WO2005007614A1 - Monoamine oxidase inhibitors - Google Patents

Abstract

The invention includes compounds of formula (I), pharmaceutically acceptable salts thereof, compositions containing compounds of formula (I), methods of inhibiting at least one monoamine oxidase using a compound of formula (I), and methods of inhibiting one amine oxidase while inhibiting another amine oxidase to a lesser degree using a compound of formula (I). Wherein each X is independently, an electron donating group, or an electron withdrawing group; n is an integer from 0 to 3 and Y is formula (II), (III), (IV), (V) (VI); wherein E is an electron donating group, and z is an integer from 0 to 3 with the proviso than when Y is formula (VII) or formula (VIII) where the cyclopropyl ring is attached at the carbon substituted with the E, X is not H; or pharmaceutically acceptable salts thereof.

Description

MONOAMINE OXIDASE INHIBITORS

This application is being filed on 1 July 2004, as a PCT International Patent application in the name of THE GOVERNMENT OF THE UNITED STATES OF AMERICA, claiming priority to U.S. Provisional Patent Application NO. 60/484,710 filed 3 July 2003.

This invention is supported by the Department of Health and Human Services. The Government of the United States of America may have certain rights in the invention disclosed and claimed herein below.

Field of the Invention The invention includes compounds that can be used to inhibit monoamine oxidases. More particularly, the invention includes compounds that can be used to inhibit one or more monoamine oxidases or selectively inhibit one monoamine oxidase without inhibiting another monoamine oxidase.

Background of the Invention

Monoamine oxidases (MAO) refer to enzymes that are important for the normal metabolism of amines including neurotransmitters such as 5-hydroxytryptamine, dopamine, and noradrenaline. In the brain, MAO converts amine neurotransmitters to their aldehyde forms, which are rapidly oxidized or reduced. Inhibition of MAOs by drags increases the levels of amine neurotransmitters in neurons and increases the levels of neurotransmitters that are released.

There are two general classes of MAO enzymes: copper- (EC: 1.4.3.6) and flavin-containing amine oxidases (EC: 1.4.3.4). Copper-containing MAOs are strongly inhibited by semicarbazide, which distinguishes them from flavin- containing MAOs that are selectively inhibited by acetylenic inhibitors. Flavin- containing monoamine oxidases are present in two catalytically distinguishable subtypes, A (MAO- A) and B (MAO-B), that have different substrate selectivities, and have physiological roles related to regulation of amine levels.

Copper-containing MAOs, also referred to as semicarbazide-sensitive amine oxidases (SSAO), have important and diverse functions in prokaryotes, including roles in nutrient metabolism. More recently, an increasing number of important roles of SSAO in eukaryotes have been identified and studied. For example, it has been suggested that SSAO expression is a source of oxidative stress in the blood vessel walls in Alzheimer's disease.

The importance of MAO inhibitors as pharmacological and medicinal agents, in particular as mood elevating agents, is evidenced by the development of hundreds of MAO inhibitors. Such inhibitors may be inhibitory of MAO-A, MAO-B, both MAO-A and MAO-B, or copper-containing MAOs, and may be reversible or irreversible. Many irreversible inhibitors are acetylenic compounds, such as the MAO-A selective, clorgyline, and the MAO B-selective, 1-deprenyl. Other irreversible inhibitors have been based on cyclopropyl amines. An example of an

irreversible inhibitor includes tranylcypromine

which can be used to treat certain depressive illnesses. Tranylcypromine is an irreversible inhibitor that shows no selectivity for MAO-A or -B. Tranylcypromine also inhibits SSAO, but in a reversible manner. Tranylcypromine is the most hazardous of the MAO inhibitors because it has an accompanying stimulant action.

Furthermore, inhibitors that non-selectively inhibit MAO-A and -B may lead to the non-desirable "cheese effect." The "cheese effect" refers to the inhibition of MAO-A, particularly in the wall of the gut, which can lead to the toxic build up of amines from amine-rich foods such as cheese, red wine and hydro lyzed protein extracts (e.g. Bovril or Marmite). The toxic build up of amines can lead to hypertension.

Therefore, there remains a need for other inhibitors of monoamine oxidases, as well as selective inhibitors of one or more monoamine oxidases. Summary of the Invention The invention includes compounds according to formula I

(i) wherein each X is independently, an electron donating group, or an electron withdrawing group; n is an integer from 0 to 3 and Y is

wherein E is an electron donating group, and z is an integer from 0 to

with the proviso that when Y is

or where the cyclopropyl ring is attached at the carbon substituted with the E , X is not H; or pharmaceutically acceptable salts thereof.

Pharmaceutical compositions and methods of inhibiting monoamine oxidase inhibitors or methods of selectively inhibiting one or more monoamine oxidase utilizing compounds of the invention are also disclosed. Brief Description of the Figures

Figure 1 illustrates the effect of the concentration of compounds 3 a, 3b, 4 and 5 of the invention on the inhibition of tyramine oxidases.

Figure 2 illustrates the effect of the concentration of compounds la, lb, 6a, and 6b on the inhibition of tyramine oxidase.

Figure 3 illustrates the effect of the concentration of compounds 7a, 7b, 8a, and 8b on the inhibition of tyramine oxidase.

Figure 4 illustrates the effect of the concentration of compounds la, lb, 6a, 6b, 71, 7b, 8a, and 8b on the inhibition of tyramine oxidase.

Figure 5 illustrates the effect of p-substitution on the inhibition of tyramine oxidase.

Figure 6 depicts the Lineweaver-Burk plot for the inhibition of tyramine oxidase by compound la, 6a, 13a, 14a, and 15a.

Figure 7 illustrates the effect of the concentration of clorglyline, R-(-) deprenyl, and compounds

Figures 8a and 8b illustrate the effect of the concentration of clorglyline, R-(- ) deprenyl, and compounds la, 6a, 13a, 14a, 15a (Figure 8a) and lb, 6b, 13b, 14b, and 15 (FIG 8b) on MAOB-B.

Figure 9 illustrates the effect of compounds 7a, 7, 8a, 8b on MAO-A and MAO-B.

Figures 10a and b illustrate the effect of compounds 3 a, 3b, 4 and 5 on MAO-A (FIG 10a) and MAO-B (FIG. 10b).

Figure 11 shows time-and concentration-dependent inactivation of MAO-A by compound 5.

Detailed Description of the Invention , Definitions

All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified. As used in this application, the following words or phrases have the meanings specified.

As used herein, the term "about" applies to all numeric values, whether or not explicitly indicated. The term "about" generally refers to a range of numbers that one of skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the term "about" may include numbers that are rounded to the nearest significant figure.

As used herein, "electron donating group" can include halogens, alkyls, amides, carboxylic acids, amines, hydroxyl, and ether.

As used herein, "electron withdrawing group" can include carboxyl, ester, carboxamide, cyano, nitro, and trifluoromethyl.

As used herein, "alkyl" includes linear or branched alkyl chains having from one to 4 (i.e. C_\ - C₄ or methyl to butyl) carbon atoms. Alkyl includes alkanes, alkenes and alkynes.

As used herein, "halogen" includes fluoro, chloro, bromo, or iodo.

As used herein, "pharmaceutically acceptable salt thereof includes an acid addition salt or a base salt.

As used herein, "pharmaceutically acceptable carrier" includes any material which, when combined with a compound of the invention, allows the compound to retain biological activity, such as the ability to inhibit one or more monoamine oxidases, and is non-reactive with the subject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsions, and various types of wetting agents. Compositions comprising such carriers can be formulated by well known conventional methods (see, for example, Remington's Pharmaceutical Sciences, Chapter 43, 14th Ed., Mack Publishing Co., Easton, PA).

Compounds of the Invention

Compounds of the invention include those of formula I

(I) wherein each X is independently, an electron donating group, or an electron withdrawing group; n is an integer from 0 to 3 and Y is

wherein E is an electron donating group, and z is an integer from 0 to

with the proviso that when Y is

or where the cyclopropyl ring is attached at the carbon substituted with the E , X is not H; or pharmaceutically acceptable salts thereof.

One of skill in the art, having read this specification will understand that the phenyl ring can be attached to any of the carbons on the cyclopropyl ring. In one embodiment, the phenyl ring is attached to the carbon substituted with E. In another embodiment, the phenyl ring is attached to the carbon that is not substituted with E or the other substituent.

In one embodiment, E is a halogen. In another embodiment, E is fluorine.

In one embodiment, z is 0. In another embodiment, z is 1. In another embodiment, z is 2. In another embodiment, z is 3.

In one embodiment, X is an electron donating group. In another embodiment, X is a halogen, such as fluorine, chlorine, bromine, or iodine. In another embodiment, X is fluorine or chlorine. In another embodiment, X is an alkoxy group. In yet another embodiment, X is a methoxy group.

In another embodiment, Y is

wherein E is fluorine, and

X is either fluorine, or chlorine. One of skill in the art, having read this specification, will also understand that any combination of X, Y, E, and z not specifically excluded herein can be utilized in compounds of the invention.

One of skill in the art, having read this specification will also understand that compounds of the invention can have either a cis or trans configuration at any relevant carbon atom. One of skill in the art, having read this specification, will also understand that compounds of the invention can have either an R or an S configuration at chiral carbons. One of skill in the art, having read this specification, will also understand that such changes in cis or trans and/or chirality may or may not change some or all activity associated with a compound.

Exemplary compounds of the invention include those given below.

Compounds of the invention also include

Synthesis of Compounds of the Invention

Compounds of the invention can be prepared by any method known to those of skill in the art, having read this specification. Exemplary methods for preparing some compounds of the invention are provided below.

Two different methods of cyclopropanation of fluorinated precursors can be used to produce either 2-fluoro-2-phenyl, or 2-fluorp-l -phenyl substituted cyclopropylcarboxylic esters. The ester group can then be converted either to the amino or methyl amino group by straightforward reactions known to those of skill in the art to give compounds of the invention.

According to scheme 1, the reaction of 1-fluorostyrene 11 with ethyl diazoacetate gives a 1 : 1 diastereomeric mixture of ethyl 2-fluoro-2-phenylcyclo- propylcarboxylates 12a and 12b. These can be separated either chromatographically or, after saponification, by recrystallization of the coπesponding carboxylic acids 13a and 13b. Curtius degradation to the Boc protected amines 14a and 14b and deprotection with hydrogen chloride produces compounds 6a and 6b as hydrochlorides.

Scheme 1

12a (trans-) 13a (trans-) 12b (cis-) 13b (cis-)

(trans-) 6a (trans-) 14b (cis-) 6b (cis-)

Esters can serve as starting materials for the preparation of the homologous fluorinated amines 7a and 7b, using known chain elongation methodologies. After saponification, the carboxylic acids 13a and 13b are transformed to the primary carboxamides 9a and 9b via in situ formation of the acid chlorides and treatment with concentrated aqueous ammonia. Reduction of the carboxamides 9a and 9b with borane and precipitation with HCI will give the amine hydrochlorides 7a and 7b (Scheme 2). Scheme 2

13a (trans-) 9a (trans-) 7a (trans-) 13b (cis-) 9b (cis-) 7b (cis-)

The next higher homologues can be prepared by reduction of the ethyl carboxylates 12a and 12b, subsequent tosylation to 16a and 16b and nucleophihc substitution of the tosyl group by cyanide to form 17a and 17b. Reduction of the cyano group with borane gives the amines 8a and 8b, which can be isolated by precipitation of the hydrochlorides (Scheme 3).

Scheme 3

12a (trans-) 15a (trans-) 12b (cis-) 15b (cis-) TsCI, NEt₃ 16a (trans-) CH₂CI, 20 h 16b (cis-) -

17a (trans-) 8a (trans-) 17b (cis-) 8b (cis-)

The isomeric 2-fluoro-l-phenylcyclopropylamines and methylamines can be obtained by cyclopropanation of ethyl 3-fiuoro-2-phenylacrylates 18a and 18b with diazomethane. Subsequent reduction to the corresponding cyclopropylmethanols 20a, and 20b, tosylation (to give 21a and 21b) and nucleophihc displacement of the tosyl group by ammonia gives the methylamines 3a and 3b (Scheme 4).

Scheme 4

21a, X = F, Y = H 3a, X = F, Y = H 21b, X = H, Y = F 3b, X = H, Y = F

The cyclopropylamines 5a and 5b can be prepared from the carboxylic esters 19a and 19b. (Scheme 5).

Scheme 5

1) HCI, NaN0₂, ether

_19a,b H Α 2) f-BuOH, reflux

EtOH 3)3N HCI, EtOAc

4, X = F, Y = H 5, X = F, Y = H

Salts

Compounds of the invention are capable of forming both pharmaceutically acceptable acid addition and/or base salts. Base salts are formed .with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Also included are heavy metal salts such as, for example, silver, zinc, cobalt, and cerium. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamene, N-methylglucamine, and procaine. Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and the like. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either a mono or di, etc. salt in the conventional manner. The free base forms can be regenerated by treating the salt form with a base. For example, dilute solutions of aqueous base can be utilized. Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose. The free base forms differ from their respective salt fonns somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for the purposes of the invention.

An example of a pharmaceutically acceptable salt includes hydrochloride salts of compounds of the invention.

Methods of the Invention

In one embodiment of the invention, compounds are used in methods of inhibiting at least one monoamine oxidase. In one embodiment of the invention, compounds are used in inhibiting monoamine oxidases, such as a copper-containing amine oxidase, a flavin-containing amine oxidase, or some combination thereof. In one embodiment of the invention, compounds are used to inhibit monoamine oxidase A, monoamine oxidase B, tyramine oxidase or some combination thereof. In one embodiment of the invention, compounds are used in methods of inhibiting monoamine oxidase A while inhibiting another monoamine oxidase to a lesser degree. In one embodiment of the invention, compounds are used in methods of inhibiting monoamine oxidase B while inhibiting another monoamine oxidase to a lesser degree. In one embodiment of the invention, compounds are used in methods of inhibiting tyramine oxidase while inhibiting another monoamine oxidase to a lesser degree. In one embodiment of the invention, compounds are used in methods of inhibiting monoamine oxidase A while inhibiting monoamine oxidase B to a lesser degree.

In one embodiment of the invention, a method of inhibiting a monoamine oxidase includes administering one or more compounds according to formula I, as given above. In another embodiment of the invention, a method of inhibiting a monoamine oxidase includes administering one or more of the following

compounds: ΛU . o- o

h one embodiment of the invention, methods of inhibiting one or more monoamine oxidases can be utilized to treat patients with various depressive or emotional disorders, phobic patients, depressed patients with atypical, hypochondriacal, or hysterical features, or patients that are refractory to treatment with other antidepressants.

Potent and selective reversible inhibitors of copper-containing MAOs, (CAOs, also referred to as semicarbazide-sensitive amine oxidases, SSAOs) may have important clinical applications, hi particular, it is thought that over-expression of CAO in blood vessels of patients with advanced diabetes, congestive heart failure and Alzheimer's disease may be responsible for vascular deterioration in these patients. Furthermore, it has been suggested that selective inhibitors could be useful in treatment of these conditions. Administration Methods

The compounds of the present invention can be formulated as pharmaceutical compositions and administered to a mammalian host, including a human patient, in a variety of forms adapted to the chosen route of administration. The compounds are preferably administered in combination with a pharmaceutically acceptable carrier, and can be combined with or conjugated to specific delivery agents, including targeting antibodies and/or cytokines.

