 PCTIUSo 1/47433 concurrently but separately, or sequentially by any suitable route orally, transdermally, 00 0 or mucosally).

C In a preferred method of this embodiment, the racemic and stereomerically pure sibutramine-based compound is administered transdemnally, orally, parenterally, or mucosally nasally, sublingually, or buccally). In a more preferred method of this Sembodiment, the racemic and stereomerically pure sibutramine-based compound and the 3 antagonist are both administered orally, transdermally, or mucosally. In another Spreferred method of this embodiment, the racemic and stereomerically pure sibutramine- 00 8 based compound and the phosphodiesterase inhibitor are both administered orally, 00 10 transdermally, or mucosally. In still another preferred method of this embodiment, the Sracemic and stereomerically pure sibutramine-based compound and the lipase inhibitor are S"both administered transdermally, orally, or mucosally.

Disorders that can be alleviated or prevented by adjunctively administering a racemic and stereomerically pure sibutramine-based compound or pharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrug thereof with a lipase inhibitor for weight or obesity management include, but are not limited to, oily fecal spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation, anal leakage, and fecal incontinence.

Another embodiment encompasses a racemic and stereomerically pure sibutraminebased compound and an additional pharmacologically active compound. Preferably the additional pharmacologically active compound is a selective serotonin reuptake inhibitors; agonists and antagonists; phosphodiesterase inhibitors; hypnotics and sedatives; drugs useful in treating psychiatric disorders; CNS stimulants; dopamine receptor agonists; antimonic agents; lipase inhibitors for obesity and weight management; antipanic agents; cardiovascular agents; antivirals; antibiotics; antifungals; or antineoplastics.

In another preferred embodiment, the pharmaceutical compositions and dosage forms comprise an additional pharmacologically active compound. In a preferred embodiment, the additional pharmacologically active compound is a drug that affects the central nervous system is a 5-HT agonists and antagonist; hypnotics and sedatives; drugs useful in treating psychiatric disorders; CNS stimulants; dopamine receptor agonists; antimonic agents; antipanic agents; cardiovascular agents; antivirals; antibiotics; -37- 1 WO (12/46138 PCT/US01/47433 antifungals; or antineoplastics. In a particular embodiment, the 5-HT3 antagonist is an 00 0 antiemetic agent.

Cr In still another preferred embodiment, the phannaceutical compositions and dosage forms comprise a 5-HT 3 antagonist that is granisetron, metoclopramide, ondansetron, renzapride, zacopride, tropisetron, stereomerically pure stereoisomers, active metabolites 'I thereof, and pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, and prodrugs thereof. In a preferred embodiment, the amount of 5-HT 3 antagonist is from about mg to about 500 mg, from about 1 mg to about 350 mg, from about 2 mg to about 250 00 mg.

S 10 In still another preferred embodiment, the pharmaceutical compositions and dosage Sforms comprise a phosphodiesterase inhibitor including, but are not limited to, PDE5 and 4 PDE6 inhibitors, sildenophil (Viagra®), desmethylsildenophil, vinopocetine, milrinone, amrinone, pimobendan, cilostamide, enoximone, peroximone, vesnarinone, rolipram, R020- 1724, zaprinast, and dipyridamole. In a preferred embodiment, the amount of phosphodiesterase inhibitor is from about 0.5 mg to about 500 mg, from about 1 mg to about 350 mg, from about 2 mg to about 250 mg.

Additional pharmacologically active compounds that can be used in the methods and compositions of the invention include, but are not limited to, drugs that act on the central nervous system such as, but not limited to: 5-HT 5-HT 3 and agonists and antagonists; selective serotonin reuptake inhibitors ("SSRIs"); hypnotics and sedatives; drugs useful in treating psychiatric disorders including antipsychotic and neuroleptic drugs, antianxiety drugs, antidepressants, and mood-stabilizers; CNS stimulants such as amphetamines; dopamine receptor agonists; antimonic agents; antipanic agents; cardiovascular agents beta blockers and angiotensin converting enzyme inhibitors); antivirals; antibiotics; antifungals; and antineoplastics.

More specific drugs that act on the CNS include, but are not limited to, SSRIs, benzodiazepine compounds, tricyclic antidepressants, antipsychotic agents, anti-anxiolytic agents, B-adrenergic antagonists, 5-HTIA receptor antagonists, and 5-HT 3 receptor agonists. Even more specific drugs that act on the CNS include, but are not limited to, lorazepam, tomoxetine, olanzapine, respiradone, buspirone, hydroxyzine, and valium.

Selective serotonin reuptake inhibitors are compounds that inhibit the central nervous system uptake of serotonin while having reduced or limited affinity for other -38 WO 02/46138 PCT/US 1/147433 neurologically active receptors. Examples of SSRIs include, but are not limited to, 00 O citalopram (CELEXA'); fluoxetine (PROZAC®) fluvoxamine (LUVOX®); paroxetine

O

N (PAXL®); sertraline (ZOLOFT); venlafaxine (EFFEXOR®); and stereomerically pure Sstereoisomers, active metabolites, and phannaceutically acceptable salts, solvates, hydrates, esters, clathrates, and prodrugs thereof.

Benzodiazepine compounds that can be used in the methods and compositions of the invention include, but are not limited to, those described in Goodman Ginan, The Pharmacological Basis of Therapeutics, 362-373 (9 th ed. McGraw-Hill, 1996). Examples of specific benzodiazepines include, but are not limited to, alprazolam, brotizolarn, 00 10 chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, 0flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, 4 oxazepam, prazepam, quazepam, temazepam, triazolam, phannacologically active metabolites and stereoisomers thereof, and pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, and prodrugs thereof. The tradenames of some of these compounds are provided below.

The clinician, physician, or psychiatrist will appreciate which of the above compounds can be used in combination with a racemic or stereomerically pure sibutraminebased compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof, for the treatment or prevention of a given disorder, although preferred combinations are disclosed herein.

Disorders that can be treated or prevented using a racemic or stereomerically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or )I prodrug thereof, in combination with a benzodiazepine such as those listed above include, but are not limited to, depression, affective disorders, anxiety, eating disorders, and cerebral function disorders such as those described herein.

The invention further encompasses methods of using and pharmaceutical compositions comprising racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof, in combination with an antipsychotic agent. Antipsychotic agents are used primarily in the management of patients with psychotic or other serious psychiatric illness marked by agitation and impaired reasoning. These drugs have other properties that possibly are useful clinically, including antiemetic and antihistamine effects and the ability to potentiate -39- WO (12/46138 PCT/LJS1/47433 analgesics, sedatives, and general anesthetics. Specific antipsychotic drugs are tricyclic antipsychotic drugs, of which there are three subtypes: phenothiazines, thioxanthenes, and C" other heterocyclic compounds, all of which can be used in the methods and compositions of the invention. See, Goodman Gilman, The Pharmacological Basis of Therapeutics, 404 9 ed. McGraw-Hill, 1996).

C Specific tricyclic antipsychotic compounds include, but are not limited to, chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, 0 trifluoperazine, chlorprothixene, thiothixene, clozapine, haloperidol, loxapine, molindone, 00 O pimozide, risperidone, desipramine, pharmacologically active metabolites and stereoisomers C 10 thereof, and pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, and 00 prodrugs thereof. The tradenames of some of these compounds are provided herein.

SDisorders that can be treated or prevented using racemic or stereomerically pure sibutramine-based compounds or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof, in combination with an antipsychotic compound, and particularly a tricyclic antipsychotic compound, include, but are not limited to, affective disorders depression), anxiety, eating disorders, and cerebral function disorders schizophrenia) such as those described herein.

The invention further encompasses methods of using and pharmaceutical compositions comprising a racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof, in combination with a 5-HTIA receptor antagonist and/or a B-adrenergic antagonist. Examples of 5-HTIA receptor antagonists and B-adrenergic antagonists that can be used in the methods I and compositions of the invention include, but are limited to: alprenolol; WAY 100135; spiperone; pindolol; (S)-UH-301; penbutolol; propranolol; tertatolol; a compound of the formula I as disclosed in U.S. Patent No. 5,552,429, which is incorporated herein by reference; pharmacologically active metabolites and stereoisomers thereof; and pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, and prodrugs thereof.

Disorders that can be treated or prevented using racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof, in combination with a 5-HTA^ receptor antagonist include, but are not limited to, depression, obsessive-compulsive disorders, eating disorders, WO (12/46138 PCT/UIS(11/47433 hypertension, migraine, essential tremor, hypertrophic subaortic stenosis and O pheochromocytoma. A specific disorder that can be treated or prevented is posttraumatic c depression disorder.

3 Disorders that can be treated or prevented using racemic or stereomerically pure S 5 sibutramine-based compound or a racemic or stereonerically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, in combination with a 13n adrenergic antagonist include, but are not limited to, post myocardial infarction depression.

^Q Specific B-adrenergic antagonists include, but are not limited to, S(-)-pindolol, penbutolol, and propranolol.

00 10 The invention further encompasses methods of using and pharmaceutical Scompositions comprising racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof, in combination with a non-benzodiazepine or non-tricyclic agents. Examples of such additional pharmacologically active compounds include, but are limited to: olanzapine, buspirone, hydroxyzine, tomoxetine, pharmacologically active metabolites and stereoisomers thereof, and pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, and prodrugs thereof.

Disorders that can be treated or prevented using racemic or stereomerically pure sibutramine-based compound or a pharmaceutically acceptable salt, solvate, or clathrate thereof, in combination with a compound include, but are not limited to, lorazepam, tomoxetine, olanzapine, respiradone, buspirone, hydroxyzine, valium, pharmacologically active metabolites and stereoisomers thereof, and pharmaceutically acceptable salts, U| solvates, hydrates, esters, clathrates, and prodrugs thereof include, but are not limited to, anxiety, depression, hypertension, and attention deficit disorders.

While all combinations of racemic or stereomerically pure sibutramine-based compounds or pharmaceutically acceptable salts, solvates, hydrates, esters, clathrates, and prodrugs thereof, and one or more above described pharmacologically active compounds can be useful and valuable, certain combinations are particularly preferred. Examples of preferred combinations include those wherein a racemic or stereomerically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, is combined with one of the following: -41 WO (12/46138 WO (214138PCT/(JSOI/47433 alprazolam; brotizolam; chiordiazepoxide; clobazam;, clonazepami; clorazepate; demoxepam; di~azepam; estazo lam; flumazenfil; flurazeparn; halazeparn; lorazepam;midazolarn; nitrazepam; nordazeparn; oxazepam;, prazepamn; quazepam; temazepain; triazolain; chiorpromazine; mesoridazine; thioridazine; acetophenazine; fluphienazine;* perphenazine;, tritluoperazine; chiorprothixene; thiothixene; clozapine; haloperidol; loxapine; molindone; pimozide; risperidone; aiprenolol; WAY 100135; spiperone; S(-)-pindolol;, R(+)-pindolol; racernic pindolol; (S)-UH-301; penbutolol; propranolol; tertatolol; desiprarnine; clonidine; olanzapmne; methyiphenidate; buspirone; hydroxyzine, tomoxetine.

sildenophil; desmethylsildenophlfl vinopocetine;, mininone; amrinone; pimobendan;, cilostamide; enoxinone; peroxinione; vesnarimone; rolipran; R020-1724; zapnnast; and dipyridamole.

In one embodiment, pharmaceutical compositions and dosage forms of the invention comprise a dopamine reuptake inhibitor, such as racemic or stereomerically pure sibutramidne-based compounds or a pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof, and optionally an additional pharmacologically active compound, such as a 5-HT 3 antagonist. The pharmaceutical compositions and dosage forms can contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients known to those skilled in the art- 42 WO 02/46138 PCT/US01/47433 Suitable daily dosage ranges of additional pharmacologically active compounds that can be adjunctively administered with a racemic or stereomerically pure sibutramine-based compound can be readily determined by those skilled in the art following dosages reported in the literature and recommended in the Physician 's Desk Reference® 5 4 t h ed., 2000).

For example, suitable daily dosage ranges of 5-HT 3 antagonists can be readily determined by those skilled in the art and will vary depending on factors such as those described above and the particular 5-HT 3 antagonists used. hi general, the total daily dose of a 5-HT 3 antagonist for the treatment or prevention of a disorder described herein is from about 0.5 mg to about 500 mg, preferably from about 1 mg to about 350 mg, and more preferably from about 2 mg to about 250 mg per day.

The therapeutic or prophylactic administration of an active ingredient of the invention is preferably initiated at a lower dose, from about 0.01 mg to about 1 mg of racemic or stereomerically pure sibutramine-based compound and optionally from about mg to about 60 mg of 5-HT 3 antagonist, and increased, if necessary, up to the recommended daily dose as either a single dose or as divided doses, depending on the global response of the patient. It is further recommended that patients aged over 65 years should receive doses of racemic or stereomerically pure sibutramine-based compound in the range of from about 0.01 mg to about 10 mg per day depending on global response. It may be necessary to use dosages outside these ranges, which will be readily determinable by one of ordinary skill in the pharmaceutical art.

Adjunctively administering of two or more active ingredients in accordance with the methods of the invention can be concurrent, sequential, or both. For example, a dopamine reuptake inhibitor and a 5-HT 3 antagonist can be administered as a combination, concurrently but separately, or by sequential administration.

SYNTHESIS

Sibutramine and its potential metabolites can be depicted by the following scheme: -43- NVO 02/46138 0 0/46138PCT/US0I11-17433 Sibutramine and Metabolites 7 C1 Sibutramine 00 00 I1 d emethylation C1 H 2 c1 V DDMS DM Ihydroxylation ~'N.OH demnethylation C1 N H 2 demethylation

IN

s hydroxylation demethylation

OH

K 3 C1 NH 2 demethylation

OH

3 C1 HN\ As discussed below, this invention encompasses a methods of preparing each of the metabolites of sibutramnine, as well as stereomnerically pure forms, derivatives, salts, solvates, clathrates, and prodrugs thereof.

4.5.1. SYNTHESIS OF 1-HYDROXY DERIVATIVES OF SIBUTRAMINE The synthesis of the 1 -hydroxyalted derivatives of sibutramine metabolites involves the diastereoselective addition of an organoinetallhc reagent to a common synthon, e.g., (R)-tert-butylsulfininide (Scheme 12). See Liu, et al., J. Ain. Chem. Soc. 119:9913- 9914 (1997). This method provides access to all four [-hydroxyl didesmethyl isomers, -44- WO (12/46138 PCT/USII1/47433 enantioselectively and in high yield by proper choice of reaction conditions. These can 00 O easily then be converted to stereomerically pure 1-hydroxyl-desmethyl isomers by 1 N-methylation and further N-methylated to 1-hydroxyl sibutramine.

c in to 0

O/

C CHO S N ,O CH xS'NH 2 CI s 00 9X C0 C I

X

2 (R)-6 N X is an auxialiary group 00 J NRR' CI "OH 8 R and H or Me Scheme 12 As used herein and unless otherwise stated, the term "auxiliary group" refers to any group that is used to induce asymmetry in a reaction or influence the addition of a substrate across a double bond and then removed. Examples of auxiliaries include, but are not limited to, phenyl, tolyl, naphthyl, and tert-butyl. One of skill in the art will recognize that auxiliaries used in compounds of the invention can be removed and replaced by a different f) 10 auxiliary. One of skill in the art will also recognize that some auxiliaries induce greater asymmetry or have a greater influence over addition across a double bond then others.

The four hydroxyl DDMS iomers have been made as free bases and as the corresponding (D)-tartrate salt in stereomerically pure form, and have been used for biological testing (Scheme 13). The stereochemistry at C-2 was determined by the X-ray crystallography.

WO 2/46(i138 PCT/USo 1/47433 4S ,2S O OH HO OH 'HO Cl OH HO O0 (2S,4S)-8-Tartrate salt 4S 2R 0 OH S OH S NH 2 HO KS l OH HO O (2R,4S)-8-Tartrate salt 4R 2S, O OH Is, S OH Cl NH., HO :S C OH HO O (2S,4R)-8-Tartrate salt 4R 2R 0 OH I S- OH Cl NH 2 HO ~SI l O HO O (2R,4R)-8-Tartrate salt lu Scheme 13 The synthesis of the hydroxylated DMS isomers employs a similar approach, as in preparing the free-base of hydroxylated DDMS, which are converted into the desired compounds by a sequence of formylation and reduction (Scheme 14). For example, one preparation sequence starts with the condensation of (R)-tert-butylsulfinamide 4 with aldehyde 2 in THF, catalyzed by Ti(OEt) 4 to provide the sulfinimine Addition of the Grignard reagent 5 to R-6 in CHC1l proceeded at room temperature to give (2S,4S)-7 and (2S,4R)-7' in a ratio of 96.4:3.6. Separation of the major isomer by colunm chromatography, followed by cleavage of the chiral auxiliary, afforded the primary amine (2S,4S)-8. N-Methylation of(2S,4S)-8 was achieved by heating with formic acid in toluene at 100 followed by reduction of formamide using borane at room temperature to produce the secondary amine (2S,4S)-N-Me-8. Treatment of 8 with D-tartaric acid in methanol formed the corresponding (2S,4S)-N-Me-8 tartrate salt as a white solid. Treatment of N- Me-8 free base a second time with a methylating agent afforded the (2S,4S)-N,N-Me,-8.

