HK1201518B

HK1201518B - Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives

Info

Publication number: HK1201518B
Application number: HK15102110.4A
Authority: HK
Inventors: L．巴特; K．阿迪; S．R．巴特
Original assignee: 雷维瓦药品公司
Priority date: 2011-12-30
Filing date: 2012-12-31
Publication date: 2017-12-15

Description

Compositions, synthesis, and methods of use of phenylcycloalkylmethylamine derivatives

Technical Field

The present invention relates to phenylcycloalkylmethylamine derivatives, the synthesis of phenylcycloalkylmethylamine derivatives, and methods of using phenylcycloalkylmethylamine derivatives for the pharmacological treatment of obesity, depression, and co-morbid (co-morbid) indications associated with obesity.

Background

Obesity is a chronic disease that affects millions of people worldwide, particularly in developed countries. It is defined as being extra-fatty and is generally measured by calculating the BMI (body mass index) of a person. A person is considered obese if his or her BMI is 30 or more. Obesity can directly or indirectly cause a number of health problems, such as type 2 diabetes, coronary heart disease, high blood triglycerides, hypertension and stroke. Obesity also increases the risk of certain types of cancer. Obese men are more likely to die of colon, rectal and prostate cancers than normal-weight peers. Obese women are more likely to die of gallbladder, breast, uterine, cervical and ovarian cancer than non-obese women. Death due to some cancers may be more likely due to obesity making the cancer more difficult to detect at an early stage (e.g., breast cancer may not be felt in the first small mass in obese women). Recent studies have shown that obesity increases the risk of dementia of the alzheimer type. Other diseases and health problems associated with obesity include: gallbladder disease, gallstones, osteoarthritis, gout or joint pain, sleep apnea, psychological and social problems.

Obesity is caused by a variety of factors, the main factor being genetics, a factor associated with obesity that is not controlled by an individual. Other important factors involved in obesity are: a fat storage mechanism; a balance between energy intake and energy expenditure; personal lifestyle: dietary habits and exercise; as well as psychological, cultural and socioeconomic effects. Although the disease appears to progress poorly, there has been limited progress in the drug treatment of this condition. Drugs for the treatment of obesity can be divided into three categories: those that reduce food intake or appetite suppressants; those that alter metabolism or block fat absorption; and those that increase thermogenesis. Currently, only two drugs are FDA approved for long-term treatment of obesity, which are orlistat, a fat absorption blockerAnd appetite suppressant sibutramineThe only thermogenic drug combinations that have been tested are ephedrine and caffeine, but the treatment has not been approved by regulatory agencies.

The fat absorption blocker, orlistat, acts in the gastrointestinal tract by blocking the enzymes required to digest fat. Up to one third of the fat ingested by humans is not absorbed from the intestine, but is excreted in the feces. In addition, orlistat blocks the absorption of the essential fat soluble vitamins A, D, E and K as well as β -carotene. This is one of the major limitations of this drug for long-term use in the treatment of obesity. Other side effects most commonly reported with orlistat are bloating, diarrhea and oily stools.

Among the class of appetite suppressants, some noradrenergic drugs and 5-hydroxytryptamine drugs belonging to the family of 2-arylethylamines are currently available on the market for the treatment of obesity. Noradrenergic agents, such as phenylpropanolamineBupropionAnd phentermineApproved for short-term treatment of obesity. However, the noradrenergic drug and the 5-hydroxytryptamine drug sibutramineIs currently the only drug in the class of appetite suppressants approved for long-term treatment of obesity. Sibutramine has a cyclobutanemethylamine backbone, and it is this backbone that primarily confers its unique pharmacological properties.

In the last 10 years, numerous reports have been published on the possible use of sibutramine, alone or together with other therapeutic agents, for the treatment and/or prevention of a variety of diseases and/or conditions other than obesity (see, Montana, J.G., WO 2004/058237; Lulla, A. et al, WO 2004/096202; Jerussi, T.P. et al, WO 02/060424; Senana yake, C.H. et al, WO 01/51453; Heal, D.J., WO 01/00205; Birch, A.M. et al, WO 01/00187; Mueller, P. 00/32178; Bailey, C. 98/11884; Kelly, P. 98/13034). For example: treating nausea, vomiting, and related conditions; cognitive dysfunction; eating disorders; weight gain; irritable bowel syndrome; obsessive-compulsive disorder; platelet adhesion; apnea, affective disorders such as attention deficit disorder, depression and anxiety; male and female sexual dysfunction; restless leg syndrome; osteoarthritis; substance abuse including nicotine and cocaine addiction; narcolepsy; pain such as neuropathic pain, diabetic neuropathy, and chronic pain; migraine headache; brain dysfunction; chronic conditions such as premenstrual syndrome; and incontinence.

Generally, sibutramine has a variety of therapeutic benefits due to its unique pharmacological properties. However, the therapeutic use of sibutramine for the treatment of obesity and other diseases and disorders is currently underutilized due to certain limitations and adverse side effects associated with this drug. Major adverse events reported, in some cases life threatening, include elevated blood pressure, and side effects from drug-drug interactions, such as 5-hydroxytryptamine syndrome. Most of these adverse events are, to some extent, metabolic-based. Sibutramine mainly passes through its secondary (M)₁) And primary (M)₂) Exerts its pharmacological effect. Sibutramine is metabolized primarily in the liver by the cytochrome P450(3A4) isoenzyme to the demethylated metabolite M₁And M₂. These active metabolites are further metabolized to pharmacologically inactive metabolite M by hydroxylation and conjugation₅And M₆. Therapeutically active primary and secondary amine metabolites M₁And M₂The elimination half-life of (a) was 14 and 16 hours, respectively. A number of literature reports demonstrate cytochrome P450-mediated metabolism and active metabolites (M)₁And M₂) Is largely responsible for adverse events such as elevated blood pressure and other side effects resulting from drug-drug interactions of sibutramine.

Therefore, there is a need and great demand for a safer and effective next generation appetite suppressant for obesity treatment. The ideal drug in this class should have potent appetite suppressant activity, proven fat reducing effects, good tolerability in both rapid and long term administration, and reduced side effects when compared to sibutramine and phentermine.

Disclosure of Invention

The present invention relates to novel compositions of phenylcycloalkylmethylamine derivatives, and the use of such compositions for the treatment of obesity and related co-morbid conditions, as well as depression and related co-morbid conditions. The present invention provides a method for synthesizing such phenylcycloalkylmethylamine derivatives. The invention also provides methods of treating or preventing obesity and co-morbidities and/or conditions and for treating or preventing depression and co-morbidities and/or conditions using pharmaceutical compositions of phenylcycloalkylmethylamine derivatives and phenylcycloalkylmethylamine derivatives.

The compounds of the present disclosure are advantageous because they have good metabolic, pharmacokinetic and pharmacological properties.

The present invention provides phenylcycloalkylmethylamine derivatives of the formula (I):

or an isomer or a pharmaceutically acceptable salt thereof, wherein:

n is 0, 1,2, 3,4 or 5;

SP is a spacer, wherein the spacer is C_1-6Alkylene and wherein the C_1-6One or more carbons of the alkylene group being optionally O, S or NR⁶In which R is⁶Is H or C_1-6An alkyl group;

x is O, S, NR⁶Or S (O);

R¹、R²、R³、R⁴and R⁵Each independently is hydrogen, C_1-6Alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl, heteroarylalkyl, acylalkoxycarbonyl, acylalkoxycarbonyloxy, acylalkoxycarbonylamino, C_1-6Alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylamino, alkylsulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino, arylalkylamino, dialkylamino, arylalkoxy, arylalkoxycarbonylalkoxy, arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy, aryloxycarbonylalkylamino, carboxyl, carbamoyl, carbamate, carbonate, cyano, halo, heteroaryloxycarbonyl, hydroxyl, phosphate, phosphonate, sulfate, sulfonate or sulfonamide; optionally R¹、R²、R³、R⁴And R⁵Quilt isotope²H (deuterium),³H (tritium),¹³C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S and³⁶cl substitution; and

"" indicates carbon which can be optically active.

The compounds of the present disclosure include the (R) -isomer, (S) -isomer, and mixtures of the (R) -and (S) -isomers.

Detailed Description

The present invention provides compounds, pharmaceutical compositions and methods for the pharmacological treatment of obesity and related co-morbid diseases and/or conditions. The invention also provides methods for synthesizing novel appetite suppressants.

Definition of

According to the inventionThe compounds may contain one or more chiral centers and/or double bonds, and thus, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Thus, the chemical structures described herein encompass all possible enantiomers and stereoisomers of the illustrated compounds, including stereoisomerically pure (e.g., geometrically pure (e.g., enantiomerically pure), enantiomerically pure, or diastereomerically pure) forms, as well as enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers and stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The compounds of the present invention may also exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures shown herein encompass all possible tautomeric forms of the compounds shown. The compounds of the present invention also include isotopically-labeled compounds in which one or more atoms have an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be included in compounds of the invention include, but are not limited to²H、³H、¹³C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶Cl。

"alkyl" refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyl groups (ethyls) such as ethyl, vinyl, ethynyl; propyls such as prop-1-yl, prop-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-en-1-yl, prop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, and the like; butyl-like (butyl), such as but-1-yl, but-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, cyclobut-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl,but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl, but-1-yn-3-yl, but-3-yn-1-yl and the like. The term "C_1-6Alkyl "covers C₁Alkyl radical, C₂Alkyl radical, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

The term "alkyl" is specifically intended to include groups having any degree or level of saturation, i.e., groups having only single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having a mixture of single, double, and triple carbon-carbon bonds. Where specific saturation levels are intended, the expressions "alkyl", "alkenyl" and "alkynyl" are used. Preferably, the alkyl group contains 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms.

The term "alkylene" refers to the removal of one hydrogen atom from an "alkyl".

"alkyl" refers to a saturated branched, straight-chain, or cyclic alkyl group resulting from the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl; an ethyl group; a propyl group such as prop-1-yl, prop-2-yl (isopropyl), cycloprop-1-yl, and the like; butyl groups such as but-1-yl, but-2-yl (sec-butyl), 2-methyl-prop-1-yl (isobutyl), 2-methyl-prop-2-yl (tert-butyl), cyclobut-1-yl, and the like.

"alkenyl" refers to an unsaturated, branched, straight-chain, or cyclic alkyl group having at least one carbon-carbon double bond resulting from the removal of one hydrogen atom from a single carbon atom of a parent olefin. The group may be in either the cis or trans configuration with respect to the double bond. Typical alkenyl groups include, but are not limited to, vinyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, prop-1-en-1-yl, prop-2-en-1-yl; butenyl, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl and the like.

"alkylene" refers to a divalent group comprising a branched or straight chain hydrocarbon segment of the indicated number of carbon atoms and having two points of attachment. Alkylene is optionally substituted with one, two or three substituents. The term "C_1-6Alkylene "embraces C₁Alkylene radical, C₂Alkylene radical, C₃Alkylene radical, C₄Alkylene radical, C₅Alkylene radical, C₆Alkylene, and any subrange thereof. Examples of alkylene groups include, but are not limited to: methylene (-CH)₂–，C₁Alkylene), ethylene (-CH)₂CH₂–，C₂Alkylene), propylene (-CH)₂CH₂CH₂–，C₃Alkylene) and butylene (-CH)₂CH₂CH₂CH₂–，C₄Alkylene).

"alkynyl" refers to an unsaturated, branched, straight-chain, or cyclic alkyl group having at least one carbon-carbon triple bond resulting from the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl groups such as prop-1-yn-1-yl, prop-2-yn-1-yl and the like; butynyl groups such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl and the like.

"acyl" refers to the group-C (O) R, wherein R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl.

"Acyloxyalkoxycarbonyl" refers to the group-C (O) OCR 'R "OC (O) R'", wherein R ', R "and R'" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents such asA substituent as defined herein. Representative examples include, but are not limited to, -C (O) OCH₂OC(O)CH₃、–C(O)OCH₂OC(O)CH₂CH₃、–C(O)OCH(CH₃)OC(O)CH₂CH₃、–C(O)OCH(CH₃)OC(O)C₆H₅。

"Acylalkoxycarbonyl" refers to the group-C (O) OCR ' R "C (O) R '", wherein R ', R ", and R" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, -C (O) OCH₂C(O)CH₃、–C(O)OCH₂C(O)CH₂CH₃、–C(O)OCH(CH₃)C(O)CH₂CH₃、–C(O)OCH(CH₃)C(O)C₆H₅。

"Acyloxyalkoxycarbonylamino" refers to the group-NRC (O) OCR 'R "OC (O) R'", wherein R, R ', R "and R'" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to-NHC (O) OCH₂OC(O)CH₃、–NHC(O)OCH₂OC(O)CH₂CH₃、–NHC(O)OCH(CH₃)OC(O)CH₂CH₃、–NHC(O)OCH(CH₃)OC(O)C₆H₅。

"acylalkoxycarbonylamino" refers to the group-NRC (O) OCR 'R "C (O) R'", wherein R, R ', R "and R'" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to-NHC (O) OCH₂C(O)CH₃、–NHC(O)OCH₂C(O)CH₂CH₃、–NHC(O)OCH(CH₃)C(O)CH₂CH₃、–NHC(O)OCH(CH₃)C(O)C₆H₅。

"alkylamino" refers to the group-NHR, wherein R represents alkyl or cycloalkyl as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, methylamino, ethylamino, 1-methylethylamino, cyclohexylamino.

"alkoxy" refers to the group-OR, wherein R represents alkyl OR cycloalkyl as defined herein, optionally substituted with one OR more substituents as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy.

"alkoxycarbonyl" refers to the group-C (O) -alkoxy, wherein alkoxy is as defined herein.

"Alkoxycarbonylalkoxy" refers to the group-OCR' R "C (O) -alkoxy, where alkoxy is defined herein. Similarly, wherein R' and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to-OCH₂C(O)OCH₃、-OCH₂C(O)OCH₂CH₃、-OCH(CH₃)C(O)OCH₂CH₃、-OCH(C₆H₅)C(O)OCH₂CH₃、-OCH(CH₂C₆H₅)C(O)OCH₂CH₃、-OC(CH₃)(CH₃)C(O)OCH₂CH₃。

"Alkoxycarbonylalkylamino" refers to the group-NRCR' R "C (O) -alkoxy, where alkoxy is as defined herein. Similarly, wherein R, R ', R', and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroheteroarylArylalkyl, as defined herein, may be optionally substituted with one or more substituents, as defined herein. Representative examples include, but are not limited to-NHCH₂C(O)OCH₃、-N(CH₃)CH₂C(O)OCH₂CH₃、-NHCH(CH₃)C(O)OCH₂CH₃、-NHCH(C₆H₅)C(O)OCH₂CH₃、-NHCH(CH₂C₆H₅)C(O)OCH₂CH₃and-NHC (CH)₃)(CH₃)C(O)OCH₂CH₃。

"alkylsulfonyl" means a radical-S (O)₂R, wherein R is alkyl or cycloalkyl as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, and butylsulfonyl.

"Alkylsulfinyl" refers to the group-S (O) R, wherein R is alkyl or cycloalkyl as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, and butylsulfinyl.

"alkylthio" refers to the group-SR, wherein R is alkyl or cycloalkyl as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio.

"aryl" refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from: acenaphthene anthracene, acenaphthene phenanthrene, anthracene, azulene, benzene, naphthalene, and naphthalene,(chrysene), coronene, phenylfluorene, fluorine, hexacene, hexaphene, hexalene, as-dicyclopentadiene (core) cycloacene (as-indacene), s-dicyclopentadiene (core) ringAcene (s-indacene), indane, indene, naphthalene, octabenzene, octaphene, itacene (octalene), ovalene, penta-2, 4-diene, pentacene, pentalene (slow) ring, pentaphene, perylene, grass-leaved, phenanthrene, picene, pleidene, pyrene, conene, prince, terphenyl (triphenylene), and trinaphthylene (trinaphthalene). Preferably, the aryl group contains 6 to 20 carbon atoms, more preferably 6 to 12 carbon atoms.