Compounds can be administered by known techniques, such as orally, parentally (including subcutaneous injection, intravenous, intramuscular, intrasternal or infusion techniques), by inhalation spray, topically, by absorption through a mucous membrane, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. Pharmaceutical compositions of the invention can be in the form of suspensions or tablets suitable for oral administration, nasal sprays, creams, sterile injectable preparations, such as sterile injectable aqueous or oleagenous suspensions or suppositories.

For oral administration as a suspension, the compositions can be prepared according to techniques well-known in the art of pharmaceutical formulation. The compositions can contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents. As immediate release tablets, the compositions can contain microcrystalline cellulose, starch, magnesium stearate and lactose or other excipients, binders, extenders, disintegrants, diluents, and lubricants known in the art.

For administration by inhalation or aerosol, the compositions can be prepared according to techniques well-known in the art of pharmaceutical formulation. The compositions can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, or other solubilizing or dispersing agents known in the art. For administration as injectable solutions or suspensions, the compositions can be fomiulated according to techniques well-known in the art,^' using suitable dispersing or wetting and suspending agents, such as sterile oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

For rectal administration as suppositories, the compositions can be prepared by mixing with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ambient temperatures, but liquefy or dissolve in the rectal cavity to release the drug.

Solutions or suspensions of the compounds can be prepared in water, isotonic saline (PBS), and optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene, glycols, DNA, vegetable oils, triacetin and mixtures thereof. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage form suitable for injection or infusion use can include sterile, aqueous solutions, dispersions, or sterile powders comprising an active ingredient which can be adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. The final dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol such as glycerol, propylene glycol, or liquid polyethylene glycols, and the like, vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size, in the case of dispersion, or by the use of nontoxic surfactants. The prevention of the action of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be desirable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the inclusion in the composition of agents delaying absorption such as, for example, aluminum monosterate hydrogels and gelatin.

Sterile injectable solutions are prepared by incorporating the conjugates in the required amount in the appropriate solvent with various other ingredients as enumerated above and, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying tecnniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

Working Examples

The following examples provide nonlimiting illustrations of various embodiments of the invention.

General methods. 1H (300 MHz), ¹³C (75 MHz) and ¹⁹F (282 MHz) NMR spectra, if not stated otherwise, were recorded on 300 MHz spectrometers, and chemical shifts are reported in ppm relative to TMS or CFC1₃. Solvents and other reagents were purchased from Sigma- Aldrich Chemical Co. Analytical TLC was performed on Kieselgel 60 GF254 (Merck), and flash chromatography was performed with silica gel 60 (230-400 mesh, Merck).

Example 1: Preparation and characterization of c/s-(2-Fluoro-2-phenylcyclopropyl)- amine Hydrochloride (6b)

A mixture of c;^'_'-2-fluoro-2-phenylcyclopropanecarboxylic acid (13b), prepared as previously described, Meyer et al. Synthesis 2000, 1479-1490, (500 mg, 2.78 mmol), dry triethylamine (323 mg, 3.2 mmol), dry tert-butanol (2.06 g, 27.8 mmol) and diphenylphosphoryl azide (845 mg, 3.07 mmol) were dissolved in dry cyclohexane (85 mL) under argon. The mixture was refluxed for 18 h after which time di-tert-butyl carbonate (714 mg, 4.1 mmol) was added to the reaction mixture. After heating for an additional 2 hours the mixture was cooled to room temperature. The residue was concentrated under vacuum and diluted with ethyl acetate (70 mL). The organic phase was washed with 5% citric acid, water, saturated NaHCO₃ and brine. Non-converted di-tert-butyl carbonate was removed by bulb-to- bulb distillation (60 °C/1.2T0^_1 mbar). The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate, 6:1). (Yield: 278 mg, 87 %). Data for tert-butyl cz5-(2-fluoro-2-phenylcyclopropyl)carbamate 14b: Mp 123 °C; 1H NMR (CD₃OD) δ 1.31 (9 H, s, CH₃), 1.56 (1 H, ddd, J= 6.0 Hz, J= 8.1 Hz, J= 11.7 Hz, CH_AH_B), 1.74 (1 H, ddd,J= 8.1 Hz, J= 9.8 Hz, J= 21.9 Hz, CH_AH_B), 3.20-3.30 (1 H, m, CHx), 7.30-7.50 (5 H, m, aromatic); ¹³C NMR (CDC1₃) δ 18.5 (br s, CH_AH_B), 28.1 (q, CH₃), 34.2 (br s, CH_X), 79.9 (s, O-C(CH₃)), 81.1 (ds, J= 217.4 Hz, CF), 126.9 (d, aromatic), 128.3 (d, aromatic), 137.7 (ds, J= 20.3, aromatic), 155.7 (s, N-C(O)-O); ¹⁹F NMR (CD₃OD) δ 170.05 (m); MS (GC/MS) m/z (%) 249 (1), 230 (1), 195 (4), 177 (7), 175 (4), 151 (12), 150 (9), 148 (14), 130 (66), 103 (16), 77 (10), 59 (32), 57 (100), 51 (9), 41 (49); Anal. (C₁₄Hι₈FNO₂) C, H, N, F.

A suspension of tert-butyl cz^'s-(2-fluoro-2-phenylcyclopropyl)carbamate (14b) (145 mg, 0.58 mmol) in 1.2 N aqueous HCl/glacial acetic acid (1:1, 5 mL) was stirred at room temperature for 1 h. After removal of all volatiles, the residue was washed with Et₂O and placed under vacuum. The product was isolated as a white solid. (Yield: 70 mg, 64 %). Data for 6b: Mp > 150 °C (dec); 1H NMR (methanol- d₄) δ 1.80-2.05 (2 H, m, CHAH_B), 3.44 (1 H, ddd, J= 10.3 Hz, J= 6.0 Hz, J= 14.1 Hz, CHx), 7.50-7.70 (5 H, m, aromatic); ¹³C NMR (methanol-d₄) δ 16.3 (dt, J= 12.7 Hz, CH_AH_B), 33.0 (dd, J= 21.6 Hz, CH_X), 80.6 (ds, J= 220.0 Hz, CF), 130.8 (d, aromatic), 131.0 (dd, J= 3.8 Hz, aromatic), 132.1 (d, aromatic), 132.2 (ds, J- 21.6 Hz, aromatic); ¹⁹F NMR (methanol-d₄) δ 159.69 (m); MS m/z (%) 151 (8), 150 (19), 131 (11), 130 (100), 103 (32), 102 (5), 101 (5), 77 (16), 74 (15), 51 (11); Anal. (C₉H_πClFN) C, H, N, F.

Example 2: Preparation and characterization of c/_^ι-2-Fluoro-2-phenylcyclopropane- carboxylic amide (9b).

To a solution of ct_*-2-fluoro-2-phenylcyclopropancarboxylic acid (13b) (0.50 g, 2.78 mmol) in 15 mL of benzene was added thionylchlori.de (2.4 g, 20 mmol) dropwise. The reaction mixture was heated under reflux for about 7 to 8 h after which all volatiles were removed by distillation. The resulting residue was dissolved in 10 mL of 1,4-dioxane and the solution was chilled in ice. To this was added 15 mL of concentrated aqueous NH₄OH. The mixture was stiπed at 0 °C for 30 min and at room temperature for an additional 30 min. The aqueous phase was then extracted with ethyl acetate (x3) and the combined organic layers were washed two times with saturated NH₄C1 and dried over MgSO . The solvent was removed under reduced pressure and the residue was recrystallised from cyclohexane/ethyl actetate (1:2) to give 0.41 g (82 %) of pure cz_^,-2-Fluoro-2-phenylcyclopropane- carboxylic amide (9b) Data for 9b: Mp 114 °C; 1H NMR (DMSO-d₆) δ 1.66 (1 H, \ ddd, J= 6.7 Hz, J= 10.3 Hz, J= 20.0 Hz, CHAH_B), 1.76-1.82 (1 H, m, CH_AH_B), 2.53 (1 H, ddd, J= 7.9 Hz, J= 10.3 Hz, J= 20.3 Hz, CHχ)₅ 7.28-7.44 (5 H, m, aromatic); ¹³C NMR (DMSO-d₆) δ 14.7 (dt, J= 16.2 Hz, CH_AH_B), 28.5 (dd, J= 14.0 Hz; CHx), 82.9 (ds, J= 216.2 Hz, CF), 128.2 (d, aromatic), 128.3 (dd,J= 3.8 Hz, aromatic), 128.9 (d, aromatic), 134.0 (ds, J= 20.4 Hz, aromatic), 168.5 (s, CONH₂); ¹⁹F NMR (DMSO-d₆) δ -151.88 (m); GC/MS m/z (%) 179 (37), 162 (19), 159 (23), 135 (61), 134 (26), 133 (63), 130 (40), 124 (20), 115 (100), 109 (25), 107 (15), 89 (14), 83 (14), 77 (13), 63 (17), 57 (15), 51 (19), 44 (35), 39 (17); IR (KBr) v 3458 (br), 3299 (br), 3168 (m), 1671 (s), 1619 (m), 1507 (w), 1461 (w), 1415 (w), 1349 (w), 1304 (w), 1280 (w), 1187 (m), 954 (w), 885 ( ), 874 (m), 777 ( ), 750 (w), 703 (s), 624 (m), 573 (m), 550 (m); Anal. (Cι₀H₁₀FNO) C, H, N, F. The structure of 9b was also confirmed by X-ray structural analysis.

Example 3: Preparation and characterization of tr ns -(+)-2-Fluoro-2- phenylcyclopro-panecarboxylic Amide (9a). The trans amide 9a was synthesized from tra/JS-2-fTuoro-2- phenylcyclopropane-carboxylic acid (13a) (0.50 g, 2.78 mmol) by the same method as described for the cis isomer 9b. (Example 2) The trans amide was recrystallized from ethyl acetate. (Yield: 0.41 g, 82 %). Data for trα»_--(±)-2-FIuoro-2- phenylcyclopropanecarboxylic amide 9a: Mp 199 °C; ^lHNMR (DMSO-d₆) δ 1.53- 1.62 (1 H, m, CHAH_B), 2.00-2.11 (1 H, m, CHAH_B), 2.16-2.23 (1 H, m, CHχ)₃ 7.28- 7.44 (5 H, m, aromatic); ¹³C NMR (DMSO-d₆) δ 17.2 (dt, J= 11.5 Hz, CH_AH_B), 30.3 (dd, J= 12.7 Hz, CH_X), 80.7 (ds, J= 223.8 Hz, CF), 124.3 (dd,J= 7.6 Hz, aromatic), 127.9 (d, aromatic), 128.6 (d, aromatic), 138.7 (ds, J= 21.6 Hz, aromatic), 167.1 (ds, J= 2.5 Hz, CONH₂); ¹⁹F NMR (DMSO-d₆) δ -188.97 (m); GC MS m/z (%) 179 (50), 162 (26), 159 (23), 135 (83), 134 (28) [162 - CO], 133 (64), 130 (39), 124 (21), 115 (100), 109 (25), 107 (14), 89 (10), 83 (13), 77 (12), 63 (10), 57 (10), 51 (14), 44 (27), 39 (11); IR (KBr) v 3350 (br), 3174 (br), 3035 (w), 1651 (s), 1462 (m), 1448 (m), 1416 (m), 1344 (m), 1274 (w), 1243 (w), 1141 (m), 1101 (m), 1042 (w), 1031 (w), 1011 (m), 971 (m), 922 (w), 894 (m), 857 (m), 823 (w), 812 (w), 762 (m), 746 (m), 695 (s), 571 (m); Anal. (C₁₀Hι₀FNO.) The structure of 9a was also confirmed by X-ray structural analysis. Example 4: Preparation and characterization of ct-^,-(2-Fluoro-2-phenylcyclopropyl)- methylamine Hydrochloride (7b). A 1 M borane-THF solution (4.8 mL) was added to dry THF (10 mL) under argon. The mixture was chilled in an ice bath and a solution of cis amide 9b (358 mg, 2 mmol) (as prepared above) in 20 mL of dry THF was added dropwise. After the reaction mixture was heated under reflux for 6-7 h it was quenched by careful addition of 10 ml of 6 M aqueous HCI. The THF was removed by distillation under vacuum and the residual aqueous solution was washed two times with Et₂O, neutralized with 40% NaOH and then extracted three times with Et₂O. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum until the volume was reduced to about 20 mL. The solution was cooled in an ice bath and gaseous HCI was passed through leading to immediate precipitation of a white solid. The mixture was stirred for an additional 15 min at 0°C and then concentrated under vacuum. The product was purified by recrystallization from ethanol/Et₂O (1:4) to give 204 mg (51 %) of 7b as a white solid. Data for 7b: Mp > 230 °C; 1H NMR (CD₃OD, 600.0 MHz) δ 1.49 (1 H, ddm, J= 7.5 Hz, J= 9.7 Hz, CH_AH_B), 1.64 (1 H, ddd, J= 7.5 Hz, J= 10.9 Hz, J= 19.1 Hz, CH_AH_B), 1.96-2.05 (1 H, m, CHx), 2.06-2.10 (1 H, m, CH₂NH/), 3.09-3.12 (1 H, m, CH_NH₃), 4.86 (3 H, s, NH₃ ⁺), 7.42-7.50 (5 H, m, aromatic); ¹³C NMR (CD₃OD) δ 15.7 (dt, J= 12.7 Hz, CH_AH_B), 22.9 (dd, J= 22.9 Hz, CH_X), 40.8 (t, CH₂NH₃t), 83.1 (ds, J= 214.9 Hz, CF), 129.5 (dd,J= 3.8 Hz, aromatic), 130.2 (d, aromatic), 130.7 (dd, ⁴J= 2.5 Hz, aromatic), 135.4 (ds, J= 20.3 Hz, aromatic); ¹⁹F NMR (CD₃OD, 564.3 MHz) δ -160.57 (ddm, J= 9.7 Hz, J= 19.1 Hz); MS/ESI m z (%) 166 (15), 149 (100), 129 (28); IR (NaCl) v 3116 (br), 3000 (s), 2975 (s), 2898 (s), 2688 (w), 1953 (br), 1599 (m), 1579 (m), 1490 (s), 1454 (s), 1401 (w), 1336 (m), 1210 (s), 1186 (w), 1105 (w), 1069 (w), 1042 (w), 1029 (w), 980 (w), 944 (w), 884 (m), 872 (m), 810 (w), 770 (s), 702 (s), 600 (w); Anal. (C₁₀H₁₃C1FN) C, H, N, F. 'H^H-COSY supported analysis of 1H NMR.

Example 5: Preparation and characterization of trøπ_--(2-Fluoro-2- phenylcyclopropyD-methylamine Hydrochloride (7a). The trans methylamine 7a was synthesized from trΩ7M-2-fiuoro-2- phenylcyclopropane-carboxylic amide (9a) (358 mg, 2 mmol) (as prepared above) by the same method as described for the cis isomer 7b. (Example 4) (Yield: 206 mg, 51 %). Data for 7a: Mp 160 °C; 1H NMR (methanol-d , 600 MHz) δ 1.42-1.57 (2 H, m, CHAH_B), 1.68-1.79 (1 H, m, CHx), 3.21-3.35 (2 H, m, CH_NH₃ ⁺), 4.75 (3 H, s, NH₃ ⁺), 7.32-7.42 (5 H, m, aromatic); ¹³C NMR ( ethanol-α , MHz) δ 19.5 (dt, J= 12.4 Hz, CH_AH_B), 23.9 (dd, J= 11.0 Hz, CH_X), 40.0 (dd, J= 8.5 Hz, CH₂NH₃ ⁺), 82.6 (ds, J= 218.2 Hz, CF), 126.0 (dd, J= 5.5 Hz, aromatic), 129.4 (d, aromatic), 129.9 (d, aromatic), 139.6 (ds, J= 21.0 Hz, aromatic); ¹⁹F NMR (methanol-d₄, 564.3 MHz) δ -190.65 (m); MS (ESI) m/z (%) 166 (12), 149 (100), 129 (34); IR (NaCl) v 3043 (br), 3006 (s), 2960 (s), 2920 (s), 2578 (w), 2485 (w), 2014 (br), 1603 (m), 1525 ( ), 1453 (m), 1411 (s), 1336 (w), 1228 (m), 1144 (w), 1121 (w), 1079 (w), 1037 (m), 984 (m), 873 (m), 857 (w), 764 (w), 752 (m), 695 (s); Anal. (CioHi_.ClFN) C, H, F, N. ¹H,¹H-COSY supported analysis of 1H NMR. The structure of 7a was confirmed by X-ray structural analysis.