,i WO (12/46138 ~vO 1214138PCT/LJS( 1/47433 00 0 ON Dibal-H CHO S'- C& CTHF C& C Ti(OEt) 4

DID

c-K12 (R)-6 MgBf OMgCl 4 S O 00 I N.iKO 00 7 (4S)/7'(4R)

CH,)CI

2 96.4: 3.6 TF AI(OCt) 3 14 :86 TF (1.2 eq) HC0 2

H

OH HCIToue -10000; HNr. NH 2 OH BH .TH: 'PrOHH 22 *C; (2S,4S)-7 (2S,4S)-8 -TA 25 O .0 O

~:OH

ciNHM OHMeH- H HO -S ClO eH Cl NH OH HO (2S,4S)-8-N-Me (2S,4S)-8-N-Me-D-Tartrate Salt Scheme 14 The diastereomner was prepared by the same sequence, except the addition of the Grignard reagent 5 to was carried out in THF in the presence of 1.2 eq of.AI(Oct) 3 giving 14:86 ratio of(2S,4S)-7 and It is worthy to note that the formation of salt.

in this case has to be treated with HGI in ethanol, to afford the corresponding HC1 ethanol solvate (Scheme 47 WO (12/46138 PCTfUSO 1/47433 00

HGOH

CK1 Toluene 4R M2S *EtOH NH, BH 3 -THF N- NHM EIH x NHM Cl 2OH 3-Cl OH Cl OH 522

-*HCI

C1(2S,4R)-8 (2S,4R)-8-N-Me (2S,4R)-8-N-Me-HCI Ethanol solvate HC0 2

H

00 Toluene C4R2 100 tC 4 S NHM BH -THF I x& NMe EtOH Ne C O We, OHClHCi OH 00 10 22

HCI

(2S,4R)-8 (2S,4R)-8-N N-Me 2 (2S,4R)-8-N.N-Me 2 HCI Ethanol solvate 4 Scheme Similiary, the other two diastereomers (2R,4S)-5 and (2R,4R)-5 were prepared by addition of to 6 in dichioromethane catalyzed by 1.2 eq of AI(Oc) 3 and in TI-F in the absence of A1(Oct) 3 respectively (Schemne 16). In the former case, the addition delivered the diastereomers (2R,4S)-7 and (2R,4R)-7' in the ratio of 95:5, while in the latter case, the reaction afforded the diastereomnrc mixture in the ratio of 15:85, favoring the form-ation of the 4R isomer. Conversion of (2R,4S)-7 and (2R,4R)-7' into the corresponding sibutrarnine metabolites was achieved by the same sequence as described above. Exposure of the (2R,4S)-8-N-Me free base to HCI in ethanol at room temperature gave the corresponding HCI salt as ethanol solvate. Alternatively, the salt formation of (2R,4S)-8-N-Me was I achieved by treatment with L-tartaric acid in methanol, to provide the corresponding tartrate.

48 WO (12/46138 WO O246t3~PCTF/US0 1/47433 00 MgBr Ogl42R I y H4 OH S HC N 0 (R)-6 7 (4S) /7T (4R) InCH 2 C- AI(Oct) 3 9: 2C1 (1.2eq) 9: 00 THF no LA 15:85 C1 i. HOI/IPA 00 10ii.

HCO

2

H;

BH

3 -THF NOH HCI NH (2R,4S)-7I N e O Cl NH~e I JH Me (2R,4S)-8-N-Me -EtOH-HCI (2R,4S)-8-N-Me- HCI-Ethanol solvate i. HOI/IPA

HCO

2 H;

L-TA

BH

3 -THF NOH NO (2R,4R)-7- 7 He MO NHIle Me- NHMe:- *L-TA (2R,4R)-8-N-Me (2R,4R)-8-N-Me- L-Tartrate Salt Schemie 16 Alternatively, the diasteromers (2R,4R)-8 and (2S,4S)-8 could be prepared via a highly diastereoselective reduction of the imine intermediate 10 by taking advantage of the pre-existing chiral center at C-2. For example, addition of Grignard reagent to 1-(4-Chloro-phenyl)-cyclobutanecarbonitrile (CCBC) in ethyl ether gave the imine intermediate 10 which was reduced efficiently by novel reducing agents such as [1,3,2]Dioxaborepane-4,7-dione (12) or Benzo[1',3,2]dioxaboririin-4-one Anmixture of diastereomers (2R,4R)-8 and (2S,4S)-8 was obtained in the ratio of up to 95:5, favoring the formation of (2R,4R)-8. Reducing agent 12 or 14 were generated by treatment of B11 3

-TRF

with succinic acid or salicylic acid, respectively (Scheme 17).

49 WO (12/46138 PCT/US(II/47433 00 00 00

(.N

00 Br .OH

I

CCBC

BrMg J OMgCI

[H]

-78 °C (2R, 4R)-8 (2R, 4S)-8 (2R, 4R)-8 (2R, 4S)-8=95:5 0 [Hl= I BH or 0 12 12 O O 0 BH 3 -THF OH

I-

'OBH OH 14 Scheme 17 Because 1-hydroxylated desmethylsibutramine and didesmethylsibutramine are basic anmines, diastereomeric salts of these compounds that are suitable for separation by fractional crystallization are readily formed by addition of stereomerically pure chiral acid resolving agents. Suitable resolving agents include, but are not limited to, stereomerically pure tartaric, camphorsulfonic acid, mandelic acid, and derivatives thereof. Stereomerically pure isomers of sibutramine, desmethylsibutramine, and didesmethylsibutramine can be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid enantiomer used. The identity and optical purity of the particular sibutramine-based compound or isomer so recovered can be determined by polarimetry or other analytical methods.

\N/O (12/46138 WO (i246I~PUMSO0l! 7433 4.5.2. SYNTHESIS OF 3-IIYDROXYL SIBUTRAMINE

DERIATIVES

The synthesis of the 3-hydroxyl sibutramine derivatives can be synthesized is various ways. One synthesis utilizes a pair of enantiorners and which were obtained by condensation of aldehyde 2 with and (R)-tert-butylsulfinamide 4, respectively (Scheme 18).

00 2 2 X NH-, 1 Ti(OEt) 4

THF

rt, 2 h 98.5% yield X =tert-buty) X INH 2

U

Ti(OEt) 4

THF

rt, 1 h 93% yield X tert-butyl (R)-6 (S)-6 Scheme 18 Addition of 2 equivalents of racemnic (oc-methoxymethoxy) isobutyl lithium 18, which was readily prepared in situ from the exchange reaction of (a-methoxymethoxy) isobutyl tri-n-butylstannane 16 with n-butyllithium. in THF at -78 to sulfininu-nne (R)-6 produced in 79% isolated yield, a mixture of diastereomers (3R,45)-20 and (3S,4S)-20, in the ratio of 72:28, favoring the formation of (3R,4S)-20. Cleavage of protecting group by refluxing in methanolic HCl gave the unseparable mixture of hte aminoalcohol (3R,4S)-24 and (3S,4S)-24 as the corresponding HC1 salt. Cyclization of the mixture (3,4S)-24 and (35,4S)-24, by treatment with carbonyliimidazole and Et 3 N in CH 2 C 12, afforded a separable mixture of (3R,4S)-22 and (3S,4S)-22' in 73 percent yield. Hydrolysis of the separated carbamnate (3R,4S)-22 or (3S,4S)-22 with potassium hydroxide in ethylene glycol, in the presence of catalytic amount of Nl 2 Nil 2 and subsequently treatment of the frec -51 WO (12/46138 PCT/US0 1/47433 00 amninoalcohols with ntethanotic HCl, obtained in 84 percent overall Yield for 2 steps, in corresponding HCI salt of (3R,4S)-24 and (3S,48)-24, respectively.

0- 0- 0/ n-BuL, THF 0-/ r-K1 SnBu-n 3 -78 0 C, 10 minL 16 18 00mom OMOM 8 K Li NIS -78 0 C,THF Cl HN, Y 0 0 Table 1. Results of the reaction of (alpha-metlioxynethoxy)isobuity lithium with aldimnine 6.

Entry Ratio of [mnine lithiumn Temp( 0 C) Time 13 ()anti :syn 1 1:2' -78 3 100(90) 72:28 2 11.1 -78 2 100(93) 60:40 3 1:5 -78 0.5 100 84:16 4 1:10 -78 0.2 100 84:16 5* 1:5 -78-rt 27 *The litiumn reagent was prepared in situ and mixed with 5 eq. MgBr 2 -OEt,.

?Omom 1. 2 N HCI/MeOH reflux. 1 h ci H 2. 1.1'-Carbonyl- ci ~ci H 0 di imidazole, 0 0 EtN 1h(3R,4S)-22 (3S,4S)-22 73% yield Scheme 19a 52 NVO (12/461i38 PCT/US0 1/47433 00 1. KOH, NH 2

NH

2

H

2 0

O

c=KI ethylene glycol 120 0 C, 2hrs Y +H C N- 2. 2 N HCI/ether 1CI 0 (3R4S)2284% yield (3R,4S)-24 tn 1. KOH, NH 2

NH

2

H

2 0 00-.ethylene glycol

O

lzz150 0 C, 6hrs 10 &iNH 00~' 10C 2. 2 N HOI/ether Cl C 0 57% yield (3S,4S)-22 (3S,4S)-24 4 Scheme 19b Alternatively, the two chiral centers of these arninoalcohols could be created by addition of stereomeri cally pure (ci-methoxymethioxy) isobutyl lithium (IS) to aldirnine or Therefore, treatment of organolithium derived from the corresponding stannane (R)-16 ee), with aldimine in THF at -78 afforded exclusively (3S,4R)-20 in 92% isolated yield (Scheme 20). In this case, only less than 1% of (3S,4S)-20 was observed. Cleavage of the protecting group by refluxing in 2N HC1 aqueous solution, provided the fr-ee arninoalcohol, which was then converted into the correspondig HCI salt (3S,4R)-24 by treatment dry methanolic HCl Similiarly, addition of organolithiurn reagent 8, derived from the corresponding stannane to in THE at -78 gave a mixture of diastereomers (3R,4R)-20 and (3R,4S)-20 in the ratio of 99: 1, with (3R,4R)-20 as the major product. (3R,4R)-20 was isolated in 6 1% yield and then converted into (3R,4R)-24 by the same sequence as described above for (3S,4R)24.

53 WO (12/46138 PCT/IjS(I 1/47433 0- SnBu-n 3 (S)-16 n-BuLi, THF -78 10 min Li (S)-18 00 00 0mom OMAOM Li THF, -78 0 C, 3h CI s N -0 (3S,4R)-20 Yield: 92% d.s. 99:1 (S)-6 0- S 'nBu-n 3 (R)-16 n-BuLl, THF -78 00C, 10 min Li 8

>(OMOM

THF, -78 0 C, 3h Yield: 61 d.s. 99: 1 (S)-6 (3R,4R)-20 1. 5-6 N HCI/i-PrOH Methanol, reflux, 1 h 2. NaOH 3. 2.0 M HCI/Ether 83% yield

OH

Cll (3S,4R)-20 (3S,4R)-24 1. 5-6 N HCI/i-PrOH Methanol, reflux, 1 h 2. NaOH 3. 2.0 M HCVEther 89% yield O9 H CI NH- 3 Cie (3R,4R)-20 (3S,4R)-24 54 WO (12/46138 PCT/LJS(II/47433 00 00 00 4.5.3. SYNTHESIS OF 7-HfYDROXY SIBUTRAMINE METABOLITE DERIVATIVE S The asymimetric syntheses of 7-hydroxyl sibut-ramine-based compounds involves form-ation of the chiral center by the addition of an organometallic reagent, such as isobutyl, lithium to or (S)-tert-butylsulfinyl imine 7, which could be derived f-rm the condensation of or (S)-tert-butylsulfinyl amide with the correspondig cis and trans hydroxyl. aldehyde 28. The structure of the cis and trans isomers 7-hydroxyl desmethylsibutrami-ine and 7-hydroxyl didesmiethylsibutramnine are set forth. below: C1 7

OH

4 NHMe 2

C'

OH

NHMe (S)-cis-1 5-N-Me (R)-cis-1 5-N-Me (S-Irans-15-N-Me (R)-trans-1 C1 7

OH

4

NH

2 2 (S)-cis-1 5 C1

OH

'NH

2 (R)-cis-1 5 (S)-trans-15 (R)-trans-1 For example, the chiral. center of (R)-configuration was created by the addition of an organolithium reagent to the (R)-tert-butylsulffminide, prepared from the condensation of (R)-tert-butylsulfinyl amide 6 with the corresponding hydroxyl aldehyde 28 (Scheme 271).

55 WO (12/46138 \VO ~2I4 138PCT/USO 1/4 7433 0 X NH 2

,HO

3 X =tert butyl

OH

Separation of cis and tra ns-1 3

OH

0 Li (R)-cis-32 Scheme 21 It was reported that the hydroxyl nitrile could be prepared fr-om 4-chiorophenylacetonitrile [See Jeffrey et a, J1. Chein. Soc. Perkin Tranis 1, 1996, 2583] (Schemne 22). The route involves deprotonation with methyllithiurn in THE at -78 followed by treatment with epibroinohydrin and methylinagnesiumn iodide. This approach gives hydroxylnitrile 34 as an epimeric mixture, in a ratio of approximately 2.6: 1, favoring the cis epimer.

0 HO Hi O MeLi MeMgl 115, Br H ON -78 -220C I Cr TH, 78C1c 18 h Ci- 34 HF,-8 36 cis/lantJ 2.6:1 Scheme 22 Conversion of hydroxyl nitrile mixture 36 to the corresponding cis/trans aldehydes 28 was achieved successfiully in an 83% yield by using 2.2 equiv of Dibal-H (1.0 M in hexane) in TI-F at 0 TC. Condensation of the hydroxyl aldehydes 28 (cis/trans 2.6 1) with one equivalent of (R)-tert-butylsulfinyl amide 6 in the presence of Ti(OEt) 4 in THE at 22 0

C

56 WO (12/46138 PCT/US 11/47433 for 10 h was incomplete, and provided a mixture of the cis and trans aldimines with the trans 00 O isomer as the major product. In this case, only the cis-aldehyde was recovered, indicating that there was a kinetic resolution effect for the formation of sulfinimines 30. It is possible Sto achieve the separation of isomers at this step by controlling the formation of the trans sulfinimine kinetically.

The condensation reaction was completed in a 91% isolated yield by heating the l "'mixture in toluene to 100 OC for 1 h. A careful and difficult separation of the aldimines by 00 column chromatography gave the corresponding two isomers trans- and cis-30 (Scheme 23).

00 0

(N

4 OH OH SNH 2 A1 N H2 CI" 'S.sO Dibal-H R cis-30 CN CHO (R)-6 THF-hexane Ti(OEC 4 CI Cl Toluene 36 cis /trans 2.6:1 28 cis /trans 2.6:1 100 "c Scheme 23 Addition of iso-butyllithium (3.2 eq) to cis-30 in THF at -78 "C proceeded smoothly (Scheme 23). The reaction completed in 2 h, providing in a nearly quantitative yield, a mixture of two diastereomers in the ratio of 3:97, presumably in favor of cis-38'. Other conditions were investigated, including the effect of Lewis acid. The results are summarized in Table 2. It was found that the addition of 2.2 equiv ofBF 3 -EtO could further improve the diastereoselectivity, and give a mixture ofcis-38 and cis-38' in the ratio of 2:98 (entry 4, The reaction was much slower in toluene, with only 45% of the products formed after 8 h at -78 In this case, the diastereoselectivity was also low (cis-38'/cis-38 48:52).

-57- WNO (12/46138 PCT/UlS 114 7433 00 00 00

OH

7 -Li cis-38' cis-38 Scheme 24 10 Table 2: Addition of i-BuLi to Entry i-BuLi(eq.) LA(eq.) Solvent 1 3.2

THF

2 3.2 Toluene 3 3.2 Et 2

O

4 3.2 BF 3 EtO(2.2) TH-F 3.2 BF 3 Et 2 O(3.2) THfF 6 3.2 AI(Oct) 3

TI-IF

Temp.( 0

C)

-78 2 -78 8 -78 -78 2 -78 2? -78 2 Time(h) d.r. (cis-3 8'/cis-3 8)Conv.(%) 97:3 100 48:52 so 98:2 98.4:1.6 99:1 The addition of iso-butyllithiium (3.2 eq.) to trans-30 in THfF at -78 'C was completed in 2 h, producing a mixture of two diastereomers, trans-38 and trans-38e, in a ratio of 89:11, presumably in favor of trans- 14. The product was isolated in a 74% yield, and the ratio of the isomer increased to 97:3 after chromatography (Scheme

HO,,.

0 7 0 )cii0 trans-38 HO,,7 0s trans-38' Scheme Deprotection then affords the desired 7-hydroxy didesmethylsibutramine metabolites. Methylation using conditions known to those skilled in the art then gives the 58 WO (12/46138 PCT/USo1/47433 7-hydroxy desmethylsibutramine metabolites and a second methylation can afford 7-hydroxy 00 0 sibutramine.