"arylalkyl" refers to a radical in which the carbon atom is typically a terminal carbon atom or sp³An acyclic alkyl group in which one of the carbon atom-bonded hydrogen atoms is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl. Where a specific alkyl group is intended, the nomenclature arylalkyl, arylalkenyl, and/or arylalkynyl is used. Preferably, arylalkyl is (C)₆-C₃₀) The alkyl, alkenyl or alkynyl moiety of an arylalkyl group, e.g. arylalkyl group, is (C)₁-C₁₀) And the aryl moiety is (C)₆-C₂₀) More preferably, arylalkyl is (C)₆-C₂₀) The alkyl, alkenyl or alkynyl moiety of an arylalkyl group, e.g. arylalkyl group, is (C)₁-C₈) And the aryl moiety is (C)₆-C₁₂)。

"arylalkoxy" refers to an-O-arylalkyl group, wherein the arylalkyl group is as defined herein, optionally substituted with one or more substituents as defined herein.

"arylalkoxycarbonylalkoxy" refers to the group-OCR' R "C (O) -arylalkoxy, wherein arylalkoxy is as defined herein. Similarly, where R' and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, may be optionally substituted with one or more substituents as defined herein, representative examples include, but are not limited to-OCH₂C(O)OCH₂C₆H₅、-OCH(CH₃)C(O)OCH₂C₆H₅、-OCH(C₆H₅)C(O)OCH₂C₆H₅、-OCH(CH₂C₆H₅)C(O)OCH₂C₆H₅、-OC(CH₃)(CH₃)C(O)OCH₂C₆H₅。

"arylalkoxycarbonylalkylamino" refers to the group-NRCR' R "C (O) -arylalkoxy, wherein arylalkoxy is as defined herein. Similarly, where R, R ', R', and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein, representative examples include, but are not limited to, -NHCH₂C(O)OCH₂C₆H₅、-N(CH₃)CH₂C(O)OCH₂C₆H₅、-NHCH(CH₃)C(O)OCH₂C₆H₅、-NHCH(C₆H₅)C(O)OCH₂C₆H₅、-NHCH(CH₂C₆H₅)C(O)OCH₂C₆H₅、-NHC(CH₃)(CH₃)C(O)OCH₂C₆H₅。

"Aryloxycarbonyl" refers to the group-C (O) -O-aryl, wherein aryl is as defined herein, optionally substituted with one or more substituents as defined herein.

"Aryloxycarbonylalkoxy" refers to the group-OCR' R "C (O) -aryloxy, where aryloxy is as defined herein. Similarly, wherein R' and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to-OCH₂C(O)OC₆H₅、-OCH(CH₃)C(O)OC₆H₅、-OCH(C₆H₅)C(O)OC₆H₅、-OCH(CH₂C₆H₅)C(O)OC₆H₅、-OC(CH₃)(CH₃)C(O)OC₆H₅。

"Aryloxycarbonylalkylamino" refers to the group-NRCR' R "C (O) -aryloxy, wherein aryloxy is as defined herein. Similarly, where R, R ', R', and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to-NHCH₂C(O)OC₆H₅、-N(CH₃)CH₂C(O)OC₆H₅、-NHCH(CH₃)C(O)OC₆H₅、-NHCH(C₆H₅)C(O)OC₆H₅、-NHCH(CH₂C₆H₅)C(O)OC₆H₅、-NHC(CH₃)(CH₃)C(O)OC₆H₅。

"carbamoyl" refers to the group-C (O) NRR where each R group is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein.

"carbamate" refers to a group-NR 'c (o) OR "wherein R' and R" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein. Representative examples include, but are not limited to, methyl carbamate (-NHC (O) OCH)₃) Ethyl carbamate (-NHC (O) OCH)₂CH₃) Benzyl carbamate (-NHC (O) OCH)₂C₆H₅)。

"carbonate" refers to the group-OC (O) OR, where R is alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR moreA plurality of substituents as defined herein. Representative examples include, but are not limited to, methyl carbonate (-C (O) OCH)₃) Cyclohexyl carbonate (-C (O) OC)₆H₁₁) Phenyl carbonate group (-C (O) OC₆H₅) And carbobenzoxy (-C (O) OCH)₂C₆H₅)。

"dialkylamino" means a group-NRR ', wherein R and R' independently represent alkyl or cycloalkyl as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di- (1-methylethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl) amino, (cyclohexyl) (propyl) amino.

"halo" means fluoro, chloro, bromo, or iodo.

"heteroaryl" refers to a monovalent heteroaromatic group obtained by removing one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from: acridine, arsenoline, carbazole, carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene. Preferably, the heteroaryl group is a 5-20 membered heteroaryl group, particularly preferably a 5-10 membered heteroaryl group. Preferred heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

"heteroaryloxycarbonyl" refers to the group-C (O) -OR, wherein R is heteroaryl as defined, optionally substituted with one OR more substituents as defined herein.

' Heteroarene"arylalkyl" refers to an alkyl group wherein the carbon atom is typically a terminal carbon atom or sp³An acyclic alkyl group in which one of the carbon atom-bonded hydrogen atoms is replaced with a heteroaryl group. Preferably, the heteroarylalkyl is a heteroarylalkyl of 6-30 carbon members, e.g., the alkyl, alkenyl or alkynyl portion of the heteroarylalkyl is 1-10 membered and the heteroaryl portion is a 5-20 membered heteroaryl, more preferably, the alkyl, alkenyl or alkynyl portion of the heteroarylalkyl is 1-8 membered and the heteroaryl portion is a 5-12 membered heteroaryl.

"isomers" means compounds, racemates, diastereomers, enantiomers, geometric isomers, structural isomers, and individual isomers of the present invention having an asymmetric carbon atom (optical center) or double bond are all intended to be encompassed within the scope of the present invention.

As used herein, the term "patient" includes mammalian patients. Examples of mammals include, but are not limited to, any member of the class mammalia: human, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs.

"pharmaceutically acceptable" means approved or approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

"pharmaceutically acceptable salt" refers to salts of the compounds of the present invention which are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, acid addition salts of 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2,2,2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; or (2) salts formed when the acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or a salt formed by complexing with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine.

"pharmaceutically acceptable carrier (vehicle)" refers to a diluent, adjuvant, excipient, or carrier with which the compound of the invention is administered.

"phosphate group" refers to the group-OP (O) (OR '), wherein R ' and R ' are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein.

"phosphonate" refers to the group-p (o) (OR ') (OR "), wherein R' and R" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein.

"preventing" or "prevention" refers to reducing the risk of acquiring a disease or disorder (i.e., leaving at least one of the clinical symptoms of a disease absent from a patient who may be exposed to or predisposed to the disease but does not yet experience or present symptoms of the disease).

"protecting group" refers to a group of atoms that shields, reduces, or prevents the reactivity of a reactive group in a molecule when attached to it. Examples of protecting Groups can be found in Green et al, "Protective Groups in Organic Chemistry" (Wiley, 2 nd edition, 1991) and Harrison et al, "Synthetic Organic Methods in general" (Compendium of Synthetic Organic Methods) volumes 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitroveratryloxycarbonyl ("NVOC"). Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is either acylated or alkylated, such as benzyl, and trialkylsilyl and allyl ethers.

"racemate" refers to an equimolar mixture of enantiomers of a chiral molecule.

"spacer" means C_1-6Alkylene radical, wherein C_1-6One or more carbons of the alkylene group may optionally be replaced by O, S or NR⁶In which R is⁶May be H or C_1-6An alkyl group. C_1-6The alkylene is optionally substituted. In certain aspects, C_1-6The alkylene group is optionally substituted with an acylalkoxycarbonyl, acyloxyalkoxycarbonyl, acylalkoxycarbonylamino, acyloxyalkoxycarbonylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylamino, alkylsulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino, arylalkylamino, dialkylamino, arylalkoxy, arylalkoxycarbonylalkoxy, arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy, aryloxycarbonylalkylamino, carboxyl, carbamoyl, carbamate, carbonate, cyano, halo, heteroaryloxycarbonyl, hydroxyl, phosphate, phosphonate, sulfate, sulfonate, or sulfonamide.

"substituted" refers to groups in which one or more hydrogen atoms are each independently replaced by one or more of the same or different substituents. Typical substituents include, but are not limited to, -X, -R⁵⁴、-O^-、＝O、-OR⁵⁴、-SR⁵⁴、-S、＝S、-NR⁵⁴R⁵⁵、＝NR⁵⁴、-CX₃、-CF₃、-CN、-OCN、-SCN、-NO、-NO₂、＝N₂、-N₃、-S(O)₂O^-、-S(O)₂OH、-S(O)₂OR⁵⁴、-OS(O)₂O³¹、-OS(O)₂R⁵⁴、-P(O)(O-)₂、-P(O)(OR¹⁴)(O³¹)、-OP(O)(OR⁵⁴)(OR⁵⁵)、-C(O)R⁵⁴、-C(S)R⁵⁴、-C(O)OR⁵⁴、-C(O)NR⁵⁴R⁵⁵、-C(O)O^-、-C(S)OR⁵⁴、-NR⁵⁶C(O)NR⁵⁴R⁵⁵、-NR⁵⁶C(S)NR⁵⁴R⁵⁵、-NR⁵⁷C(NR⁵⁶)NR⁵⁴R⁵⁵and-C (NR)⁵⁶)NR⁵⁴R⁵⁵Wherein each X is independently halogen; each R⁵⁴、R⁵⁵、R⁵⁶And R⁵⁷Independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl.

"sulfate group" means a group-OS (O) OR, wherein R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein.

"sulfonamide" refers to the group-s (o) NR ' R "where R ' and R" are independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein, or optionally R ' and R "together with the atoms to which they are both attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. Representative examples include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4- (NR' ") -piperazinyl, or imidazolyl, wherein said groups may be optionally substituted with one or more substituents as defined herein. R' "is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein.

"sulfonate" refers to the group-S (O) OR, wherein R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein.

"thio" means the group-SH.

"treatment" or "management" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the progression of at least one of the disease or its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter that may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to inhibiting the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a patient for the treatment of a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity and the age, weight, etc. of the patient to be treated, and may be determined by one of ordinary skill in the art without undue experimentation.

Compounds of the invention

The present invention provides phenylcycloalkylmethylamine derivatives of formula (I):

or an isomer or a pharmaceutically acceptable salt thereof, wherein:

n is 0, 1,2, 3,4 or 5; preferably n is 0 (cyclopropyl), 1 (cyclobutyl), 2 (cyclopentyl) or 3 (cyclohexyl), more preferably n is 1.

SP is a spacer, wherein said spacer is C_1-6Alkylene, wherein said C_1-6One or more carbon atoms of the alkylene group being optionally substituted by O, S or NR⁶Is substituted in which R⁶Is H or C_1-6An alkyl group;

x is O, S, NR⁶Or S (O);

R¹、R²、R³、R⁴and R⁵Each independently is hydrogen, C_1-6Alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl, heteroarylalkyl, acylalkoxycarbonyl, acylalkoxycarbonyloxy, acylalkoxycarbonylamino, C_1-6Alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylamino, alkylsulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino, arylalkylamino, dialkylamino, arylalkoxy, arylalkoxycarbonylalkoxy, arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy, aryloxycarbonylalkylamino, carboxyl, carbamoyl, carbamate, carbonate, cyano, halo, heteroaryloxycarbonyl, hydroxyl, phosphate, phosphonate, sulfate, sulfonate or sulfonamide; optionally R¹、R²、R³、R⁴And R⁵Quilt isotope²H (deuterium),³H (tritium),¹³C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S and³⁶cl; and

"" indicates carbon which can be optically active.

The compounds of the present invention include (R) -isomers, (S) -isomers and mixtures of (R) -and (S) -isomers. In one embodiment, the compounds are optically pure (R) -isomers because they are generally more active. In another embodiment, the compound is an optically pure (S) -isomer. In yet another embodiment, the compound is a racemic compound.

In a preferred embodiment, R¹And R²Independently is H, C_1-6Alkoxy (e.g., methoxy, ethoxy), halo (e.g., fluoro, chloro), or hydroxy.

In a preferred embodiment, R³Is H or C_1-6Alkyl (e.g., isobutyl).

In a preferred embodiment, R⁴Is H.

In a preferred embodiment, SP is C_1-6An alkylene group.

In a preferred embodiment, R⁵Is C_1-6An alkyl group.

In a preferred embodiment, R⁶Is C_1-6An alkyl group.

The compounds of the invention described herein may have one or more of the following characteristics or properties:

1. the compounds of the invention may have dopamine transporter (DAT), norepinephrine transporter (NET) and 5-hydroxytryptamine transporter (SERT) inhibitory properties;

2. the oral bioavailability of the compounds is consistent with oral administration using standard pharmacological oral dosage forms; however, any delivery system that produces continuous or controllable blood levels over a period of time may be used to administer the compounds and compositions thereof.

In some embodiments, the subject invention provides compounds having any two or more of the above-identified features or properties. In a preferred embodiment, the compounds of the invention have all four characteristics or properties.

Additional modifications to the compounds disclosed herein can be readily made by those skilled in the art. Thus, analogs and salts of the exemplary compounds are within the scope of the subject invention. Based on the knowledge of the compounds of the present invention, the skilled chemist can synthesize these compounds from available substrates using known methods. As used herein, the term "derivative" refers to a compound that is substantially identical to another compound but has been modified, for example, by the addition of additional pendant groups. The term "derivative" as used herein may also refer to a compound that is substantially identical to another compound but has substitution of atoms or molecules at certain positions of the compound.

The subject invention also relates to enantiomerically separated compounds and compositions comprising the compounds. The isolated enantiomeric forms of the compounds of the present invention do not substantially contain each other (i.e., are in enantiomeric excess). In other words, the "R" form of the compound is substantially free of the "S" form of the compound, and, thus, is in enantiomeric excess of the "S" form. In contrast, the "S" form of the compound is substantially free of the "R" form of the compound and, thus, is in enantiomeric excess of the "R" form. In one embodiment of the invention, the isolated enantiomeric compound is at least about 80% enantiomeric excess. In a preferred embodiment, the compound is in at least about 90%, 95%, 97% or 99% enantiomeric excess.

Synthesis of Compounds of the invention

The compounds of the present invention can be obtained via the synthetic methods illustrated in scheme 1. Several methods for synthesizing cycloalkylmethylamine analogs have been described in the art (see, e.g., U.S. Pat. No. 5,596,019; WO 2004/096202; WO 02/083631; WO 02/36540; WO 02/060424; Jeffery, J.E. et al, J.chem.Soc.Perkin Trans1,1996, 2583-2589.). Other methods for synthesizing cycloalkylmethylamines are known in the art and readily appreciated by those skilled in the art. The starting materials and intermediates used in the Synthesis of the target molecule (schemes 1-8) are commercially available or can be prepared by established Methods (see, for example, Green et al, "Protective Groups in Organic Synthesis" (Wiley, 4 th edition, 2006); Harrison et al, "synthetic Organic Methods Large complete (Complex of synthetic Organic Methods)" Vol.1-8 (John Wiley and Sons,1971-1996), "Belstein Organic Chemistry Manual (Beilstein Handbook of Organic Chemistry)," Frankfurt, Germany; Feiser et al, "Organic Synthesis Reagents (Reagents for Organic Synthesis)" Vol.1-45, Karger, 1991; March, "Advanced Organic Chemistry (Advanced Organic Chemistry, Wiley, Interorgans)" Vol.1-45, Wilford, Encyclopedia, "Wiley, 4 th edition, Wiley, 2-enchan, and" Organic Transformations of Organic Chemistry ", Wiley, 2, Japan, Inc. (pages of synthetic Methods 1999), 1 st edition, 1995).

Thus, the starting materials for preparing the compounds of the invention and intermediates thereof are commercially available or may be prepared by well-known synthetic methods. Other methods for synthesizing cycloalkylmethylamines described herein, either as described in the art or as would be apparent to one of skill in the art in view of the references provided above, can be used to synthesize the compounds of the present invention. Thus, the methods presented in the flow charts herein are illustrative and not all-inclusive.