Example 6: Preparation and characterization of c ^,-(2-phenyl-cyclopropyl)- methylamine hydrochloride (lb).

To a suspension of 80 mg (2.1 mmol) of LiAlH₄ (80 mg, 2.1 mmol) in 3 mL of dry THF a solution of 179 mg (1 mmol) of cis amide 9b (179 mg, 1 mmol) was added dropwise (as prepared above) in 10 mL of dry THF. The resulting mixture was refluxed for 45 min and then chilled and quenched with water (2 mL). The resulting white precipitate was filtered and washed with THF. The combined organic layers were dried over Na₂SO₄ and gaseous HCI was passed through the resulting yellow solution at 0 °C. The solution was stirred for 15 min during which time a white solid precipitated. After removal of volatile material the residue was recrystallized from Et₂O/T_thanol (3:1) to give 50 mg (27 %) of a product identified as ct_--(2-phenyl-cyclopropyl)-methylamine hydrochloride (lb). Data for lb: Mp 217-217.5 °C; 1H NMR (DMSO-d₆) δ 0.96-1.11 (2 H, m, CH_AH_B), 1.34-1.38 (1 H, m, Ph-CH), 2.01-2.09 (1 H, m, CH-CH₂NH₃ ⁺), 2.75-2.92 (2 H, m, CH₂NH₃ ⁺), 7.11- 7.28 (5 H, m, aromatic); ¹³C NMR (DMSO-d₆) δ 14.3 (t, CH_AH_B), 20.2 (d, Ph-CH), 21.8 (d, CH-CH₂NH₃ ⁺), 42.8 (t, CH₂NH₃ ⁺), 125.7 (d, aromatic), 126.1 (d, aromatic), 128.3 (d, aromatic), 142.0 (s, aromatic); MS m/z (%) 185/183 (0.3/1), 147 (5), 130 (8), 129 (16), 115 (34), 106 (100), 104 (21), 99 (7), 91 (25), 78 (21), 77 (19), 65 (9), 63 (10), 56 (24), 51 (16). Several ¹³C NMR data are available in the literature.

Example 7: Preparation and characterization of ct.,-(2-Fluoro-2-phenylcyclopropyl)- ethylamine Hydrochloride (8b) To an ice-cooled solution of 0.60 g (3.6 mmol) of cw-(2-fluoro-2- phenylcyclopropyl)-methanol (15b), prepared as previously described, Rosen et al, Tetrahedron Assymetry 2002 13. 1397-1405, and 0.73 mg (7.2 mmol) of triethylamine in 20 mL of dry CH₂CI₂ was added slowly to a solution of 0.82 g (4.3 mmol) of 4-toluenesulfonyl chloride (0.82 g, 4.3 mmol) in 10 mL of dry CH₂C1₂. The solution was allowed to warm to room temperature and stirred for 24 h. The organic phase was poured onto a mixture consisting of 15 g of ice and 5 mL of cone. HCI. The organic layer was washed two times with water and dried over MgSO₄. After removal of all volatiles under vacuum, the resulting residue was recrystallized from pentane/Et₂O (6:1) to give 0.95 g (82 %) of the tosylate 16b as a white solid. This product was stable at -20 °C but decomposed at room temperature. Data for 16b: Mp 72 °C; 1H NMR (CDC1₃) δ 1.14-1.22 (1 H, m, CH_AH_B)_. 1.49-1.61 (1 H, m, CHAHB), 1.94-2.12 (1 H, m, CHx), 2.42 (3 H, s, CH_.3), 3.60-3.75 (2 H, m, CH_O), 7.25-7.93 (10 H, m, aromatic); ¹³C NMR (CDC1₃) δ 14.0 (dt, J= 11.5 Hz, CH_AH_B), 21.5 (q, CH₃), 22.8 (dd, J- 16.5 Hz, CH_X), 69.3 (t, CH₂O), 81.9 (ds, J= 216.2 Hz, CF), 127.7 (d, aromatic), 128.2 (dd, J= 3.8 Hz, aromatic), 128.6 (d, aromatic), 129.2 (dd, ⁴J= 2.5 Hz, aromatic), 129.7 (d, aromatic), 133.1 (s, aromatic), 133.5 (d, J= 20.4 Hz, aromatic), 144.7 (s, aromatic); ¹⁹F NMR (CDCI₃) δ -160.01 (m); MS m/z (%) 322 (1), 301 (1), 283 (1), 263 (1), 190 (1), 165 (2), 155 (29)/l48 (100), 135 (29), 133 (38), 128 (30), 115 (56), 105 (49), 91 (72), 77 (22), 75 (48), 57 (32), 51 (23); IR (NaCl) v 3066 (w), 3045 (w), 2993 (w), 1604 (m), 1506 (w), 1462 (m), 1413 (w), 1360 (s), 1336 (m), 1310 (w), 1293 (w), 1262 (w), 1194 (s), 1180 (s, v(SO₃)), 1119 (w), 1098 (m), 1074 (m), 938 (s), 827 (s), 808 (m), 793 (m), 758 ( ), 694 (s), 668 (s), 574 (s), 556 (s), 522 (m), 489 (s); Anal. (C₁₇H₁₇FO₃S) C, H, N, F, S? The structure of 16b was confirmed by X-ray structural analysis.

To a solution of 0.64 g (2.0 mmol) of cis tosylate 16b dissolved in 20 mL of anhydrous DMF was added 0.21 g (4.0 mmol) of NaCN. The solution was stirred at room temperature for 22 h and then poured into 50 mL of 5% NaHCO₃. The aqueous solution was extracted four times with cyclohexane, and the combined organic layers were washed with brine and dried over MgSO₄. All volatiles were removed under vacuum and the residue was purified by silica gel chromatography (cyclohexane/ethyl acetate 15:1) to give 0.31 g. (89 %) of the cis nitrile 17b as an oil. (When the reaction was perfoπned at 100 °C crs/trαns-isomerization was detected by ¹⁹F NMR.) Data for 17b: Bp 131-133 °C, 6.5-10^"2 mbar; 1H NMR (CDCI₃) δ 1.17-1.25 (1 H, m, CHAH_B), 1.55-1.70 (1 H, m, CHAH_B), 1.89-2.13 (3 H, m, CHx and CH₂CN), 7.37-7.50 (5 H, m, aromatic); ¹³C NMR (CDC1₃) δ 15.1 (dt, J= 12.8 Hz, CH_AH_B), 17.4 (t, CH2CN), 19.7 (dd, J= 17.8 Hz, CHx), 81.6 (ds, J=

217.4 Hz, CF), 117.8 (s, CN), 128.3 (dd, J= 3.8 Hz, aromatic), 128.8 (d, aromatic),

129.5 (dd, ⁴J= 2.5 Hz, aromatic), 133.0 (ds, J= 20.3 Hz, aromatic); ¹⁹F NMR (CDCI₃) δ -160.99 (m). GC/MS: m/z (%) 175 (9), 154 (5), 135 (100), 115 (64), 109 (12), 83 (7), 77 (7), 75 (7), 63 (7), 51 (9), 39 (6); IR (NaCl) v 3094 (m), 3067 (m), 2252 (s), 1608 (w), 1504 (m), 1453 (s), 1419 (s), 1383 (m), 1345 (s), 1298 (m), 1231 (m), 1198 (s), 1133 (m), 1103 (m), 1067 (m), 976 (m), 884 (m), 809 (w), 768 (s), 703 (s), 605 (m); Anal. (C_πH₁₀FN) C, H, N, F.

To a solution of 175 mg (1 mmol) of cz^'_*-(2-fluoro-2-phenylcyclopropyl)- acetonitrile (17b) in 10 mL anhydrous Et₂O stirred under argon was added slowly 2 mL of a 1 M borane-THF solution. The reaction mixture was refluxed for 2 h, cooled to room temperature, and 2 mL of cone. HCI was added. The mixture was concentrated under vacuum, the remaining aqueous phase neutralized with 40% NaOH and extracted with Et₂O (x3). The combined organic layers were dried over Na₂SO₄. The obtained solution was concentrated under vacuum to a volume of 20 mL. Gaseous HCI was passed through this solution at 0 °C. A white solid formed after 15 min stirring at 0 °C. All volatiles were removed under vacuum. The product was recrystallized from Et₂O/ethanol (4:1) and isolated as a white powder. (Yield: 56 mg, 26 %). Data for 8b: Mp 170 °C; 1H NMR (CD₃OD) δ 1.08-1.28 (2 H, m, CH_AH_B), 1.42-1.80 (3 H, m, CHxCHz), 2.80-2.96 (2 H, m, CH_NH₃ ⁺), 4.88 (3 H, s, NH₃ ⁺), 7.36-7.47 (5 H, m, aromatic); ¹³C NMR (CD₃OD) δ 15.9 (dt, J= 13.0 Hz, CH_AH_B), 22.9 (dd, J= 15.1 Hz, CH_X), 28.0 (t, CHχCH₂), 40.1 (t, CH₂NH₃ ⁺), 83.3 (ds, J= 221.4 Hz, CF), 129.0 (d, aromatic), 129.8 (d, aromatic), 129.9 (d, aromatic), 136.5 (ds, J= 23.0 Hz, aromatic); ¹⁹F NMR (CD₃OD) δ -161.31 (m); MS/ESI m/z (%) 180 (100), 163 (7), 160 (66), 143 (12), 132 (11), 117 (53); IR (KBr) v 3057- 2901 (br), 2583 (w), 2494 (w), 2032 (br), 1620 (m), 1607 (m), 1527 ( ), 1475 (w), 1457 (m), 1385 (w), 1344 (w), 1322 (w), 1265 (m), 1202 (m), 1176 (m), 1068 (w), 1018 (m), 982 (w), 905 (m), 867 (m), 767 (s), 702 (s), 604 (w); Elemental analysis calculated for C_πH₁₅ClFN.

Example 8: Preparation and characterization of trα«.,-(2-Fluoro-2- phenylcyclopropyD-ethylamine hydrochloride (8a)

The trans tosylate 16a was synthesized from tmns-(2-fluoro-2- phenylcyclopropyl)-methanol (15a) (0.60 g, 3.6 mmol) by the same method as described for the cis isomer 16b. (Yield: 0.91 g, 79 %). Data for 16a: Mp 63 °C; 1H NMR (CDC1₃) δ 1.24-1.40 (2 H, m, CHAH_B), 1.59-1.71 (1 H, m, CHx), 2.42 (3 H, s, CH₃), 4.20-4.45 (2 H, m, CH_O), 7.19-7.81 (m, 10 H, aromatic); ¹³C NMR (CDCI₃) δ 17.9 (dt, J= 12.7 Hz, CH_AH_B), 21.6 (q, CH₃), 23.4 (dd, J= 11.4 Hz, CHx), 69.0 (t, J= 10.2 Hz, CH₂O), 80.8 (ds, J= 220.0 Hz, CF), 124.7 (dd, J= 6.4 Hz, aromatic), 127.8 (d, aromatic), 128.5 (d, aromatic), 129.8 (d, aromatic), 13314 (s, aromatic), 137.8 (d, J= 20.3 Hz, aromatic), 144.7 (s, aromatic); ¹⁹F NMR (CDCI₃) δ -190.30 (m). MS: m/z (%) 321 (1), 205 (7), 171 (3), 165 (2), 155 (19), 148 (100), 135 (9), 133 (43), 127 (36), 115 (28), 105 (48), 99 (43), 91 (30), 77 (22), 75 (48), 57 (58), 51 (24); IR (NaCl) v 3072 (w), 3040 (w), 2964 (w), 2926 (w), 1639 (w), 1618 (w), 1597 (w), 1500 (w), 1457 (m), 1412 (w), 1364 (s, v(SO₃)), 1336 (m), 1192 (m), 1174 (s), 1099 (w), 1038 (w), 998 (w), 944 (s), 839 (s), 874 (m), 839 (s), 822 (m), 793 (m), 748 (m), 696 (s), 670 (s), 588 (m), 556 (s), 538 (m); Anal. (C₁₇H₁₇FO₃S) C, H, N, F.

The trans nitrile 17a was synthesized from the corresponding trans tosylate 16a (0.64 g, 2.0 mmol) by the same method as described for the cis isomer 17b (Example 7). (Yield: 0.32 g, 92 %). Data for 17a: Bp 113 °C, 7.2- 10^"2 mbar; 1H NMR (CDC1₃) δ 1.26-1.63 (3 H, m, CHAH_B and CHx), 2.69 (2 H, d, J= 6.9 Hz, CH₂CN), 7.24-7.40 (5 H, m, aromatic); ¹³C NMR (CDC1₃) δ 16.1 (dt, J= 10.2 Hz, CH_AH_B), 18.9 (dt, J= 11.4 Hz, CH₂CN), 20.9 (dd, J= 11.5 Hz, CH_X), 80.2 (ds, J= 222.0 Hz, CF), 118.4 (s, CN), 124.6 (dd, J= 6.4 Hz, aromatic), 128.2 (d, aromatic), 128.6 (d, aromatic), 137.6 (ds, J= 21.6 Hz, aromatic); ¹⁹F NMR (CDC1₃) δ -190.69 (m); GC/MS m/z (%) 175 (12), 155 (7), 147 (8), 135 (100), 115 (57), 109 (13), 83 (6), 77 (7), 63 (7), 51 (9), 39 (6); IR (NaCl) v 3093 (m), 3066 (m), 3036 (m), 2970 (w), 2935 (w), 2254 (s), 1607 (m), 1502 (s), 1456 (s), 1421 (s), 1399 (m), 1318 (m), 1291 (m), 1242 (s), 1116 (s), 1080 (m), 1057 (w), 1034 (s), 1006 (s), 880 (m), 802 (w), 758 (s), 699 (s), 623 (m); Anal. (C„H₁₀FN) C, H, N, F. trαns-(2-Fluoro-2-phenylcyclopropyl)-ethylamine hydrochloride (8a) was synthesized from the corresponding trans nitrile 17a (175 mg, 1 mmol) by the same method as described for the cis isomer 8b (Example 7). (Yield: 75 mg, 35 %). Data for 8a: Mp 175 °C; 1H NMR (DMSO-d₆, 400 MHz) δ 1.19-1.28 (1 H, m, CH_AH_B), 1.33-1.39 (1 H, m, CHAHB), 1.42-1.50 (1 H, m, CHx), 1.85-2.01 (2 H, m, CH_xCEb), 2.81-2.98 (2 H, m, q__₂NH₃ ⁺) 3.40 (3 H, s, NH₃ ⁺) 7.27-7.41 (5 H, m, aromatic); ¹³C NMR (DMSO-d₆, ??? MHz) δ 19.3 (dt, J= 10.2 Hz, CH_AH_B), 23.0 (dd, J= 11.4 Hz, CHx), 25.5 (dt, J=7.6 Hz, CHχCH₂), 38.7 (t, CH₂NH₃ ⁺), 81.3 (ds, J= 216.2 Hz, CF), 124.0 (dd,J= 6.8 Hz, aromatic), 127.5 (d, aromatic), 128.6 (d, aromatic), 139.6 (ds, J= 21.6 Hz, aromatic); ¹⁹F NMR (DMSO-d₆, ??? MHz) δ -192.31 (m); GC/MS m/z (%) 179 (5), 162 (2), 155 (12), 149 (10), 147 (9), 135 (9), 125 (11), 115 (12), 109 (18), 99 (60), 97 (33), 95 (22), 91 (7), 83 (58), 78 (21), 77 (15), 71 (68), 69 (72), 60 (44), 57 (100), 55 (100), 51 (16); IR (KBr) v 3031-2976 (br), 2035 (br), 1600 (w), 1499 (s), 1454 (m), 1305 (w), 1242 (w), 1148 (w), 1119 (w), 1072 (m), 1031 (w), 1015 (w), 988 (w), 913 (w), 753 (s), 697 (s), 616 (m), 536 (w); Elemental analysis calculated for CπHι₅ClFN.