C

In summary, the invention includes the synthesis of an asymmetric route to two D isomers, involving the separation of the cis- and trans-tert-butyl-sulfinimides 13, followed t 5 by a highly diastereoselective addition of iso-butyllithium to cis- and trans-13, respectively.

Similiarly, by using the corresponding (S)-tert-butylsulfinimides, another two isomers could be obtained via the same sequence.

00 The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, 00 10 can be practiced without departing from the scope of this invention. It should also be noted Sthat names of compounds below may differ from those set forth above in backbone numbering and positional numbering due to use of International Union of Pure and Applied Chemistry (IUPAC) naming below. Wherever a discrepancy between the depicted structure and the name of the compound, the depicted structure will take preference.

EXAMPLES

5.1. SYNTHESIS OF HYDROXYLATED SIBUTRAMINE

METABOLITES

5.1.1. 1-HYDROXYL EXPERIMENTAL DATA O 0 (R)-6 (R)-N-(1-(4-Chlorophenyl)cyclobutanemethylene)-t-butanesulfinamide: To a solution of 1-(4-chlorophenyl)cyclobutanecarbaldehyde (10.0 g, 51.0 mmol), was added (R)-t-butansulfinamide (5.0 g, 41.0 mmol) in THF (60 mL), Ti(OEt) 4 (46.8 g, 205 mmol). The reaction mixture was stirred at room temperature for 3 h and poured into icewater. The solid was filtered off, and the filtration was extracted with ethyl acetate. The -59- WO 02/46138 PCT/LJS1il/47433 extracts were dried over magnesium sulfate and the solvent was removed on rotovapor. The O residue was purified by chromatography on silica gel eluting with heptane/ethyl acetate 9/1 to give 11.2 g of product in 92% yield. 'H NMR (CDCI 3 /TMS): 6 8.03 1H), 7.30 J 8.4 Hz, 2H), 7.10 J 8.4 Hz, 2H), 2.85-2.60 2H), 2.60-2.40 2H), 2.15tn 5 1.85 2H), 1.19 9H). "CNMR(CDC1 3 8 170.6, 142.5, 132.5, 128.7, 127.5, 57.0, 51.8, 31.1, 30.8, 22.3, 15.9. Anal. Calcd for C 5 sH 20 CINOS: C, 60.49; H, 6.77; N, 4.70.

n Found: C, 60.61; H, 6.80; N, 4.64.

00 'I B rOTHP 00 romo-2-methylpropoxy) tetrahydropyran To the solution of (S)-3-bromo-2-methylpropanol (15.0 g, 98 numol) in dichloromethane (20 mL) at 0 oC, was added 3,4-dihydro-2H-pyran (10.0 g, 119 rmmol) and p-toluenesulfonic acid monohydrate (0.19 The mixture was stirred at rt overnight and distilled under vacuum to give 6.0 g of product as a colorless oil (26% yield). 'H NMR

(CDCI

3 /TMS): 8 4.60 1H), 3.86 1H), 3.69 1H), 3.60-3.40 3H), 3.33 1H), 2.11 1H), 1.95-1.40 6H), 1.05 J 6.8 Hz, 1.5Hz), 1.04 J 6.8 Hz, 1.5Hz). 3

C

NMR (CDCI 3 8 99.3, 98.5, 70.0, 69.7, 62.3, 61.9, 38.3, 38.1, 35.6, 30.6, 25.4, 19.5, 19.3, 15.9, 15.8.

Li ,OTHP (R)-3-(Tetrahydropyran-2-yloxyl)-2-methylpropyl-lithium To the suspension of lithium (0.3 g, 43.2 mmol) in ether (5 mL) at 0 bromo-2-methylpropoxy) tetrahydropyran (4.22 g, 17.8 mmol) in ether (7 mL) was slowly added. After the reaction was initiated, the reaction mixture was stirred at -10 to -5 °C while the rest of the bromide was added within 1.5 hour. After the addition of the bromide was complete, the reaction mixture was stirred at -10 to -5 OC for 1 hour. The concentration of this lithium reagent was 0.77 M and the yield is 51%.

WO (12/46138 PCT/LJIS 1/47433 00

.\OTHP

00 (I (1R,3R)-N-{1-[1-(4-Chlorophenyl)cyclobut7yl-3-methyl-4-(tetralydropyran-2- 00 yloxy)butyl}-(R)-t-butanesulfinamide The reaction of organolithium with tert butyl-sulfinamide was carried out under 4 C'1 various conditions. Typical procedure: To the solution ofsulfinamide (0.595 g, 2.0 mmol) in THF (10 mL) at -78 was added Al(Oct),(5 mL, 25 wt in hexane, 2.4 nmmol). After the mixture was stirred at -78 °C for 5 min., organolithium (5.2 niL, 0.77 M in ether, 4 mmol) was added. The reaction mixture was stirred at -78 °C for 2 hours and then quenched with methanol (5 mL). The reaction mixture was allowed to warm to room temperature, diluted with TBME, washed with brine, and dried over anhydrous MgSO 4 A small amount of the crude product was treated with 2 N HCI in methanol and HPLC analysis of free amino alcohols showed the diastereoselectivity of this reaction is 98.6:1.4. After removal of the solvents, the crude product was purified by chromatography on silica gel (eluting with ethyl acetate in heptane) to give 0.75 g of product in 82% yield. 'H NMR (CDC13/TMS): 8 7.27 4H), 4.46 1H), 3.80-3.60 1H), 3.44 3H), 3.08 1H), 2.87(d, J 10.4 Hz, 1H), 2.71 1H), 2.41 2H), 2.14 1H), 2.0-1.3 10H), 1.16 9H), 1.0-0.8 4H). 13C NMR (CDCI 3 8 142.1, 131.9, 130.0, 127.7, 98.7, 98.5, 73.1, 73.0, 62.9, 62.0, 61.8, 56.6, 50.7, 35.5, 35.4, 34.6, 32.2, 30.5, 29.5, 25.4, 22.8, 19.4, 19.2, 16.0, 15.2.

WO (12/46138 PCT/LSO 1/47433 00 0 CI

HN

n 5

C

l I Stn (1R,3S)-7 roO 0 (1R,3S)-N-{1-[1-(4-Chlorophenyl)cyclobutyIl-4-hydroxy-3-methyl-butyl}-(R)-t- C 10 butytanesulfinamide 0 To the solution of(R-3-bromo-2-methylpropanol (15.3 g, 100 mmol) in THF mL) at -35 C, was added i-PrMgCI (51 mL, 2.0 M in THF, 102 mmol) via syringe. After the addition was complete, the reaction mixture was continued to stir at 0 °C for 1 hour. The resulting magnesium salt solution was then slowly added into a suspension of magnesium turnings (4.0 g, 165 nmol) in THF (20 nL). After the reaction was initiated, the reaction mixture was maintained with an inner temperature of 40-50 °C while the solution of magnesium salt in THF was added. After the addition was complete, the reaction mixture was stirred at ambient temperature for 2 h.

To the solution ofsulfinamide (5.95 g, 20.0 mmol) in THF (60 mL) at 0 was added the Grignard reagent (58 mL, 0.7 M in THF, 40.6 mmol). The reaction mixture was allowed to warm to room temperature and completed in 2 hours. The reaction mixture was quenched by the addition of water (20 mL), and extracted with TBME. The extracts were dried over MgS04. After the solvent was removed, a small amount of the crude product was treated with 2 N HCI in methanol. HPLC analysis of the free amino alcohols showed the diastereoselectivity of this reaction is 40.5:59.5. The major diastereomer (4.24 g) and the minor diastereoiner (2.82 g) were isolated in 95% combined yield by chromatography on silica gel, eluting with a mixture of ethyl acetate/heptane Major diastereomer: 'H NMR (CDCI3/TMS): 6 7.30-7.20 4H), 3.65-3.45 3H), 2.94 J 10.2 Hz, 1H), 2.75- 2.60 1H), 2.45-2.30 2H), 2.30-1.50 6H), 1.18 9H), 0.88 J 6.8 Hz, 3H), 0.58 1H). 3 C NMR (CDCl 3 5 142.1, 132.0, 130.1, 127.9, 66.2, 63.5, 56.7, 50.7, 35.6, 34.5, 32.2, 31.6, 22.9, 18.5, 15.2. Anal. Calcd for C,,H 3

CCINO

2 S: C, 61.35; H, 8.13; N, 3.77.

Found: C, 61.32; H, 8.26; N, 3.40.

-62- WO 02/46138 PCT/US 1/47433 00

H

1

HN

tn (1R,3S)-7 00 (1S,3S)-N-{1-[1-(4-ChIorophenyl)cyclobutyl-4-hydroxy-3-methyl-butyl}-(R)-t- Sbutanesulfinamide STo a solution of (R)-3-bromo-2-methylpropanol (6.0 g, 39 nmnol) in ether (20 mL) at 00 -25 oC, was added i-PrMgCI (20 mL, 2.0 M in ether, 40.0 mmol) via syringe. After the C1 addition was complete, the reaction mixture was continued to stir at 0 OC for 1 h. The resulting magnesium salt solution was then slowly added into a suspension of magnesium turnings (1.46 g, 60.0 mol) in ether (5 mL). After the reaction was initiated, the ether solution was gently refluxed. After the addition was complete, the reaction mixture was stirred at ambient temperature for 2 h. The solution of the Grignard reagents became two phases. After vigorously stirring, an aliqutor was taken and titrated to measure the concentration. The Grignard reagent was used for the addition reaction under various conditions and the results are shown in Table 1 (entries The following procedure (Table 1, entry 1) is resentative: To the solution of sulfinamide (2.98 g, 10.0 mmol) in dichloromethane (100 mL) at 0 OC was added the Grignard reagent (53 mL, 0.38 M in ether, 20.0 unmol). The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was quenched by addition of water (10 mL) and extracted with TBME. The extracts were dried over MgSO 4 After the solvent was removed, a small amount of the crude product was treated with 2 N LiCI in methanol. HPLC analysis of free amino alcohols showed the diastereoselectivity of this reaction is 96.4:3.6. The major diastereomer (2.75 g) and the minor diastereoiner (0.10 g) were isolated in 77% yield by chromatography on silica gel, eluting with ethyl acetate/heptane Major Diastereomer: 'H NMR (CDC13/TMS): 8 7.27 J 8.4 Hz, 2H), 7.07 J 8.4 Hz, 2H), 3.60-3.3 8 (m, 2H), 3.15-2.90 3H), 2.45-1.70 7H), 1.40-0.95 2H), 1.25 9H), 0.92 J 6.8 Hz, 3H). 3 C NMR (CDCl 3 8 143.9, 132.3, 129.1, 128.1, 68.7, 64.8, 57.2, 51.2, 37.1, 33.3, 32.5, 32.2, 23.4, 17.7, 15.2. Anal. Calcd for C, 9

H

3 0 CINOS: C, 61.35; H, 8.13; N, 3.77.

Found: C, 61.25; 11, 8.42; N, 3.28.

-63 WO (12/46138 PCT/JUS01/47433 00

OH

HN

CI S (1S,3R)-7 OO (1S,3R)-N-{1-[1-(4-Chlorophenyl)cyclobutyl]-4-hydroxy-3-nethyl-butyl}-(R)-t- O butanesulfinamide To a solution of (S)-3-bromo-2-methylpropanol (15.3 g, 0.10 mol) in ether (50 mL) 0 at -25 was added i-PrMgCl (51 mL, 2.0 M in ether, 0.102 mol) via syringe. After the C addition was complete, the reaction mixture was continued to stir at 0 oC for 1 h. The resulting magnesium salt solution was then slowly added into a suspension of magnesium turnings (4.0 g, 0.16 mol) in ether (30 mL). After the reaction was initiated, the ether solution was gently refluxed. After the addition was complete, the reaction mixture was stirred at ambient temperature for 2 h. The solution of the Grignard reagents became two S phases. After vigorously stirring, an aliqutor was taken and titrated to measure the concentration. The Grignard reagent was used for the addition reaction under various conditions and the results are shown in Table 1 (entries 6-10). The following procedure (Table 1, entry 8) is representative: To the solution of sulfinanide (4.0 g, 13.4 mnol) in dichoromethane (110 mL) at 0 OC, Grignard reagent (54 mL, 0.5 M in ether, 27.0 mmol) was added. The reaction was allowed to warm to at room temperature and completed in hours. The reaction mixture was quenched by addition of water (10 mL), and extracted with TBME. The extracts were dried over MgSO 4 After the solvent was removed, a small amount of the crude product was treated with 2 N HC1 in methanol. HPLC analysis of free, amino alcohols showed the diastereoselectivity of this reaction is 90.6:9.4. The major diastereoiner (3.82 g) and the minor diastereoiner (0.40 g) were isolated in 87% combined yield by chromatography on silica gel, eluting with ethyl acetate/heptane Major Diastereomer: 'H NMR (CDCl3/TMS): 8 7.27 J 8.2 Hz, 2H), 7.11 J =8.2 Hz, 2H), 4.04 1H), 3.70-3.40 2H), 3.23 (brs, 1H), 2.72 J 8.2 Hz, 1H), 2.35 2H), 2.16 2H), 2.04 2H), 1.92-1.70 1H), 1.54 1H), 1.28 9H), 0.95-0.65 4H).

"C NMR (CDC1 3 8 143.6, 131.8, 129.0, 127.6, 68.4, 61.5, 56.5, 51.0, 37.8, 32.2, 31.8, 30.7, 23.1, 18.8, 15.0. Anal. Calcd for CH 30 C1NO 2 S: C, 61.35; H, 8.13; N, 3.77. Found: C, -64- WO 02146138 PCT/IUS 1/47433 OO 61.41; H, 8.17; N, 3.60. The absolute configuration of 15 was assigned by x-ray of the

OH

O crystals.

0 C, HN 00 (1R,3R)-7 00 5 (1R,3R)-N-{1-[1-(4-Chlorophenyl)cyclobutyll-4-hydroky-3-methyl-butyl}-(R)-t- O butanesulfinamide C1 To the solution of (S)-3-bromo-2-methylpropanol (6.0 g, 39 mmol) in THF (10 mL) at -35 was slowly added i-PrMgCl (20 mL, 2.0 M in THF, 40 rmnol) via syringe. After the addition was complete, the reaction mixture was continued to stir at 0 oC for 1 h. The resulting magnesium salt solution was then slowly added into a suspension of magnesium turnings (1.46 g, 60 mmol) in THF (10 mL). After the reaction was initiated, the reaction mixture was stirred at an irnner temperature of 40-5 0 "C while the solution ofmagenesium salt in THF was added. After the addition was complete, the reaction mixture was stirred at ambient temperature for 2 h. This homogeneous solution was then used for the addition reaction under various conditions and the results are shown in Table 1 (entries 12, 13).

The following procedure (Table 1, entry 12) is a representative: To the solution of sulfinamide (4.0 g, 13.4 mmol) in THF (90 mL) at 0 oC, Grignard reagent (35 mL, 0.6 M in p THF, 21.0 mmol) was added. The reaction was allowed to warm to room temperature and completed in 2 hours. The reaction mixture was quenched by addition of water (10 mL), and extracted with TBME. The extracts were dried over MgSO 4 After the solvent was removed, a small amount of the crude product was treated with 2 N HC1 in methanol. HPLC analysis of free amino alcohols showed the diastereoselectivity of this reaction is 15.3:85.7.

The major diastereoiner (3.74 g) and the minor diastereoiner (0.67 g) were isolated in 88% combined yield by chromatography on silica gel, eluting with ethyl acetate/heptane Major Diastereomer: 'H NMR (CDCl3/TMS): 5 7.29 4H), 3.55-3.30 3I), 2.94 J 10.2 Hz, 1H), 2.75-2.65 1H), 2.47-2.35 2H), 2.20-2.10 1H), 2.00-1.80 (m, 4H), 1.17 9H), 0.94 J 6.7 Hz, 3H), 1.25-0.85 2H). "C NMR (CDCIL): 5 142.1, WO (12/46138 PCT/LSOU147433 00 132.0,130.1, 127.9, 68.5, 63.0, 56.7, 50.7, 34.9, 34.6, 32.3, 31.9, 22.8, 15.6, 15.2. Anal.

Calcd for CjqH 3 0 C1N0 2 S: C, 61.35; H, 8.13; N, 3 .77. Found: C, 61.17; H, 8.36; N, 3.44.

NHH

00 (2S,4R)-8 00 (2S,4R)-4-Amino-4-[1-(4-cblorophenyl)cyclobutyll-2-methyrl-butan-1-oI To the solution of hydroxy sulfinarnide (3.50 g, 9.4 minol) in methanol (50 mL) at rt, was added the solution of HCl in i-PrOH (10 rnL, 5-6 The reaction mixture was stirred at room temperature overnight. After the solv'ent was removed under vacuum, the residue was puri fied by chromatography on silica gel, eluting with heptane/ethylacetate/triethylamine to give the amino alochol 2.52 g in 100% Yield. 'H NR(CDCI 3

/TMS):

7.31 J 8.4Hz, 2H), 7.07 J 8.4 Hz, 2H), 3.49 (in, 2H), 3.14 J 10.9 Hz, IH), 2.64 (brs, 3H), 2.50-2.10 (mn, 4H), 2.10-1.80(m, 3H), 1.64-1.57 (in, IH), 1.01 J 7.1 Hz, 3H), 0.78 (mn, I 3 C NMR(CDCls): 8 143.6, 131.8, 128.6, 127.8, 66.7, 53.4, 51.2, 36.6, 32.9, 31.7, 31.4, 16.1,15.0.