Method of producing a composite material

In one method, phenylcycloalkylmethylamine derivatives of formula (I) (7,8) are prepared as described in scheme 2. The starting phenylcycloalkylamine building block (6) was prepared by a modified procedure reported by Jeffery et al (J.chem.Soc., Perkin Trans.1,1996,2583-2589) as shown in scheme 1. A typical procedure involves the reaction of a cycloalkylnitrile (3) with a suitable Grignard reagent (R)³MgBr) in the presence of toluene at mild reflux temperature for 10 to 24 hours and then with methanolOr sodium borohydride in ethanol to give the corresponding cycloalkylmethylamine (6). The cycloalkylnitrile (3) used in the preparation of the cycloalkylamine (6) was either purchased from sigma aldrich or synthesized from the corresponding phenylacetonitrile (1) using standard chemistry. The selected racemic amine (6) was separated into the corresponding optically pure (R) -and (S) -isomers by standard chiral crystallization methods using optically pure tartaric acid.

Scheme 1

As shown in scheme 2, phenylcycloalkylmethylamine (6) is alkylated with the appropriate 4-nitrobenzenesulfonyl ester (9) using cesium carbonate in N, N-Dimethylformamide (DMF) solvent at room temperature to obtain the corresponding cycloalkylmethylamine ether derivative (7,8) in moderate to good yield. The building block 4-nitrobenzenesulfonyl ester (9) was synthesized as shown in scheme 6.

Scheme 2

In another method, as shown in scheme 2, phenylcycloalkylmethylamine ether derivatives (7,8) are prepared in moderate yield by coupling with the appropriate alkoxyalkyl carboxylic acid (10) followed by reduction of the amide intermediate (11) with Lithium Aluminum Hydride (LAH) in anhydrous THF. An alkoxyalkyl carboxylic acid (10) is prepared as shown in scheme 7.

In another method, a phenylcycloalkylmethylamine derivative of formula (I) (12,13) is prepared as shown in scheme 3. The phenylcycloalkylamine (6) is coupled with the appropriate alkylthioalkyl carboxylic acid (14) to give the amide (15), which is then reduced with lithium aluminium hydride to give the corresponding phenylcycloalkylmethylamine thioether derivative (12, 13). An alkylthioalkyl carboxylic acid (14) was synthesized as shown in scheme 8.

Scheme 3

In another method, a phenylcycloalkylmethylamine derivative of formula (I) (17) is prepared as shown in scheme 4. Phenyl cycloalkylamine (15) was oxidized using m-chloroperoxybenzoic acid (mCPBA) to yield amide (16), which was then reduced with lithium aluminum hydride to yield the corresponding phenyl cycloalkylmethylamine derivative (17).

Scheme 4

In another method, a phenylcycloalkylmethylamine derivative of formula (I) (19) is prepared as shown in scheme 5. The phenyl cycloalkylamine (6) is coupled with the appropriate alkylaminoalkylcarboxylate (20) in the presence of trimethylaluminum in toluene to yield the amide (21), followed by borane-dimethyl sulfide (BH) in toluene₃-DMS) or LAH in THF to produce the corresponding phenylcycloalkylmethylamine derivative (19).

Scheme 5

Optically pure (R) -and (S) -phenylcycloalkylmethylamine derivatives of formula I are prepared from the corresponding optically pure amine (6) or by applying chiral HPLC separation techniques on the corresponding racemic phenylcycloalkylmethylamine derivatives (7,8,12,13,17 and 19). All phenylcycloalkylmethylamine derivatives (7,8,12,13,17 and 19) were converted to the corresponding hydrochloride salts by treatment with 2N HCl solution in ether under standard conditions.

The p-nitrobenzenesulfonyl-protected ether (9), the building block used in the synthesis of phenylcycloalkylmethylamine derivatives, was synthesized in a four-step procedure as shown in scheme 6. The mono-benzyl protected diol (24) was synthesized in good yield by benzylating the corresponding diol (23) with sodium hydride as a base in anhydrous Tetrahydrofuran (THF) at 0 ℃ followed by refluxing the reaction mixture. The benzyl protected alcohol (24) is alkylated with the appropriate halogenated hydrocarbon in anhydrous N, N-Dimethylformamide (DMF) using sodium hydride as the base to yield the ether (25). The benzyl protecting group is cleaved under standard hydrogenation conditions to yield the corresponding alcohol (26), which is reacted with p-nitrobenzenesulfonyl chloride in dichloromethane solvent with the mild base triethylamine to afford the p-nitrobenzenesulfonyl protected ether (9) in good overall yield.

Scheme 6

As shown in scheme 7, the starting building block, 4-alkoxyalkyl carboxylic acid (10), is synthesized in a two-step procedure. Reaction of gamma butyrolactone (28) with ethyl orthoformate (29) in the presence of ethanol and sulfuric acid produces the corresponding 4-ethoxybutyrate ester (30) in good yield. Saponification of ester (30) under standard reaction conditions produces the corresponding 4-ethoxybutanoic acid (10) in good yield.

Scheme 7

As shown in scheme 8, in a two step procedure, the starting building block, alkylthioalkyl carboxylic acid (14), is synthesized. Sodium thiolate (32) is alkylated with bromoalkylcarboxylic acid (31) in anhydrous DMF to yield ester (33), which upon saponification yields the corresponding alkylthioalkyl carboxylic acid (14).

Scheme 8

Therapeutic use of compounds of formula (I)

In various aspects, the present disclosure provides methods of treating or preventing obesity, depression, and related co-morbid conditions in a patient. The method comprises administering to a patient in need of such treatment an effective amount of any one of the compounds of structural formula (I). In other aspects, the methods treat obesity, depression, and associated co-morbid symptoms.

The present invention provides methods of treating and preventing obesity and related co-morbid conditions. The term "obesity-related co-morbid condition" as used herein means a medical condition known to those skilled in the art to be associated with obesity. The term includes, but is not limited to, the following: diabetes in mammals, particularly humans, includes non-insulin dependent diabetes mellitus, impaired glucose tolerance, hypertension, coronary artery thrombosis, stroke, depression, anxiety, psychoses (e.g. schizophrenia), tardive dyskinesia, drug addiction, drug abuse, cognitive disorders, alzheimer's disease, cerebral ischemia, obsessive compulsive behaviour, panic attacks, social phobia, eating disorders such as bulimia, anorexia, snaking and binge eating (binge eating), lipid syndrome, hyperglycemia, hyperlipidemia and stress (stress).

In addition, the compounds, compositions and methods of the invention are useful for treating or preventing metabolic disorders and conditions caused thereby, or thermogenesis and increased metabolic rate, e.g., non-exercise activity, sexual dysfunction, sleep apnea, premenstrual syndrome, urinary incontinence including stress urinary incontinence, hyperactivity, hiatal hernias (hiatal hernias) and reflux esophagitis, pain, particularly neuropathic pain, weight gain associated with drug therapy, chronic fatigue syndrome, osteoarthritis and gout, cancer associated with weight gain, menstrual disorders, cholelithiasis, orthostatic hypotension and pulmonary hypertension.

The compounds, compositions and methods of the invention are useful for preventing cardiovascular disease, and for reducing platelet adhesion, aiding weight loss after pregnancy, reducing craving for smoking, and aiding weight loss after smoking cessation. The invention is also useful for reducing uric acid levels and lipid levels in mammals, particularly humans.

According to the present invention, a compound and/or a composition comprising a compound of formula (I) is administered to a patient, preferably a human suffering from obesity and associated co-morbidities and/or disorders. In certain embodiments, the compounds and/or compositions of the present invention are administered to a patient, preferably a human, as a prophylactic measure against various diseases or conditions. Thus, the compounds and/or compositions comprising compounds of structural formula (I) may be administered as a prophylactic measure to patients predisposed to obesity and associated co-morbidities and/or conditions (see, WO 2004/058237; WO 2004/096202; WO 02/060424; WO 01/51453; WO 01/00205; WO 01/00187; Mueller, P. International application publication No. WO 00/32178; WO 98/11884; WO 98/13034).

Thus, one skilled in the art can readily test and use the compounds and/or compositions comprising compounds of formula (I) to treat obesity and related co-morbidities and/or conditions.

Therapeutic/prophylactic administration

The compounds and/or compositions of the present invention may be administered or administered to a patient, either alone or in combination with other pharmaceutically active agents.

The compounds and/or compositions of the present invention are preferably administered orally. The compounds and/or compositions of the present invention may also be administered by any other convenient route, for example, by infusion or bolus injection (bolus injection), by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administration may be systemic or local. Various delivery systems are known, (e.g., encapsulated in liposomes, microparticles, microcapsules, capsules, etc.) and may be used to administer the compounds and/or compositions of the present invention. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal (intravaginal), transdermal, rectal, by inhalation or topical, particularly to the ear, nose, eye or skin.

In a particularly preferred embodiment, the compounds and/or compositions of the present invention may be delivered via a sustained release system, preferably an oral sustained release system. In one embodiment, a pump may be used (see, Langer, supra; Sefton,1987, CRCCrit. Ref biomed. Eng.14: 201; Saudek et al, 1989, N.Engl. J.Med.321: 574).

In another embodiment, polymeric materials may be used (see "medical applications for Controlled Release", Langer and Wise (ed.), Wiley, New York (1984); Ranger and Peppas,1983, J.Macromol. Sci.Rev. Macromol chem.23: 61; see also Levy et al, 1985, Science228: 190; During et al, 1989, Ann.Neurol.25: 351; Howard et al, 1989, J.Neurosurg.71: 105). In a preferred embodiment, the polymeric material is used in oral sustained release delivery. Preferred polymers include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose (more preferably hydroxypropylmethylcellulose). Other preferred cellulose ethers have been described in the art (Bamba et al, int.j. pharm.,1979,2, 307).

In another embodiment, the enteric coated formulations may be used for oral sustained release administration. Preferred coating materials include polymers with pH-dependent solubility (i.e., pH-controlled release), polymers with slow or pH-dependent swelling, dissolution or erosion rates (i.e., timed release), polymers that are degraded by enzymes (i.e., enzyme-controlled release), and polymers that form a solid layer that is destroyed by pressurization (i.e., pressure-controlled release).

In yet another embodiment, the osmotic delivery system is used for oral sustained release administration (Verma et al, drug Dev. Ind. pharm.,2000,26: 695-. In a preferred embodiment of the process according to the invention,osmotic delivery systems (alza corporation, Mountain View, CA) are used in oral sustained release delivery devices (see, e.g., U.S. patent nos. 3,845,770 and 3,916,899).

In yet another embodiment, a Controlled Release system may be placed adjacent to the target of the compounds and/or compositions of the invention, thus, requiring only a fraction of the systemic dose (see, e.g., Goodson, "medical applications of Controlled Release", supra, Vol.2, pp.115-138 (1984)). Other controlled release systems discussed in Langer,1990, Science249: 1527-.

The compounds of the invention and/or compositions comprising compounds of formula (I) may be cleaved chemically and/or enzymatically. One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain or any other suitable tissue of a mammal can enzymatically cleave the compounds and/or compositions of the present invention.

Compositions of the invention

In various aspects, the present disclosure provides pharmaceutical compositions comprising any of the compounds of structural formula (I), and a pharmaceutically acceptable carrier.

When administered to a patient, the compounds of the invention and pharmaceutically acceptable carriers are preferably sterile. Water is a preferred carrier when the compounds of the invention are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, or pH buffering agents. In addition, adjuvants, stabilizers, thickeners, lubricants, and colorants may be used.

The pharmaceutical compositions may be prepared by conventional mixing, dissolving, granulating, and emulsifying, encapsulating, entrapping (entropping) or lyophilizing processes. The pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries in order to process the compounds of the invention into preparations which can be used pharmaceutically. The appropriate formulation will depend on the route of administration chosen.

The compositions may take the form of solutions, suspensions, emulsions, tablets, pills, pellets and capsules, liquid-containing capsules, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions or any other form suitable for use. In one embodiment, the pharmaceutically acceptable carrier is a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examples of suitable Pharmaceutical carriers are described in the art (see Remington's Pharmaceutical Sciences, Philadelphia College of Pharmacy and science, 17 th edition, 1985). Preferred compositions of the invention are formulated for oral delivery, particularly for oral sustained release administration.

Compositions for oral delivery may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Compositions for oral administration may comprise one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, oil of wintergreen, or cherry coloring agents and preservatives, to provide a pharmaceutically palatable preparation. When in tablet or pill form, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period. Selectively permeable membranes surrounding osmotically active driven compounds are also suitable for orally administered compounds of the present invention. In these subsequent platforms, fluid from the environment surrounding the capsule is absorbed by the driving compound, which expands to displace the agent or agent composition through the pores. These delivery platforms may provide a substantially zero order delivery profile rather than a spike pattern for immediate release formulations. Time delay materials such as glyceryl monostearate or glyceryl stearate may also be used. Oral compositions may include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Such carriers are preferably of pharmaceutical grade.

For oral liquid formulations, e.g., suspensions, elixirs and solutions, suitable carriers (carriers), excipients or diluents include water, saline, alkylene glycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol), oils, alcohols, slightly acidic buffers between pH4 and pH6 (e.g., acetate, citrate, ascorbate between about 1mM and about 50 mM), and the like. In addition, flavoring agents, preservatives, coloring agents and bile salts may be added.

Compositions for administration via other routes are also contemplated. For buccal administration, the compositions may be in the form of tablets, lozenges, and the like formulated in a conventional manner. Liquid pharmaceutical formulations suitable for use with nebulizers and liquid spray devices, as well as EHD aerosol devices, may typically include a compound of the invention together with a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is a liquid, such as ethanol, water, polyethylene glycol, or a perfluorocarbon. Optionally, another material may be added to modify the spray properties of a solution or suspension of a compound of the present invention. Preferably, the material is a liquid, such as an alcohol, glycol, polyethylene glycol or fatty acid. Other methods of formulating liquid drug solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (see, e.g., U.S. Pat. nos. 5,112,598 and 5,556,611). The compounds of the invention may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa, milk fat or other glycerides. In addition to the formulations described previously, the compounds of the present invention may be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention may be formulated with suitable polymeric or hydrophobic materials (e.g., emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

When the compound of the present invention is acidic, it may be included in any of the above-described formulations as a free acid, a pharmaceutically acceptable salt, solvate or hydrate. Pharmaceutically acceptable salts substantially retain the activity of the free acid, can be prepared by reaction with a base, and tend to be more soluble in aqueous and other protic solvents than the corresponding free acid form.

Methods of use and dosages

The present invention provides a method of treating or preventing obesity in a patient, comprising administering to a patient in need of such treatment an effective amount of any one of the compounds of structural formula (I).

The amount of a compound of the invention effective to treat a particular disorder or condition disclosed herein depends on the nature of the disorder or condition and can be determined as described previously by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may optionally be used to help determine optimal dosage ranges. The amount of the compound of the invention to be administered depends on, among other factors, the subject being treated and the weight of the subject, the severity of the condition, the mode of administration, and the judgment of the prescribing physician. For example, a dose in a pharmaceutical composition can be delivered by a single administration, multiple administrations, or controlled release. In a preferred embodiment, the compounds of the present invention are delivered by oral sustained release administration. Preferably, in this embodiment, the compounds of the present invention are administered twice daily (or, preferably, once daily). The administration can be repeated intermittently, can be provided alone or in combination with other agents, and can be continued as long as effective treatment of the disease state or condition is desired.

A compound of formula (I) may be administered in one or more doses per day in an amount ranging from 0.1 to 500mg, preferably 1 to 100mg, and more preferably 5mg, 10mg, 15mg, 20mg, 25mg, 35mg or 50mg per day, most preferably 25mg per day.

The compounds of the invention are preferably tested in vitro and in vivo for the desired therapeutic or prophylactic activity prior to administration to humans. Animal model systems may also be used to confirm the efficacy and safety of the compounds of the invention.