'H^H-COSY and 1H,¹³C-correlation supported analysis of 1H NMR and ¹³C NMR.

Example 9: Preparation and characterization of tra;ω^,-(2-Fluoro-3- phenylc vclopropyD-methylamine (3 a)

A mixture of trans- and ct^"_^,-2-fluoro-3-phenyl-cyclopropanecarboxylic acid ethyl ester (19a, 19b) (2 g, 9.6 mmol), prepared as previously described, Sloan et al., Tetrahedron Lett. 1997 38, 1677-1680, was dissolved in anhydrous toluene (20 mL) and stirred at -74°C. DIBAL was added slowly and the reaction solution was stirred for 4 hrs at the same temperature. The cooling bath was removed and the solution was stirred overnight at room temperature. The solution was then cooled to 0°C and a toluene/methanol mixture (1/1) was added slowly. This was followed by the addition of 2N aqueous HCI, and the mixture was then extracted with ether (x3). The ether layer was washed with saturated NaHCO₃ and brine, and dried over MgSO₄. After evaporation, the obtained residue was purified and cis- and trans- isomers separated by silica gel chromatography (ethyl acetate/π-hexane = 1/5). The products were obtained as oils (Yield: trans isomer; 1.0 g, 63%; cis isomer; 0.3 g 19%). Data for 20a: 1H-NMR (CDC1₃) δ 1.17 (1H, ddd, J= 11.1 Hz, J= 6.3 Hz, J= 7.2 Hz, CH_AH_B), 1.31 (1H, ddd, J= 21.9 Hz, J= 7.2 Hz, J= 2.7 Hz, CH_AH_B), 1.62 (1H, broad, -OH), 3.49 (1H, dd, J= 11.4 Hz, 2.4 Hz, -CHH-OH,), 3.56 (1H, d, J= 11.4 Hz, -CHH-OH,), 4.69 (1H, ddd, J= 64.8 Hz, J= 6.3 Hz, J= 2.7 Hz, CFH), 7.26-7.41 (5H, m, aromatic); ¹³C NMR (CDC1₃) δ 15.82 (d, J= 10.3 Hz, C H_AH_B), 33.00 (d, J= 9.2 Hz, Ph(CH₂OH)C<), 68.12 (d, 2.3 Hz, -CH₂OH), 74.43 (d, J= 225.0 Hz, FHC), 127.71 (s, aromatic), 128.76 (s, aromatic), 130.87 (s, aromatic), 136.79 (d, J- 3.5 Hz, aromatic).

Triethylamine (0.38 mL, 2.7 mmol) and methanesulfonyl chloride (0.15 mL, 1.9 mmol) were added to a methylene chloride solution (6.6 mL) of compound (20a) from Example 14 (0.3 g, 1.8 mmol). The mixture was stirred at 0°C for 2 hrs. The reaction mixture was washed with water, 10% aqueous HCI, saturated NaHCO₃ and brine in succession, was dried over MgSO₄. Solvent was removed by the evaporation, and the residue was purified by silica gel chromatography (petroleum ether/ ethyl acetate = 2/1). The product was obtained as an oil (Yield: 0.37g, 84%). Data for 21a: 1H-NMR (CDC1₃) δ 1.33 (IH, ddd, J= 12.0 Hz, J= 6.3 Hz, J= 7.5 Hz, CH_AH_B), 1.48 (IH, ddd, J= 21.6 Hz, J= 7.5 Hz, J- 3.0 Hz, CH_AH_B), 3.14 (3H, s, -SO₃CH₃), 4.11 (IH, dd, J= 10.8 Hz, J= 2.4 Hz, -CHH-OMs), 4.20 (IH, d, J= 11.1 Hz, -CHH-OMs), 4.78 (IH, ddd, J= 63.9 Hz, J= 6.3 Hz, J= 3.0 Hz, CFH), 7.28-7.43 (5H, m, aromatic).

Mesylate (21a) was dissolved in THF and NH3 gas was introduced dropwise by a using cold-finger condenser at -74°C. After the cooling bath was removed, the mixture was stirred overnight at room temperature. The excess NH₃ was then flushed out with N₂, the solvent was removed by evaporation, and IN aqueous NaOH and ethyl acetate were added. The product was extracted with ethyl acetate (x3), and the organic layer was washed successively with IN NaOH (x3) and brine (xl), then dried over MgSO₄. After removal of the solvent, the product was purified by silica gel chromatography. Elution with ethyl acetate removed impurities and the target compound was eluted with a mixture of ethyl acetate/acetic acidmethanol (10/1/10). The solvent was removed by evaporation, ethyl acetate was added, and the organic layer was washed with 6N NaOH and brine (xl) and dried over MgSO₄. The product was obtained as a clear oil. (Yield: 82 mg, 57%). Data for 3a: 1H-NMR (CDCI₃): δ 1.08 (IH, ddd, J= 10.8 Hz, J= 6.9 Hz, J= 6.3 Hz, CH_AH_B), 1.24 (2H, broad, -NH₂), 1.28 (IH, ddd, J= 21.9 Hz, J= 6.9 Hz, J= 2.7 Hz, CH_AH_B), 2.52 (IH, broad doublet, J= 12.9 Hz, -CHH-NH₂), 2.86 (IH, broad doublet, J= 13.5 Hz, -CHH-NH₂), 4.62 (IH, ddd, J= 65.1 Hz, J= 6.3 Hz, J= 2.7 Hz, CFH), 7.26-7.39 (5H, m, aromatic); ¹³C-NMR (CDC1₃) δ 16.46 (d, J= 10.3 Hz, CH_AH_B), 34.06 (d, J- 8.6 Hz, Ph(CH₂NH₂)C<), 49.69 (d, J= 1.7 Hz, -CH₂-NH₂), 75.05 (d, J= 225.0 Hz, FHC), 127.41 (s, aromatic), 128.61 (s, aromatic), 130.78 (s, aromatic), 137.36 (d, J= 4.0 Hz, aromatic); HRMS (FAB⁺) Calcd for C₁₀H₁₃NF (M⁺H⁺) m/z = 166.1032, Found 166.1035.

Example 10: Preparation and characterization of czs-β-Fluoro-l- phenylcyclopropyD-methylamine (3b) A mixture of trans- and cz^'s-2-fluoro-3-phenyl-cyclopropanecarboxylic acid ethyl ester (19a, 19b) (2 g, 9.6 mmol), prepared as previously described, Sloan et al., Tetrahedron Lett., 1997 38, 1677-1680, was dissolved in anhydrous toluene (20 mL) and stirred at -74°C. DIBAL was added slowly and the reaction solution was stirred for 4 hrs at the same temperature. The cooling bath was removed and the solution was stirred overnight at room temperature. The solution was then cooled to 0°C and a toluene/methanol mixture (1/1) was added slowly. This was followed by the addition of 2N aqueous HCI, and the mixture was then extracted with ether (x3). The ether layer was washed with saturated NaHCO₃ and brine, and dried over MgSO₄. After evaporation, the obtained residue was purified and cis- and trans- isomers separated by silica gel chromatography (ethyl acetate/n-hexane = 1/5). The products were obtained as oils (Yield: trans isomer; 1.0 g, 63%; cis isomer; 0.3 g 19%). Data for 20b: 1H NMR (CDC1₃) δ 1.29 (IH, ddd, J= 10.8 Hz, J= 7.2 Hz, J= 6.3 Hz, CH_AH_B), 1.35 (IH, ddd, J= 22.8 Hz, J= 7.2 Hz, J= 2.7 Hz, CH_AH_B), 1.64 (IH, broad, -OH), 3.91 (IH, dd, J= 11.7 Hz, 1.5 Hz, -CHH-OH,), 4.04 (IH, d, J= 11.7 Hz, -CHH-OH,), 4.83 (IH, ddd, J= 64.8 Hz, J= 6.3 Hz, J= 2.7 Hz, CFH), 7.24-7.37 (5H,m, aromatic); ¹³C-NMR δ 17.55 (d, J= 10.3 Hz, CH_AH_B), 33.04 (d, J = 10.3 Hz, Ph(CH₂OH)C<), 65.64 (d, J= 9.1 Hz, -CH₂OH), 77.73 (d, J= 226.8 Hz, FHC), 127.38 (s, aromatic), 128.85 (s, aromatic), 129.02 (d, J= 1.2 Hz, aromatic), 140.19 (s, aromatic).

The cώ-isomer 21b was synthesized from cis-(2- uoro-l- phenylcyclopropyl)-methanol (20b) from above by the same method as described for the tr rø-isomer 21a (Example 9). To complete the reaction, the addition of trimethylamine (100 μL, 1.3 mmol) and methane sulfonyl chloride (250 μL, 1.8 mmol) was repeated three times at hourly intervals. Purification was carried out by silica gel chromatography (ethyl acetate/n-hexane = 1/5 (v/v). (Yield: 0.27 g, 92%). Data for 21b: 1H-NMR (CDCI₃) δ 1.36 (IH, dddd, J= 11.4 Hz, J= 7.8 Hz, J= 6.0 Hz, J= 0.9 Hz, CH_AH_B), 1-49 (IH, ddd, J= 23.1 Hz, J= 7.8 Hz, J= 3.0 Hz, CH_AH_B), 2.78 (3H, s, -OSOOCH_.3), 4.48 (IH, ddd, J= 11.1 Hz, J= 1.8 Hz, J= 0.9 Hz, -CHH-OMs), 4.63 (IH, dd, J= 11.1 Hz, J= 1.8 Hz, -CHH-OMs), 4.88 (IH, ddd, J= 63.9 Hz, J= 6.0 Hz, J= 3.0 Hz, CFH), 7.28-7.35 (5H, m, aromatic); ¹³C- NMR (CDCI₃) δ 18.51 (d, J= 10.8 Hz, CH_AH_B), 29.94 (d, J= 9.7 Hz, Ph(CH₂OMs)C<), 37.44 (s, -OSOOCH3), 72.91 (d, J= 9.7 Hz, -CH₂-OMs), 77.11 (d, J= 229.6 Hz, FHC), 128.06 (s, aromatic), 129.07 (s, aromatic), 129.14 (d, J= 28.6 Hz, aromatic), 138.54 (s, aromatic).

The cώ-isomer 3b of (2-fluoro-l-phenylcyclopropyl)-methylamine was synthesized from mesylate 21b of the corresponding alcohol by the same method as described for the tr ws-isomer (Example 9). The reaction was carried out for 5 days. (Yield: 47.1 mg, 31%). Data for 3b: 1H-NMR (CDC1₃) δ 1.13 (IH, ddd, J= 10.5 Hz, J= 6.9 Hz, J= 6.3 Hz, CHAH_B), 1.22 (IH, ddd, j = 22.5 Hz, J= 6.9 Hz, J= 2.7 Hz, CH_AH_B), 1.48 (2H, broad s, -NH_), 3.06 (IH, broad,d, 13.8 Hz, -CHH-NH₂), 3.13 (IH, broad d, 14.01 Hz, -CHH-NH₂), 4.80 (IH, ddd, J= 65.1 Hz, J= 6.3 Hz, J = 2.7 Hz, FHC), 7.22-7.37 (5H, m, aromatic); ¹³C-NMR (CDC1₃) δ 17.98 (d, J= 10.3 Hz, CH_AH_B), 34.12 (d, J= 6.3 Hz, Ph(CH₂NH₂)C<), 46.40 (d, J= 8.1 Hz, - CH2-NH2), 77.80 (d, J= 225.6 Hz, FHC), 127.32 (s, aromatic), 128.92 (s, aromatic), 129.28 (d, J= 1.74 Hz, aromatic), 140.75 (s, aromatic); Anal. Calcd. for C₁₀H₁₂FN, C(72.70) H (7.32) F (11.50) N (8.48), Found C (69.77) H (7.29) N (7.70); HRMS (FAB⁺) Calcd for C₁₀H₁₃NF (M⁺H⁺) m/z = 166.1032, Found 166.1023.

Example 11: Preparation and characterization of traw_^,-2-Fluoro-l- phenylcyclopropane carboxyhydrazide (4) A mixture of trans and cis isomers (19a and 19b) (0.3 g, 1.44 mmol) was added to an ethanol solution (3.9 mL) containing 3.6 mL (74.2 mmol) of hydrazine monohydrate. After the reaction mixture was stirred overnight, the solvent was removed in vacuo. The trarø-isomer 4 was obtained by crystallization from ethanol. (Yield 0.13 g, 45%). Data for 4: 1H-NMR (CD₃OD) δ 1.61 (IH, ddd, J= 22.2 Hz, J = 6.6 Hz, J= 3.6 Hz, CH_AH_B), 1.78 (IH, ddd, J= 13.5 Hz, J= 6.6 Hz, J= 6.3 Hz, CH_AH_B), 5.06 (IH, ddd, J= 65.7 Hz, J= 6.3 Hz, J= 3.6 Hz, FHΔ), 7.34-7.43 (5H, m, aromatic); ¹³C-NMR (d6-DMSO) δ 18.54 (d, J= 8.6 Hz, CH_AH_B), 33.72 (d, J= 10.9 Hz, Ph(CONHNH₂)C<), 74.47 (d, J= 227.4 Hz, FHC), 127.79 (s, aromatic),

128.48 (s, aromatic), 131.23 (s, aromatic), 133.46 (d, j = 3.5 Hz, aromatic), 169.25 (s, >CO); Anal. Calcd. for C₁₀H„FN₂O C (61.85) H (5.71) F (9:78) N (14.42) O (8.24), Found C (61.57) H (5.74) N (14.53) O (8.28); HRMS (FAB⁺) Calcd for C₁₀H₁₂ON₂F (M⁺H⁺) m z = 195.0934, Found 195.0925.