A mixture of amidno alcohol (1.0g, 3.74 inm-ol) and D-tartaric acid (0.56 g,3.74 nmol) was dissolved into methanol (20 mnL). To the resulting solution, TBIEf (50 mL) was added and solid was precipitated out. The salt was filtered and dried in a vacuum oven 1.37:g of the D-tartaric acid salt was obtained (88% yield). 'H NUIR (DMSO): 5 7.43 d, =7.7 Hz, 2)7.1(,J 7.7 Hz, 2H), 6.89 (brs, 6H), 3.98 J 3.8 Hz, 2H), 3.65 106Hz, 1W), 2.55-2.40 (in, IH), 2.40-2.20 (mn, 3H), 2.05-1.85 (in, 1IM, 1.80-1.65 (in, 2H), 1.54 (in, 1H), 0.80 J 6.3 Hz, 3H), 0.90-0.70 (in, 1W). 3 C NMIR (DMSO): 8 175.1, 142.8, 131.9, 130.4, 128.6, 72.4, 65.6, 56.2, 49.3, 33.9, 32.5, 32.0, 31.5, 18.9, 15.6. Anal. Calod for CqH 2 8 C1N0 7 C, 54.61; H, 6.75; N, 3.35. Found: C, 54.17; H,7.41; N, 2.87.

66 WO 02/46138 PCT/US01/47433 00

OH

O

CI NH 2

SCI

n (2R,4S)-8 (2R, 4S)-4-Amino-4-[1-(4-chlorophenyl)cyclobutyl]-2-methyl-butan-l-ol I To the solution of hydroxy sulfinamide (3.36 g, 9.0 mmol) in methanol (50 mL) at 00 room temperature, the solution of HCI in i-PrOH (10 mL, 5-6 N) was added. The reaction 0 S 5 mixture was stirred at room temperature overnight. After the solvent was removed under 00 vacuum, the residue was purified by chromatography on silica gel, eluting with 0 heptane/ethyl acetate/triethylamine to give the amino alcohol: 2.35 g in 97% yield.

1 The 'H and 3 C NMR are identical to amino alcohol above.

A mixture of amino alcohol (1.0g, 3.74 mmnol) and D-tartaric acid (0.56 g, 3.74 rnmol) was dissolved into methanol (20 mL) by heating. After it was cooled down, solid was precipitated out. The salt was filtered and dried in a vacuum oven (<40 1.28 g (82% yield) of the D-tartaric acid salt was obtained. 'H NMR (DMSO): 5 7.43 J Hz, 2H), 7.28 J 8.5 Hz, 2H), 6.92 (brs, 6H), 3.98 2H), 3.57 J 9.0 Hz, 1H), 3.33 J 5.0 Hz, 2H), 2.55-2.20 5H), 2.05-1.85 1H), 1.80-1.50 3H), 0.81 J Hz, 3H), 0.80-0.60 (in, 1H). "C NMR (DMSO): 6 175.0, 142.9, 131.9, 130.3, 128.6,72.0, 65.5, 56.3, 49.4, 34.0, 32.4, 32.2, 31.5, 18.9, 15.6. Anal. Calcd for CqH 28 C1N0 7 C,54.61; H, 6.75; N, 3.35. Found: C, 54.54; H, 6.78; N, 3.20.

NH

2 (2S,4S)-8 (2S, 4S)-4-Amino-4-[l-(4-chlorophenyl)cyclobutyl]-2-methyl-butan-l-ol To the solution ofhydroxy sulfinamide (3.21 g, 8.6 .mmol) in methanol (50 mL) at room temperature, the solution of HCI in i-PrOH (10 mL, 5-6 N) was added. The reaction mixture was stirred at room temperature overnight. After the solvent was removed under vacuum, the residue was purified by chromatography on silica gel, eluting with -67- WO (12/46138 PCTIUS0 1/4 7433 heptane/ethyl acetate/triethylamine to give amino alcohol:2.30 g in 100% yield. 'H 00 NIM (CDCI 3 /TMS): 5 7.31 J 8.3 Hz, 2H), 7.06 J 8.4 Hz, 2H1), 3.49 (dd, J 3.2, 11.5 Hz, 1H), 3.30-2.80 (in, 5H), 2.50-2.10 (mn, 4H), 2.10-1.60 (mn, 3H), 1.64-1.57 (mn, 1H), 0.85 J 6.8 Hz, 3H), 0.46-0.35 (in, IlH). 3 CNMIR (CDC 3 8 143.7, 13 2.2, 128.9, 128.1, 69.2, 58.7, 51.7, 40.1, 37.9, 32.0, 31.8, 19.5, 15.1.

The mixture of amino alcohol (1.0g. 3.74 mmol) and D-tartaric acid (0.56 g, 3.74 inmol) was dissolved into methanol (20 inL) by heating. After it was cooled down, solid was precipitated out. The salt was filtered and dried in a vacuum oven (<40 1.25 g 00 (77% yield) of the tartrate salt was obtained. 'H NIRM (DMSO): 8 7.43 J =7.2 Hz, 2H), 00 10 7.31 J 7.2 Hz, 2H), 6.74 (brs, 6H), 3.98 2H), 3.49 J 10. 1 Hz, IH), 3.25-3.08 (mn, 2H), 2.60-2.40 (in, IH), 2.40-2.15 3H), 2.05-1.85 (rn, IH), 1.80-1.58 (mn, 2H1), 1.22 (mn, IH), 1.06 (mn, 1H), 0.84 J 5.9 Hz, 3H). 3 C NMI DMSO): 8 175.1, 143.0, 131.9, 130.4, 128.6, 72.4, 67.3, 56.3, 49.4, 33.7, 32.3, 32.0, 16.8, 15.5. Anal. Calcd for

C,

9

H

28 C1N0 7 C, 52.35; H, 6.94; N, 3.21. Found: C, 52.73; 11, 6.76; N, 3.11.

OH

C1 1 N H 2 1s (2R,4R)-8 (2R, 4

R)-

4 -Aniino4-[1-(4-chlorophenyl)cyclobuy]..2-.methy l-butan 1 -01 To the solution of amino alcohol (3.08 g, 8.3 inmol) in methanol (50 niL) at room P temperature, the solution of HCL in i-PrOH (10 mL, 5-6 N) was added. The reaction mixture was stirred at room temperature overnight. After the solvent was removed under vacuum, the residue was purified by chromatography on silica gel, eluting with heptane/ethyl acetate/triethylamiine to give amino alcohol: 2.22 g in 99% Yield. The 'H and 3

C

NMR are identical to amino alcohol (2S,4S)-6.

The mixture of amino alcohol (1.0g, 3.74 mmol) and D-tartaric acid (0.56 g, 3.74 mmol) was dissolved into methanol (20 mL) by heating. A-fter it was cooled down, solid was precipitated out. The salt was filtered and dried in a vacuum oven (<40 1.27 g (8 1% yield) of the tartrate salt was obtained. 'H NMvR (DMSO): 6 7.43 J 8.6 Hz, 2H), 7.28 J 7.2 Hz, 7.03 (brs, 6H), 3.92 2H), 3.45 J =10.5 Hz, IH) -68 t.

WIO (02/46138 PCT/USO 1/47433 003.25-3.07 (in, 2H), 2.48 (in, IH), 2.29 (mn, 3H), 1.95 (mn, IH), 1.80-1.55 2H), 1.21 (mn, 1H), 1.03 (in, 1H), 0.84 J =6.5 Hz, 3H1). 3 C NMR (DMSO): 8 175.0, 143.1, 131.9, 130.3,128.6, 72.2, 67.3, 56.4, 49.4, 33.8, 32.4, 16.8, 15.5. Anal. Calcd for C 19

H

28 C1N0 7 C, 5 4.61; H, 6.7 5; N, 3.3 5. Found: C, 5 4.68;- H, 6.S 7; N, 3.20.

1(n 000 H CI

H

3 C N 00 (2S,4R)-N-Me-8 (2S, 4R)-4-Metliylarnino-4-[1-(4-chloroplieny)cyclobutyl-2-rethyl-butan-i.-ol 4 A solution of amino alcohol (2.52 g, 9.4 mmol) with formic acid (4.3 g, 94 mmiol) in toluene (30 mQL was heated to reflux for 5 h. After the solvent was removed on rotary evaporator, THE (20 mQL and borane-T-IF (20 mL, 1.0 M in THF) were added under argon at 0 TC. After the reaction mixture was stirred at room temperature for 24 h, the reaction was quenched with 2 N NaOH. After separation, the aqueous phase was extracted with TBME. The organic phase was dried over NaSO 4 After the-solvent was removed, the residue was isolated by chromatography on silica gel, eluting with heptane/ethyl acetate/trietliyl amine to give 5:1.79 g (68% yield). 'H NMR (CDCl 3 /TMS): 8 7.34 J 8.6 Hz, 2H), 7.24 J 8.6 Hz, 2H), 3.45-3.30 (mn, 2H), 3.21 (brs, 2H), 2.78 J 9.9 Hz, IH), 2.55 3H), 2.60-2.15 (mn, 4H), 1.95-1.70 (in, 3H), 1.50-1.40 (in, 1H), 0.93 J= 7.1 Hz, 3H), 0.95-0.80 (in, 1H). 3 C NMR (CDC1 3 6142.5, 132.0, 129.0, 128.0, 66.8, 63.1, 9 52.2, 35.6, 35.5, 35.1, 33.4, 32.9, 17.0, 16.2.

To the flask containing the amino alcohol (1.0 g, 3.5 5 minol), was added LiCi inL, 2.0 M in ether) and anhydrous ethanol (1 mL). A-fter the mixture was stirred at room temperature for 3 0 min, the white solid was fonined and filtered. The solid was dried under vacuum. 0.8 g (62% yield) of the HCI ethanol solvate (C, 6

H

24 C1N0-EtOH-HCI) was obtained. 'H NMR (DMSO): 8 8.62 (brs, 1H), 8.23 (brs, 1H), 7.47 (mn, 4H), 4.68 (brs, 1M), 4.40 (brs, 1H), 3.60 (in, 1W), 3.46 J 6.7 Hz, 2H), 3.26 (in, 2H), 2.56 3H), 2.70-2.20 (in, 4H1), 1.94 (in, 1W), 1.80-1.40 (mn, 3H), 1.07 J 6.7 Hz, 3H), 1.00 (in, lB 0.88 (di, J 5.3 Hz, 3H). 1 3 C NMR (DMSO): 6 14922132.2,130.8, 128.8, 66.3, 64.8, 56.7, 49.9, 3 3.7. 33.5, 3 3.1, 3 2.5. 19.3, 18.0, 16.2.

69 WO (12/46138 PCT/US(I /47433 00 (2R,4S)-N-Me-8 lt) (2R, 4S)-4-Methylamino-4-[1-(4-chlorophenyl)cyclobutyl]-2-methyl-butan- -ol 00 A solution of amino alcohol (2.0 g, 7.5 mmol) and formic acid (3.45 g, 75 rrmol) in 0 O toluene (30 mL) was heated to reflux for 5 h. After the solvent was removed on rotary 00 5 evaporator, the residue was dissolved into THF (20 mL). Borane-THF (20 mL, 1.0 M in ITHF) was added under argon at 0 After being stirred at room temperature for 24 h, the reaction mixture was quenched with 2 N NaOH. After separation, the aqueous phase was extracted with TBME. The organic phase was dried over NaSO 4 After the solvent was removed, the residue was isolated by chromatography on silica gel, eluting with heptane/ethyl acetate/triethyl amine(1/9/0.2) to give 6:1.41 g (67% yield).

To the flask containing the amino alcohol (1.0 g, 3.55 mmol), was added HCI mL, 2.0 M in ether) and anhydrous ethanol (1 mL). After the mixture was stirred at room temperature for 30 min, the white solid formed was filtered and dried under vacuum. 0.8 g (62% yield) of HC1 salt (C,6H, 2 CINO-EtOH-HCI) was obtained. The 'H NMR and "C NMR of amino alcohol as well as the HC1 salt are identical to those of amino alcohol above.

9H C1 H 3

C

N

(2S,4S)-N-Me-8 (2S, 4S)-4-Methylamino-4-[1'-(4-chlorophenyl)cyclobutyl]-2-methyl-butan-l-ol A solution of amino alcohol 3 (2.30 g, 8.6 mmol) and formic acid (4.0 g, 86 mmol) in toluene (30 mL) was heated to reflux for 5 h. After the solvent was removed on rotary evaporator, the residue was dissolved into THF (20 mL). Borane-THF (20 mL, 1.0 M in THF) was added under argon at 0 After the reaction mixture was stirred at room temperature for 24 h, the reaction was quenched with 2 N NaOH. After separation, the WO (12/46138 PCT/US 1/47433 OO aqueous phase was extracted with TBME. The organic phase was dried over NaSO 4 After O the solvent was removed, the residue was isolated by chromatography on silica gel, eluting I with heptane/ethyl acetate/triethyl aniine=1/9/0.2 to give 1.79 g of?? (74% yield). 'H NMR (CDC1 3 /TMS): 6 7.35 J 8.6 Hz, 2H), 7.25 J 8.6 Hz, 2H), 3.60 (brs, 2H), 3.45 (m, in 5 IH), 3.07 1H), 2.73 3 10.3 Hz, IH), 2.56 3H), 2.60-2.15 4H), 1.95-1.70 (m, 3H), 1.50 IH), 0.86 3 7.0 Hz, 3H), 0.60-0.47 IH). 'H NMR(CDCI 3 8 141.9, t 132.1, 129.0, 128.1, 68.9, 68.4, 52.4, 39.1, 37.3, 36.2, 35.3, 33.6, 19.2, 17.1.

OO To the flask containing 7 (1.0 g, 3.55 mmol), was added the solution of D-tartaric O acid (0.53g, 3.55 mmol) in methanol (15 mL). The solution was concentrated to about 5 mnL 00 10 by evaporation and put in refrigerator for crystallization. The solid was filtered and dried Sunder vacuum. 1.38 g (85% yield) of the D-tartrate salt (CiH 2 4

CINO-C

4 H 0 6 -1.5H 2 0) was obtained. 'H NMR (DMSO): 5 7.42 3 8.7 Hz, 2H), 7.37 3 8.7 Hz, 2H), 5.85 (brs, 6H), 4.00 2H), 3.30-3.20 2H), 3,11 1H), 2.52 3H), 2.60-2.20 4H), 1.91 (m, 1H), 1.80-1.50 2H), 1.18 2H), 0.82 3 6.6 Hz, 3H). "C NMR (DMSO): 5 174.9, 143.2, 131.9, 130.5, 128.6, 72.4, 66.9, 64.5, 50.2, 34.3, 34.1, 33.0, 32.8, 32.7, 17.1, 16.0.

Anal. Calcd for C, 0

H

3 oCINO-1.5H 2 0: C, 52.34; H, 7.25; N, 3.05. Found: C, 52.25; H, 7.30; N. 2.90.

H

,NH CI NH3C (2R,4R)-N-Me-8 (2R, 4R)-4-Methylamo-4-[1-(4-chlorophenyl)cyclobutyl-2-methylbutan-l-ol A solution of amino alcohol (1.84 g, 6.89 mmol) with formic acid (3.2 g, 70 mmol) in toluene (30 mL) was heated to reflux for 5 h. After the solvent was removed by rotary evaporator, the residue was dissolved into THF (20 mL) and Borane-THF (20 mL, 1.0 M in THF) was added under argon at 0 After the reaction mixture was stirred at room temperature for 24 h, the reaction was quenched with 2 N NaOH. After separation, the aqueous phase was extracted with TBME. The organic phase was dried over NaSO 4 After -71- WO (12/46138 PCT/US(I1/47433 00 the solvent was removed, the residue was isolated by chromatography on silica gel, eluting with heptane/ethyl acetate/triethyl amine l/9/0.2(v/v/v) to give 0.88 g of 8 (45% yield).

To a flask containing 8 (0.81 g, 2.9 mmol), was added the solution ofL-tartaric acid j (0.44 g, 2.9 minol) in methanol (15 mL). The mixture was concentrated to about 5 mL by r 5 evaporation and standed in a refrigerator for crystallization. The solid was filtered and dried under vacuum. 1.10 g (83% yield) of the L-tartrate salt (C, 6

H,

4 ClNO-C 4 H0,-1 .5H20) was n obtained. The 'H NMR and "C NMR of amino alcohol: 8 as well as the tartaric acid salt are 0 00 identical to those of amino alcohol 7. Anal. Calcd for C, 0

H

3 0 C1NO 7 -1.5H20: C, 52.34; H, S7.25; N, 3.05. Found: C, 52.47; H,7.15; N, 2.93.

00 0

O

S| ,B-H 0 12 To a dried 100 mL three-neck flask, equipped with a thermometer and an outlet, was added phthalic acid (4.58 g, 27.6 rmnol) and THF (32 mL, degassed with Ar) under argon.