Therapeutically effective dosages of the compounds of the invention described herein may provide therapeutic benefit without causing substantial toxicity. Toxicity of the compounds of the present invention can be determined using standard pharmaceutical procedures and can be readily determined by one of skill in the art. The dose ratio between toxic and therapeutic effects is the therapeutic index. The dosages of the compounds of the present invention described herein are within the range including circulating concentrations which are effective in dosages that are minimally or non-toxic.

The invention is further defined by the following examples describing in detail the preparation of the compounds and compositions of the invention, and the testing using the compounds and compositions of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Examples

In the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

General procedure for the Synthesis of phenylcycloalkylmethylamine 6 (scheme 1)

To a stirred solution of Grignard reagent (2M solution in ether, 0065mol) was added dropwise a solution of phenylcycloalkylcarbonitrile (3) (0.026mol) in 50mL of toluene at 0 ℃ under nitrogen. The reaction mixture was then slowly heated at 92 ℃ for 18 h. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in 30mL of anhydrousDiluted with methanol and cooled to 0 deg.C, NaBH was added slowly in portions₄(2.5 g). The resulting mixture was stirred until the imine intermediate was completely converted to the corresponding amine. After completion of the reaction, methanol was removed by evaporation. The residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate, and MgSO₄Dried and evaporated under reduced pressure to give the corresponding phenylcyclobutylmethylamine (6), which is purified by column chromatography on silica gel with a gradient of hexane and ethyl acetate. The pure product 6a-m exhibited satisfactory 1HNMR and/or mass spectral data.

Example 1

3-methyl-1- (1- (p-tolyl) cyclopropyl) butan-1-amine (6 a). A colorless oil (1.66g, 61%).¹HNMR(400MHz,CDCl₃)：0.65-0.70(m,3H)；0.77-0.80(m,1H)；0.85(d,J＝6.8Hz,6H)；0.98-1.11(m,2H)；1.22-1.30(m,2H)；1.70-1.77(m,1H)；2.10-1.13(m,1H)；2.28(s,3H)；7.09(d,J＝8.0Hz,2H)；7.20(d,J＝8.0Hz,2H)。MS(ESI)：m/z＝218.20(M+H⁺)。

Example 2

1- (1- (4-chlorophenyl) cyclopropyl) -3-methylbutan-1-amine (6 b). Colorless oil (1.60g, 60%).¹HNMR(400MHz,CDCl₃)：0.65-0.70(m,3H)；0.77-0.80(m,1H)；0.85(d,J＝6.8Hz,6H)；0.87-1.01(m,1H)；1.18-1.27(m,3H)；1.69-1.73(m,1H)；2.16(d,J＝10.4Hz,1H)；7.23-7.24(m,4H)。MS(ESI)：m/z＝238.20(M+H⁺)。

Example 3

1- (1- (4-fluorophenyl) cyclobutyl) -3-methylbutan-1-amine (6 c). Colorless oil (2.2g, 70%).¹HNMR(400MHz,CDCl₃)：0.58-0.65(m,1H)；0.84(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；1.15-1.21(m,1H)；1.67-1.70(m,1H)；1.80-1.86(m,1H)；1.93-1.98(m,1H)；2.12-2.18(m,1H)；2.28-2.37(m,3H)；2.97(dd,J＝2.0Hz；10.8Hz,1H)；6.93-7.08(m,3H)；7.12-7.16(m,1H)。

Example 4

1- (1- (4-chlorophenyl) cyclobutyl) -3-methylbutan-1-amine (6 d). Colorless oil (4.7g, 72%).¹HNMR(400MHz,CDCl₃)：0.84(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；1.13-1.23(m,2H)；1.66-1.68(m,1H)；1.79-1.84(m,1H)；1.90-1.96(m,1H)；2.15-2.16(m,1H)；2.25-2.33(m,3H)；2.98(d,J＝10.8Hz,1H)；7.06(dd,J＝1.6；8.4Hz,2H)；7.24(dd,J＝1.6；8.4Hz,2H)。

Example 5

1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methylbutan-1-amine (6 e). Colorless oil (3.6g, 70%).¹HNMR(400MHz,CDCl₃)：0.53-0.60(m,1H)；0.84(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；1.10-1.13(m,1H)；1.63-1.67(m,1H)；1.77-1.83(m,1H)；1.91-1.97(m,1H)；2.12-2.16(m,1H)；2.21-2.33(m,3H)；2.97(d,J＝10.8Hz,1H)；6.96(dd,J＝2.0Hz；8.4Hz,1H)；7.19(d,J＝2Hz；1H)；7.32(d,J＝8.4Hz,1H)。

Example 6

1- (1- (2, 4-dichlorophenyl) cyclobutyl) -3-methylbutan-1-amine (6 f). Colorless oil (1.5g, 72%).¹HNMR(400MHz,CDCl₃)：0.84(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；1.13-1.15(m,1H)；1.23-1.26(m,1H)1.71-1.81(m,2H)；1.92-2.03(m,1H)；2.35-2.43(m,4H)；3.24(dd,J＝2.0Hz；10.8Hz,1H)；7.02(d,J＝8.4Hz,1H)；7.16(dd,J＝2Hz；8.4Hz,1H)；7.29(d,J＝2.4Hz,1H)。

Example 7

1- (1- (3, 4-dimethoxy)Phenylphenyl) cyclobutyl) -3-methylbutan-1-amine (6 g). Colorless oil (3.6g, 70%).¹HNMR(400MHz,CDCl₃)：0.53-0.60(m,1H)；0.84(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；1.10-1.13(m,1H)；1.63-1.67(m,1H)；1.77-1.83(m,1H)；1.91-1.97(m,1H)；2.12-2.16(m,1H)；2.21-2.33(m,3H)；2.97(d,J＝10.8Hz,1H)；3.87(s,6H)；6.77-6.82(m,3H)。

Example 8

11- (1- (4-ethoxyphenyl) cyclobutyl) -3-methylbutan-1-amine (6 h). Colorless oil (1.06g, 72%).¹HNMR(400MHz,CDCl₃)：0.57-0.64(m,1H)；0.84(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；1.15-1.21(m,1H)；1.40(t J＝6.8Hz,3H)；1.67-1.69(m,1H)；1.79-1.84(m,1H)；1.90-1.96(m,1H)；2.14-2.16(m,1H)；2.27-2.36(m,3H)；2.98(dd,J＝2.0Hz；10.8Hz,1H)；4.02(q,J＝6.8Hz,2H)；6.83(d,J＝8.4Hz,2H)；7.05(dd,J＝8.4Hz,2H)。

Example 9

3-methyl-1- (1- (4- (methylthio) phenyl) cyclobutyl) butan-1-amine (6 i). Colorless oil (1.7g, 34%).¹HNMR(400MHz,CDCl₃): 0.56-0.62(m, 1H); 0.83(d, J ═ 6.8Hz, 3H); 0.88(d, J ═ 6.8Hz, 3H); 1.04-1.06(s broad, 2H); 1.13-1.20(m, 1H); 1.64-1.68(m, 1H); 1.79-1.83(m, 1H); 1.90-1.95(m, 1H); 2.11-2.17(m, 1H); 2.26-2.37(m, 3H); 2.46(s, 3H); 2.96(d, J ═ 10.8Hz, 1H); 7.05(d, J ═ 8.4Hz, 2H); 7.19(d, J ═ 8.4Hz, 2H). Ms (esi): 264.20(M + H)⁺)。

Example 10

3-methyl-1- (1- (p-tolyl) cyclopentyl) butan-1-amine (6 j). Colorless oil (1.46g, 60%).¹HNMR(400MHz,CDCl₃): 0.68-0.78(m, 1H); 0.83(d, J ═ 6.8Hz, 6H); 0.99(s broad, 2H); 1.20-1.24(m, 1H); 1.50-1.56(m, 2H);1.58-1.68(m,3H)；1.72-1.78(m,1H)；1.84-1.91(m,1H)；2.02-2.08(m,2H)；2.28(s,3H)；2.73(d,J＝10.8Hz,1H)；7.09(d,J＝8.0Hz,2H)；7.20(d,J＝8.0Hz,2H)。MS(ESI)：m/z＝246.20(M+H⁺)。

example 11

1- (1- (4-methoxyphenyl) cyclopentyl) -3-methylbutan-1-amine (6 k). A colorless oil (1.43g, 55%).¹HNMR(400MHz,CDCl₃): 0.66-0.77(m, 2H); 0.81(d, J ═ 6.8Hz, 6H); 0.97-1.02(s broad, 2H); 1.12-1.18(m, 1H); 1.48-1.55(m, 1H); 1.58-1.68(m, 3H); 1.71-1.77(m, 1H); 1.82-1.89(m, 2H); 2.07-2.06(m, 1H); 2.70(d, J ═ 10.8Hz, 1H); 3.78(s, 3H); 6.82(d, J ═ 8.8Hz, 2H); 7.23(d, J ═ 8.8Hz, 2H). Ms (esi): 262.20(M + H)⁺)。

Example 12

3-methyl-1- (1- (p-tolyl) cyclohexyl) but-1-amine (6 l). Colorless oil (1.46g, 60%).¹HNMR(400MHz,CDCl₃)：0.63-0.76(m,1H)；0.77(d,J＝6.8Hz,3H)；0.83(d,J＝6.8Hz,3H)；1.17-1.32(m,5H)；1.37-1.66(m,6H)；2.24-2.36(m,4H)；2.52(d,J＝10.4Hz,1H)；7.09(d,J＝8.0Hz,2H)；7.20(d,J＝8.0Hz,2H)。MS(ESI)：m/z＝260.20(M+H⁺)。

Example 13

1- (1- (4-chlorophenyl) cyclohexyl) -3-methylbutan-1-amine (6 m). Colorless oil (0.8g, 32%).¹HNMR(400MHz,CDCl₃): 0.60-0.66(m, 1H); 0.75(d, J ═ 6.8Hz, 3H); 0.81(d, J ═ 6.8Hz, 3H); 0.95-1.00(s broad, 2H); 1.11-2.25(m, 5H); 1.41-1.62(m, 5H); 2.20-2.30(m, 2H); 2.53(d, J ═ 10.8Hz, 1H); 7.22(d, J ═ 8.8Hz, 2H); 7.27(d, J ═ 8.8Hz, 2H). Ms (esi): 280.20(M + H)⁺)。

General procedure for the Synthesis of phenyl cyclobutylmethyl Ether derivatives 7 and 8 (scheme 2)

To a stirred solution of cesium carbonate (1.4g,5.0eq) in 10mL of DMF was added the appropriate phenylcyclobutylmethylamine (6) (0.0009mol) and the resulting mixture was stirred at room temperature for 4 hr. Then, a solution of the appropriate 4-nitrobenzenesulfonate (0.0045mol.5eq) in 5mL of DMF was added over 5 minutes. The resulting mixture was stirred at rt temperature overnight. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). The reaction mixture was filtered, diluted with 10mL ethyl acetate, washed with brine, and Na₂SO₄Drying, evaporation to give the corresponding phenylbutylmethylether derivative (7,8) which was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate the pure product (7,8) exhibited satisfactory 1H NMR and/or mass spectral data chiral HPLC was performed on the selected racemic ether derivative (7,8) to give the corresponding optically pure (R) -and (S) -isomers chiral HPLC conditions column-CHIRAL PAK IA4.6 × 250mm,5 μ M, mobile phase-0.1% DEA/hexane and ethanol, isocratic method at 0.8 ml/min flow rate, injection volume 1.00ul, and run time 20min all ether derivatives (7,8) were converted to the corresponding HCl salt by treating them with 1N HCl dioxane/water followed by freeze drying.

Example 14

1- (1- (4-ethoxyphenyl) cyclobutyl) -N- (2-methoxyethyl) -3-methylbutan-1-amine (7 a). A colorless oil (100mg, 28% yield).¹HNMR(400MHz,CDCl₃): 0.57-0.66(m, 1H); 0.83(d, J ═ 6.8Hz, 3H); 0.88(d, J ═ 6.8Hz, 3H); 1.08-1.12(m, 1H); 1.41(t, J ═ 9.2Hz, 3H); 1.59-1.68(m, 1H); 1.71-1.89(m, 2H); 2.16-2.38(m, 4H); 2.73(d broad, J ═ 3.2Hz, 1H); 2.88(t, J ═ 6.8Hz, 2H); 3.32(s, 3H); 3.45(t, J ═ 7.2Hz, 2H); 4.03(q, J ═ 7.2Hz, 2H); 6.83(d, J ═ 8.4Hz, 2H); 7.16(d, J ═ 8.4Hz, 2H). Ms (esi): 320.61(M + H)⁺)。

Example 15

N- (2-ethoxyethyl) -1- (1- (4-ethoxyphenyl) cyclobutyl) -3-methylbutan-1-amine (7 b). A colorless oil (70mg, 27% yield).¹HNMR(400MHz,CDCl₃): 0.57-0.66(m, 1H); 0.83(d, J ═ 6.8Hz, 3H); 0.88(d, J ═ 6.8Hz, 3H); 1.08-1.12(m, 1H); 1.21(t, J ═ 9.6Hz, 3H); 1.38-1.44(m, 4H); 1.59-1.66(m, 1H); 1.75-1.86(m, 2H); 2.15-2.18(m, 1H); 2.28-2.37(m, 3H); 2.73(d broad, J ═ 11.6Hz, 1H); 2.73-2.92(m, 2H); 3.43-3.50(m, 3H); 4.03(q, J ═ 7.2Hz, 2H); 6.83(d, J ═ 8.4Hz, 2H); 7.16(d, J ═ 8.4Hz, 2H). Ms (esi): 334.72(M + H)⁺)。

Example 16

1- (1- (4-ethoxyphenyl) cyclobutyl) -3-methyl-N- (2-propoxyethyl) butan-1-amine (7 c). A colorless oil (80mg, 27% yield).¹HNMR(400MHz,CDCl₃): 0.57-0.66(m, 1H); 0.83(d, J ═ 6.8Hz, 3H); 0.88(d, J ═ 6.8Hz, 3H); 0.91-0.92(m, 6H); 1.00-1.08(m, 1H); 1.39-1.46(m, 4H); 1.52-1.64(m, 3H); 1.73-1.86(m, 2H); 2.17-2.40(m, 4H); 2.73(s broad, 1H); 2.88-2.94(m, 2H); 3.36(t, J ═ 6.8Hz, 2H); 3.48(d, J ═ 10.8Hz, 2H); 4.03(q, J ═ 7.2Hz, 2H); 6.83(d, J ═ 8.4Hz,7.16(d, J ═ 8.4Hz,1H), ms (esi) M/z ═ 348.40(M + H)⁺)。

Example 17

N- (2-butoxyethyl) -1- (1- (4-ethoxyphenyl) cyclobutyl) -3-methylbutan-1-amine (7 d). A colorless oil (100mg, 27% yield).¹HNMR(400MHz,CDCl₃): 0.57-0.66(m, 1H); 0.83(d, J ═ 6.8Hz, 3H); 0.88(d, J ═ 6.8Hz, 3H); 0.92(t, J ═ 9.6Hz, 3H); 1.08-1.12(m, 1H); 1.32-1.44(m, 5H); 1.49-1.64(m, 3H); 1.78-1.86(m, 1H); 2.04-2.15(m, 1H); 2.26-2.39(m, 2H); 2.73(d broad, J ═ 11.6Hz, 1H); 2.86-2.91(m, 2H); 3.38-3.48(m, 4H); 3.64(t, J ═ 7.2H, 1H); 4.03(q, J ═ 7.2Hz, 2H); 4.277(t, J)＝6.8Hz,1H)；6.82(d,J＝8.4Hz,2H)；7.15(d,J＝8.4Hz,2H)。MS(ESI)：m/z＝362.57(M+H⁺)。

Example 18

1- (1- (4-ethoxyphenyl) cyclobutyl) -N- (2-isobutoxyethyl) -3-methylbutan-1-amine (7 e). A colorless oil (90mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.66(m,1H)；0.83(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；0.90-1.04(m,6H)；1.08-1.12(m,1H)；1.38-1.44(m,4H)；1.60-1.68(m,1H)；1.70-1.91(m,3H)；2.13-2.20(m,1H)；2.27-2.42(m,3H)；2.71(d,J＝8.4Hz,1H)；2.85-2.92(m,2H)；3.17(d,J＝6.4Hz,2H)；3.58(t,J＝7.2H,1H)；4.03(q,J＝7.2Hz,2H)；6.82(d,J＝8.4Hz,2H)；7.15(d,J＝8.4Hz,2H)。MS(ESI)：m/z＝362.57(M+H⁺)。

Example 19

N- (2-ethoxyethyl) -3-methyl-1- (1- (4- (methylthio) phenyl) cyclobutyl) butan-1-amine (7 f).