Example 12: Preparation and characterization of trαH_^,-2-Fluoro-l- phenylcyclopropyl-amine hydrochloride (5) Hydrazide (4) (0.1 g, 0.52 mmol) (as made above) and water in a 50 mL round bottom flask were cooled in an ice bath and stirred while 6N HCI (1.18 mL) was added. A layer of ether (1.0 mL) was added. After a few minutes, a solution of 0.8 rnM NaNO₂ (0.93 L) was slowly added dropwise. The reaction mixture was stirred for an additional 40 minutes at the same temperature. The mixture was then extracted five times with ether, the ether solution was washed with brine, dried over MgSO₄ and evaporated in vacuo. tert-Butanol (10 ml) was added to the residue, and the solution was refiuxed overnight. The reaction mixture was evaporated to give crude carbamate that was placed on a column of silica gel and eluted with ethyl acetate and π-hexane (1:5). Purified carbamate was dissolved in 0.5 mL of ethyl acetate and 3N HCI (0.5 mL) was added. The mixture was vigorously stirred overnight at room temperature. Solvents were removed in vacuo to give 5 as a white powder (147-150°C) (Yield 67.3 mg, 52%). Data for 5: 1H-NMR (D₂O) δl.81 (IH, ddd, J= 12.6 Hz, J= 9.6 Hz, J= 7.2 Hz, CH_AH_B), 1.97 (IH, ddd, J= 23.1 Hz, J= 9.6 Hz, J= 3.6 Hz, CH_AHB), 5.26 (IH, ddd, J= 62.1 Hz, J= 7.2 Hz, J= 3.6 Hz, FHC), 7.53-7.67 (5H, m, aromatic); ¹³C-NMR (D₂O) δ 16.84 (d, J= 10.9 Hz, CHAH_B), 39.26 (d, J= 12.6 Hz, Ph(NH₂)C<), 72.21 (d, J= 228.5 Hz, HFC), 129.60 (s, aromatic), 130.45 (s, aromatic), 130.55 (s, aromatic), 130.97 (d, J= 1.9 Hz, aromatic); Anal. Calcd. for C₉HπClFN C (57.61) H (5.91) Cl (18.89) F (10.12) N (7.46), Found C (54.62) H (6.15) Cl (18.18) N (7.12); HRMS (FAB⁺) Calcd for C₉H_nNF (M⁺H⁺) m/z = 152.0876, Found 152.0869.

The following general procedure for hydrolysis with KOH was used in some of the following examples. A solution of the corresponding cyclopropanecarboxylic ethyl ester (4 mmol) in methanol (5 ml) was added to KOH (2.24 g, 40 mmol) in methanol (15 ml) at 0 °C. The reaction mixture was warmed to room temperature and stirred over night. The mixture was poured into water and extracted with CH₂CI₂ (100 ml). The aqueous phase was acidified with cone. HCI to pH 1 and extracted with CH₂Ci₂ (200 ml). The organic phases were dried (Na₂SO₄) and all volatiles removed under vacuum. The acids were isolated as white powders and further ' purified by recrystallization.

The following general procedure was used for Curtius degradation of 2-Fluoro-

2-phenylcyclopropane-carboxylic acids in some of the following examples. Under argon the corresponding 2-Fluoro-2-phenylcyclopropanecarboxylic acid

(1.25 mmol), anh. NEt₃ (152 mg, 1.5 mmol), anh. ''BuOH (927 mg, 12.5 mmol) and diphenylphosphorylazide (DPP A) (378 mg, 1.38 mmol) were dissolved in anh. cyclohexane (15 ml). The reaction mixture was refiuxed for 15-18 h. Di-tert- butyl carbonate (B0C2O) (410 mg, 1.9 mmol) was added and the resulting solution refiuxed for 2 h. The mixture was cooled to room temperature and ethyl acetate (40 ml) added. The organic phase was washed with 5% citric acid, H O, sat. NaHCO3 and brine (20 ml). Unreacted B0C₂O was removed by bulb-to-bulb destination. After silica gel chromatography the corresponding amines were isolated.

The following general procedure for deprotection with THF/HCl was used in some of the following examples. The corresponding Boc protected amine (1 mmol) was dissolved in a mixture of THF (10 ml) and 6 M HCI (10 ml). The reaction mixture was stirrd for 12 h at room temperature. All volatiles were removed under vacuum.. The obtained white residue was dried for 24 h over P O₅ under vacuum. The product was further purifed by recrystallization from Methanol/Et₂O.

The following general procedure for deprotection with HCI in methanol was used in some of the following examples. The corresponding Boc protected amine (1 mmol) was dissolved in methanolic HCI (20 ml) and stirred for 2-3 h at room temperature. All volatiles were removed under vacuum. The obtained white residue was washed with Et₂O (40 ml). The product was further purifed by recrystallization from Methanol/Et₂O.

Example 13: Preparation and characterization of czs-(+)-2-Fluoro-2-(4- fluorophenvDcyclopropylamine Hydrochloride (13a)

Analogous to the general procedure for hydrolysis with KOH, cis-MN4 was synthesized using cis-MN2 (204 mg, 0.90 mmol) (cis- 2-Fluoro-2-(4-fluoro-phenyl)- cyclopropanecarboxylic acid ethyl ester - prepared as is example 18 for the preparation of TR110, with the exception that/>-fluorinated 4-methylstyrene is utilized). After recrystallization from CH₂Cl₂/pentane at -20 °C cz_--MN4 was isolated as colorless, crystalline solid. (Yield: 167 mg, 93 %) Data for cis-MN4: Mp

98 °C (CH₂Cl₂/pentane); 1H NMR (CDCI3) δ 1.77- 1.93 (2 H, ITI CH_AH_B), 2.48

(1 H, ddd, J= 7.5 Hz, J= 10.0 Hz, J= 17.4 Hz, CHx), 6.90-7.50 (4 H, m, aromatic),

11.06 (si H„ COOH); ¹³C NMR (CDCI3) δ 17.4 (dt, J= 10.2 Hz, CH_AH_B), 27.5 (dd,

J= 17.8 Hz, CHx), 82.9 (ds, J= 222.6 Hz, CF), 115.4 (dd, J= 21.7 Hz, aromatic),

128.5 (dds, J= 3.2 Hz, J= 20.8 Hz, aromatic), 130.5 (ddd, J= 3.2 Hz, J= 8.2 Hz, aromatic), 163.3 (dds, J= 3.2 Hz, J= 248.6 Hz, aromatic), 175.2,(s, C=O); ¹⁹F NMR

(CDCI3) δ -111.93 (1 F, m, aromatic), -151.26 (1 F, m, aliphatic); MS as trimethylsilylester m/z (%) 270 (7), 255 (14), 225 (5), 215 (21), 180 (51), 152 (16), 133 (42), 123 (41), 115 (6), 107 (2), 77 (21), 73 (100), 47 (3), 45.(8); Anal. (C₁₂H₁₃FO₂). The structure of cz^'_^,-MN4 was confirmed by X-ray structural analysis.

Analogous to the general procedure for Curtius degradation, cw-TR104 was synthesized using cis-MN4 (284 mg, 1.43 mmol). After silica gel chromatography (cyclohexane/ethyl acetate 4:1) cz,_-TR104 was isolated. For elemental analysis the product was recrystallized from ethyl acetate/pentane at -20 °C. (Yield: 307 mg, 80 %) Data for cz_-TR104: Mp 131 °C (ethyl acetate / pentane); 1H NMR (CDC1₃) δ 1.25-1.39 (1 H, m, CHAH_B), 1.32 (9 H, s, CH₃), 1.75 (1 H, ddd,J= 8.2 Hz, J= 9.7 Hz, J= 21.5 Hz, CH_AH_B), 3.25-3.30 (1 H, m, CHx), 4.38 (1 H, br s, NH), 7.03- 7.09 (2 H, m, aromatic), 7.35-7.45 (2 H, m, aromatic); ¹³C NMR (CDC1₃) δ 17.8- 18.2 (mt, CH_AH_B), 28.1 (q, CH₃), 33.8-34.1 (md, CHx), 79.9 (s, O-C), 80.8 (ds, J= 217.4 Hz, CF), 115.2 (dd, J= 21.6 Hz, aromatic), 129.0-129.8 (m, aromatic), 155.7 (s, CO), 162.8 (ds, J= 246.7 Hz, aromatic); ¹⁹F NMR (CDCI₃) δ -113.59 (1 F, br s, aromatic), -167.58 (1 F, br s, aliphatic); MS m/z (%) 213 (2), 195 (3), 168 (8), 166 (14), 153 (8), 148 (100), 140 (21), 133 (7), 121 (28), 101 ,(22), 96 (7), 95 (4), 75 (7), 59 (4), 57 (20), 51 (1), 41 (9); IR (KBr) v 3383 (s), 3010 (w), 2993 (w), 2972 (w), 2939 (w), 1682 (s), 1611 (w), 1602 (w), 1520 (s), 1445 (w), 1395 (w), 1387 (w), 1370 (m), 1350 (w), 1280 (m), 1259 (w), 1228 (m), 1203 (w), 1165 (m), 1093 (w), 1062 (m), 1022 (w), 1013 (w), 988 (w), 946 (w), 917 (w), 883 (w), 869 (w), 825 (m), 814 (w), 784 (w), 760 (w), 752 (w), 633 (w); Anal. (C₁₄H₁₇F₂NO₂).

Analogous to the general procedure for deprotection with THF/HC1, compound 13a was synthesized using cz^'_^,-TR104 (148 mg, 0.55 mmol). After recrystallization from methanol/Et₂O of 13a was isolated as white solid. (Yield: 104 mg, 93 %) Data for 13a: Dec 155 °C (Et₂O/methanol); 1H NMR (Methanol-d₄) δ 1.78 (1 H, ddd,J= 6.0 Hz, J= 9.5 Hz, J= 10.0 Hz, CH_AH_B), 1.95 (1 H, ddd,J= 9.5 Hz, J= 10.0 Hz, J= 20.0 Hz, CH_AH_B), 3.40 (1 H, ddd,J= 6.0 Hz, J= 10.0 Hz, J = 13.9 Hz, CHx), 4.78 (3 H, s, NH₃ ⁺), 7.23-7.29 (2 H, m, aromatic), 7.67-7.72 (2 H, m, aromatic); ¹³C NMR (Methanol-d₄) δ 16.4 (dt, J= 14.0 Hz, CH_AH_B), 32.9 (dd, J= 21.6 Hz, CHx), 80.0 (ds, J= 220.0 Hz, CF), 117.5 (dd, J= 22.9 Hz, aromatic), 128.3 (dds, J= 3.8 Hz, J= 20.3 Hz, aromatic), 133.6 (ddd, J= 2.5 Hz, J= 8.9 Hz, aromatic), 162.8 (dds, J_C)F= 3.8 Hz, J= 249.2 Hz, aromatic); ¹⁹F NMR (Methanol- d₄) δ -110.47 (1 F, dm, J= 3.8 Hz, aromatic), -158.47 (1 F, dm, J= 3.8 Hz, aliphatic); MS (ESI) m/z (%)170 (20), 153 (100), 150 (10), 133 (38), 127 (5), 123 (22), 30 (38); IR (KBr) v 3553 (m), 3484 (s), 3414 (s), 2934 (br), 1636 (m), 1608 (s), 1564 (m), 1520 (s), 1489 (m), 1459 (m), 1412 (w), 1397 (w),-1314 (m), 1242 (s), 1191 (w), 1158 (w), 1096 (w), 1071 (m), 1048 (w), 1014 (m), 960 (w), 915 (m), 880 (m), 846 (s), 823 (m), 792 (w), 726 (w), 655 (w). Anal. (C₉H₁₀C1F₂N).

Example 14: Preparation and characterization of tr /?_'-(+)-2-Fluoro-2-(4- fluorophenypcyclopropylamine Hydrochloride (13b),

Analogous to the general procedure for hydrolysis with KOH, tr «_--TR102 was synthesized using trans-MN2 (226 mg, 1.00 mmol) (tr «_'-2-Fluoro-2-(4- fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester- prepared as is example 18 for the preparation of TR110, with the exception that 7-fluorinated 4-methylstyrene is utilized). After recrystallization from C^CVpentane at -20 °C trans-TR102 was isolated as colorless, crystalline solid. (Yield: 190 mg, 95 %) Data for tr< s-TR102: Mp 114 °C (CH₂Cl₂/pentane); 1H NMR (CDC1₃) δ 1.67 (1 H, ddd, J= 7.2 Hz, J= 9.3 Hz, J= 10.6 Hz, CHx), 2.16 (1 H, ddd, J= 7.6 Hz, J= 9.3 Hz, J- 11.8 Hz, CH_AH_B), 2.30 (1 H, ddd, J= 7.2 Hz, J= 1.6 Hz, J= 19.9 Hz, CH_AH_B), 7.04-7.36 (4 H, m, aromatic), 11.30 (1 H, br, COOH); ¹³C NMR (CDCI3) δ 19.1 (dt, J= 12.7 Hz, CH_AH_B), 28.3 (dd, J= 11.4 Hz, CH_X), 81.2 (ds, J= 228.9 Hz, CF), 115.7 (dd, J = 21.7 Hz, aromatic), 127.3 (ddd, J= 5.7 Hz, J= 8.3 Hz, aromatic), 132.7 (dds, J= 3.8 Hz, J= 21.6 Hz, aromatic), 162.9 (dds, J= 249.2 Hz, aromatic), 174.2 (s, CO); ¹⁹F NMR (CDCI₃) δ -113.12 (1 F, m, aromatic), -183.47 (1 F, m, aliphatic); MS as trimethylsilylester m/z (%) 270 (6), 255 (23), 225 (6), 215 (35), 180 (51), 151 (17), 133 (57), 123 (36), 115 (7), 107 (2), 77 (26), 73 (100), 47 (2), 45^l(7); Anal. (C₁₂H₁₃FO₂). The structure of trans -ΥR102 was confirmed by X-ray structural analysis.

Analogous to the general procedure for Curtius degradation, trans-TR105 was synthesized using trαz„_-TR102 (191 mg, 0.96 mmol). After silica gel chromatography (cyclohexane/ethyl acetate 10:1) trαzw-TR105 was isolated. (Yield: 172 mg, 66 %) For elemental analysis the product was recrystallized from ethyl acetate/pentane at -20 °C. Data for trara._-TR105: Mp 126 °C (ethyl acetate/pentane); ^!H NMR (CDC1₃) δ 1.39 (1 H, ddd, J= 6.0 Hz, J= 8.1 Hz, J= 21.7 Hz, CH_AH_B), 1.47 (9 H, s, CH₃), 1.46-1.56 (1 H, m, CH_AH_B), 2.93 (br s, 1 H, CHx), 4.98 (1 H, br s, NH), 7.02-7.08 (2 H, m, aromatic), 7.32-7.39 (2 H, m, aromatic); ¹³C NMR (CDC1₃) δ 19.4 (dt, J= 11.4 Hz, CH_AH_B), 28.3 (q, CH₃), 33.5 (dm, J= 10.2 Hz, CHx), 78.7 (ds, J= 218.7 Hz, CF), 79.9 (s, C-O), 115.4 (dd, J= 21.6 Hz, aromatic), 127.7-128.4 (md, aromatic), 133.1 (dds, J= 4.4 Hz, J= 22.3 Hz, aromatic), 156.3 (s, CO), 162.6 (ds, J= 246.7 Hz, C-7 aromatic); ¹⁹F NMR (CDCI₃) δ -113.91 (1 F, s, aromatic), -187.20 (1 F, s, aliphatic); MS m/z (%) 213 (4), 195 (5), 193 (3), 168 (23), 166 (38), 153 (11), 148 (100), 140 (40), 133 (17), 121 (70), 101 (66), 96 (21), 95 (17), 75 (19), 59 (7), 57 (38), 51 (5), 41 (21); IR (KBr) v 3370 (s), 3093 (w), 3051 (w), 3014 (w), 2988 (m), 2941 (w), 1685 (s), 1610 (w), 1518 (s), 1445 (w), 1395 (w), 1386 (s), 1375 (m), 1301 (w), 1278 (m), 1251 (m), 1231 (m), 1210 (m), 1162 (s), 1119 (w), 1104 (w), 1076 (w), 1062 (w), 1030 (w), 1001 (w), 894 (w), 883 (w), 870 (w), 823 (s), 809 (m), 783 (w), 756 (w), 675 (w), 600 (w); Anal. (Cι₄Hι₇F₂NO₂).