The mixture was stirred at room temperature for 10 mm to dissolve the solid. After cooling to -20 oC, BH3-THF (27.6 mL, 1 M in THF, 27.6 mmol) added via syringe. The mixture was stirred at -20 °C for approximately 30 min until the evolution of hydrogen ceased. The resulting homogeneous solution was cooled to -78 OC and used for next reaction.

j 1 MgCI

N..

CI MgBr (2R)-10 (2R)-4-Imino-2-methyl-4-[1-(4-chlorophenyl)-cyclobutyl]-butau-l-ol magnesium salt A 100 mL three-neck flask, equipped with a thermomate, a reflux condenser and an addition funnel, was dried and flashed with argon. Isopropylmagnesium chloride (2.0 M in Et2O, 3.3 mL, 6.6 mmol) was charged and cooled to -25 oC. (S)-3-Broino-2-methvl-propan- -72- WO 02/46138 PCT/USO1l/47433 l-ol (1.0 g, 6.54 nmlol) in Et,O (5 mL) was added over 15 mm. The mixture was allowed to 00 O warm to ambient temperature over I h to form a homogeneous solution. Magnesium turnings (300 mng, 12.5 mmol) were added in one portion, and the mixture was stirred Swithout heating for 1 h. The reaction was exothennic and the mixture refluxed. The internal temperature fell gradually to 25 oC when the reaction ceased. The solution was titrated (0.6 M, 80% yield). A solution of l-(4-chloro-phenyl)-cyclobutanecarbonitrile (880 t mg, 4.6 rmnol) in THF (2 mL) was added dropwise. The reaction was stirred at ambient 00 temperature for 2 h, and cooled to -78 °C for next reaction.

00 N H C"

NH

2

CI

(2R,4R)-8 (2R,4R)-4-Methylamnino-4-[1-(4-chloro-phenyl)-cyclobutyl]-2-methyl-butan-l-oI The precooted solution of magnesium salt (R)-10 was added dropwise to the above phthalic borane solution at -78 The addition rate was controlled so that the internal temperature was kept below -70 The mixture was stirred at -78 'C for I h. The reaction was monitored by HPLC. After the reaction was complete, 3 N NaOH (5 mL) was added to quench the reaction. The mixture was warmed to ambient temperature and filtered off the white solid. The filtration was extracted with CH 2 C1 2 (3 X 15 mL) and dried (CaCO 3 Removal of the solvents and purification of the residue by flash chromatography on silica Sgel (elute with AcOEt-MeOH-Et 3 N 90:9:1) gave a mixture of diasteromers in the ratio of 98:2, favoring (2R,4R)-1-OH DDMS as the major product.

73 WO 02/46138 WO (~246 138PCT/USO 1/47433 )MgCI MgBr (2S)-1 0 (2S)-4-Imino-2-methyi--I1-(4-chlorophenyl)-cyclobutyll-butan-1-oI magnesium salt The same procedure as described above for the preparation of was applied, except using -broino-2-methyl-propan-lI-ol, instead of -broino-2-methyl-pro pan- I -ol1.

(2S,4S)-8 (2S, 4S)-Methylaniino-4-I -(4-chlorophenyl)-cyclobutyll-2-methl-buan-lot The same procedure as described above for the preparation of (2R,4R)-lI-OH-DDMS was applied, except using The reaction gave a mixture of diasteroiners in the ratio of greater than 95:5, favoring (2S,4S)-1I-OH DDMS as the major product.

5.1.2. 7-IIYDROXYL EXPERIMENTAL DATA 1-(4-Chloro.-phenyI)-3-Ihydroxy-cycobutanecarbaldehyde To a solution of 1-(4-chloro-phenyl)- 3 -hydroxy-cyclobutanecarbonitrile (cis/trans 2-6:1) (25.0 g, 0. 12 mol) in THY (100 mL) at 0 oC, was slowly added the solution of Dibal (260 mL, 1 .0 M in hexane, 0.26 mol). After the reaction mixture was stirred at 0 oC for I h, IH NIVR of the reaction mixture showed the reaction was complete. The reaction was then 74 WO 0(1246138 PCT/USO 1/47433 00 quenched by the addition of 10% aqueous citric acid (200 mL) at -78 oC. After the reaction Smixture was warmed to room temperature, the solid was filtered off and rinsed with TBME.

The organic phase was separated and aqueous phase was extracted with TBME (2x60 mL).

SThe organic layers were combined and dried over magnesium sulfate. The solvent was n) 5 removed and the residue was purified by silica gel chromatography, eluting with 25% ethyl acetate in heptane to give the a mixture of cis and trans aldehyde (cis/trans 21.0 g m in 83% yield. 1H NMR (CDC13/TMS): d 9.52 1H), 7.40-7.05 4H), 4.32 1H), 00 3.15-3.08 0.6H), 2.80-2.70 1.4H), 2.70-2.60 1.4H), 2.35-2.25 0.6H). 13C O NMR (CDC13): d 200.0, 199.7,139.3, 137.7, 133.7, 133.6, 129.4, 129.0, 128.9, 128.2, 63.2, 00 10 62.0, 50.5, 49.9, 40.0, 39.9.

4 OH HO- Cl t N Cl IN 0 0 N-(1-(4-Chlorophenyl)-3-hydroxy-cyclobutanemethylene)-(R)-tert-butanesu finamide To a solution of 1-(4-chlorophenyl)-3-hydroxy-cyclobutanecarbaldehyde (12.8 g, 61.0 mmol) in THF (20 mL), was added (R)-t-butanesulfinamide (7.4 g, 61.0 mmol), toluene (100 mL) and Ti(OEt) 4 (69.4 g, 304 mmol). The reaction mixture was heated and stirred at 100 OC for 1 h. TLC showed the reaction was complete. The reaction mixture was then poured into ice water and the solid was filtered off. The product was extracted with ethyl acetate and the solution was dried over magnesium sulfate. After the solvent was removed, the residue was purified by silica gel chromatography eluting with heptane/ethyl acetate l/l(v/v) to give trans-11 (higher Rf): 5.3 g and cis-isomer (lower Rf): 12.1 g in 91% combined yield. Trans-isomer: 'H NMR (CDCI 3 /TMS): 6 7.99 1H), 7.31 J 8.7 Hz, 2H), 7.08 J 8.7 Hz, 2H), 4.39 1H), 3.25-3.07 2H), 2.44-2.35 2H), 1.72 (brs, 1H), 1.18 9H). "C NMR (CDCI 3 8 170.9, 142.4, 133.1, 129.2, 127.8, 62.5, 57.5, 44.2, 42.4, 42.2, 22.6. Cis-11: 'H NMR (CDC 3 /TMS): 8 8.00 1H), 7.34 J 8.5 Hz, 2H), 7.21 J 8.7 Hz, 2H), 4.32 1H), 2.94-2.87 2H), 2.75-2.60 2H), 2.35 (brs, 1H), 1.18 9H). "C NMR (CDCI 3 8 171.8, 140.5, 133.2, 129.2, 128.7, 63.1, 57.5, 45.1, WO (12/46138 PCT/US1/47433 42.4, 22.6. Anal. Calcd for C15H20CINO 2 S: C, 57.40; H, 6.42; N, 4.46. Found: C, 57.49; 00 SH, 6.44; N, 4.33.

,f 'OH HO cl 0 C NS,° n Cis-30 00 N-(1-(4-Chlorophenyl)-3-hydroxy-cyclobutanenlethylene)-(S)-tert-butanesulfinamide 00 To a solution of 1-(4-chlorophenyl)-3-hydroxy-cyclobutanecarbaldehyde (12.4 g, 59.0 mmol) in THF (20 mL), was added (R)-t-butanesulfinamide (5.95 g, 49.0 mmol), 4 toluene (120 mL) and Ti(OEt) 4 (68.5 g, 0.30 mol). The reaction mixture was heated and stirred at 100 oC for 1 h. TLC showed the reaction was complete. The reaction mixture was then poured into ice water and the solid was filtered off. The product was extracted with ethyl acetate and the solution was dried over magnesium sulfate. After the solvent was removed, the residue was purified by silica gel chromatography eluting with heptane/ethyl acetate 1/l(v/v) to give trans-12 (higher Rf): 4.55 g and cis-12 (lower Rf): 9.67 g in 92% yield. The 'H NMR and 3 C NMR data of these compounds are identical to those of the enantiomers: cis-11 and trans-ll. Cis-12: Anal. Calcd for CisH 20 C1NOS: C, 57.40; H, 6.42; N, 4.46. Found: C, 57.56; H, 6.47; N, 4.32.

Reaction of cis-30 with isobutyllithium (Table General Procedure: To the W solution of cis-ll (25 mg, 0.08 mmol) in various solvent (5 mL) at -78 was added the solution of isobutyllithium in hexane (3.2 or 2.2 The reaction mixture was continued to stir at -78 The yield and diastereoselectivity of the addition product were obtained by achiral HPLC method.

Procedure for the reaction in the presence of Lewis acid (entries To the mixture of cis-11 (25 mg, 0.08 mmol) in THF (5 mL) and Lewis acid at -78 was added the solution of isobutyllithium (0.18 mL, 1.47 M in hexane, 0.26 nmmol). The reaction mixture was continued to stir at -78 The yield and diastereoselectivity of the addition product were obtained by achiral HPLC method.

-76- WO (12/46138 WO (1246138PCT/US(I 1/47433 00 c-I 4 0 38 Cis-(1 {1-[I1-(4-chlo ro p heny)-3-hyd roxycycob utyI -3-methylb u tyI}-(R)-tert-b utan esulfinamide 00 0 C for 10 min, isobutyllithium (23 mL, 1.47 M in hexane, 33.8 mmnol) wvas slowly added.

ri After the addition was complete, the reaction mixture was stirred at -78 'C for 1 h. TLC showed the reaction was complete. The reaction was then quenched by methanol (10 m-L) and aqueous saturated sodium bicarbonate (50 The reaction mixture was allowved to warmn to room temperature. HPLC showed the ratio of the products was 97.8:2.2. The two phases were separated. The aqueous phase was extracted with TBME (2030 maL). The organic layers were combined and dried over magnesium sulfate. After solvent was removed, the residue was purified by silica gel chromatography eluting with a mixture of solvents: ethyl acetate/heptane =7/3 to give 13:3.62 g in 93% yield. 'H NMiR

(CDCI

3 /TMS): 8 7.40-7.25 (in, 4Hf), 4.01 (in, lH), 3.41 (mn, 1H1), 3.00-2.90 (mn, 2H), 2.87-2.75 (in, 11f), 2.47-2.39 (in, IH), 2.11-2.04 (in, 111), 1.56 (mn, 1H), 1.20-0.65 (in, 2H), 1. 17 9H), 0.85 J 6.5 Hz, 3H), 0.82 J 6.7 Hz, 3H). 1 3 C NMR (CDCI 3 8 140.3, *132.5, 131.0, 128.3, 66.3, 61.8, 57.0, 47.0, 43.2, 43.1, 40.6, 24.09, 24.06, 23.0, 21 Anal.

Calcd for C1 9

H

30 C1N0 2 S: C, 61.35; H, 8.13; N, 3.77. Found: C, 61.41; H, 8.33; N4,3.67.

I HN--S-l

CI

Cis-(LS)-N- I 1 -f1-(4-chlorophenyl)-3-hydroxycyclobutyII-3-methylb utyl}-(S)-tert-bu tan esulfinanjide 77 WO 12/46138 PCT/LJS01/47433 To the solution of cis-30 (6.86 g, 21.9 rmnol) in THF (150 mL) at -78 was added O boron trifluoride etherate (9.97 g, 8.9 mL, 70.0 numol). After the mixture was stirred at CN -78 °C for 10 min, isobutyllithium (60.9 mL, 1.15 M in hexane, 70.0 mmnol) was slowly Sadded. After the addition was complete, the reaction mixture was stirred at -78 "C for 1 h.

S 5 TLC showed the reaction was complete. The reaction was then quenched by methanol mL) and aqueous saturated sodium bicarbonate (50 mL). The reaction mixture was allowed t to warm to room temperature. HPLC showed the ratio of the products was 96.4:3.6. The 00 two phases were separated. The aqueous phase was extracted with TBME (2x30 mL). The 0organic layers were combined and dried over magnesium sulfate. After solvent was 00 10 removed, the residue was purified by silica gel chromatography eluting with a mixture of O solvents: ethyl acetate/heptane 7/3 to give 15: 7.88 g in 97% yield. The 'H NMR and 3 C NMR data of 15 are identical to those of enantiomer: 13. Anal. Calcd for C19H 3 0

CINO

2 S: C, 61.35; H, 8.13; N, 3.77. Found: C, 61.05; H, 8.18; N, 3.63.

HO

CI HN-s' Trans-(1R)-N-{1-[1-(4-chlorophenyl)-3-hydroxycyclobutyll-3-methylbutyl}-(R)-tert-bu tanesulfinamide Reaction of trans-30 with isobutyllithium (Table General Procedure: To the solution of trans-30 (25 mg, 0.08 mmol) in various solvent (5 mL) at -78 oC, was added the solution of isobutyllithium in hexane (3.2 or 2.2 The reaction mixture was continued to stir at -78 The yield and diastereoselectivity of the addition product were obtained by achiral HPLC method. Procedure for the reaction in the presence of Lewis acid (entries 4-6): To the mixture of trans-11 (25 mg, 0.08 mmol) in THF (5 mL) and Lewis acid at -78 was added the solution of isobutyllithiun (0.18 mL, 1.47 M in hexane, 0.26 mmol). The reaction mixture was continued to stir at -78 The yield and diastereoselectivity of the addition product were obtained by achiral HPLC method. The major product 17 (74% yield, Table 3, entry 1) was isolated by silica gel chromatography, eluting with heptane/ethyl acetate 1/1 'H NMR (CDCl 3 /TMS): 8 7.28 J 8.0 Hz, 2H), 7.09 J 8.0 Hz, -78 (12/46138 PCTr/US(I 1/47433 0 211), 4.46 (in, lH), 3.40 (brs, 111), 3,40-3.25 (mn, 2H), 3.05 J 9.S Hz, 1H1), 2.66 (in, IH), .32 (dd, 1=7.0, 11.8 Hz, 1H), 2.18 (dd, J= 7.0, 12.6 Hz, lH), 1.59 (mn, lH), 1-36-0-70(na, 2H), 1. 15 911), 0.90 J =6.5 Hz, 3H), 0.83 J 6.6 Hz, 3H). 3 C NMR (CDC 3 6 144.0, 132.21 129.5, t128.3, 62.6, 62.4, 57.1, 44.1, 43.2,42.6, 42.0, 24.3, 24.1, 23.1, 2 1.1.

00~ 00 T ran s-N-(1 -(4-ch lo ro ph enyl)-3- meth o xyrneth oxy-eylobutan emethylen e)-(R)-tert-b uta nes u fluamide To the mixture of trans-I 11 (6.45 g, 20.6 nunol) and diisopropylethylamine (28.8 niL, 165.4 mnmol) in dichloromnethane (100 niL) at 0 was added methoxymethyl bromide (10.6 g, 82.0 inmol). The reaction mixture was stirred at room temperature for 24 h. After dichioromethane was removed by rotary evaporator, toluene (30 mL) was added and the mixture was stirred at room temperature for I h. TLC checked the reaction midxture and showed about 10% starting material left. To the reaction mixture, was added additional diisopropylethylainine (2.5 rnL, 14.3 n-unol) and inethoxyi-nethyl bromide (1.5 g 12.0 no) at 0 c. The reaction mixture was then stirred at room temperature for 12 h. TLC showed no starting material left. After usual work-up, the product: 19 (5.45 g, 74% yield) was isolatedby silica gel chromatography eluting with 25% ethyl acetate in heptane. 'HNM

(CDCI

3 /TMS): 868.01 IM, 7.31 J =8.7 Hz, 211), 7.08 J 8.7 Hz, 2H), 4.61 (s, 211, 4.22 (in, 111, 3.36 3H), 3.20-3.10 (in, 2H), 2.52-2.42 (in, 2H), 1.17 9H1). 13C NMIR(CDC13): d 170.7, 142.4, 133.0, 129.1, 127.7, 95.5, 66.6, 57.5, 55.8, 45.1, 40.0, 22.6.

Anal. Calcd for C, 7

H

24 C1N0 3 S: C, 57.05; H, 6.76; N, 3.91. Found: C, 57.11; H, 6.75; N, 3.87.

CiI N S 79 WO (12/4138 PCT/USOI/47433 Trans-N-(l-(4-chlorophenyl)-3-methoxymethoxy-cyclob utanemethylene)-(S)-tert-b utan 0 esulfinaniide 0 To the mixture of trans-12 (4.42 g, 14.1 mmol) and diisopropylethylamine (10.1 mL, S58 rmnol) in ether (10 mL) and dichloromethane (10 mL) at 0 oC, was added methoxymethyl [T 5 chloride (2.30 g, 28.6 mmol). The reaction mixture was stirred at room temperature for 16 h. TLC showed no starting material left. After usual work-up, the product: 20 (4.51 g, 89% yield) was isolated by silica gel chromatography eluting with 25% ethyl acetate in heptane.