Colorless oil (0.20g, 20%).¹HNMR(400MHz,CDCl₃)：0.60-0.66(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；1.06-1.09(m,1H)；1.17(t,J＝7.2Hz,3H)；1.61-1.60(m,1H)；1.70-1.77(m,1H)；1.82-1.88(1H)；2.14-2.19(m,3H)；2.23-2.29(m,2H)；2.35-2.41(m,1H)；2.46(s,3H)；2.72(d,J＝10Hz,1H)；2.88(t,J＝7.2H,2H)；3.42-3.48(m,3H)；7.02(d,J＝8.8Hz,2H)；7.20(d,J＝8.8Hz,2H)。MS(ESI)：m/z＝336.20(M+H⁺)。

Example 20

N- (4-ethoxybutyl) -3-methyl-1- (1- (4- (methylthio) phenyl) cyclobutyl) butan-1-amine (7 g).

Colorless oil (0.21g, 20%).¹HNMR(400MHz,CDCl₃)：0.60-0.66(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；1.87(t,J＝7.2Hz,3H)；1.47-1.83(m,6H)；2.04-2.22(m,3H)；2.27-2.32(m,2H)；2.46(s,3H)；3.40-3.49(m,5H)；4.10-4.15(m,4H)；7.02(d,J＝8.8Hz,2H)；7.20(d,J＝8.8Hz,2H)。MS(ESI)：m/z＝364.20(M+H⁺)。

Example 21

1- (1- (4-chlorophenyl) cyclobutyl) -N- (2-ethoxyethyl) -3-methylbutan-1-amine (7 h).¹HNMR(400MHz,CDCl₃)：0.63-0.71(m,1H)；0.81(d,J＝6.8Hz,3H)；0.86(d,J＝6.8Hz,3H)；1.01-1.07(m,1H)；1.17(t,J＝7.2Hz,3H)；1.59-1.66(m,1H)；1.70-1.77(m,1H)；1.83-1.90(m,1H)；2.12-2.17(m,1H)；2.22-2.29(m,2H)；2.36-2.43(m,1H)；2.73(dd,J＝2.4Hz；10.0Hz,1H)；2.88(t,J＝5.6Hz,2H)；3.43-3.48(m,4H)；7.16(d J＝8.4Hz,2H)；7.23(d,J＝8.4Hz,2H)。MS(ESI)：m/z＝325.10(M+H⁺)。

Example 22

N- (2-ethoxyethyl) -1- (1- (4-fluorophenyl) cyclobutyl) -3-methylbutan-1-amine (7 i).¹HNMR(400MHz,CDCl₃)：0.64-0.71(m,1H)；0.82(d,J＝6.8Hz,3H)；0.86(d,J＝6.8Hz,3H)；1.02-1.08(m,1H)；1.17(t,J＝7.2Hz,3H)；1.59-1.66(m,1H)；1.70-1.78(m,1H)；1.83-1.92(m,1H)；2.12-2.17(m,2H)；2.21-2.31(m,2H)；2.36-2.43(m,1H)；2.72(dd,J＝2.4Hz；10.0Hz,1H)；2.88(t,J＝5.6Hz,2H)；3.43-3.44(m,4H)；6.95(t,J＝8.8Hz,2H)；7.18(dd,J＝5.2Hz；8.8Hz,2H)。MS(ESI)：m/z＝308.67(M+H⁺)。

Example 23

N- (2-ethoxyethyl) -3-methyl-1- (1- (p-tolyl) cyclopropyl) butan-1-amine (7 j). Colorless oil (0.24g, 22%).¹HNMR(400MHz,CDCl₃)：0.46-0.50(m,1H)；0.67-0.72(m,1H)；0.75-0.79(m,1H)；0.80(d,J＝6.8Hz,3H)；0.83(d,J＝6.8Hz,3H)；；1.04-1.13(m,1H)；1.16-1.20(m,4H)；1.23-1.31(m,1H)；1.70-1.76(m,1H)；1.94-1.98(m,1H)；2.30(s,3H)；2.75-2.80(m,1H)；3.21-3.27(m,1H)；3.45-3.54(m,4H)；7.06(d,J＝7.2Hz,2H)；7.20(d,J＝7.2Hz,2H)。MS(ESI)：m/z＝290.20(M+H⁺)。

Example 24

1- (1- (4-chlorophenyl) cyclopropyl) -N- (2-ethoxyethyl) -3-methylbutan-1-amine (7 k). Colorless oil (0.22g, 24%).¹HNMR(400MHz,CDCl₃): 0.47-0.52(m, 1H); 0.65-0.71(m, 1H); 0.75-0.89(m, 7H); 1.02-1.09(m, 1H); 1.18(t, J ═ 7.2Hz, 3H); 1.19-1.27(m, 1H); 1.44(s broad, 2H); 1.68-1.73(m, 1H); 1.95-1.98(m, 1H); 2.73-2.79(m, 1H); 3.17-3.23(m, 1H); 3.47-3.53(m, 2H); 7.06(d, J ═ 7.2Hz, 2H); 7.17(d, J ═ 7.2Hz, 2H). Ms (esi): 310.20(M + H)⁺)。

Example 25

N- (2-ethoxyethyl) -3-methyl-1- (1- (p-tolyl) cyclopentyl) butan-1-amine (7 l). Colorless oil (0.27g, 22%).¹HNMR(400MHz,CDCl₃)：0.60-0.75(m,1H)；0.75(d,J＝6.8Hz,3H)；0.78(d,J＝6.8Hz,3H)；1.06-1.21(m,1H)；1.18(t,J＝7.2Hz,3H)；1.26-1.47(m,3H)；1.57-1.65(m,3H)；1.72-1.80(m,1H)；1.84-2.00(m,3H)；2.34(s,3H)；2.54(d,J＝8.4Hz,1H)；2.78-2.85(m,1H)；2.86-2.90(m,1H)；3.15-3.49(m,4H)；；6.81(d,J＝8.8Hz,2H)；7.26(d,J＝8.8Hz,2H)。MS(ESI)：m/z＝317.20(M+H⁺)。

Example 26

N- (2-ethoxyethyl) -1- (1- (4-methoxyphenyl) cyclopentyl) -3-methylbutan-1-amine (7m)

Colorless oil (0.27g, 22%).¹HNMR(400MHz,CDCl₃)：0.60-0.75(m,1H)；0.75(d,J＝6.8Hz,3H)；0.78(d,J＝6.8Hz,3H)；1.06-1.21(m,1H)；1.18(t,J＝7.2Hz,3H)；1.26-1.47(m,3H)；1.57-1.65(m,3H)；1.72-1.80(m,1H)；1.84-2.00(m,3H)；2.51(d,J＝8.4Hz,1H)；2.78-2.85(m,1H)；2.86-2.90(m,1H)；3.15-3.45(m,4H)；3.77(s,3H)；6.81(d,J＝8.8Hz,2H)；7.26(d,J＝8.8Hz,2H)。MS(ESI)：m/z＝334.20(M+H⁺)。

Example 27

N- (4-ethoxybutyl) -3-methyl-1- (1- (p-tolyl) cyclohexyl) butan-1-amine (7N). Colorless oil (0.18g, 20%).¹HNMR(400MHz,CDCl₃)：0.67-0.72(m,1H)；0.75(d,J＝6.8Hz,3H)；0.78(d,J＝6.8Hz,3H)；1.13-1.26(m,8H)；1.36-1.44(m,3H)；1.49-1.59(m,7H)；2.16(d,J＝12.8Hz,1H)；2.21-2.35(m,5H)；2.44-2.50(m,1H)；2.65-2.69(m,1H)；3.34-3.48(m,4H)；7.23(d,J＝8.8Hz,2H)；7.28(d,J＝8.8Hz,2H)。MS(ESI)：m/z＝360.20(M+H⁺)。

Example 28

1- (1- (4-chlorophenyl) cyclohexyl) -N- (4-ethoxybutyl) -3-methylbutan-1-amine (7 o). Colorless oil (0.18g, 20%).¹HNMR(400MHz,CDCl₃)：0.58-0.65(m,1H)；0.75(d,J＝6.8Hz,3H)；0.78(d,J＝6.8Hz,3H)；1.07-1.13(m,1H)；1.56-1.26(m,6H)；1.38-1.63(m,10H)；2.13(d,J＝14.0Hz,1H)；2.21(d,J＝10Hz,1H)；2.28(d,J＝13.6Hz,1H)；2.45-2.51(m,1H)；2.68-2.74(m,1H)；3.36-3.48(m,4H)；7.23(d,J＝8.8Hz,2H)；7.28(d,J＝8.8Hz,2H)。MS(ESI)：m/z＝381.20(M+H⁺)。

Example 29

1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (2-ethoxyethyl) -3-methylbutan-1-amine (8 a). A colorless oil (87mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.61-0.68(m,1H)；0.84(d,J＝6.8Hz,3H)；0.89(d,J＝6.8Hz,3H)；1.03-1.04(m,1H)；1.08(t,J＝7.2Hz,3H)；1.62-1.63(m,1H)；1.75-1.78(m,1H)；1.88-1.91(m,1H)；2.21-2.38(m,4H)；2.75(dd,J＝2.4Hz；10.0Hz,1H)；2.96-3.02(m,2H)；3.41(q,J＝7.2Hz,2H)；3.44(t,J＝4.4Hz,2H)；7.06(dd,J＝2.4Hz；8.4Hz,1H)；7.31(d,J＝2.0Hz,1H)；7.34(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝360.10(M+H⁺)。

Example 30

(R) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (2-methoxyethyl) -3-methylbutan-1-amine (8 b).

A colorless oil (60mg, 28% yield).¹HNMR(400MHz,CDCl₃): 0.64-0.71(m, 1H); 0.84(d, J ═ 6.8Hz, 3H); 0.88(d, J ═ 6.8Hz, 3H); 1.04(t, J ═ 12Hz, 1H); 1.53(s broad, 1H); 1.62-1.65(m, 1H); 1.73-1.81(m, 1H); 1.88-1.91(m, 1H); 2.15-2.25(m, 3H); 2.37-2.44(m, 1H); 2.74(d, J ═ 8.4Hz, 1H); 2.75-2.94(m, 2H); 2.96(s, 3H). 3.44(t, J ═ 10.8Hz, 2H); 7.06(d, J ═ 8.0Hz, 1H); 7.33(s, 1H); 7.34(d, J ═ 8.0Hz, 1H). Ms (esi): 346.03(M + H)⁺)。

Example 31

(S) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (2-methoxyethyl) -3-methylbutan-1-amine (8 c).

A colorless oil (100mg, 27% yield).¹HNMR(400MHz,CDCl₃): 0.64-0.71(m, 1H); 0.84(d, J ═ 6.8Hz, 3H); 0.88(d, J ═ 6.8Hz, 3H); 1.04(t, J ═ 12Hz, 1H); 1.53(s broad, 1H); 1.62-1.65(m, 1H); 1.73-1.81(m, 1H); 1.88-1.91(m, 1H); 2.15-2.25(m, 3H); 2.37-2.44(m, 1H); 2.74(d, J ═ 8.4Hz, 1H); 2.75-2.94(m, 2H); 2.96(s, 3H). 3.44(t, J ═ 10.8Hz, 2H); 7.06(d, J ═ 8.0Hz, 1H); 7.33(s, 1H); 7.34(d, J ═ 8.0Hz, 1H). Ms (esi): 346.03(M + H)⁺)。

Example 32

(R) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (3-propoxypropyl) -3-methylbutan-1-amine (8 d). A colorless oil (87mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.66(m,1H)；0.83(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；0.91(t,J＝9.6Hz,3H)；1.00-1.08(m,1H)；1.56-1.64(m,5H)；1.66-1.80(m,2H)；1.83-1.96(m,1H)；2.09-2.30(m,3H)；2.37-2.46(m,1H)；2.72-2.94(m,3H)；3.37(t,J＝10.8Hz,2H)；3.49(t,J＝10.8Hz,2H)；7.07(dd,J＝3.2Hz,11.2Hz,1H)；7.32(s,1H)；7.33(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝388.30(M+H⁺)。

Example 33

(S) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (3-propoxypropyl) -3-methylbutan-1-amine (8 e). A colorless oil (60mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.66(m,1H)；0.83(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；0.91(t,J＝9.6Hz,3H)；1.00-1.08(m,1H)；1.56-1.64(m,5H)；1.66-1.80(m,2H)；1.83-1.96(m,1H)；2.09-2.30(m,3H)；2.37-2.46(m,1H)；2.72-2.94(m,3H)；3.37(t,J＝10.8Hz,2H)；3.49(t,J＝10.8Hz,2H)；7.07(dd,J＝3.2Hz,11.2Hz,1H)；7.32(s,1H)；7.33(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝388.30(M+H⁺)。

Example 34

(R) -N- (3-butoxypropyl) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methylbutan-1-amine (8 f). A colorless oil (130mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.59-0.64(m,1H)；0.83(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；0.91(t,J＝9.6Hz,3H)；1.04-1.07(m,1H)；1.32-1.40(m,2H)；1.50-1.56(m,3H)；1.57-1.79(m,4H)；1.87-1.92(m,1H)；2.10-2.27(m,3H)；2.38-2.42(m,1H)；2.72-2.94(m,3H)；3.37(t,J＝10.8Hz,2H)；3.49(t,J＝10.8Hz,2H)；7.07(dd,J＝2.0Hz,8.0Hz,1H)；7.32(s,1H)；7.33(d,J＝8.0Hz,1H)。MS(ESI)：m/z＝402.03(M+H⁺)。

Example 35

(S) -N- (3-butoxypropyl) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methylbutan-1-amine (8 g). A colorless oil (130mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.59-0.64(m,1H)；0.83(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；0.91(t,J＝9.6Hz,3H)；1.04-1.07(m,1H)；1.32-1.40(m,2H)；1.50-1.56(m,3H)；1.57-1.79(m,4H)；1.87-1.92(m,1H)；2.10-2.27(m,3H)；2.38-2.42(m,1H)；2.72-2.94(m,3H)；3.37(t,J＝10.8Hz,2H)；3.49(t,J＝10.8Hz,2H)；7.07(dd,J＝2.0Hz,8.0Hz,1H)；7.32(s,1H)；7.33(d,J＝8.0Hz,1H)。MS(ESI)：m/z＝402.03(M+H⁺)。

Example 36

(R) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (4-methoxybutyl) -3-methylbutan-1-amine (8 h). A colorless oil (60mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.66(m,1H)；0.84(d,J＝8.8Hz,3H)；0.89(d,J＝8.8Hz,3H)；1.00-1.08(m,1H)；1.43-1.68(m,6H)；1.71-1.94(m,2H)；2.10-2.45(m,4H)；2.66-2.84(m,3H)；3.31(s,3H)。3.37(t,J＝10.8Hz,2H)；7.07(dd,J＝3.2Hz,11.6Hz,1H)；7.32(s,1H)；7.34(d,J＝11.6Hz,1H)。MS(ESI)：m/z＝374.26(M+H⁺)。

Example 37

(S) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (4-methoxybutyl) -3-methylbutan-1-amine (8 i). A colorless oil (60mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.66(m,1H)；0.84(d,J＝8.8Hz,3H)；0.89(d,J＝8.8Hz,3H)；1.00-1.08(m,1H)；1.43-1.68(m,6H)；1.71-1.94(m,2H)；2.10-2.45(m,4H)；2.66-2.84(m,3H)；3.31(s,3H)。3.37(t,J＝10.8Hz,2H)；7.07(dd,J＝3.2Hz,11.6Hz,1H)；7.32(s,1H)；7.34(d,J＝11.6Hz,1H)。MS(ESI)：m/z＝374.26(M+H⁺)。

Example 38

(R) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (4-ethoxybutyl) -3-methylbutan-1-amine (8 j).