Analogous to the general procedure for deprotection with THF/HCl, 13b was synthesized using trans-TRlQ5 (107 mg, 0.40 mmol). After recrystallization from methanol/Et_O 13b was isolated as white solid. (Yield: 68 mg, 83 %) Data for 13b: Dec > 160 °C (Et₂O/methanol); 1H NMR (Methanol-d₄, 400 MHz) δ 1.79-1.86 (2 H, m, CH_AH_B), 3.05-3.09 (1 H, m, CHx), 4.84 (3 H, s, NH ), 7.16-7.20 (2 H, m, aromatic), 7.50-7.53 (2 H, m, aromatic); ¹³C NMR (Methanol-d₄, 100.63 MHz) δ 17.8 (dt, J= 12.4 Hz, CH_AH_B), 32.5 (dd, J= 10.4 Hz, CH_X), 79.1 (ds, J= 219.2 Hz, CF), 117.0 (dd, J= 22.1 Hz, aromatic), 130.0 (ddd, J= 5.0 Hz, J= 8.6 Hz, aromatic), 132.7 (dds, ⁴J_C,_F= 3.2 Hz, J= 21.3 Hz, aromatic), 164.9 (dds, ⁵J_C,F= 2.2 Hz, J= 247.5 Hz, aromatic); ¹⁹F NMR (Methanol-d₄) δ -112.57 (1 F, m, aromatic), -184.81 (1 F, m, aliphatic); MS (ESI) m/z (%) 170 (100), 153 (4), 150 (42); IR (KBr) v 3550 (m), 3476 (m), 3375 (s), 3100 (w), 3016 (w), 2997 (w), 2972 (w), 2938 (w), 2924 (w), 1691 (s), 1515 (s), 1457 (w), 1445 (w), 1393 (w), 1369 (m), 1348 (w), 1281 (m), 1259 (w), 1227 (w), 1195 (w), 1166 (m), 1096 (w), 1064 (m), 1022 (w), 989 (w), 920 (w), 886 (w), 813 (m), 785 (w), 759 (w), 751 (w), 620 ( ), 585 (m); Anal. (C₉H₁₀C1F₂N).

Example 15: Preparation and characterization of ct,_-(±)-2-Fluoro-2-(4- chlorophenyl) cyclopropylamine Hydrochloride (14a)

Analogous to the general procedure for hydrolysis with KOH, czs-MNδ was synthesized using cz^'_"-MN9 (231 mg, 0.95 mmol) (cis- 2-(4-Chloro-phenyl)-2- fluoro-cyclopropanecarboxylic acid- prepared as is example 18 for the preparation of TR110, with the exception that '-chlorinated 4-methylstyrene is utilized). After recrystallization from CH2Cl₂/pentane cw-MN8 was isolated as colorless, crystalline solid. (Yield: 188 mg, 92 %) Data for cw-MN8: Mp 103 °C (CH₂Cl₂/pentane); 1H NMR (CDC1₃, 400 MHz) δ 1.83 - 2.04 (2 H, m, CH_AH_B), 2.52 (ddd, J= 7.6 Hz, J= 10.1 Hz, J= 17.6 Hz, 1 H, CHx), 7.32 - 7.39 (4 H, m, aromatic); ¹³C NMR (CDC1₃, 100 MHz) δ 17.3 (dt, J= 10.4 Hz, CH_AH_B), 27.6 (dd, J= 17.3 Hz, CHx), 82.8 (ds, J = 222.0 Hz, CF), 128.6 (d, aromatic), 129.7 (dd, J= 4.4 Hz, aromatic), 131.1 (ds, J= 20.5 Hz, aromatic), 135.4 (ds, ⁵J_C,F = 3.2 Hz, aromatic), 174.1 (s„CO); ¹⁹F NMR (CDCI₃, 188.30 MHz) δ -153.56 (m); MS as trimethylsilylester m/z (%) 288/286 (7/15), 273/271 (20/53), 251 (2), 235 (27), 233/231 (22/60), 207 (14), 198/196 (22/69), 171/169 (1/3), 161 (52), 151/149 (12/37), 141/139 (14/57), 133 (56), 115 (24), 107 (6), 101 (3), 77 (26), 73 (100), 63 (2), 45 (8); IR (KBr) v 3112 (w), 3064 (w), 2922 (w), 2762 (w), 2663 (w), 2572 (w), 1700 (s), 1603 (w), 1500 (m), 1456 (m), 1427 (m), 1385 (w), 1359 (w), 1336 (m), 1254 (s), 1185 (s), 1097 (s), 1017 (m), 966 (w), 888 (s), 834 (s), 765 (w), 734 (w), 660 (m), 572 (w), 528 (m); Anal. (C₁₀H₈C1FO₂). The structure of czj-MNδ was confirmed by X-ray structural analysis.

Analogous to the general procedure for Curtius degradation, cz^'s-TRlOO was synthesized using cz_*-MN8 (346 mg, 1.61 mmol). After silica gel chromatography (cyclohexane/ethyl acetate 10:1) cw-TRlOO was isolated as a white, voluminous solid. (Yield: 250 mg, 55 %) For elemental analysis the product was recrystallized from ethyl acetate/pentane at -20 °C. Data for cw-TRlOO: Mp 147 °C (ethyl acetate/pentane); 1H NMR (CDCI₃) δ 1.25-1.46 (1 H, m, CH_AH_B), 1.31 (9 H, s, CH₃), 1.77 (1 H, ddd,J= 8.2 Hz, J= 9.6 Hz, J= 21.5 Hz, CH_AH_B), 3.22-3.30 (1 H, m, CHx), 4.39 (1 H, br s, NH), 7.30-7.45 (4 H, m, aromatic); ¹³C NMR (CDC1₃) δ 18.3 (br m, CH_AH_B), 28.0 (q, CH₃), 34.4 (br s, CHx), 80.1 (s, C-O), 80.7 (ds, J= 216.4 Hz, CF), 128.4 (d, aromatic), 132.5 (ds, J= 20.3, aromatic), 134.3 (ds, J= 6.4 Hz, aromatic), 155.6 (s, CO); ¹⁹F NMR (CDCI₃) δ -170.45 (m); MS m/z (%)231/229 (3/1), 213/211 (2/1), 185 (14), 176 (14), 165 (8), 163 (29), 154 (7), 137 (5), 133 (12), 130 (7), 121 (6), 101 (6), 77 (1), 59 (17), 57 (100), 51 (2), 41 (18); IR (KBr) v 3378 (s), 3013 (w), 2988 (w), 2974 (w), 2940 (w), 1675 (s), 1516 (s), 1498 (s), 1444 (w), 1386 (m), 1371 (m), 1345 (w), 1277 (m), 1256 (w), 1231 (w), 1202 (w), 1164 (w), 1097 (m), 1060 (m), 1012 (m), 987 (w), 918 (w), 883 (w), 866 (w), 819 (m), 785 (w), 758 (w), 735 (w), 717 (w), 602 (w); Anal. (Cι₄H₁₇ClFNO₂).

Analogous to the general procedure for deprotection with HCI in methanol, cis-TRlll was synthesized using cώ-TRlOO (98 mg, 0.343 mmol). After recrystallization from methanol/Et₂O (1:3) cis-TRlll wAS isolated as white solid. (Yield: 61 mg, 80 %) Data for cis-TR117: Dec > 145 °C (Methanol/Et₂O); 1H NMR (Methanol-d₄) δ 1.80 (1 H, ddd, J= 6.2 Hz, J= 6.2 Hz, J= 9.3 Hz, CH_AH_B), 1.96 (1 H, ddm,J= 6.2 Hz, J= 19.8 Hz, CH_AH_B), 3.41 (1 H, ddd, J= 6.2 Hz, J= 10.1 Hz, J= 14.0 Hz, CHx), 4.77 (3 H, s, NH ), 7.52-7.65 (4 H, m, aromatic); ¹³C NMR (Methanol-d₄) δ 16.0 (dt, J= 12.7 Hz, CH_AH_B), 32.7 (dd, J= 22.9 Hz, CH_X), 79.6 (ds, J= 221.3 Hz, CF), 130.5 (d, aromatic), 132.2 (ds, J= 5.1, aromatic), 137.7 (s, aromatic); ¹⁹F NMR (Methanol-α ) δ -160.33 (m); MS (ESI) m/z (%) 188/186 (100/32), 102 (57); IR (KBr) v 3418 (br), 2925 (s), 2858 (s), 1748 (w), 1645 (m), 1466 (w), 1458 (w), 1386 (m), 1263 (w), 1127 (m), 837 (w); Anal. (C₉Hι₀Cl₂FN).

Example 16: Preparation and characterization of trαπ,_-(+)-2-Fluoro-2-(4- chlorophenvDcyclopropylamme Hydrochloride (14b) Analogous to the general procedure for Curtius degradation, trans-TRlll was synthesized using trα«_--MN9 (190 mg, 0.89 mmol) (trαn5-2-(4-Chloro-phenyl)- 2-fluoro-cyclopropanecarboxylic acid- prepared as is example 18 for the preparation of TR110, with

4-methylstyrene is utilized). After silica gel chromatography (cyclohexane/ethyl acetate 10:1) trans-TRlll was isolated as a white, voluminous solid. (Yield: 146 mg, 58 %) For elemental analysis the product was recrystallized from ethyl acetate/pentane at -20 °C. Data for trans- TRlll: Mp 141 °C (ethyl acetate/pentane); 1H NMR (CDC1₃) δ 1.35-1.53 (2 H, m, CH_AH_B), 1.47 (9 H, s, CH₃), 2.94 (1 H, br s, CH*), 4.92 (1 H, br s, NH), 7.25-7.36 (4 H, m, aromatic); ¹³C NMR (CDC1₃) δ 19.9 (dt, J- 14.4 Hz, CH_AH_B), 28.3 (q, CH₃), 34.0 (dd, J= 9.2 Hz, CH_X), 78.5 (ds, J= 218.3 Hz, CF), 80.0 (s, C-O), 126.6 (d, aromatic), 128.7 (d, aromatic), 134.0 (s, aromatic), 136.1 (ds, J= 19.2, aromatic), 156.2 (s, CO); ¹⁹F NMR (CDC1₃) δ -190.68 (br s); MS m/z (%) 231/229 (3/1), 213/211 (2/1), 185 (16), 176 (6), 165 (11), 163 (32), 156 (5), 137 (5), 133 (7), 130 (8), 121 (4), 101 (6), 94 (2), 77 (3), 59 (17), 57 (100), 51 (2), 41 (17); IR (KBr) v 3342 (s), 3009 (w), 2986 (w), 2933 (w), 1683 (s), 1525 (s), 1498 (m), 1441 (w), 1386 (m), 1371 (m), 1310 (w), 1290 (m), 1252 (m), 1211 (w), 1171 (m), 1115 (w), 1095 (w), 1074 (w), 1032 (w), 1013 (w), 998 (w), 897 (w), 872 (w), 836 (w), 813 (m), 783 (w), 756 (w), 736 (w), 654 (w), 619 (w); Anal. (C₁₄H₁₇ClFNO₂).

Analogous to the general procedure for deprotection wit THF/HCl, 14b was synthesized using trans-TRlll (113 mg, 0.395 mmol). 14b was isolated as white solid. (Yield: 61 mg, 80 %) Data for 14b: Dec > 166 °C; 1H NMR (Methanol-d₄) δ 0.64-0.73 (2 H, m, CH_AH_B), 1.90-1.95 (1 H, m, CHx), 3.17 (3 H, s, NH₃ ⁺), 6.25- 6.32 (4 H, m, aromatic); ¹³C NMR (Methanol-d₄) δ 17.9 (dt, J= 12.7 Hz, CH_AH_B), 32.5 (dd, J- 10.2 Hz, CHx), 78.7 (ds, J= 218.7 Hz, CF), 126.6 (dd, J= 5.1 Hz, aromatic), 130.0 (d, aromatic), 135.3 (ds, J= 21.6 Hz, aromatic), 136.1 (ds, J- 2.5 Hz, aromatic); ¹⁹F NMR (Methanol-α^) δ -188.35 (m); MS (ESI) m/z (%) 186 (30), 168 (13), 166 (100), 131 (39); IR (KBr) v 3553 (s), 3479 (s), 3418 (s), 2916 (br), 2923 (w), 2678 (w), 1639 (m), 1619 (m), 1522 (w), 1499 (w), 1450 (w), 1315 (w), 1287 (w), 1244 (w), 1104 (w), 1073 (w), 1016 (w), 1008 (w), 966 (w), 900 (w), 876 (w), 830 (m), 795 (w), 741 (w), 624 (m); Anal. (C₉H₁₀C1₂FN).

Example 17: Preparation and characterization of ct_^ι-(±)-2-Fluoro-2-(4- methylphenyDcyclopropylamine Hydrochloride (15a) To an ice cooled solution of 4-methylstyrene (9.45 g, 80.0 mmol) in anhydrous CH₂C1₂ (80 ml), Et₃N-3HF (40 ml, 244 mmol) and N-Bromosuccinimide j

(ΝBS) (17.0 g, 95.5 mmol) were added. After 30 min at 0 °C the reaction mixture was warmed to room temperature and stirred over night. The reaction mixture was poured into ice water (500 ml) and neutralized with ΝH₄OH. After separation of the phases the aqueous phase was extratced with CH₂C1 (600 ml). The combined organic layers were washed with 0.1 M HCI (600 ml), 5% NaHCO₃ and H₂O (200 ml). The phases were dried (MgSO₄) and all volatiles removed under reduced pressure. After silica gel chromatography (pentane) bromofluoride TR121 was obtained as a colorless oil which contained 4 % of the regioisomeric terminale bromofluoride (TR121b). (Yield: 14.95 g, 86 %) Data for TR121: 1H NMR (CDC1₃) δ 2.36 (3 H, s, CHs), 3.60 (1 H, ddd, J= 4.3 Hz, J=l 1.2 Hz, J= 26.7 Hz, CH_), 3.69 (1 H, ddd, J= 7.9 Hz, J= 11.2 Hz, J= 15.3 Hz, CH₂), 5.57 (1 H, ddd, J= 4.3 Hz, J= 7.9 Hz, J= 46.9 Hz, CH), 7.13-7.25 (4 H, m, aromatic); ¹³C NMR (CDCI₃) δ 21.6 (q, CH₃), 34.2 (dt, J= 29.3 Hz, CH₂), 92.8 (dd, J= 178.0 Hz, CHF), 125.7 (dd, J= 5.1 Hz, aromatic), 129.4 (d, aromatic), 134.2 (d, J= 20.3 Hz, aromatic), 139.2 (s, aromatic); ¹⁹F NMR (CDCI3, 282 MHz) δ -172.75 (ddd, J= 15.3 Hz, J= 26.7 Hz, J= 46.9 Hz); MS m/z (%) 218/216 (8/9), 198/196 (2/2), 137 (5), 123 (100), 118 (7), 117 (7), 115 (16), 103 (12), 91 (7), 77 (9), 65 (6), 63 (4), 58 (2), 51 (2), 39 (5). IR (NaCl) v 3029 ( ), 2966 (m), 2923 (m), 2863 (w), 1915 (w), 1615 (m), 1518 (s), 1453 (w), 1420 (s), 1381 (w), 1346 (m), 1290 (w), 1242 (w), 1219 (s), 1207 (s), 1184 (m), 1113 (w), 1065 (s), 4026 (w), 985 (s), 945 (w), 924 (w), 867 (m), 823 (s), 772 (m), 726 (m), 694 (w), 652 (s); Anal. (C₉H₁₀BrF). The chemical shifts in the 1H NMR spectra are in good agreement with those described in the literature

Data for TR121b: ¹⁹F NMR (CDC1₃) δ -177.28 (ddd, J= 13.4, J= 38.2, J= 47.7); MS m/z (%) 218/216 (15/16), 198/196 (1/1), 137 (7), 135 (6), 123 (100), 117 (16), 115 (17), 103 (10), 91 (16), 77 (17), 65 (16), 63 (8), 58 (5), 51 (10), 39 (17).