'H NMR and 3 C NMR data 20 is identical to those of enantiomer 19. Anal. Calcd for 0010 00 NN0 CI

N

Traos-N-(l-(4-chlorophenyl)-3-tert-butyldimethylsi oxy-cyclobutanemethylene)-(R)-ter t-butanesulfinamide To the solution of cis-I1 (0.116 g, 0.37 mmol) and imidazole (0.101 g, 1.48 mmol) in DMF (10 mL), was added TBDMSC1 (0.112g, 0.74 mmol). After the reaction mixture was stirred at rt for 4 h, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride, dried over magnesium sulfate. After solvent was removed, the residue was purified by preparative TLC plate with 10% ethyl acetate as solvent to give 19a: 0.106 g, 67% yield. 'H NMR (CDC1 3 /TMS): 6 8.02 1H), 7.31 J 8.7 Hz, 2H), 7.08 J 8.7 Hz, 2H), 4.36 1H), 3.20-3.10 1H), 3.10-2.95 1H), 2.50-2.35 2H), 1.19 9H), 0.88 9H), 0.06 6H). "C NMR (CDCl 3 6 171.0, 142.3, 132.7, 128.8, 127.6, 62.2, 57.2, 44.2, 42.6, 25.7, 22.4, 17.9, -4.9.

General Procedure: To the solution of 30 (0.06-0.07 mmol) in THF (2 mL) in the presence or in the absence of Lewis acid (2.0 eq) at -78 OC, was added the solution of isobutyllithium in hexane The reaction mixture was continued to stir at -78 The yield and diastereoselectivity of the addition product were obtained by achiral HPLC method.

80 WO 02/46138 PCT/US(o1/47433 00

TBDMSO

t Trans-(1 R)-N-{1-[l-(4-chlorophenyl)-3-tert-butyldimethylsiloxy-cyclobutyl]-3-methylb 00 utyl}-(R)-tert-butanesulfinamide This compound was prepared by the above described procedure in 84% yield. 1

H

NMR (CDCl 3 /TMS): 6 7.28 J 8.3 Hz, 2H), 7.10 J 8.3 Hz, 2H), 4.39 1H), 00 0 5 3.40-3.22 2H), 3.01 J 9.9 Hz, 1H), 2.63 1H), 2.31 (dd, J 7.2, 11.7 Hz, 1H), (N 2.16 (dd, J 7.2, 12.2 Hz, 1H), 1.60 1H), 1.20-0.60 8H), 1.19 9H), 0.84 9H), 0.03 6H). 3 "C NMR (CDC1 3 6 144.3, 132.1, 129.6, 128.1, 62.9, 62.4, 57.0, 44.2, 43.5, 43.2, 42.0, 25.9, 24.4, 24.1, 23.1, 21.2, 18.1, -4.6.

CI A HN.sK Trans-(lR)-N-{1-[1-(4-chlorophenyl)-3-methoxymethoxy-cyclobutyll-3-methylbutyl}- (R)-tert-butanesulfinamide To the solution of MOM protected trans-sulfinamide 19 (4.77 g, 13.3 mmol) in THF S(170 mL) at -78 "C under an argon atmosphere, was added the solution of isobutyllithium in hexane (23.1 mL, 1.15 M, 26.6 mmol). After the reaction mixture was stirred at -78 "C for 1 h, TLC showed the reaction was complete. The reaction was then quenched with methanol mL) and water (10 mL) at -78 The cold bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was washed with brine and dried over magnesium sulfate. HPLC showed the ratio of the products was 99.3:0.7. After solvent was removed, the residue was purified by silica gel chromatography eluting with 30% ethyl acetate in heptane to give 21: 5.53 g, 100% yield. 'H NMR (CDC13/TMS): 6 7.29 J 8.5 Hz, 2H), 7.12 J 8.5 Hz, 2H), 4.58 2H), 4.31 1H), 3.45-3.25 2H), 3.33 3H), 2.97 J 10.1 Hz, 1H), 2.65 1H), 2.39 (dd, J 7.2, 12.1 Hz, 1H), 2.25 -81 WO (12/46138 PCT/USo 1/47433 (dd, J 7.1, 12.6 Hz, 1H), 1.61 1H), 1.36-0.70 2H), 1.18 9H), 0.91 J 00 g Hz, 3H), 0.83 J 6.7 Hz, 3H). 'C NMR (CDC1 3 5 143.9, 132.3, 129.6, 128.3, 95.1, r 66.8, 62.5, 57.1, 55.7, 44.0, 41.9, 41.4, 40.5, 24.3, 24.2, 23.1, 21.2. Anal. Calcd for

SC

21

H

34

CINO

3 S: C, 60.63; H, 8.24; N, 3.37. Found: C, 60.54; H, 8.24; N, 3.17.

,0i in O 0oo

H

00 O Trans-(1S)-N-{1-([-(4-chlorophenyl)-3-methoxymethoxy-cyclobutyl]-3-methylbutyl}- (S)-tert-butanesulfinamide To the solution of MOM protected trans-sulfinamide (4.44 g, 12.4 mmol) in THF (150 mL) at -78 °C under an argon atmosphere, was added the solution of isobutyllithium in hexane (23.7 mL, 1.15 M, 27.3 mmol). After the reaction mixture was stirred at -78 oC for 1 h, TLC showed the reaction was complete. The reaction was then quenched with methanol (10 mL) and water (10 mL) at -78 oC. The cold bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was washed with brine and dried over magnesium sulfate. HPLC showed the ratio of the products was 99.8:1.2. After solvent was removed, the residue was purified by silica gel chromatography eluting with 30% ethyl acetate in heptane to give 23: 4.86 g, 94% yield. 'H NMR and "C NMR spectra are identical to those of enantiomer 21. Anal. Calcd for C 21

H

34

CINO

3 S: C, 60.63; H, 8.24; N, 3.37. Found: C, 60.47; H, 8.33; N, 3.06.

HO

c NH 2 Trans-(1R)-3-(1-amino-3-methyl-butyl)-3-(4-chlorophenyl)-cyclobutanol The mixture of 21 (2.00 g, 4.8 mmol) with 2 N HC1 in methanol (10 mL) was heated to reflux for 30 min. After it was cooled down, the solvent was removed and the residue was dissolved into water (150 mL), washed with TBME (30 mL). The aqueous phase was -82 WO (12/46138 PCT/US01/47433 0 basified with" sodium hydroxide (1.2 g, 30 mmol), extracted with TBME (3x50 mL). The STBME solution was dried over magnesium sulfate. After the solvent was removed, the crude product with D-tartaric acid (0.72 g, 4.8 mmol) was dissolved into methanol (10 mL) Sand toluene (20 mL). After methanol was evaporated, white solid was precipitated out. The 5 solid was filtered, rinsed with hexane (2x10 miL) and dried under vacuum. 1.69 g (82% yield) of the D-tartaric acid salt was obtained. 'H NMR (DMSO): 6 7.40 J 7.8 Hz, 2H), t 7.19 J 7.8 Hz, 2H), 6.04 (brs, 9H), 4.23 1H), 3.95 2H), 3.27 J 10.3 Hz, 00 1H), 2.95 1H), 2.65 1H), 2.15-1.95 2H), 1.62 1H), 1.28 J 12.7 Hz, 1H), 0 0.93 J 11.6 Hz, 1H), 0.86 J 6.2 Hz, 3H), 0.81 J 6.4 Hz, 3H). "C NMR 00 10 (DMSO): 5 174.3, 143.8, 131.1, 129.3, 127.9, 71.6, 60.4, 55.1, 42.9, 42.4, 41.1, 38.3, 23.8, 23.4, 20.9. Anal. Calcd for C, 9

H,

8 CINO0-1.5 H 2 0: C, 52.90; H, 6.89; N, 3.25. Found: C, 53.11; H, 6.81; N, 3.11.

HO

C NH 2 Trans-(1S)-3-(1-amino-3-methyl-butyl)-3-(4-chlorophenyl)-cyclobutanol The mixture of 32 (1.87 g, 4.5 mmol) with 2 N HC1 in methanol (10 mL) was heated to reflux for 30 min. After it was cooled down, the solvent was removed and the residue was dissolved into water (150 mL), washed with TBME (30 mL). The aqueous phase was basified with sodium hydroxide (1.2 g, 30 mmol), extracted with TBME (3x50 mL). The TBME solution was dried over magnesium sulfate. After the solvent was removed, the crude product with L-tartaric acid (0.68 g, 4.5 mmol) was dissolved into methanol (10 mL) and toluene (20 mL). After methanol was evaporated, white solid was precipitated out. The solid was filtered, rinsed with hexane (2x10 mL) and dried under vacuum. 1.56 g yield) of the L-tartaric acid salt was obtained. The 'H NMR and 'C NMR data are identical to those of 1. Anal. Calcd for C, 9

H

2 8CINO-0.75H 2 0: C, 52.90; H, 6.89; N, 3.25. Found: C, 52.91; H, 6.86; N, 2.96.

83 WO (12/46138 PCT/USI 11/47433 00

,OH

C Cl NH 2 t Cis-(l R)- 3 -(1-anino-3-methyl-butyl)- 3 4 -chlorophenyl)-cyclobutanol The solution (2.08 g, 5.6 mmol) in methanol (10 mL) was treated with 2 N HCI in methanol (15 miL). The reaction mixture was stirred at room temperature for 22 h. The 0 methanol was removed and the residue was dissolved into water (150 mL), washed with TBME (30 mL). The aqueous phase was basified with sodium hydroxide (2.0 g, 50 nmmol), extracted with TBME (3x50 mL). The TBME solution was dried over magnesium sulfate.

After the solvent was removed, the crude product with L-tartaric acid (0.84 g, 5.6 mmol) was dissolved into methanol (10 mL). After the mixture was stirred at room temperature for min, TBME (10 mL) was added and the mixture was stirred at room temperature for additional 30 min. The white solid was filtered, rinsed with hexane (2x10 mL) and dried under vacuum. 1.87 g (82% yield) of the L-tartaric acid salt was obtained. 'H NMR (DMSO): 6 7.42 4H), 6.35 (brs, 7H), 3.93 2H), 3.73 1H), 3.34 J 9.3 Hz, 1H), 2.80-2.60 2H), 2.20 (dd, J 7.4, 10.9 Hz, 1H), 2.03 (dd, J 7.8, 10.9 Hz, 1H), 1.59 1H), 1.11 J 13.1 Hz, 1H), 0.90-0.60 7H). "C NMR (DMSO): 6 174.3, 140.2, 131.4, 130.4, 128.1, 71.5, 60.4, 58.0, 43.5, 43.2, 41.5, 38.0, 23.6, 23.2, 21.1. Anal. Calcd for C,gHsCINO: C, 54.61; H, 6.75; N, 3.35. Found: C, 54.58; H, 6.79; N, 3.44.

.,\OH

CI

NH

2 Cis-( S)-3-(1-amino-3-methyl-butyl)-3-(4-chlorophenyl)-cyclob u tanol The compound (2.08 g, 5.6 mmol) in methanol (15 mL) was treated with 2 N HCI in methanol (20 mL). The reaction mixture was stirred at room temperature for 22 h. The methanol was removed and the residue was dissolved into water (150 mL), washed with TBME (30 mL). The aqueous phase was basified with sodium hydroxide (2.0 g, 50 mmol), -84- WO (12/46138 PCT/LUSoI1/47-33 00 extracted with TBME (3x50 mL). The TBME solution was dried over magnesium sulfate.

After the solvent was removed, the crude product with D-tartaric acid (0.84 g, 5.6 mmnol) was dissolved into methanol (10 mL). After the mixture was stirred at room temperature for min, TBME (10 mL) was added and the mixture was stirred at room temperature for t 5 additional 30 min. The white solid was filtered, rinsed with hexane (2x 10 mL) and dried under vacuum. 1.96 g (85% yield) of the D-tartaric acid salt was obtained. 'H NMR and 1 3

C

tn NMR data are identical to those of 3. Anal. Calcd for C, 9

H

28 CLNO,: C, 54.61; H, 6.75; N, 00 3.35. Found: C, 54.31; H, 6.82; N, 3.29.

O

HO

00

C

1 NHMe Trans-(1R)-3-(1-methylamino-3-methyl-butyl)-3-(4-chlorophenyl)-cyclobutanol Typical procedure for the preparation 7-OH DMS: The crude amino alcohol, which was prepared from the deprotection of 30 (2.60 g, 6.2 mmol), was dissolved into toluene mL). To the resulting solution, was added formic acid (2.85 g, 62 mmol). The reaction mixture was then heated to reflux for 5 h. After the solvent was removed, the residue was mixed with borane-THF (20 mL, 1.0 M in THF, 20.0 mmol) at 0 OC. After the reaction mixture was stirred at room temperature for 24 h, the reaction was quenched with 2 N HCI mL), diluted with water (150 mL). After separation, the aqueous phase was basified with KOH, extracted with TBME (3x50 mL). The organic layers were combined and dried over magnesium sulfate. The solvent was removed and the residue was dried under vacuum to give crude amino alcohol: 1.33 g in 76% yield. The crude product (1.33 g, 4.7 mmol) with (R)-mandelic acid (0.715 g, 4.7 mmol) was dissolved into methanol (5 mL). After the mixture was stirred at room temperature for 30 min, TBME (10 mL) was added and white solid was precipitated out. The solid was filtered, rinsed with TBME (10 mL), hexane mL) and dried under vacuum to give 1.60 g (78% yield) of the (R)-mandelic acid salt. 'H NMR (DMSO): 8 7.60-7.00 9H), 4.75 1H), 4.70 (brs, 5H), 4.25 1H), 2.95-2.80 2H), 2.63 1H), 2.47 3H), 2.10-1.90 2H), 1.54 1H), 1.23 1H), 1.0-0.6 7H). 13C NMR (DMSO): 8 174.3, 145.6, 142.1, 130.6, 129.1, 127.7, 126.8, 126.4, 73.0, MiO 0I2/46 138 PCT/UJS( 1/47433 00 63.4, 60.8, 43.2, 42.5, 35.4, 25.5, 23.5, 21.6. Anal. Calcd for C,,H 32 C1N0 4 -O.5 H,O: C, 65.07; H, 7.5 1; N, 3.16. Found: C, 64.90; H, 7.38; N, 3.07.

HO

C1 NHMe 00 Tra as-(1 S)-3-(1-methyla mino-3-methyl-b utyl)-3-(4-chlo roph enyl)-cyclo b utano I 00 5 The crude amino alcohol 32 (0.96 g, 52% yield), which was prepared from 38 (2.71 g, 6.5 mnmol) via the typical procedure outlined above, was mixed with (S)-mandelic acid (0.52 g, 3.4 mmol) in methanol (5 mL). After the mixture was stirred at room temperature for 30 min, TBME (10 raL) was added and white solid was precipitated out. The solid was filtered, rinsed with TBME (10 mL), hexane (10 miL) and dried under vacuum to give 1. (78% yield) of the (S)-mandelic acid salt. The 'H NMR and 1 3 C NMR data are identical to those of the (R)-mandelic acid salt of enantiomer. Anal. Calcd for C 2

,H

32 C1N0 4 C, 66.42; Hi, 7.43; N, 3.23. Found: C, 66.07; H, 7.38; N, 3.07.

,OH

x NHMe

UC

Cis-(1 R)-3-(1-niethylainino-3-methyl-butl)-3-(4-chloropienyl).cyclob utanol The crude amino alcohol (2.17 g, 84% yield), which was prepared (3.41 9.16 minol) via the typical procedure outlined above, was mixed with (R)-mandelic acid (1.065 g inmol) in methanol (5 After the mixture was stirred at room temperature for min, TBME (10 mL) was added and white solid was precipitated out. The solid was filtered, rinsed with TBME (10 mL), hexane (10 mL) and dried under vacuum to give 2.32 g (77% yield) of the (R)-mandelic acid salt. 'H NVIR (DMSO): 8 7.40-7.20 (mn, 911), 5.90 (brs, 411), 4.76 1H), 3.67 111), 2.86 (in, 111), 2.79-2.59 (mn, 2H), 2.47 3H), 2.19 (dd, J =8.4, 10.6 Hz, 1H), 2..03 (dd, J 8.1, 10.6 Hz, 1H), 1.59 (in, 111), 1.01 (in, LUf), 0.9-0.6 (mn, 7H).

86 XVO (12/46138 PCT/UISO 1/47433 00 3 C NIMR (DMSO): 8 174.*2, 142.0, 141.7, 130.8, 130.3, 127.7, 126.8, 126.4, 72.9, 66.7, 61.0, 43.9, 43.5, 42.4, 38.6, 34.8, 24.4, 23.2, 22.0. Anal. Calcd for C 24

H

32 C1N0 4 C, 66.42; H, 7.43; N, 3.23. Found: C, 66.29; H, 7.47; N, 3.13.

C1 NHMe 00 10 Cis-(1 S)-3-(1-nethylamino-3-methy[1-butyl)-3-(4-chlorophenyl)-cyclobutauoI The crude amino alcohol 32 (2.01 g, 67% yield), which was prepared (3.97 g,10.7 niiriol) v'ia the typical procedure outlined above, was mixed with (S)-mandelic acid (1.02 g 6.7 nmmo1) in methanol (5 mL). After the mixture was stirred at room temperature for min, TBME (10 mL) was added and white solid was precipitated out. The solid was filtered, rised with TBME (10 mL), hexane (10 mL) and dried under vacuum to give 2.25 g (78% yield) of the (S)-rnandelic acid salt. The 'H NMIR and 1 3 C NMR data are identical to those of the (R)-mandelic acid salt of entiomer 7. Anal. Calcd for C 24

H

3 2 C1N0 4 -0.5 HO: C, 65.07; H, 7.5 1; N, 3.16. Found: C, 65.33; H, 7.28; N, 3.04.