A colorless oil (100mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.66(m,1H)；0.84(d,J＝9.2Hz,3H)；0.89(d,J＝9.2Hz,3H)；1.01-1.08(m,1H)；1.20(t,J＝9.2Hz,3H)；1.43-1.64(m,6H)；1.71-1.94(m,2H)；2.09-2.41(m,4H)；2.66-2.84(m,3H)；3.40-3.51(m,4H)。7.08(dd,J＝2.8Hz,10.8Hz,1H)；7.32(s,1H)；7.34(d,J＝10.8Hz,1H)。MS(ESI)：m/z＝388.26(M+H⁺)。

Example 39

(S) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (4-ethoxybutyl) -3-methylbutan-1-amine (8 k). A colorless oil (100mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.66(m,1H)；0.84(d,J＝9.2Hz,3H)；0.89(d,J＝9.2Hz,3H)；1.01-1.08(m,1H)；1.20(t,J＝9.2Hz,3H)；1.43-1.64(m,6H)；1.71-1.94(m,2H)；2.09-2.41(m,4H)；2.66-2.84(m,3H)；3.40-3.51(m,4H)。7.08(dd,J＝2.8Hz,10.8Hz,1H)；7.32(s,1H)；7.34(d,J＝10.8Hz,1H)。MS(ESI)：m/z＝388.26(M+H⁺)。

Example 40

1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (4-isobutoxybutyl) -3-methylbutan-1-amine (8 l). A colorless oil (87mg, 27% yield).¹HNMR(400MHz,CDCl₃): 0.59-0.64(m, 1H); 0.84(d, J ═ 9.2Hz, 3H); 0.89(d, J ═ 9.2Hz, 3H); 0.91(s broad, 6H); 1.01-1.07(m, 1H); 1.45-1.63(m, 6H); 1.66-1.92(m, 3H); 2.10-2.31(m,2H)；2.37-2.49(m,2H)；2.68-2.82(m,3H)；3.16(d,J＝6.4Hz,2H)；3.40(t,J＝6.4H,2H)；7.08(dd,J＝2.8Hz,10.8Hz,1H)；7.32(s,1H)；7.33(d,J＝10.8Hz,1H)。MS(ESI)：m/z＝416.26(M+H⁺)。

EXAMPLE 41

1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (2-ethoxyethyl) propan-1-amine (8N).¹HNMR(400MHz,CDCl₃)：0.69-0.74(m,1H)；0.89(d,J＝6.8Hz,3H)；1.19(t,J＝6.8Hz,3H)；1.39-1.47(m,1H)；1.71-1.78(m,1H)；1.86-1.96(m,1H)；2.17-2.27(m,3H)；2.36-2.43(m,1H)；2.54(dd,J＝2.4Hz；10.0Hz,1H)；2.79-2.85(m,1H)；2.88-2.94(m,1H)；3.43-3.49(m,4H)；7.06(dd,J＝2.4Hz；8.4Hz,1H)；7.30(s,1H)；7.32(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝332.60(M+H⁺)。

Example 42

1- (1- (3, 4-dimethoxyphenyl) cyclobutyl) -N- (2-methoxyethyl) -3-methylbutan-1-amine (8 o). A colorless oil (100mg, 27% yield).¹HNMR(400MHz,CDCl₃): 0.72-0.78(m, 1H); 0.84(d, J ═ 6.8Hz, 3H); 0.88(d, J ═ 6.8Hz, 3H); 1.06-1.12(m, 1H); 1.60-1.68(m, 1H); 1.77-1.91(m, 2H); 2.13-2.20(m, 1H); 2.28-2.40(m, 3H); 2.72(d broad, J ═ 9.2Hz, 1H); 2.89(t, J ═ 5.6Hz, 2H); 3.32(s, 3H); 3.45(t, J ═ 7.2Hz, 2H); 3.87(s, 6H); 6.77-6.82(m, 3H). Ms (esi): 336.70(M + H)⁺)。

Example 43

1- (1- (3, 4-dimethoxyphenyl) cyclobutyl) -N- (2-ethoxyethyl) -3-methylbutan-1-amine (8 p). A colorless oil (88mg, 27% yield).¹HNMR(400MHz,CDCl₃): 0.72-0.78(m, 1H); 0.84(d, J ═ 6.8Hz, 3H); 0.88(d, J ═ 6.8Hz, 3H); 1.06-1.12(m, 1H); 1.18(t, J ═ 6.8Hz, 3H); 1.52(s broad, 1H); 1.62-1.67(m, 1H);1.77-1.89(m,2H)；2.15-2.18(m,1H)；2.29-2.32(m,2H)；2.36-2.40(m,1H)；2.72(dd,J＝3.2Hz；6.8Hz,1H)；2.88(t,J＝1.6Hz,2H)；3.45-3.49(m,3H)；3.87(s,6H)；6.77-6.82(m,3H)。MS(ESI)：m/z＝350.80(M+H⁺)。

example 44

1- (1- (3, 4-dimethoxyphenyl) cyclobutyl) -N- (3-methoxypropyl) -3-methylbutan-1-amine (8 q). A colorless oil (80mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.70-0.74(m,1H)；0.83(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；1.06-1.12(m,1H)；1.63-1.72(m,3H)；1.76-1.88(m,2H)；2.13-2.16(m,1H)；2.27-2.32(m,2H)；2.37-2.40(m,1H)；2.71(dd,J＝2.4Hz；9.6Hz,1H)；2.80-2.84(m,2H)；3.32(s,3H)；3.45(t,J＝6.4Hz,2H)；3.87(s,6H)；6.76-6.82(m,3H)。MS(ESI)：m/z＝350.80(M+H⁺)。

Example 45

1- (1- (3, 4-dimethoxyphenyl) cyclobutyl) -N- (3-ethoxypropyl) -3-methylbutan-1-amine (8 r). A colorless oil (100mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.70-0.74(m,1H)；0.83(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；1.08-1.12(m,1H)；1.19(t,J＝6.8Hz,3H)；1.63-1.72(m,3H)；1.76-1.88(m,2H)；2.13-2.16(m,1H)；2.27-2.32(m,2H)；2.37-2.40(m,1H)；2.71(dd,J＝2.4Hz；9.6Hz,1H)；2.82(t,J＝6.4Hz,2H)；3.43-3.50(m,4H)；3.87(s,6H)；6.76-6.82(m,3H)。MS(ESI)：m/z＝364.62(M+H⁺)。

Example 46

1- (1- (3, 4-dimethoxyphenyl) cyclobutyl) -N- (4-methoxybutyl) -3-methylbutan-1-amine (8 s). A colorless oil (130mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.70-0.74(m,1H)；0.83(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；1.08-1.12(m, 1H); 1.57-1.64(m, 6H); 1.78-1.89(m, 3H); 2.13-2.16(m, 1H); 2.27-2.32(m, 2H); 2.37-2.40(m, 1H); 2.74(s broad, 1H); 3.27(s broad, 3H); 3.36(t, J ═ 5.6Hz, 2H); 3.87(s, 6H); 6.76-6.82(m, 3H). Ms (esi): 364.62(M + H)⁺)。

Example 47

1- (1- (3, 4-dimethoxyphenyl) cyclobutyl) -N- (4-ethoxybutyl) -3-methylbutan-1-amine (8 t). A colorless oil (100mg, 27% yield).¹HNMR(400MHz,CDCl₃)：0.69-0.74(m,1H)；0.83(d,J＝6.8Hz,3H)；0.88(d,J＝6.8Hz,3H)；1.04-1.12(m,1H)；1.19(t,J＝6.8Hz,3H)；1.24-1.30(m,3H)；1.45-1.51(m,2H)；1.58-1.65(m,2H)；2.14-2.18(m,1H)；2.27-2.40(m,3H)；2.69-2.78(m,3H)；3.39-3.42(m,4H)；3.87(s,6H)；6.76-6.82(m,3H)。MS(ESI)：m/z＝378.20(M+H⁺)。

General procedure for the Synthesis of Phenylcyclobutylmethylamine thioether derivatives 12 and 13 (scheme 3)

To a stirred solution of phenylcycloalkylmethylamine (6) (1eq), alkylthioalkylcarboxylic acid (14) (1.2eq) and DMAP (0.6g,1eq) in 20mL DCM was added dropwise a solution of Dicyclohexylcarbodiimide (DCC) (1.4g.,0.0070mol.1.2eq) in 10mL DCM at 0 ℃ under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature for 15 h. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the corresponding amide (15) as a white solid in a yield of 70-90%. To a suspension of Lithium Aluminum Hydride (LAH) (0.417g,4.2eq) in 20mL of anhydrous THF at 0 deg.C under a nitrogen atmosphere was added dropwise a solution of amide (15) (1eq) in 20mL of THF. After the addition was complete, the reaction mixture was brought to rt and then refluxed for 24 h. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). The reaction mixture was cooled to 0 ℃ and quenched by the addition of 2.5mL of water, followed by 4.5mL of 10% NaOH, and finally 2mL of water. After stirring for a while, ether was added. The material was filtered through celite, washing with ethyl acetate. The combined filtrates were evaporated and the residue was purified by chromatography on silica gel using a gradient of hexane and ethyl acetate as eluent to give the corresponding pure thioether derivative (12, 13). The pure thioether (12,13) exhibited satisfactory 1H NMR and/or mass spectral data. Chiral HPLC was performed on selected racemic ether derivatives (12,13) using similar conditions as described for ether derivatives (7,8) in scheme 2, to yield the corresponding optically pure (R) -and (S) -isomers. All thioether derivatives (12,13) were converted to the corresponding HCl salts by treating them with 1N HCl dioxane/water followed by lyophilization. The hydrochloride salt of the thioether derivative (12,13) was tested in an in vitro pharmacological test with a monoamine transporter (MAT).

Example 48

N- (4- (ethylthio) butyl) -1- (1- (4-fluorophenyl) cyclobutyl) -3-methylbutan-1-amine (12 a). A colorless oil (0.47g, 51% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.63(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；1.03-1.06(m,1H)；1.26(t,J＝7.2Hz,3H)；1.47-1.54(m,2H)；1.56-1.67(m,3H)；1.71-1.77(m,1H)；1.84-1.92(m,1H)；2.10-2.17(m,1H)；2.20-2.26(m,2H)；2.34-2.38(m,1H)；2.50-2.55(m,3H)；2.65-2.72(m,2H)；2.74-2.80(m,2H)；6.97(dd,J＝8.4Hz；11.6Hz,1H)；7.06(dd,J＝1.6Hz；7.6Hz,1H)；7.12-7.17(m,2H)。MS(ESI)：m/z＝352.20(M+H⁺)。

Example 49

1- (1- (4-chlorophenyl) cyclobutyl) -N- (4- (ethylsulfanyl) butyl) -3-methylbutan-1-amine (12 b). A colorless oil (0.48g, 51% yield).¹HNMR(400MHz,CDCl₃)：0.60-0.66(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；1.03-1.09(m,3H)；1.25(t,J＝7.2Hz,3H)；1.47-1.54(m,2H)；1.58-1.65(m,2H)；1.73-1.78(m,1H)；1.84-1.91(m,1H)；2.11-2.18(m,1H)；2.21-2.29(m,2H)；2.35-2.42(m,1H)；2.50-2.55(m,4H)；2.67-2.77(m,3H)；7.16(d,J＝8.8Hz,2H)；7.25(d,J＝8.8Hz,2H)。MS(ESI)：m/z＝369.20(M+H⁺)。

Example 50

1- (1- (4-ethoxyphenyl) cyclobutyl) -N- (2- (ethylthio) ethyl) -3-methylbutan-1-amine (12 c). Colorless oil (0.37g, 52% yield)¹HNMR(400MHz,CDCl₃)：0.69-0.75(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；1.05-1.11(m,1H)；1.26(t,J＝7.2Hz,3H)；1.40(t J＝7.2Hz,3H)；1.54-1.66(m,2H)；1.72-1.74(m,1H)；1.82-1.88(m,1H)；2.03-2.18(m,1H)；2.25-2.36(m,2H)；2.52(q,J＝7.6Hz,2H)；2.61(t,J＝6.8Hz,2H)；2.70(dd,J＝2.0Hz；9.6Hz,1H)；2.90(t,J＝6.8Hz,2H)；4.01(q,J＝7.2Hz,2H)；6.82(d,J＝8.4Hz,2H)；7.15(d,J＝8.4Hz,2H)。MS(ESI)：m/z＝350.20(M+H⁺)。

Example 51

4- (butylsulfanyl) -N- (1- (1- (4-ethoxyphenyl) cyclobutyl) propyl) butan-1-amine (12 d).

Colorless oil (0.47g, 53% yield)¹HNMR(400MHz,CDCl₃)：0.72-0.80(m,1H)；0.84-0.91(m,6H)；1.34-1.46(m,6H)；1.48-1.65(m,6H)；1.71-1.80(m,1H)；1.82-1.89(m,1H)；2.15-2.37(m,4H)；2.46-2.51(m,5H)；2.63-2.75(m,2H)；4.01(q,J＝7.2Hz,2H)；6.82(d,J＝8.4Hz,2H)；7.15(d,J＝8.4Hz,2H)。MS(ESI)：m/z＝378.20(M+H⁺)。

Example 52

1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (2- (ethylsulfanyl) ethyl) -3-methylbutan-1-amine (13 a). A colorless oil (0.41g, 53% yield).¹HNMR(400MHz,CDCl₃)：0.60-0.67(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；1.03-1.06(m,2H)；1.26(t,J＝7.2Hz,3H)；1.55-1.61(m,1H)；1.70-1.74(m,1H)；1.80-1.86(m,1H)；2.08-2.14(m,1H)；2.18-2.23(m,2H)；2.30-2.35(m,1H)；2.43-2.50(m,2H)；2.53-2.60(m,2H)；2.68(d,J＝10.0Hz,1H)；2.81-2.91(m,2H)；7.04(dd,J＝2.0Hz；8.4Hz,1H)；7.30(d,J＝2.0H,1H)；7.32(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝376.20(M+H⁺)。

Example 53

N- (2- (butylthio) ethyl) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methylbutan-1-amine (13 b). A colorless oil (0.27g, 50% yield).¹HNMR(400MHz,CDCl₃)：0.60-0.67(m,1H)；0.81-0.92(m,9H)；1.04-1.10(m,1H)；1.34-1.45(m,2H)；1.50-1.58(m,2H)；1.60-1.65(m,1H)；1.73-1.78(m,1H)；1.85-1.91(m,1H)；2.15-2.19(m,1H)；2.23-2.30(m,2H)；2.35-2.40(m,1H)；2.46-2.50(m,2H)；2.58-2.62(m,2H)；2.68(dd,J＝2.4Hz；10.0Hz,1H)；2.85-2.93(m,2H)；7.04(dd,J＝2.0Hz；8.4Hz,1H)；7.30(d,J＝2.0H,1H)；7.32(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝403.20(M+H⁺)。

Example 54

1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (4- (ethylsulfanyl) butyl) -3-methylbutan-1-amine (13 c).