2-Bromo-l-fluoro-l-(4-methylphenyl)ethane (TR121) (14.22 g, 65.5 mmol) was dissolved in pentane (400 ml). Under ice cooling KO^tBu (14.7 g, 131 mmol) was added slowly. The reaction mixture was refiuxed for 1 h. After cooling to room temperature the mixture was poured into ice water (400 ml). After separation of the phases, the aqueous phase was extracted with pentane (300 ml). The combined organic layers were washed with 5% NaHCO₃ (300 ml), 0.05 M HCI (150 ml), and H₂O (300 ml). The organic phase was dried (MgSO ). All volatiles were removed under reduced pressure. After fractional destination pure regioisomer TR124 was isolated as a colorless liquid. (Yield: 7.55 g, 85 %) Data for TR124: Bp 68 °C / 11 mbar; 1H NMR (CDC1₃) δ 2.34 (3 H, s, CH₃), 4.76 (1 H, dd, J= 3.3 Hz,J= 17.9 Hz, CH_AH_B), 4.94 (dd, J= 3.3 Hz, J= 49.8 Hz, 1 H, CH_AH_B), 7.14 (2 H, dd, J= 8.0 Hz, J= 0.7 Hz, aromatic), 7.42 (2 H, d, J= 8.0 Hz, aromatic); ¹³C NMR (CDCI3) δ 21.2 (q, CH₃), 88.5 (dt, J= 22.9 Hz, CH_AH_B), 124.6 (dd, J= 6.4 Hz, aromatic), 129.1 (dd, aromatic), 129.3 (ds, J- 29.3 Hz, aromatic), 139.4 (s, aromatic), 163.2 (ds, J= 250.5 Hz, CF); ¹⁹F NMR (CDCI₃) δ -107.98 (dd, J= 17.2 Hz, J= 49.7 Hz); MS m/z (%) 137 (100), 136 (96), 122 (10), 116 (38), 110 (17), 102 (4), 92 (7), 89 (5), 84 (6), 65 (3), 63 (4), 57 (2), 51 (3); IR (NaCl) v 3298 (w), 3134 (w), 3095 (w), 3037 (m), 3014 (w), 2953 (w), 2924 (m), 2868 (w), 1909 (w), 1809 (m), 1653 (s), 1615 (m), 1573 (w), 1514 (s), 1453 (m), 1410 (m), 1374 (m), 1319 (s), 1301 (s), 1281 (s), 1186 (m), 1122 (w), 1095 (s), 1039 (w), 1019 (w), 927 (s), 840 (s), 822 (s), 792 (w), 744 (w), 726 (w), 704 (w), 692 (w), 643 (w), 607 (m), 572 (w), 535 (m); Anal. (C₉H₉F). The chemical shifts in the 1H NMR spectra and absorptions in the IR spectra are in good agreemnet with those described in reference.

Under dry conditions Cu(acac)₂ (84 mg, 0.98 mmol) was dissolved in anhydrous CH₂C1₂ (5 ml). After stirring for some minutes some drops of phenylhydrazine were added and the solution was further stirred. To this solution (1- fluorovinyl)-4-methylbenzene (TR124) (1.36 g, 10.0 mmol) was added. Under reflux a solution of ethyl diazoacetic acid (1.70 g) in anhydrous CH₂C1 (10 ml) was added via a syringe pump over 5 - 6 h. After addition of the CH₂C1₂, the reaction mixture was refiuxed for 4 h more. The reaction mixture was diluted with CH₂C1 (150 ml) and washed with saturated NaCO₃ and H₂O (300 ml). The organic phases were dried (MgSO₄) and all volatiles were removed under vacuum. A conversion of 75 % was detected by GC analysis. The cisltrans isomers formed in a 1:1 ratio. The diastereomers were separated by silica gel chromatography (pentane/Et O 40: 1). Besides the diastereopure esters a fraction containing both diastereomers (303 mg, 1.34 mmol, 14 %) was obtained. The esters were isolated as as colorless oils. Data for cw-TRllO: (Yield: 420 mg, 19 %) 1H NMR (CDC1₃) δ 1.03 (3 H, q, J= 7.2 Hz, CH₂CH₃), 1.77 (1 H, ddd, J= 7.2 Hz, J= 10.3 Hz, J= 19.1 Hz, CH_AH_B), 1.93 (1 H, ddd, J= 7.2 Hz, J= 7.4 Hz, J= 12.2 Hz, CH_AH_B), 2.34 (3 H, d, J= 1.9 Hz, C_ar- CH3), 2.53 (1 H, ddd, J= 7.4 Hz, J= 10.3 Hz, J= 17.9 Hz, CHx), 3.93 (t, J= 7.2 Hz, 2 H, CEbCH,), 7.14-7.17 (2 H, m, aromatic), 7.33-7.37 (2 H, m, aromatic); ¹³C NMR (CDCI₃) δ 13.9 (q, CH₂CH₃), 16.5 (dt, J= 10.2 Hz, CH_AH_B), 21.2 (q, C_ar- CH₃), 27.7 (dd, J= 16.5 Hz, CHx), 60.6 (t, CH₂CH₃), 83.0 (ds, J= 220.0 Hz, CF), 128.5 (dd, J= 2.5 Hz, aromatic), 128.9 (d, aromatic), 130.2 (ds, J= 20.3 Hz, aromatic), 139.2 (ds, J= 2.5 Hz, aromatic), 169.0 (s, CO); ¹⁹F NMR (CDCI₃) δ -152.52 (dm, J= 19.1 Hz); MS m/z (%) 222 (63), 207 (6), 193 (20), 177 (13), 174 (15), 172 (15), 166 (36), 164 (30), 149 (100), 147 (28), 139 (60), 133 (31), 129 (33), 119 (14), 115 (8), 109 (10), 101 (4), 9Ϊ (7), 77 (5), 65 (2), 55 (3), 39 (2); IR (NaCl) v 3104 (w), 3061 (w), 2984 (s), 2930 (m), 2877 (w), 1731 (s), 1617 (w), 1522 (m), 1466 (m), 1439 (s), 1397 (s), 1380 (s), 1362 (m), 1342 (s), 1267 (m), 1220 (s), 1163 (s), 1101 (m), 1076 (w), 1039 (m), 1001 (w), 961 (m), 887 (s), 866 (m), 823 (s), 800 (w), 760 (m), 721 (w); Anal. (C₁₃Hι₅FO₂). Analogous to the general procedure for hydrolysis with KOH, ct_"-TR113 was synthezised using cz^'s-TRHO (333 mg, 1.47 mmol). After recrystallization from CH₂Cl₂/pentane (1:10) cz,_-TR113 was isolated as white, amorphous solid. (Yield: 212 mg, 74 %) Data for ct_--TR113: Mp 86 °C (CH₂Cl₂/ρentane); 1H NMR (CDC1₃) δ 1.79 (1 H, ddd, J= 7.2 Hz, J= 10.0 Hz, J= 18.8 Hz, CH_AH_B), 1.87 (ddd, J= 7.2 Hz, J= 7.4 Hz, J= 12.9 Hz, 1 H, CH_AH_B), 2.34 (3 H, s, CH₃), 2.46 (1 H, ddd, J = 7.4 Hz, J= 10.0 Hz, J= 17.6 Hz, CHj ), 7.11-7.32 (4 H, m, aromatic), 11.04 (1 H, br, CO₂H); ¹³C NMR (CDCI₃) δ 17.3 (dt, J= 10.2 Hz, CH_AH_B), 21.2 (q, CH₃), 27.4 (dd, J- 17.8 Hz, CH_X), 83.5 (ds, J= 221.3 Hz, CF), 128.4 (dd, J- 3.8 Hz, aromatic), 129.0 (d, aromatic), 129.6 (ds, J= 19.1 Hz, aromatic), 139.4 (ds, J= 2.5 Hz, aromatic), 175.3 (s, CO); ¹⁹F NMR (CDCI₃) δ -150.34 (m); MS as trimethylsilylester m/z (%) 266 (13), 251 (16), 235 (1), 221 (6), 211 (19), 207 (5), 176 (47), 160 (2), 149 (4), 147 (7), 133 (16), 129 (31), 119 (33), 115 (7), 109 (2), 91 (3), 77 (12), 73 (100), 51 (1), 45 (10); IR (KBr) v 3108 (w), 3069 (w), 3044 (w), 3023 (w), 2957 (br), 2928 (br), 2857 (w), 1691 (s), 1617 (w), 1524 (w), 1452 (s), 1426 (m), 1364 (w), 1338 (m), 1247 (s), 1182 (s), 1119 (w), 1100 (w), 1082 (w), 1043 (w), 1023 (w), 1008 (w), 964 (w), 932 (m), 918 (m), 883 (s), 823 (s), 756 (w), 666 (m), 625 (w), 571 (w), 521 (w), 488 (w); Anal. (C_uHπFO₂.

Analogous to the general procedure for Curtius degradation, cz^'.y-TR115 was synthesized using cz,s-TR113 (310 mg, 1.60 mmol). After silica gel chromatography (cyclohexane/ethyl acetate 10:1) ct_--TR115 was isolated as a white, voluminous solid. (Yield: 327 mg, 77 %) of For elemental analysis the product was recrystallized from ethyl acetate/pentane at -20 °C. Data for cw-TR115: Mp 125 °C (ethyl acetate/pentane); 1H NMR (CDCI3) δ 1.34 (10 H, s, CH_AH_B and C-(CH_.3)₃), 1-74 (1 H, ddd, J= 8.6 Hz, J= 9.1 Hz, J= 21.5 Hz, CH_AH_B), 2.37 (3 H, s, CHs), 3.20-3.36 (1 H, m, CHx), 4.18 (1 H, br s, NH), 7.18-7.32 (4 H, m, aromatic); ¹³C NMR (CDCI₃) δ 18.4 (dt, J= 11.9 Hz, CH_AH_B), 21.1 (q, C-(CH₃)₃), 28.1 (q, CH₃), 33.9 (dm, CH_X), 79.8 (s, C-O), 81.1 (ds, J= 216.1 Hz, CF), 127.3 (dm, aromatic), 129.1 (d, aromatic), 130.6 (ds, J= 22.0 Hz, aromatic), 138.5 (ds, J= 8.2 Hz, aromatic), 155.8 (s, CO); ¹⁹F NMR (CDC1₃) δ -167.63 (br s); MS m/z (%)^'209 (1), 191 (2), 189 (4), 176 (6), 172 (2), 164 (4), 162 (9), 148 (7), 144 (100), 135 (7), 133 (5), 130 (47), 117 (19), 115 (39), 109 (4), 103 (7), 91 (20), 89 (5), 77 (4), 65 (7), 59 (3), 57 (22), 44 (10), 41 (22); IR (KBr) v 3383 (s), 3091 (w), 3038 (w), 3013 (w), 2986 (m), 2933 (w), 2875 (w), 1687 (s), 1525 (s), 1513 (s), 1442 (w), 1395 (w), 1371 (m), 1348 (w), 1277 (m), 1255 (m), 1227 (w), 1178 (s), 1121 (w), 1097 (w), 1062 (m), 1020 (w), 983 (m), 918 (m), 883 (w), 866 (w), 813 (m), 784 (w), 760 (w), 751 (w); Anal. (C₁₅H₂₀FNO₂).

Analogous to the general procedure for deprotection with HCI in methanol, 15a was synthesized using cis-TR115 (286 mg, 1.08 mmol). 15a was isolated as white solid. (Yield: 193 mg, 89 %) Data for 15a: Dec >145 °C; 1H NMR (Methanol- d₄) δ 1.74 (1 H, ddd, J= 6.0 Hz, J= 9.8 Hz, J= 10.0 Hz, CH H_B), 1.90 (1 H, ddd,J = 9.8 Hz, J= 9.8 Hz, J= 19.6 Hz, CHAH_B), 2.39 (3 H, s, CH₃), 3.36 (1 H, ddd, J= 6.0 Hz, J= 9.8 Hz, J= 13.8 Hz, CHx), 4.78 (3 H, s, NH₃ ⁺), 7.34 (2 H, d, J= 7.9 Hz, aromatic), 7.52 (2 H, d, J- 7.9 Hz, aromatic); ¹³C NMR (Methanol-d₄) δ 15.9 (dt, J = 14.0 Hz, CH_AH_B), 21.4 (q, CH₃), 32.5 (dd, J= 21.6 Hz, CH_X), 80.0 (ds, J= 220.0 Hz, CF), 130.6 (ds, J= 20.3 Hz, aromatic), 130.6 (dd, J= 3.8 Hz, aromatic), 130.9 (d, aromatic), 142.1 (ds, ⁵Jc,F = 2.5 Hz, aromatic); ¹⁹F NMR (Methanol-d₄) δ -158.48 (m); MS (ESI) m/z (%) 167 (11), 166 (100), 102 (5); IR (KBr) v 3061 (m), 2875 (br s), 2775 (s),'2683 (m), 2647 (m), 2598 (m), 2007 (w), 1615 (w), 1592 (w), 1522 (w), 1499 (m), 1449 (w), 1386 (m), 1344 (m), 1204 ( ), 1181 (w), 1123 (m), 1112 (m), 1066 (w), 1037 (w), 1012 (w), 956 (w), 915 (m), 865 (w), 826 (s), 806 (w), 733 (w); Anal. (Cι₀Hι₃ClFN-l/3H₂O).