5.1.3. 3-HYDROXYL EXPERIMENTAL DATA

N

(R)-N-(1-(4-Chlo rophenyl)cyclob utanemethylene)-t-b utanesuliarnide To a solution of 1-(4-chlorophenyl)cyclobutanecarbaldehyde (10.0 g, 51.0 mmol), (R)-t-butansulfinamnide (5.0 g, 41.0 mmol).in TBHF (60 mL), Ti(OEt) 4 (46.8 g, 205 Mmol.) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice-water and the *solid was filtered off. The product was extracted with ethyl acetate and the solution was dried over magnesium sulfate. After the solvent was removed, the residue was purified by silica gel chromatography eluting with heptane/ethyl -87- WO (02/46 138 PCT/USO /47433 00 acetate 8.5/i to give product 12.02 g in 98.5% Yield. 'H NMvR (CDCI3/rMS): 8 8.03 IH), 7.30 J 8.4 Hz, 2H), 7. 10 J =8.4 Hz, 2H), 2.85-2.60 (in, 211), 2.60-2.40 (in, 2H), 2.15-1.85 (in, 2H), 1. 19 9H). 3 C NMIR (CDC1 3 6 170.6, 142.5, 132.5, 128.7, 127.5, 57.0, 51.8, 31.1, 30.8, '22.3, 1 5.9. Anal. Calcd for C, 5

H

20 ClNOS: C, 60.49; H, 6.77; 5 N, 4.70. Found: C, 60.6 1; H, 6. 80; N, 4.64.

00 111/ 00" -(4-Ch lorop heny[)cyclo b u ta nemetbylene)-t-bu tan esuI fin a mide 11.36 g (93% yield) was prepared via the procedure described for the preparation of imine (R)-sulinamnide 'H NMR and 1 3 C NUR data of 8 are identical to those above.

Cl HN 4 -Choropheny)-cyclobutyl]2-methoxymethoyethyl}yR).tert.b u tanesul fin amide.

1s To the solution of (methoxymiethoxymethy)-tri-n-butylstannane (4.02 g, 11 rnol) in TJ{F (20 m-L) under an argon atmosphere at -78 was added ii-BuLi (6.88 mL, 1.6 M in hexane, 11 mmol). After the mixture was stirred at -78 'C for 5 min., the organolitbiunm solution was transferred via a double-ended needle into the solution of (R)-iniuine sulfinamide (2.98 g, 10 mmol) in THF (20 mL) at -78 0 C. The reaction mixture was stirred at -78 'C for 2 h. KPLC analysis showed the selectivity of the reaction is 88:12. The reaction. was quenched with methanol (1 mL) and water (3 mL). After warmed to room temperature, the reaction mixture was washed with brine and dried over magnesium sulfate.

88 1 WO (12/46138 PCT/US 11/47433 To the solution ofsulfinamide (3.66 g, 9.8 mmol) in methanol (20 mL), was added g the solution of 5-6 N HCI in isopropanol (10 mL). The reaction mixture was heated to Ci reflux for 1 h. HPLC checked the deprotection was complete. After the solvent was removed, the residue was basified with aqueous 2 N NaOH, extracted with TBME. The organic layers were combined and dried over magnesium sulfate. After solvent was removed, the residue was purified by silica gel chromatography, eluting with 2% t triethylamine in ethyl acetate to give free amino alcohol: 1.68 g (76% yield). The free amino 0 alcohol (1.68 g, 7.4 rmnol) was mixed with the solution of 2 N HCI in diethyl ether (5 mL, 0 10 mmol) and the mixture was stirred at room temperature for 30 min. The white solid was 00 10 filtered, rinsed with ether (3x5 mL) and dried over vacuum to give product: 1.82 g, 93% Syield. 'H NMR (DMSO/TMS): 8 8.03 (brs, 3H), 7.41 J 8.6 Hz, 2H), 7.31 J 8.6 Hz, 2H), 5.29 J 4.6 Hz, 1H), 3.63-3.50 1H), 3.50-3.40 1H), 3.10 1H), 2.65-2.45 2H), 2.40-2.20 2H), 1.94 1H), 1.72 1H). "C NMR (DMSO): 142.5, 131.1, 129.3, 128.0, 59.3, 58.8, 46.5, 31.6, 30.9, 15.5. Anal. Calcd for C,,H,,Cl2NO: C, 54.97; H, 6.54; N, 5.34. Found: C, 55.08; H, 6.46; N, 5.23.

V r OH C ®NH 3 SC1 (2R)-2-Amino-2-[1-(4-chloro-phenyl)-cyclobutyl]-ethanol Hydrochloride To the solution ofsulfinamide (2.99 g, 8.0 mmol) in methanol (15 mL), was added the solution of 5-6 N HCI in isopropanol (8 mL). The reaction mixture was heated to reflu for 1 h. HPLC checked the deprotection was complete. After the solvent was removed, the residue was basified with aqueous 2 N NaOH, extracted with TBME. The organic layers were combined and dried over magnesium sulfate. After solvent was removed, the residue was mixed with the solution of 2 N HCI in diethyl ether (8 mL, 10 mmol) and stirred at room temperature for 30 min. The white solid was filtered, rinsed with ether (3x5 mL) and dried over vacuum to give above: 1.86 g, 89% yield. 'H NMR and "C NMR data are identical to those of 1. Anal. Calcd for C,, 2

H,

7

C

2 NO: C, 54.97; H, 6.54; N, 5.34. Found: C, 54.11; H, 5.65; N, 5.17.

i WO02/46138 PCT/ISO 1/47433 00

OOO

SClO

O

0 0 00 (4S, 5R)-4-[1-(4-Chloro-phenyl)-cyclobutyll-5-isopropyl-oxazolidin-2-one and 8 (4S, 5S)-4-[1-(4-Chloro-phenyl)-cyclobutyll-5-isopropyl-oxazolidin-2-one 00 5 To the solution of racemic (1-methoxymethoxy-2-methyl-propyl) Stri-n-butylstannanes (36.6 g, 90 mmol) in THF (150 mL) at -78 was added the solution of n-BuLi in hexane (56.3 mL, 1.6 M, 90 rmnol). After the mixture was stirred at -78 °C for min, the solution was transferred and added into the solution of aldimine (14.6 g, 50 mmol) in THF (200 mL) at -78 The reaction mixture was continued to stir at -78 °C for I h.

TLC and HPLC showed no starting material left. The reaction was quenched with methanol mL). The reaction mixture was washed with water (50 mL), saturated sodium chloride mL) and dried over magnesium sulfate. After solvent was removed, the residue was purified by silica gel chromatography, eluting with 25% ethyl acetate in heptane to give a mixture of diastereomers 16.46 g, 79% yield. HPLC showed the ratio of the product of (IS, 2R) to (IS, 2S) was 72:28.

A mixture of 13 (4.80 g, 11.5 mmol) with 2 N HCI in methanol (20 mL) was heated to reflux for 30 min. HPLC showed the deprotectiou was complete. After solvent was removed, the residue was dissolved into dichloromethane (150 mL). To the resulting solution, was added triethylamine (15 mL), 1,1'-carbonyldiimidazole (4.8 g, 30 mmol). The reaction mixture was stirred at room temperature for 1 h. HPLC checked the reaction was complete. The solvent was removed, the residue was isolated by silica gel chromatography, eluting with 25% ethyl acetate in heptane to give the product: (IS, 2R) .94 g and (IS, 2S) 0.52 g in 73% combined yield. (IS, 2R): 'H NMR (CDCI 3 TMS): 6 7.56 (brs, 1H), 7.35 (s, 4H), 4.20-4.05 2H), 2.60-2.42 3H), 2.30-2.15 1H), 2.07-1.85 3H), 0.92 J 6.5 Hz, 3H), 0.43 J 6.5 Hz, 3H). 3 C NMR (CDCl 3 6 161.0, 143.6, 132.4, 128.8, 128.7, 87.6, 63.3, 48.5, 33.8, 28.9, 26.9, 20.0, 19.5, 16.6. Anal. Calcd for C, 6

H

2 0 C1NO,; C, 65.41; H, 6.86; N, 4.77. Found: C, 65.12; H, 7.01; N, 4.60. (IS, 2S): 'H NMR -91 WO (12/40138 PCT/US01/47433

(CDCI

3 /TMS): 8 7.7 5 (brs, I 7.3 1 J 8.3 Hz, 2H), 7. 11 J =8.3 Hz, 211), 3.95 (dd, J 3.5, 5.0 Hz, IH), 3.73 J 3.5 Hz, 1W), 2.50-2.20 (in, 4H), 2.15-1.70 (mn, 3H), 0.80 (d, J 6.8 Hz, 3H), 0.77 J 8.8 Hz, 3H). 1 3 C NMR (CDCI3): 8 160.7, 143.6, 132.7, 128.7, 12 8.3, 83.3, 62.4, 48.7, 32.5, 30.8, 28.5, 17.9, 16.1, 15.6. Anal. Calod for C 16

H

20 C1N0 2

C,

65.41; H, 6.86; N, 4.77. Found: C, 65.21; H, 6.86; N, 4.55.

00 OH NH 3 00 C1 ci- (IS, 2S)-1-Amino-1-[1-(4-chloro-pheuyl)-cyclob utylj1-3-methyl-butan-2-oI Hydrochloride A solution of substituted oxazolidin-2-one 15 (0.343 g, 1.17 inmol), KOH (2.0 a) and NH- 2 N11, x H.,O (0.3 mL) in ethylene glycol (10 mL) and water (2 mL) was heated in an 150 "C oil bath for 6 h. HiPLC showed the reaction was complete. The reaction mixture was poured into water (20 inL), extracted with TBME (3x20 mL). The organic layer was dried with MgSO 4 After solvent was removed, the residue was mixed with 2 N HCllether (3 mL) and stirred at room temperature overnight. The solid was filtered, rinsed with ether (3x3 mL) and dried under vacuumn to give product: 0.203 g, 57% yield. 'H NMR (DMSO/TMS): 8 7.75 (brs, 7.40 4H), 5.21 J 6.1 Hz, 1W), 3.35 (brs, 1W), 2.97 (in, IM1, 2.65-2.45 214), 2.33 (in, 1M, 2.19 (in, 114), 1.83 (mn, 1Wf), 1.75-1.60 (mn, 2H), 0.78 J Hz, 3H), 0.67 J 6.6 Hz, 3M. 1 3 C NMv~R (DMSO): 6 143.3, 131.0, 129.5, 128.1, 71.5, 57.9, 48.0, 31.9, 30.6, 29.7, 19.1, 18.2, 15.5. Anal. Calcd for C, 5 H ClNO: C, 59.21; Hj,, 7.62; N, 4.60. Found: C, 58.86; H, 7.62; N, 4.52.

OH

KY

C1 NH 3 (IS, 2R)-1-Amino-1- [1-(4-chloro-phenyl)-cyclob utyll -3-methylt-b utan-2-oI Hydrochloride -92- WO 0(12/46138 PCT/USo 1147433 A solution of substituted oxazolidin-2-one (1.176 g, 4.0 nunol), KOH (1.71 and 00

SN

2

NH

2 NHxH20 (0.25 mL) in ethylene glycol (10 mL) and water (2 mL) was heated in an 120 °C oil bath for 2 h. HPLC showed the reaction was complete. The reaction mixture was 9 poured into water (30 mL), extracted with TBME (3x30 mL). The organic layer was dried n 5 with MgSO,. After solvent was removed, the residue was mixed with 2 N HCl/ether (5 mL) and stirred at room temperature for 30 min. The solid was filtered, rinsed with ether I mL) and dried under vacuum to give product: 1.02 g, 84% yield. 'H NMR (DMSO/TMS): 00 7.72 (brs, 3H), 7.59 J 8.3 Hz, 2H), 7.44 J 8.3 Hz, 2H), 4.74 J 6.6 Hz, 1H),

O

O 3.38 (brs, 1H), 2.92 1H), 2.75 1H), 2.50-2.20 3H), 1.80 1H), 1.70-1.48 (m, 00 10 2H), 0.83 J 6.5 Hz, 3H), 0.76 J 6.6 Hz, 3H). "C NMR (DMSO): 5 141.1, 131.3, S130.5, 127.8, 73.2, 59.1, 48.4, 34.6, 33.3, 27.9, 20.2, 16.2, 14.5. Anal. Calcd for 4 CsH 23 C12NO: C, 59.21; H, 7.62; N, 4.60. Found: C, 59.16; H, 7.79; N, 4.50.

OMOM

HN ClS (1R,2S)-N-{1-[1-(4-Chlorophenyl)-cyclobut3yl]-2-methoxymethoxy-3-methyl-propyl}-(S) -tert-butanesulfinamide To the solution of (R)-(1-methoxymethoxy-2-methyl-propyl)-tri-n-butylstannanes (0.92 g, 2.26 nnmol) in THF (10 mL) at -78 was added the solution of n-BuLi in hexane (1.41 mL, 1.6 M, 2.26 nmmol). After the mixture was stirred at -78 °C for 10 min, the solution of aldimine 8 (0.672 g, 2.26 mmol) in THF (5 mL) was added. The reaction mixture was continued to stir at -78 oC for 3 h. HPLC showed about 14% starting material left and the diastereo selectivity of the reaction was 99:1. The reaction mixture was then quenched with methanol (1 mL), washed with saturated sodium chloride (10 mL) and dried over magnesium sulfate. After solvent was removed, the residue was purified by silica gel chromatography, eluting with 25% ethyl acetate in heptane to give product: 0.745 g in 92% yield. 'H NMR (CDCl3/TMS): 8 7.44 J 8.7 Hz, 2H), 7.32 J= 8.7 Hz, 2H), 4.56 tJi.

6.5 Hz, 1H), 4.50 J 6.5 Hz, 1H), 3.64 (dd, J 4.9, 10.0 Hz, 1H), 3.45 J= 10.0 Hz, 1H), 3.28 3H), 2.95 (dd, J 3.7, 4.8 Hz, 1H), 2.70-2.53 2H), 2.50-2.48 2H), 1.92-1.66 2H), 1.52-1.40 1H), 1.22 9H), 0.82 J 6.8 Hz, 3H), 0.81 J 6.6 Hz, 3H). 3 C NIMR (CDC13): 5 143.2, 132.3, 130.4, 128.3, 98.6, 87.0, 67.3, 57.1, 56.3, 50.4, -93- S WO (12/46138 lPCT/US(I 1/47433 00 35.7, 33.5, 29.4, 23.0, 21.7, 17.3, 16.7. Anal. Caicci for C 21

H

34 C1N0 3 S: C, 60.63; H, 8.24; N, 3.37. Found: C, 60.46; H, 8.19; N, 3.16.

OMOM

ci HN ,S 00 (1 R,2R)-N-{1-[1-(4-Chlorophenyl1)-cyclobutyl]-2-metboxyiniethoxy-3-methyl-propyl}- 00 5 (S)-tert-butanesulfinamide To the solution of 1-methioxymethioxy-2-methyl-propyl)-tri-n-butylstanianes ri (0.64 g, 1.6 minmol) in THF (10 mL) at -78 was added the solution of n-BuLi in hexane m.L, 1.6 M, 1.6 rnol). After the mixture was stirred at -78 'C for 10 min, the solution of aldimine 8 (0.47 g, 1.6 mi-nol) in TifF (5 niL) was added. The reaction mixture was continued to stir at -78 oC for 3 h. HIPLC showed about 11% starting material left and the diastereo selectivity of the reaction was 99: 1. The reaction mixture was then quenched with methanol (I mL), washed with saturated sodium chloride (10 mL) and dried over magnesium sulfate. After solvent was removed-, the residue was purified by silica gel chromatography, eluting with 25% ethyl acetate in heptane to give above product: 0.3 56 g in 61% yield. 'H NMR (CDC1JfTMS): 5 7.36 J 8.7 Hz, 2H), 7.29 (di, J =8.7 Hz, 2H), 4.18 J 6.2 Hz, I1H):,4.04 (di, J 10. 3 Hz, I 3.91 J 6.2 Hz, 1H1), 3.09 (mn, 111), 3.07 3H1), 2.76-2.64 (in, I11), 2.47-2.17 (mn, 3H), 2.00-1.70 (in, 3H), 1.25 9R), 0.92 J 6.8 Hz, 3H), 0.86 (di, J 6.8 Hz, 3H). 1 3 C NMR (CDC 3 5 143.7, 132.1, 129.8, 128.0, 980W 82.9, 63.8, 57.3, 55.8, 50.6, 34.3, 32.7, 31.2, 23.4, 19.0, 18.7, 15.5. Anal. Calcd for

C

21

H

34 C1N0 3 S: C, 60.63; H, 8.24; N, 3.37. Found: C, 59.02; H,8. 11; N, 3.08.

OH OH

NHY

2 z GNH 3 (1R, 2R)-1 -Anin o- 1-I1-(4-ch lo ro-p henyI)-cyctobutyll-3-methyl-butan-2-oI Hydrochloride 94 WO (12/46138 PCT/SIII/4 74(733 0 A solution of 17 (0.336 g, 0.81 mmol) with 2 N HC1 in methanol (5 mL) was 0 refluxed for 30 min. After solvent was evaporated, the residue was basified with aqueous 2 N NaOH, extracted with TBME (3x10 mL). The organic layer was dried over magnesium Ssulfate. After solvent was removed, the residue was dried under vacuum to give crude free l 5 amino alcohol: 'H NMR (CDCI 3 /TMS): 5 7.29 J 8.4 Hz, 2H), 7.16 J 8.4 Hz, 2H), 3.15 (dd, J 2.0, 6.7 Hz, 1H), 3.06 J 2.0 Hz, 1H), 2.46-2.20 4H), 2.24-1.75 (m, 2H), 1.74-1.56 1H), 1.46 (brs, 3H), 0.94-0.86 6H). 3 C NMR (CDC 3 6 145.3, 0 131.9. 128.4, 128.3, 74.1, 58.2, 50.2, 32.3, 32.1, 31.5, 19.6, 18.3, 15.8.