A colorless oil (0.37g, 52% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.63(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；1.03-1.06(m,1H)；1.26(t,J＝7.2Hz,3H)；1.47-1.54(m,2H)；1.56-1.67(m,3H)；1.71-1.77(m,1H)；1.84-1.92(m,1H)；2.10-2.17(m,1H)；2.20-2.26(m,2H)；2.34-2.38(m,1H)；2.50-2.55(m,3H)；2.65-2.72(m,2H)；2.74-2.80(m,2H)；7.04(dd,J＝2.0Hz；8.4Hz,1H)；7.30(d,J＝2.0H,1H)；7.32(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝403.20(M+H⁺)。

Example 55

N- (4- (butylthio) butanesYl) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methylbutan-1-amine (13 d). A colorless oil (0.45g, 55% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.63(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；0.88(t,J＝7.2Hz,3H)；1.02-1.05(m,1H)；1.36-1.43(m,2H)；1.48-1.65(m,7H)；1.73-1.77(m,1H)；1.85-1.90(m,1H)；2.10-2.16(m,1H)；2.18-2.25(m,2H)；2.34-2.39(m,1H)；2.48-2.52(m,4H)；2.65-2.80(m,3H)；7.04(dd,J＝2.0Hz；8.4Hz,1H)；7.30(d,J＝2.0H,1H)；7.32(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝431.20(M+H⁺)。

Example 56

1- (1- (2, 4-dichlorophenyl) cyclobutyl) -N- (4- (ethylsulfanyl) butyl) -3-methylbutan-1-amine (13 e). A colorless oil (0.57g, 51% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.63(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；1.03-1.06(m,1H)；1.26(t,J＝7.2Hz,3H)；1.47-1.54(m,2H)；1.56-1.67(m,3H)；1.71-1.77(m,1H)；1.84-1.92(m,1H)；2.10-2.17(m,1H)；2.20-2.26(m,2H)；2.34-2.38(m,1H)；2.50-2.55(m,3H)；2.65-2.72(m,2H)；2.74-2.80(m,2H)；7.02(d,J＝8.4Hz,1H)；7.16(dd,J＝2Hz；8.4Hz,1H)；7.29(d,J＝2.4Hz,1H)。MS(ESI)：m/z＝403.20(M+H⁺)。

Example 57

1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (2- (ethylsulfanyl) ethyl) propan-1-amine (13 f).

A colorless oil (0.27g, 52% yield).¹HNMR(400MHz,CDCl₃)：0.72-0.79(m,1H)；0.92(t,J＝7.6Hz,3H)；1.23(t,J＝7.6Hz,3H)；1.42-1.48(m,1H)；1.72-1.79(m,1H)；1.86-1.93(m,1H)；2.18-2.30(m,3H)；2.34-2.41(m,1H)；2.49-2.55(m,3H)；2.60-2.69(m,2H)；2.80-2.89(m,1H)；2.86-2.97(m,1H)；7.04(dd,J＝2.0Hz；8.4Hz,1H)；7.30(d,J＝2.0H,1H)；7.32(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝347.20(M+H⁺)。

Example 58

4- (butylsulfanyl) -N- (1- (1- (3, 4-dichlorophenyl) cyclobutyl) propyl) butan-1-amine (13 g).

A colorless oil (0.37g, 50% yield).¹HNMR(400MHz,CDCl₃)：0.69-0.83(m,1H)；0.84-0.91(m,6H)；1.03-1.05(m,1H)；1.34-1.41(m,4H)；1.51-1.65(m,6H)；1.72-1.77(m,1H)；1.85-1.92(m,1H)；2.17-2.30(m,2H)；2.34-2.41(m,1H)；2.45-2.50(m,4H)；2.62-2.68(m,1H)；2.72-2.78(m,1H)；7.04(dd,J＝2.0Hz；8.4Hz,1H)；7.30(d,J＝2.0H,1H)；7.32(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝403.20(M+H⁺)。

General procedure for the Synthesis of phenylcyclobutylmethylamine alkylsulfonyl derivatives 17 (scheme 4)

Synthesis of amide derivative (16, step 1): to a stirred solution of m-CPBA (m-chloroperoxybenzoic acid) (0.94g,2.1eq) in 10mL THF was added dropwise a solution of amide (15) (0.0026mol) in 10mL THF at-30 deg.C (dry ice/acetone) over 30 minutes. The progress of the reaction was monitored by TLC. After the reaction was complete, 3mL Triethylamine (TEA) was added, followed by 10mL saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and Na₂SO₄Dried and evaporated. The residue was purified by chromatography on silica gel using a gradient of hexane and ethyl acetate as eluent to give the corresponding pure amide (16).

Synthesis of alkylsulfonyl derivatives (17, step 2): to a suspension of Lithium Aluminum Hydride (LAH) (0.3g,4.2eq) in 20mL of anhydrous THF, a solution of amide (16) (1eq) in 10mL of THF was added dropwise at 0 ℃ under a nitrogen atmosphere. After the addition was complete, the reaction mixture was brought to room temperature and then refluxed for 15 h. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). The reaction mixture was cooled to 0 ℃ and quenched by the addition of 5mL of water, followed by 9mL of 10% NaOH, and finally 4mL of water. After stirring for a while, ether was added. The material was filtered through celite and washed with ethyl acetate. The combined filtrates were evaporated and the residue was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate to give the corresponding sulfonyl derivative (17). The pure sulfonyl derivative (17) exhibited satisfactory 1H NMR and/or mass spectral data. All sulfonyl derivatives (17) were converted to the corresponding HCl salts by treating them with 1N HCl dioxane/water followed by lyophilization. Hydrochloride salts of alkylsulfonyl derivatives were tested in an in vitro pharmacological test of the monoamine transporter (MAT) (17).

Example 59

N- (1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methylbutyl) -4- (ethylsulfonyl) butanamide (16 a). A colorless oil (0.85g, 73% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.71(m,1H)；0.80(d,J＝6.8Hz,3H)；0.90(d,J＝6.8Hz,3H)；1.13-1.19(m,1H)；1.24(t,J＝7.2Hz,3H)；1.78-1.84(m,1H)；2.05-2.23(m,5H)；2.25-2.32(m,2H)；2.37-2.47(m,2H)；2.96-3.07(m,4H)；4.47-4.53(m,1H)；4.93(d,J＝10.4Hz,1H)；6.94(dd,J＝2.0Hz；8.4Hz,1H)；7.16(d,J＝2.0H,1H)；7.38(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝449.20(M+H⁺)。

Example 60

4- (butylsulfonyl) -N- (1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methylbutyl) butanamide (16 b). A colorless oil (0.85g, 73% yield).¹HNMR(400MHz,CDCl₃)：0.57-0.71(m,1H)；0.80(d,J＝6.8Hz,3H)；0.91(t,J＝7.2Hz,3H)；0.95(d,J＝6.8Hz,3H)；1.13-1.19(m,1H)；1.38-1.50(m,3H)1.75-1.85(m,3H)；2.05-2.23(m,5H)；2.25-2.32(m,2H)；2.37-2.47(m,2H)；2.93-2.97(m,2H)；3.01-3.05(m,2H)；4.47-4.53(m,1H)；4.93(d,J＝10.4Hz,1H)；6.94(dd,J＝2.0Hz；8.4Hz,1H)；7.16(d,J＝2.0H,1H)；7.38(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝477.20(M+H⁺)。

Example 61

1- (1- (3, 4-dichlorophenyl) cyclobutyl) -N- (4- (ethylsulfonyl) butyl) -3-methylbutan-1-amine (17a)

Colorless oil (0.11g, 31% yield)¹HNMR(400MHz,CDCl₃)：0.58-0.65(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；1.03-1.08(m,1H)；1.38(t,J＝7.2Hz,3H)；1.52-1.59(m,3H)；1.74-1.78(m,1H)；1.84-1.93(m,3H)；2.08-2.15(m,1H)；2.17-2.28(m,2H)；2.31-2.36(m,1H)；2.66-2.71(m,2H)；2.78-2.83(m,1H)；2.93-3.00(m,4H)；7.04(dd,J＝2.0Hz；8.4Hz,1H)；7.30(d,J＝2.0H,1H)；7.32(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝435.20(M+H⁺)。

Example 62

N- (4- (butylsulfonyl) butyl) -1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methylbutan-1-amine (17 b). Colorless oil (0.07g, 37% yield)¹HNMR(400MHz,CDCl₃)：0.59-0.65(m,1H)；0.82(d,J＝6.8Hz,3H)；0.87(d,J＝6.8Hz,3H)；0.95(t,J＝7.2Hz,3H)；1.03-1.05(m,1H)；1.43-1.51(m,2H)；1.52-1.62(m,3H)；1.72-1.86(m,4H)；1.88-1.93(m,3H)；2.08-2.38(m,4H)；2.66-2.71(m,2H)；2.78-2.84(m,1H)；2.91-2.97(m,4H)；7.04(dd,J＝2.0Hz；8.4Hz,1H)；7.30(d,J＝2.0H,1H)；7.32(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝463.20(M+H⁺)。

General procedure for the Synthesis of phenylcycloalkylamine derivatives 19 (scheme 5)

Synthesis of amide (21, step 1): to a stirred solution of a 2M solution of trimethylaluminum (4mL,0.008mol) in toluene at 0 ℃ under a nitrogen atmosphere, a solution of phenylcycloalkylamine (6) (0.0053mol,1eq) and ester (20) (0.0053mol,1eq) in toluene was added dropwise in a sealed tube. The reaction mixture was stirred at 80 ℃ for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated in vacuo, quenched with crushed ice, and extracted with ethyl acetate (15mLx 3). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was passed through a short column to give pure amide (21). The amides (21a-d) are prepared according to this method. The starting ester (20) was prepared in good yield by alkylating cyclic pyrrolidine and piperidine with the appropriate bromoalkylcarboxylate in the solvent DCM using Triethylamine (TEA) as base under standard conditions.

The amide (21e-f) was prepared by coupling 4-N, N-dimethylbutyric acid with phenylcycloalkylamine (6) using HATU as a coupling agent. To a stirred solution of amine (6) (1eq), 4-N, N-dimethylbutyric acid (1eq) and HATU (2eq) in DCM, a solution of N, N-Diisopropylethylamine (DIEA) (3eq) was added dropwise at 0 ℃ under nitrogen atmosphere. The reaction mixture was stirred at rt for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with water and extracted with DCM, and the combined extracts were extracted with Na₂SO₄Dried and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of DCM and methanol as eluent to give the pure amide (21 e-f). Amide (21a-f) exhibited satisfactory 1H NMR and mass (LC/MS) mass spectral data. As representative examples, 1H NMR and mass data for amide (21d) are given herein.

Synthesis of amine (19, step 2): borane-DMS (1.5eq) in THF was added dropwise to an ice-cold solution of amide (21) (1eq) in THF. The reaction mixture was stirred at 60 ℃ for 3 h. After completion of the reaction, the reaction was quenched with ice-cold water and then extracted twice with EtOAc. The combined organic extracts were washed with brine and Na₂SO₄And (5) drying. The organic layer was evaporated under reduced pressure. The crude product is in the form of an amine-borane adduct or complex. The amine-borane complex was treated with Raney nickel/methanol (Couthiere, M. et al, Organic Letters,2001, vol3(No.3),465-467) or piperazine/methanol (Zhou, Q. et al, Organic Letters2011, vol13(No.3),526-529) according to the reported method to obtain the free base form of the amine derivative (19). The crude free base form of amine derivative (19) is purified by preparative HPLC using a gradient of hexane and ethanol as eluent to obtain the pure amine derivative (19).

Example 63

N- (1- (1- (3, 4-dimethoxyphenyl) cyclobutyl) -3-methylbutyl) -4- (piperidin-1-yl) butanamide (21d)

A colorless oil (0.85g, 39% yield);¹HNMR(300MHz,DMSOd₆)：0.73-0.76(m,6H)；0.85-0.98(m,2H)；1.39-1.59(m,8H)；1.71(b,3H)；1.83-1.89(m,2H)；2.11-2.17(m,6H)；2.27-2.49(m,4H)；3.73(s,3H)；3.74(s,3H)；4.19-4.25(m,1H),6.62(s,1H),6.64(bs,1H),6.89(d,J＝7.8Hz,1H)；7.30(bd,1H,D₂o is exchangeable); ms (esi): 431.17(M + H)⁺)。

Example 64

1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methyl-N- (4- (pyrrolidin-1-yl) butyl) butan-1-amine (19a)

A colorless oil (0.092g, 18.7% yield);¹HNMR(300MHz,DMSOd₆)：0.61-0.67(m,1H)；0.85(d,J＝7.2Hz,3H)；0.90(d,J＝6.4Hz,3H)；1.04-1.10(m,1H)；1.36-1.43(m,3H)；1.56-1.62(m,2H)；1.67-1.78(m,2H)；1.80-1.90(m,4H)；1.95-2.30(m,4H)；2.67-2.84(m,7H)；3.21(bt,2H)；7.07(dd,J＝2Hz,8Hz,1H),7.31(d,J＝2Hz,1H)；7.34(d,J＝8.4Hz,1H)；MS(ESI)：m/z＝411.16(M+)。

example 65

1- (1- (3, 4-Dimethoxyphenyl) cyclobutyl) -3-methyl-N- (4- (pyrrolidin-1-yl) butyl) butan-1-amine (19b)

A colorless oil (0.085g, 17.7% yield).¹HNMR(300MHz,CDCl₃)：0.69-0.75(m,1H)；0.84(d,J＝6.6Hz,3H)；0.88(d,J＝6.6Hz,3H)；1.07-1.14(m,1H)；1.35-1.48(m,5H)；1.80-1.86(m,6H)；2.14-2.17(m,2H)；2.30-2.35(m,2H)；2.67-2.77(m,7H)；3.19(bt,2H)；3.87(s,6H)；6.79-6.81(m,3H)；MS(ESI)：m/z＝403.23(M+H⁺)。

Example 66

1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methyl-N- (4- (piperidin-1-yl) butyl) butan-1-amine (19c)

A colorless oil (0.015g, 15.6% yield);¹HNMR(300MHz,DMSOd₆)：0.59-0.62(m,1H)；0.79(d,J＝6.6Hz,3H)；0.84(d,J＝6.6Hz,3H)；0.94-1.02(m,1H)；1.33-1.38(m,2H)；1.46-1.48(m,3H)；1.59-1.75(m,8H)；2.11-2.16(m,2H)；2.43-2.50(m,2H)；2.65-2.77(m,9H)；7.20(dd,J＝5.1Hz；8.4Hz,1H)；7.42(d,J＝1.8Hz,1H)；7.51(d,J＝8.1Hz,1H)。MS(ESI)：m/z＝425.13(M+)。

example 67

1- (1- (3, 4-dimethoxyphenyl) cyclobutyl) -3-methyl-N- (4- (piperidin-1-yl) butyl) butan-1-amine (19 d).

A colorless oil (0.060g, 15.5% yield).¹HNMR(400MHz,CDCl₃): 0.61-0.67(m, 1H); 0.85(d, J ═ 6.8Hz, 3H); 0.97(d, J ═ 6.8Hz, 3H); 1.07-1.14(m, 1H); 1.22-1.28(m, 2H); 1.33-1.47(m, 3H); 1.58-1.71(m, 2H); 1.61-1.67(m, 2H); 1.73-2.30(m, 6H); 2.35-2.42(m, 1H); 2.67-2.84(m, 8H); 3.23(s broad, 2H); 3.87(s, 6H); 6.79-6.81(m, 3H). Ms (esi): 417.20(M + H)⁺)。

Example 68

N1- (1- (1- (3, 4-dichlorophenyl) cyclobutyl) -3-methylbutyl) -N⁴,N⁴-dimethylbutane-1, 4-diamine (19e)

A colorless oil (0.045g, 11.6% yield).¹HNMR(400MHz,CDCl₃)：0.59-0.65(m,1H)；0.80(d,J＝6.8Hz,3H)；0.84(d,J＝6.8Hz,3H)；0.95-1.02(m,1H)；1.22-1.28(m,1H)；1.33-1.47(m,3H)；1.59-1.71(m,4H)；1.81-1.87(m,2H)；1.73-2.30(m,3H)；2.35-2.42(m,2H)；2.36-2.58(m,6H)；2.60-2.74(m,2H)；7.06(dd,J＝2.0Hz；8.4Hz,1H)；7.31(d,J＝2.0H,1H)；7.35(d,J＝8.4Hz,1H)。MS(ESI)：m/z＝386.20(M+H⁺)。

Example 69

N1- (1- (1- (3, 4-dimethoxyphenyl) cyclobutyl) -3-methylbutyl) -N⁴,N⁴-dimethylbutane-1, 4-diamine (19f)

A colorless oil (0.08g, 20% yield).¹HNMR(400MHz,CDCl₃)：0.59-0.65(m,1H)；0.80(d,J＝6.8Hz,3H)；0.84(d,J＝6.8Hz,3H)；0.95-1.02(m,1H)；1.22-1.28(m,1H)；1.33-1.47(m,3H)；1.59-1.71(m,4H)；1.81-1.87(m,2H)；1.73-2.30(m,3H)；2.35-2.42(m,2H)；2.36-2.58(m,6H)；2.60-2.74(m,2H)；3.87(s,6H)；6.79-6.81(m,3H)。MS(ESI)：m/z＝377.20(M+H⁺)。

General procedure for the Synthesis of alkoxyalkyl 4-nitrobenzenesulfonate 9 (scheme 6)

Synthesis of monobenzyloxy methanol (carbinol) (24, step 1): to a stirred suspension of NaH (3.5g,1.04eq) in dry THF (50mL) was added diol (23) (3eq) at 0 ℃ over 0.5 h. After the addition was complete, the mixture was refluxed and benzyl bromide (10mL,0.084mol.,1eq) was added dropwise. The reaction mixture was stirred at reflux for 12 h. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). After completion of the reaction, the mixture was cooled to room temperature and diluted with ether. The combined extracts were washed with MgSO₄Dried, filtered and concentrated under reduced pressure. The residue was passed through a short silica gel column using a gradient of hexane and ethyl acetate as eluent to give pure monobenzyloxymethyl (24) as a colorless oil in moderate yield.

Synthesis of alkoxyalkyl benzyl ethers (25, step 2): to a stirred suspension of NaH (0.75g,1.5eq) in dry DMF (20mL) was added monobenzyloxymethyl (24) (1eq)/10mL of DMF at 0 ℃. After the addition was complete, the mixture was stirred for 1h and then worked upThe appropriate solution of alkyl bromide or iodide (2eq) is added dropwise. The reaction mixture was stirred for 15h and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After completion of the reaction, the mixture was diluted with 25mL of water, extracted with ethyl acetate, and then anhydrous MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate as eluent to give the corresponding alkoxyalkyl benzyl ether (25) as a colorless oil.

Alkoxyalkyl sulfonate (9, step 3): to a stirred suspension of Pd/C (10%) (active) (0.8g) in ethanol (10mL) was added a solution of alkoxyalkyl benzyl ether (25) (0.001mol) in 10mL of ethanol. The reaction mixture was kept under hydrogen pressure for 15 h. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). After completion of the reaction, the mixture was filtered through celite, washed with ethyl acetate, and the filtrate solution was concentrated under reduced pressure. The residue was passed through a short silica gel column using a gradient of hexane and diethyl ether as eluent to give the corresponding methanol ether (26) as a colorless oil. Methanol ether (26) was treated with 4-nitrosulfonyl chloride in DCM in the presence of a mild base Triethylamine (TEA) at 0 ℃ to 5 ℃. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a gradient of hexane and ethyl acetate as eluent to give alkoxyalkyl sulfonate (9).

Example 70

2-ethoxyethyl 4-nitrobenzenesulfonate (9 a). White solid (1.87g, 93% yield).¹HNMR(400MHz,CDCl₃)：1.08(t,J＝7.2Hz,3H)；3.41(q,J＝7.2Hz,2H)；3.61(t,J＝4.4Hz,2H)；4.28(t,J＝4.4Hz,2H)；8.16(d,J＝8.8Hz,2H)；8.37(d,J＝8.8Hz,2H)。

Example 71

2-methoxyethyl 4-nitrobenzenesulfonate (9 b). White solid (1.87g, 93% yield).¹HNMR(400MHz,CDCl₃)：3.28(s,3H)；3.59(t,J＝4.4Hz,2H)；4.30(t,J＝4.4Hz,2H)；8.13(d,J＝8.8Hz,2H)；8.40(d,J＝8.8Hz,2H)。

Example 72

2-ethoxybutyl 4-nitrobenzenesulfonate (9 c). White solid (1.87g, 93% yield).¹HNMR(400MHz,CDCl₃)：1.08(t,J＝6.8Hz,3H)；1.59-1.63(m,2H)；1.76-1.83(m,2H)；3.37-3.45(m,4H)；4.19(t,J＝6.4Hz,2H)；8.11(d,J＝8.8Hz,2H)；8.40(d,J＝8.8Hz,2H)。

Example 73

2-Methoxybutyl 4-nitrobenzenesulfonate (9 d). White solid (1.87g, 93% yield).¹HNMR(400MHz,CDCl₃)：1.57-1.63(m,2H)；1.72-1.82(m,2H)；3.28(s,3H)；3.33-3.44(m,3H)；4.10(t,J＝6.4Hz,2H)；8.11(d,J＝8.8Hz,2H)；8.40(d,J＝8.8Hz,2H)。

Example 74

4-Propoxybutyl 4-nitrobenzenesulfonate (9 e). White solid (1.87g, 93% yield).¹HNMR(400MHz,CDCl₃)：0.84(t,J＝7.2Hz,3H)；1.44-1.51(m,2H)；1.91-1.97(m,2H)；3.28(t,J＝6.8Hz,2H)；3.43(t,J＝,5.6Hz,2H)；4.26(t,J＝6.4Hz,2H)；8.11(d,J＝8.8Hz,2H)；8.40(d,J＝8.8Hz,2H)。

Example 75

4-butoxypropyl 4-nitrobenzenesulfonate (9 f). White solid (1.87g, 93% yield).¹HNMR(400MHz,CDCl₃)：0.88(t,J＝7.2Hz,3H)；1.25-1.31(m,2H)；1.41-1.47(m,2H)；1.94(t,J＝6.0Hz,2H)；3.31(t,J＝6.4Hz,2H)；3.42(t,J＝,5.6Hz,2H)；4.26(t,J＝6.4Hz,2H)；8.11(d,J＝8.8Hz,2H)；8.40(d,J＝8.8Hz,2H)。

Example 76

4-Ethoxybutanoic acid ethyl ester (30) (scheme 7). Sulfuric acid 0.25mL (0.0045mmol,0.035eq) was added to an ice-cold solution of γ -butyrolactone (28) (11.2g,0.13009mmol,1.0eq), triethyl orthoformate (29) (41.1mL,0.2497mmol.,1.92eq) in 100mL ethanol. The mixture was heated at 50 ℃ for 12h while monitoring the reaction by TLC. The reaction mixture was cooled to room temperature and most of the solvent was evaporated under reduced pressure. With cold NaHCO₃The concentrated reaction mixture was quenched with saturated solution and extracted twice with ethyl acetate. The combined organic extracts were washed with anhydrous Na₂SO₄Drying and concentration in vacuo gave 20g (95%) of ethyl 4-ethoxybutyrate (30) as a pale yellow oil.¹HNMR(400MHz,CDCl₃)：1.16-1.28(m,6H)；1.87-1.91(m,2H)；2.39(t,J＝9.6Hz；2H)；3.42-3.50(m,2H)；3.57-3.64(m,2H)；4.13(q,J＝6Hz,2H)。

Example 77

4-ethoxybutanoic acid (10) (scheme 7). To an ice-cooled stirred solution of ethyl 4-ethoxybutyrate (30) (. about.1 g) in 10mL of Tetrahydrofuran (THF) was added aqueous NaOH solution (0.62g/7mL of H₂O) and stirred at room temperature for 12h while monitoring the reaction by TLC. Most of the solvent was evaporated under reduced pressure and the residue was diluted with water (10 mL). The aqueous layer was acidified with 1N HCl solution (pH 2) and extracted with ethyl acetate (15mL x 3). The combined organic extracts were washed with anhydrous Na₂SO₄Drying and concentration in vacuo afforded 0.6g (73.14) of 4-ethoxybutyric acid as a pale yellow oil.¹HNMR(400MHz,CDCl₃)：1.20(t,J＝9.2Hz,3H)；1.87-1.95(m,2H)；2.47(t,J＝10Hz；2H)；3.48(q,J＝9.2Hz,4H)。

General procedure for the Synthesis of alkylthio alkyl carboxylates (33) (scheme 8)

To a stirred solution of sodium alkanethiolate (32) (1eq) in anhydrous DMF (10mL) was added bromoalkylcarboxylate (31) (1eq) over 5min at 0 ℃. The reaction mixture was stirred at room temperature for 15 h. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). The reaction mixture was diluted with ethyl acetate (20mL) and NaHCO₃The saturated solution washes (quench the aqueous layer with bleach). The organic layer was washed with anhydrous Na₂SO₄Drying to give the corresponding alkylthio ether carboxylate (33), which was purified by silica gel column chromatography with a gradient of hexane and ethyl acetate and isolated as a colorless oil

Example 78

4- (ethylthio) butanoic acid ethyl ester (33 a). A colorless oil (6.87g, 100% yield).¹HNMR(400MHz,CDCl₃)：1.20-1.26(m,6H)；1.84-1.92(m,2H)；2.40(t,J＝9.6Hz,2H)；2.47-2.55(m,4H)；4.12(q,J＝7.2Hz,2H)。

Example 79

Ethyl 2- (ethylthio) acetate (33 b). A colorless oil (5.87g, 90% yield).¹HNMR(400MHz,CDCl₃)：1.20-1.29(m,6H)；2.63(q,J＝7.6Hz,2H)；3.19(s,2H)；4.15(q,J＝7.2Hz,2H)。

Example 80

Ethyl 4- (butylthio) butanoate (33 c). A colorless oil (14.12g, 100% yield).¹HNMR(400MHz,CDCl₃)：0.89(t,J＝7.6Hz,3H)；1.22(t,J＝7.6Hz,3H)；1.34-1.36(m,2H)；1.48-1.54(m,2H)；1.87-1.90(m,2H)；2.39(t,J＝7.6Hz,2H)；2.44-2.51(m,4H)；4.10(q,J＝7.6Hz,2H)

Example 81

Ethyl 2- (butylthio) acetate (33 d). A colorless oil (5.80g, 100% yield).¹HNMR(400MHz,CDCl₃)：0.89(t,J＝6.8Hz,3H)；1.26(t,J＝7.2Hz,3H)；1.36-1.41(m,2H)；1.52-1.61(m,2H)；2.61(t,J＝7.6Hz,2H)；3.18(s,2H)；4.15(q,J＝7.2Hz,2H)

General procedure for the Synthesis of alkylthio ether carboxylic acids (14) (scheme 8)

To a stirred solution of alkylthio ether carboxylic acid (33) (0.1mole,1eq) in ethanol (20mL), 2naq. naoh (1.5eq) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 30min (progress of reaction was monitored by TLC). After completion of the reaction, the reaction mixture was concentrated on a rotary evaporator and the residue was cooled in an ice bath. Several pieces of crushed ice were added to the flask and neutralized with 1N HCl. The product was extracted with ethyl acetate (20 × 20 mL). The combined extracts were washed with Na₂SO₄Dried and evaporated on a rotary evaporator at 0 ℃. The residue was purified by silica gel column chromatography using hexane as an eluent to give pure alkylthio ether carboxylic acid (14).

Example 82

4- (ethylthio) butanoic acid (14 a). A colorless oil (2.01g, 90% yield).¹HNMR(400MHz,CDCl₃): 1.26(t, J ═ 7.6Hz, 3H); 1.84-1.92(m, 2H); 2.40(t, J ═ 9.6Hz, 2H); 2.47-2.55(m, 4H); 10.92(s broad, 1H).

Example 83

2- (butylthio) acetic acid (14 b). A colorless oil (0.77g, 77% yield).¹HNMR(400MHz,CDCl₃): 0.89(t, J ═ 7.6Hz, 3H); 1.37-1.43(m, 2H); 1.54-1.60(m, 2H); 2.65(t, J ═ 7.6Hz, 2H); 3.23(s, 2H); 10.00(s broad, 1H).

Example 84

2- (ethylthio) acetic acid (14 c). A colorless oil (4.76g, 85% yield).¹HNMR(400MHz,CDCl₃): 1.26(t, J ═ 7.6Hz, 3H); 2.65(q, J ═ 7.6Hz, 2H); 3.22(s, 2H); 10.92(s broad, 1H).

Example 85

4- (butylthio) butanoic acid (14 d). A colorless oil (3.64g, 80% yield).¹HNMR(400MHz,CDCl₃): 0.89(t, J ═ 7.6Hz, 3H); 1.35-1.41(m, 2H); 1.50-1.56(m, 2H); 1.88-1.93(m, 2H); 2.47-2.50(m, 4H); 2.55(t, J ═ 7.2Hz, 2H); 10.89(s broad, 1H).

Example 86

In vitro pharmacological results:

herein is reported monoamine transporter inhibitory activity of selected cycloalkylmethylamines of formula (I). The compounds were evaluated using a recognized radioligand binding assay (Galli, A. et al, J.Exp. biol.1995,198, 2197-2212; Giros, B. et al, trends Pharmcol. Sci.1993,14, 43-49; Gu, H. et al, J.biol. chem.1994,269(10), 7124-7130; Shearman, L.P. et al, am.J.physiol.,1998,275(6 Pt) 1), C1621-1629; Wolf, W.A. et al, J.biol. chem.1992,267(29), 20820-20825). Human recombinant transporter proteins Dopamine (DAT), Norepinephrine (NET) and 5-hydroxytryptamine (SERT) were selected for in vitro testing. Radioligand binding assays were performed at 11 different concentrations tested, 0.1nM to 1 μ M.

The assays were performed in duplicate and quantitative data are reported as Ki in table 1.

Examples

Compound (I)

DAT

NET

SERT

		Ki(nM、)	Ki(nM、)	Ki(nM、)
					20	7g	92.02	37.21	2.99
29	8a	2.38	46.72	1.40
					32	8d	5.45	72.05	3.80
36	8h	2.39	12.69	1.19
					38	8j	1.16	11.01	0.80
49	12b	67.56	51.87	18.77
					50	12c	115.70	1422	3.31
54	13c	23.93	17.07	14.84
					55	13d	104.20	51.03	65.33
57	13f	49.19	119	224
					61	17a	29.45	44.72	38.40

Claims

1. A compound of structural formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

n is 1;

SP is a spacer of butylene;

x is O, S or S (O);

R¹and R²Independently H, C_1-6Alkoxy or halogen;

R³and R⁵Independently is C_1-6An alkyl group;

R⁴is H;

optionally R¹、R²、R³、R⁴And R⁵Quilt²H (deuterium) substitution; and

"" indicates carbon which can be optically active.

2. The compound of claim 1, wherein R¹And R²Independently is C_1-6Alkoxy or halogen.

3. The compound of claim 1, wherein X is O.

4. The compound of claim 1, wherein X is S.

5. The compound of claim 1, wherein R¹And R²Is chloro.

6. The compound of any one of claims 1 and 3-5, wherein R³Is an isobutyl group.

7. The compound of claim 6, wherein R⁵Is ethyl.

8. The compound of claim 1 which is

9. The compound of any one of claims 1-5 and 8, which is the R form in at least 95% enantiomeric excess relative to the S form.

10. The compound of any one of claims 1-5 and 8 in the S form in at least 95% enantiomeric excess relative to the R form.

11. A pharmaceutical composition comprising a compound of any one of claims 1-5 and 8 and a pharmaceutically acceptable carrier.

12. Use of a compound of any one of claims 1-5 and 8 for the manufacture of a medicament for the treatment or prevention of obesity in a mammalian patient.

13. Use of a compound of any one of claims 1-5 and 8 for the manufacture of a medicament for treating or preventing depression in a mammalian patient.