The crude free amino alcohol was mixed with 2 N HCI in ether (2 mL). The mixture 0 10 was stirred at room temperature overnight. The solid was filtered, rinsed with dry ether (3x1 O mL) and dried under vacuum to give the HCI salt: 0.22 g in 89% yield. 'H NMR 4 (DMSO/TMS) and 3 C NMR (DMSO) data are identical to those of 3: Anal. Calcd for-

CSH

23 C1NO: C, 59.21; H, 7.62; N, 4.60. Found: C, 59.33; H, 7.68; N, 4.40.

OH OH S NH; (iNH Cl Cl cIQ (1R, 2S)-l-Amino-l-[1-(4-chloro-phenyl)-cyclobutyl]-3-methyl-butan-2-ol Hydrochloride A solution of SM (0.712 g, 1.7 mmol) with 2 N HCI in methanol (5 mL) was refluxed for 30 min. After solvent was evaporated, the residue was basified with aqueous 2 N NaOH, extracted with TBME (3x10 mL). The organic layer was dried over magnesium sulfate. After solvent was removed, the residue was dried under vacuum to give crude free amino alcohol: 'H NMR (CDC3/TMS): 6 7.38 J 8.5 Hz, 2H), 7.30 J= 8.5 Hz, 2H), 2.95 J 9.4 Hz, 1H), 2.69 (dd, J 2.1, 9.4 Hz, 1H), 2.64-2.26 4H), 1.98-1.68 (m, 3H), 0.88 J 6.8 Hz, 3H), 0.84 J 7.0 Hz, 3H). "C NMR (CDC13): d 143.2, 131.8, 129.8, 127.9, 78.2, 61.2, 51.3, 34.7, 33.7, 28.9, 20.3, 16.8, 14.1.

The crude free amino alcohol was mixed with 2 N HCI in ether (3 mL). The mixture was stirred at room temperature overnight. The solid was filtered, rinsed with dry ether (3x1 mL) and dried under vacuum to give the HCI salt: 0.43 g in 83% yield. 'H NMR (DMSO/TMS) and "C NMR (DMSO) data are identical to those above: Anal. Calcd for C,sH 2 3 ClNO: C, 59.21; H, 7.62; N, 4.60. Found: C, 59.37; H, 7.59; N, 4.42.

WO (12/46138 PCT/USO1/47433 5.2. PHARMACOLOGICAL ASSAYS The compounds of the invention can readily be tested to demonstrate their utility as pharmaceutical agents. Indeed, certain compounds have been tested. The 1-OH metabolites of N-didesmethylsibutramine (1-OH-DDMS) were tested to determine thir ability to functional uptake of serotonin norepinephrine or dopamine into synaptosomes prepared from rat whole brain, hypothalamus, or corpora striata, respectively.

In addition, binding was determined at the nonselective muscarinic receptor and the P3-receptor from rat cerebral cortex and rat adipose tissue, respectively. The 1-OH-DDMS compounds tested contain two chiral centers (C2, C4): (2R,4R) (2S,4R), (2R,4S) and (2S,4S).

Compounds were tested initially at 10 JpM in duplicate, and if 50% inhibition of uptake or binding was observed, they were tested further at 10 different concentrations in duplicate in order to obtain full inhibition or competition curves. IC 5 0 values (concentration inhibiting control activity by 50%) were then determined by nonlinear regression analysis of the inhibition curves and tabulated below.

~II 1 r C~~-\~1Trr ito values fmwv) ior unI metanoltes or DlJivls In tunctional U take Assays 1-OH-DDMS 5-HT NE DA (2R,4R) 34 4.7 27 (2S,4S) 1200 150 33 (2R,4S) 2000 71 110 (2S,4R) 65 11 37 Imipramine 24/24 Prtriptyline 1.8/4.6 GBR 12909 4.2/8.8

IC

50 values for muscarinic and p3-binding were not calculated because none of the compounds showed inhibition of The maximum inhibition was 13% at the muscarinic site [(2R,4S)-1-OH-DDMS] and 30% at the P3-receptor [(2S,4S)-1-OH-DDMS].

-96 r WO 12/46138 PCT/US 1/47433 The and (S,R)-hydroxy metabolites are metabolites of (R)-DDMS and the

O

O and (R,S)-hydroxy metabolites are metabolites of (S)-DDMS. As a basis of C' comparison, the ICso values of (R)-DDMS for inhibition of uptake of 5-HT, NE, and DA were reported to be 140, 13, and 8.9 nM, respectively, and those for (S)-DDMS were 4,300, S 5 62, and 12 nM.

The 1-OH metabolites of N-desmethylsibutramine (DMS) were also tested to Iy- determine their ability to inhibit functional uptake of serotonin norepinephrine (NE), 00 or dopamine into synaptosomes prepared from rat whole brain, hypothalamus, or 0 corpora striata, respectively. In addition, binding was determined at the nonselective 00 10 muscarinic receptor and the p3-receptor from rat cerebral cortex and rat adipose tissue, O respectively. The 1-OH-DMS compounds tested contained two chiral centers (C2, C4): (2R,4R), (2S,4S), (2R,4S), and (2S,4R).

Compounds were tested initially at 10 tiM in duplicate, and if 50% inhibition of uptake or binding was observed, they were tested further at 10 different concentrations in duplicate in order to obtain full inhibition or competition curves. ICs 5 values (concentration inhibiting control activity by 50%) were then determined by nonlinear regression analysis of the inhibition curves and tabulated below.

IC, Values (nM) for 1-OH Metabolites of DMS in Functional Uptake Assays 1-OH-DMS 5-HT NE DA (2R,4R) 12 2.2 19 (2S,4S) 250 430 (2R,4S) 74 2500 (2S,4R) 160 9.3 37- Imipramine 24 -Prtriptyline 11 GBR 12909 8.8 i. "lapi .i~ ~~i indicates 50%

IC

50 values for muscarinic and 33-binding were not calculated because none of the compounds showed inhibition of 50%. The maximum inhibition was 41% at the muscarinic site [(2S,4S)-1-OH-DMS] and 24% at the p3-receptor [(2S,4R)-1-OH-DMS].

97

C

00 0 00 WO 12/46138 PCT/USO 1/47433 The (2R,4R)- and (2S,4R)-hydroxy metabolites are metabolites of (R)-DMS and the (2S,4S)- (2R,4S)-hydroxy metabolites are metabolites of(S)-DMS. As a basis of comparison, the IC 5 0 values of (R)-DMS for inhibition of uptake of 5-HT, NE, and DA were reported to be 44, 4, and 12 nM, respectively, and those for (S)-DMS were 9,200, 870, and 180 nM.

It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as 10 encompassing all stereoisomers of it.

The embodiments of the invention described above are intended to be merely exemplary and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. All such equivalents are considered to be within the scope of the invention and are encompassed by the following claims.

-98r

Claims (15)

1. 2. A compound of the formula: SOH R1NR2 or a pharmaceutically acceptable, salt, solvate, hydrate, clathrate, or prodrug thereof, wherein each of RI and R 2 is independently alkyl or hydrogen provided that if both R, and R 2 are methyl, the compound is not racemic.
2. 3. A compound of the formula: OH S R 1N R2 CI a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, wherein each of RI and R 2 is independently alkyl or hydrogen, provided that if both R, and R 2 are hydrogen, -99- 00 00 00 O fc in (N the compound is not racemic.
3. 4. A compound according to any one of claims 1 to 3 wherein at least one of RI and R 2 is hydrogen. A compound according to any one of claims 1 to 3 wherein at least one of RI and R 2 is methyl.
4. 6. A compound according to any one of claims 1 to 5 wherein the compound is 10 stereomerically pure.
5. 7. A compound according to any one of claims I to 5 wherein the compound is an enantiomeric or diastereomeric mixture that is not a racemic mixture.
6. 8. A method of treating or preventing a disease or disorder ameliorated by inhibition of neuronal monoamine uptake, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 7.
7. 9. A method according to claim 8, wherein the disease or disorder ameliorated by inhibition of neuronal monoamine uptake is an eating disorder, an obsessive-compulsive disorder, platelet adhesion, apnea, an affective disorder, anxiety, a male or female sexual function disorder, restless leg syndrome, osteoarthritis, substance abuse, pain, migraine, a cerebral function disorder, a chronic disorder, or incontinence. A method according to claim 9 wherein the eating disorder is weight gain or obesity.
8. 11. A method according to claim 9 wherein the affective disorder is depression, attention deficit disorder, a bipolar or manic condition, dysthymic disorder, or cyclothymic disorder.
9. 12. A method according to claim 9 wherein the pain is neuropathic pain.
10. 100- 00 00 (O 13. A method according to claim 9 wherein the cerebral function disorder is dementia, memory loss, autism, epilepsy, hyperkinetic syndrome, or schizophrenia. 14. A method according to claim 9 wherein the chronic disorder is narcolepsy, chronic fatigue syndrome, seasonal affective disorder, fibromyalgia, or premenstrual syndrome. 15. A method according to any one of claims 8 to 14, wherein at least one of RI and R 2 is hydrogen. 16. A method according to any one of claims 8 to 15, wherein at least one of Ri and R 2 is methyl. 17. A method according to any one of claims 8 to 16, wherein the compound is hydroxylated sibutramine or a hydroxylated sibutramine metabolite. 18. A method according to claim 17, wherein the compound is hydroxylated in the 1- position. 19. A method according to claim 17, wherein the compound is hydroxylated in the 3- position. A method according to claim 17, wherein the compound is hydroxylated in the 7- position. 21. A method according to any one of claims 8 to 20, wherein the amount administered is from about 0.01 mg to about 500mg/day. 22. A method according to any one of claims 8 to 21, wherein the amount administered is from about 0.1 mg to about 250 mg/day. 23. A method according to any one of claims 8 to 22, wherein the amount administered is from about 1 mg to about 100 mg/day. 101 00 24. A method according to any one of claims 8 to 23, wherein the compound is O 0administered orally, mucosally, parenterally, or transdermally. A method according to any one of claims 8 to 24 further comprising tn 5 administering a 5-HT 3 antagonist. 26. A method according to claim 25, wherein the 5-HT 3 antagonist is an antiemetic 00 agent. 00 00 10 27. A method according to any one of claims 26 or 27, wherein the 5-HT3 antagonist Sis granisetron, metoclopramide, ondansetron, renzapride, zacopride, tropisetron, or a (N stereomerically pure stereoisomer, active metabolite, or pharmaceutically acceptable salt, solvate, hydrate, ester, clathrate, or prodrug thereof. 28. A pharmaceutical composition comprising a therapeutically or prophylactically effective amount compound according to any one of claims 1 to 7. 29. A pharmaceutical composition according to claim 28, wherein at least one of RI and R 2 is hydrogen. A pharmaceutical composition according to claim 28, wherein at least one of Ri and R 2 is methyl. 31. A pharmaceutical composition according to any one of claims 28 to 30, wherein the compound is stereomerically pure. 32. A pharmaceutical composition according to any one of claims 28 to 30, wherein the compound is an enantiomeric or diastereomeric mixture that is not racemic. 33. A pharmaceutical composition according to any one of claims 28 to 32, wherein the compound is hydroxylated sibutramine or a hydroxylated sibutramine metabolite. -102- 00 00 00 (-N 00 34. A pharmaceutical composition according to claim 33, wherein the compound is hydroxylated in the 1-position. A pharmaceutical composition according to claim 33, wherein the compound is 5 hydroxylated in the 3-position. 36. A pharmaceutical composition according to claim 33, wherein the compound is hydroxylated in the 7-position. 10 37. A pharmaceutical composition according to any one of claims 28 to 36, wherein the pharmaceutical composition is adapted for oral, mucosal, rectal, parenteral, or transdermal administration. 38. A pharmaceutical composition according to any one of claims 28 to 37, wherein said composition is lactose-free. 39. A method of synthesizing a hydroxylated compound, which comprises contacting an aldehyde of formula: with a first sulfinamide under reaction conditions suitable for the formation of a sulfinimine of formula: s 0 wherein X is an auxiliary group; 103 contacting said sulfinimine with an organometallic reagent under reaction conditions suitable for the formation of a second sulfinamide of formula: IS- 0 00 00 00 and contacting said second sulfinamide with a reagent under reaction conditions suitable for the removal of a sulfinyl group to form a hydroxylated compound of formula: herein each of R, and R 2 is independently hydrogen or lower alkyl. A method according to claim 39, wherein the hydroxylated compound is stereomerically pure. 41. A method according to claims 39 or 40, wherein the first sulfinamide is stereomerically pure (R)-tert-butylsulfinamide or stereomerically pure (S)-tert- butylsulfinamide. 42. A method according to any one of claims 39 to 41, wherein the first sulfinimine is of the formula: NsSO
11. 104- 43. A method according to any one of claims 39 to 42, wherein the organometallic reagent is of the formula: BrMg,,;.,OMgCI o r 0 or 0- 00 00 4Cr 44. A method according to any one of claims 39 to 43, which further comprises contacting with an N-methylating agent with the hydroxylated compound under reaction conditions suitable for the formation of an N-methyl amine. 45. A method of claim 44, wherein the N-methylating agent is formic acid and borane. 46. A method according to any one of claims 39 to 45, wherein the organometallic reagent is added under reaction conditions suitable for the formation of a compound of formula: CI HN 0 wherein X is an auxiliary group. 47. A method of making a hydroxylated compound of the formula: OH N, RINR 2 Cl
12. 105- wherein each of RI and R 2 is independently hydrogen or alkyl, which comprises treating a first sulfinimine of the formula: 00 00 O( 0-0 0O wherein X is an auxiliary with an organometallic agent under reaction conditions suitable for the formation of a second sulfinamide of the formula: S-X 0 and contacting the second sulfinamide with a deprotecting agent under reaction conditions sufficient for the removal of a sulfinyl group. 48. A method according to claim 47, wherein the hydroxylated compound is stereomerically pure. 49. A method according to claim 47 or 48, wherein the hydroxylated compound is subjected to reaction conditions suitable for N-methylation to form a compound of formula: OH 20'N NHR 1 ClI wherein R, is methyl.
13. 106- 00 00 00 A method for synthesizing a hydroxylated compound, which comprises contacting 4-chlorophenylacetonitrile with a compound under reaction conditions suitable for the formation of a compound of formula: OH CICN CI reducing the nitrile under reaction conditions suitable for the formation of an aldehyde; contacting the aldehyde with a tert-butyl sulfinimine under reaction conditions suitable for the formation of a first sulfinamide compound of formula: OH I wherein X is an auxiliary; contacting said first sulfinamide compound with an organometallic agent under reaction conditions suitable for the formation of a second sulfinamide of the formula: and contacting the second sulfinamide with a deprotecting agent under reaction conditions
14. 107- 00 sufficient to form the hydroxylated compound. O 51. The method according to claim 50, wherein the hydroxylated compound is Sstereomerically pure. S 52. A method according to claim 50 or 51, wherein the4-chlorophenylacetonitrile is contacted with a compound of the formula: 00 SOTHP O O Br or Br Br 00 0 6 53. A method according to any one of claims 50 to 52, wherein the reducing agents is Dibal-H. 54. A method according to any one of claims 50 to 53, wherein the organometallic is isopropylmagnesium chloride. A compound of the formula: or a salt, solvate, or hydrate thereof. 56. A compound of the formula: .H HN H
15. 108- 00 00 00 OO O or a salt, solvate, or hydrate thereof. 57. A compound of the formula: 11 P -F 0 or a salt, solvate, or hydrate thereof. 58. A compound of the formula: or a salt, solvate, or hydrate thereof. 59. A method of synthesizing a sulfinamide of the formula: OH Cl d which comprises contacting an organometallic agent of the formula: MgBr,,/ OMgCI -109- 00 with a compound of the formula: .S, CI 00 under reaction conditions sufficient for the formation of the sulfinamide. 00 60. A method according to claim 59, wherein the sulfinamide, organmetallic agent, Sand sulfinimine are stereomerically pure. 61. A method of synthesizing a hydroxylated compound substantially as hereinbefore described with reference to any one of the Examples. -110-