Example 18: Preparation and characterization of trαn.--(+)-2-Fluoro-2-(4- methylphenvDcyclopropylamine Hydrochloride (15b) To an ice cooled solution of 4-methylstyrene (9.45 g, 80.0 mmol) in anhydrous CH₂C1₂ (80 ml), Et₃N-3HF (40 ml, 244 mmol) and N-Bromosuccinimide (ΝBS) (17.0 g, 95.5 mmol) were added. After 30 min at 0 °C the reaction mixture was warmed to room temperature and stirred over night. The reaction mixture was poured into ice water (500 ml) and neutralized with ΝH₄OH. After separation of the phases the aqueous phase was extratced with CH₂C1₂ (600 ml). The combined organic layers were washed with 0.1 M HCI (600 ml), 5% NaHCO₃ and H₂O (200 ml). The phases were dried (MgSO₄) and all volatiles removed under reduced pressure. After silica gel chromatography (pentane) bromofluoride TR121 was obtained as a colorless oil which contained 4 % of the regioisomeric terminale bromofluoride (TR121b). (Yield: 14.95 g, 86 %) Data for TR121: 1H NMR (CDCI₃) δ 2.36 (3 H, s, CH₃), 3.60 (1 H, ddd, J= 4.3 Hz, J=l 1.2 Hz, J= 26.7 Hz, CH_). 3.69 (1 H, ddd, J= 7.9 Hz, J= 11.2 Hz, J= 15.3 Hz, CH₂), 5.57 (1 H, ddd, J= 4.3 Hz, J= 7.9 Hz, J= 46.9 Hz, CH), 7.13-7.25 (4 H, m, aromatic); ¹³C NMR (CDCI₃) δ 21.6 (q, CH₃), 34.2 (dt, J= 29.3 Hz, CH₂), 92.8 (dd, J= 178.0 Hz, CHF), 125.7 (dd, J= 5.1 Hz, aromatic), 129.4 (d, aromatic), 134.2 (d, J= 20.3 Hz, aromatic), 139.2 (s, aromatic); ¹⁹F NMR (CDC1₃, 282 MHz) δ -172.75 (ddd, J= 15.3 Hz, J= 26.7 Hz, J= 46.9 Hz); MS m/z (%) 218/216 (8/9), 198/196 (2/2), 137 (5), 123 (100), 118 (7), 117 (7), 115 (16), 103 (12), 91 (7), 77 (9), 65 (6), 63 (4), 58 (2), 51 (2), 39 (5). IR (NaCl) v 3029 (m), 2966 (m), 2923 (m), 2863 (w), 1915 (w), 1615 (m), 1518 (s), 1453 (w), 1420 (s), 1381 (w), 1346 (m), 1290 (w), 1242 (w), 1219 (s), 1207 (s), 1184 (m), 1113 (w), 1065 (s), 1026 (w), 985 (s), 945 (w), 924 (w), 867 (m), 823 (s), 772 (m), 726 (m), 694 (w), 652 (s); Anal. (C₉Hι₀BrF). The chemical shifts in the 1H NMR spectra are in good agreement with those described in the literature.

Data for TR121b: ¹⁹F NMR (CDCI₃) δ -177.28 (ddd, J= 13.4, J= 38.2, J= 47.7); MS m/z (%) 218/216 (15/16), 198/196 (1/1), 137 (7), 135 (6), 123 (100), 117 (16), 115 (17), 103 (10), 91 (16), 77 (17), 65 (16), 63 (8), 58 (5), 51 (10), 39 (17).

2-Bromo-l-fluoro-l-(4-methylphenyl)ethane (TR121) (14.22 g, 65.5 mmol) was dissolved in pentane (400 ml). Under ice cooling KO'Bu (14.7 g, 131 mmol) was added slowly. The reaction mixture was refiuxed for 1 h. After cooling to room temperature the mixture was poured into ice water (400 ml). After separation of the phases, the aqueous phase was extracted with pentane (300 ml). The combined organic layers were washed with 5% NaHCO₃ (300 ml), 0.05 M HCI (150 ml), and H₂O (300 ml). The organic phase was dried (MgSO₄). All volatiles were removed under reduced pressure. After fractional destination pure regioisomer TR124 was isolated as a colorless liquid. (Yield: 7.55 g, 85 %) Data for TR124: Bp 68 °C / 11 mbar; 1H NMR (CDC1₃) δ 2.34 (3 H, s, CH₃), 4.76 (1 H, dd, J= 3.3 Hz,J= 17.9 Hz, CH_AH_B), 4.94 (dd, J= 3.3 Hz, J= 49.8 Hz, 1 H, CH_AH_B), 7.14 (2 H, dd, J= 8.0 Hz, J= 0.7 Hz, aromatic), 7.42 (2 H, d, J= 8.0 Hz, aromatic); ¹³C NMR (CDC1₃) δ 21.2 (q, CH₃), 88.5 (dt, J= 22.9 Hz, CH_AH_B), 124.6 (dd, J= 6.4 Hz, aromatic), 129.1 (dd, aromatic), 129.3 (ds, J= 29.3 Hz, aromatic), 139.4 (s, aromatic), 163.2 (ds, J= 250.5 Hz, CF); ¹⁹F NMR (CDCI₃) δ -107.98 (dd, J= 17.2 Hz, J= 49.7 Hz); MS m/z (%) 137 (100), 136 (96), 122 (10), 116 (38), 110 (17), 102 (4), 92 (7), 89 (5), 84 (6), 65 (3), 63 (4), 57 (2), 51 (3); IR (NaCl) v 3298 (w), 3134 (w), 3095 (w), 3037 (m), 3014 (w), 2953 (w), 2924 (m), 2868 (w), 1909 (w), 1809 (m), 1653 (s), 1615 (m), 1573 (w), 1514 (s), 1453 (m), 1410 (m), 1374 (m), 1319 (s), 1301 (s), 1281 (s), 1186 (m), 1122 (w), 1095 (s), 1039 (w), 1019 (w), 927 (s), 840 (s), 822 (s), 792 (w), 744 (w), 726 (w), 704 (w), 692 (w), 643 (w), 607 (m), 572 (w), 535 (m); Anal. (C₉H₉F). The chemical shifts in the 1H NMR spectra and absorptions in the IR spectra are in good agreemnet with those described in reference.

Under dry conditions Cu(acac)₂ (84 mg, 0.98 mmol) was dissolved in anhydrous CH₂C1₂ (5 ml). After stirring for some minutes some drops of phenylhydrazine were added and the solution was further stirred. To this solution (1- fluorovinyl)-4-methylbenzene (TR124) (1.36 g, 10.0 mmol) was added. Under reflux a solution of ethyl diazoacetic acid (1.70 g) in anhydrous CH₂C1₂ (10 ml) was added via a syringe pump over 5 - 6 h. After addition of the CH₂CI₂, the reaction mixture was refiuxed for 4 h more. The reaction mixture was diluted with CH₂CI₂ (150 ml) and washed with saturated NaCO₃ and H₂O (300 ml). The organic phases were dried (MgSO₄) and all volatiles were removed under vacuum. A conversion of 75 % was detected by GC analysis. The cisltrans isomers formed in a 1 : 1 ratio. The diastereomers were separated by silica gel chromatography (pentane/Et₂O 40:1). Besides the diastereopure esters a fraction containing both diastereomers (303 mg, 1.34 mmol, 14 %) was obtained. The esters were isolated as as colorless oils. Data for trαzw-TRHO: (Yield: 607 mg, 27 %) 1H NMR (CDCI3) δ 1.29 3 H, (q, J= 7.2 Hz, CH₂CH₃), 1.57 (1 H, ddd, J= 6.9 Hz, J= 8.8 Hz, J= 10.5 Hz, CHAHB), 2.15 (ddd, J= 7.6 Hz, J= 8.8 Hz, J- 10.5 Hz, 1 H, CHx), 2.25 (1 H, ddd, J= 6.9 Hz, J= 7.6 Hz, J= 20.0 Hz, CH_AH_B), 2.35 (s, 3 H, C_ar-CH₃), 4.18-4.29 (2 H, m, CH2CH₃), 7.16-7.25 (4 H, m, aromatic); ¹³C NMR (CDCI3) δ 14.2 (q, CH₂CH₃), 18.7 (dt, J= 12.7 Hz, CHAH_B), 21.0 (q, C_ar-CH₃), 28.7 (dd, J= 12.7 Hz, CHx), 61.1 (t, CH₂CH₃), 80.9 (ds, J- 227.6 Hz, CF), 124.9 (dd, J= 6.4 Hz, aromatic), 129.2 (d, aromatic), 134.5 (ds, J= 21.6 Hz, aromatic), 138.3 (s, aromatic), 167.9 (s, J= 2.5 Hz, CO); ¹⁹F NMR (CDCI₃) δ -186.37 (dm, J= 20.0 Hz). MS m/z (%) 222 (58), 207 (5), 193 (20), 177 (17), 174 (14), 172 (15), 166 (24), 164 (22), 149 (100), 147 (26), 139 (60), 133 (32), 129 (38), 119 (14), 115 (7), 109 (11), 101 (5), 91 (6), 77 (5), 65 (2), 55 (3), 39 (1); IR (NaCl) v 3099 (w), 3034 (w), 2983 (m), 2927 (m), 2874 (w), 1737 (s), 1616 (w), 1520 (w), 1438 (s), 1399 (s), 1384 (s), 1306 (s), 1268 (m), 1239 ( ), 1181 (s), 1107 ( ), 1071 (w), 1045 (w), 1002 (m), 974 (w), 903 (w), 883 (w), 860 (w), 846 (w), 815 (s), 789 (w), 721 (w); Anal. (C₁₃H₁₅FO₂).

Analogous to the general procedure for hydrolysis with KOH, trα«_--TR112 was synthesized using trans-TRH (524 mg, 2.32 mmol). After recrystallization from CH₂Cl₂/pentane (1:4) trans-TR112 was isolated as white, amorphous solid. (Yield: 335 mg, 75 %) Data for trans-TRlll: Mp 112 °C (CH₂Cl₂/ρentane); 1H NMR (CDC1₃) δ 1.66 (1 H, ddd, J= 6.9 Hz, J= 9.1 Hz, J= 10.5 Hz, CHx), 2.16 (1 H, ddd, J= 1.6 Hz, J= 9.1 Hz, J= 10.3 Hz, CHAH_B), 2.29 (1 H, ddd, J= 6.9 Hz, J= 7.6 Hz, J= 20.0 Hz, CH_AHB), 2.36 (s, CHj), 7.17-7.25 (4 H, m, aromatic), 11.29 (1 H, br, CO₂H); ¹³C NMR (CDC1₃) δ 19.2 (dt, J= 12.7 Hz, CH_AH_B), 21.1 (q, CH₃),

28.4 (dd, .7= 11.4 Hz, CH_X), 81.6 (ds, J= 230.2 Hz, CF), 125.2 (dd, J= 5.1 Hz, aromatic), 129.3 (d, aromatic), 134.0 (ds, J= 21.6 Hz, aromatic), 138.7 (s, aromatic), 174.4 (s, CO); ¹⁹F NMR (CDCI₃) δ -184.66 (ddd, J= 10.3 Hz, J=

10.5 Hz, J= 20.0 Hz); MS as trimethylsilylester m/z (%) 266 (12), 251 (31), 235 (6), 223 (6), 211 (25), 207 (10), 176 (71), 149 (13), 147 (13), 133 (21), 129 (48), 119 (41), 115 (23), 109 (3), 91 (2), 77 (28), 73 (100), 51 (1), 45 (6); IR (KBr) v 3113 (br), 3055 (br), 2999 (br), 2926 (br), 2866 (br), 1691 (s), 1523 (w), 1451 (s), 1427 (s), 1388 (w), 1297 (s), 1245 (m), 1207 (s), 1131 (w), 1106 (m), 1053 (w), 1022 (w), 1010 (m), 965 (w), 897 (m), 866 (w), 834 (w), 811 (s), 789 (m), 769 (w), 714 (w), 658 (w), 642 (w), 569 (m), 491 (w); Anal. (CnHnFO.).

Analogous to the general procedure for Curtius degradation, trαra,_-TR114 was synthesized using trans-TRlll (243 mg, 1.25 mmol). After silica gel chromatography (cyclohexane/ethyl acetate 10:1) tr< _-TR114 was isolated as a white, voluminous solid. (Yield: 252 mg, 76 %) For elemental ahalysis the product was recrystallized from ethyl acetate/pentane at -20 °C. Data for trans-TR114: Mp 98 °C (ethyl acetate / pentane); 1H NMR (CDCI3) δ 1.37 (1 H, ddd, J= 6.1 Hz, J= 8.1 Hz, J= 22.2 Hz, CH_AH_B), 1.47 (9 H, s, C-(CH₃)₃), 1.54 (1 H, ddd, J= 8.1 Hz, J = 8.3 Hz, J= 12.7 Hz, CH_AH_B), 2.35 (3 H, s, CΗ3), 2.95 (br s, 1 H, CHx), 4.95 (1 H, br s, NH), 7.15-7.25 (4 H, m, aromatic); ¹³C NMR (CDC1₃) δ 19.9 (dt, J= 11.4 Hz, CHAH_B), 21.1 (q, C-(CH₃)₃), 28.3 (q, CH₃), 33.6 (dm, CHx), 79.1 (ds, J= 218.7 Hz, CF), 79.9 (s, C-O), 125.4 (dd, J= 5.1 Hz, aromatic), 129.1 (d, aromatic), 134.4 (ds, J = 19.1 Hz, aromatic), 138.0 (s, aromatic), 156.3 (s, CO); ¹⁹F NMR (CDC1₃) δ -188.76 (br s); MS m/z (%) 209 (6), 191 (2), 189 (9), 176 (6), 171 (5), 164 (13), 148 (21), 144 (51), 137 (13), 133 (4), 130 (16), 117 (11), 115 (10), 103 (2), 91 (5), 77 (2), 65 (3), 59 (17), 57 (100), 41 (31); IR (KBr) v 3379 (s), 3096 (w), 3036 (w), 3017 (w), 2986 (m), 2929 (w), 1686 (s), 1516 (s), 1459 (w), 1445 (w), 1395 (w), 1386 (w), 1371 (m), 1308 (w), 1279 (m), 1252 (w), 1211 (w), 1168 (s), 1110 (w), 1079 (w), 1066 (w), 1033 (w), 1002 (w), 893 (w), 875 (m), 808 (m), 787 (w), 757 (w), 672 (w); Anal. (C₁₅H₂₀FNO₂).

Analogous to the general procedure for deprotection with THF/HC1, trans- TR119 was synthesized using trans-TR114 (53 mg, 0.263 mmol). After recrystallization from methanol/Et₂O trans-TR119 was isolated as white solid. (Yield: 36 mg, 89 %) Data for trans-TR119: Dec > 166 °C (Methanol / Et₂O); 1H NMR (Methanol-d₄) δ 1.72-1.82 (2 H, m, CH_AH_B), 2.36 (3 H, s, CHj), 2.98-3.04 (1 H, m, CHx), 4.78 (3 H, br s, NH₃ ⁺), 7.23-7.34 (4 H, m, aromatic); ¹³C NMR (Methanol-d₄) δ 17.9 (dt, J= 12.7 Hz, CH_AH_B), 21.5 (q, CH₃), 32.5 (dd, J= 10.2 Hz, CHx), 79.5 (ds, J= 218.7 Hz, CF), 127.3 (dd, J= 5.1 Hz, aromatic), 130.8 (d, aromatic), 133.7 (ds, J= 20.3 Hz, aromatic), 140.8 (s, aromatic); ¹⁹F NMR (CDCI₃) δ -186.07 (m); MS (ESI) m/z (%) 166 (15), 149 (4), 146 (100), 131 (7); IR (KBr) v 3050 (m), 2941 (br s), 2896 (br s), 2774 (w), 2714 (m), 2682 (m), 2659 (w), 2005 ( ), 1605 (w), 1590 (w), 1521 (s), 1449 (w), 1385 (m), 1321 (w); 1296 (w), 1244 (w), 1212 (w), 1194 (w), 1176 (w), 1120 (w), 1109 (w), 1076 (m), 1055 (w), 1023 (w), 1007 (w), 963 (m), 898 (m), 876 (w), 822 (m), 799 (s), 786 (s), 650 (w); Anal. (C₁₀H₁₃C1FN).

Example 19: Preparation and characterization of (lR,2R)-(-)- 2-Fluoro-2- phenylcyclopropylamine Hydrochloride

To a solution of trα«5^,-(±)-(2-Fluoro-2-ρhenyl)cyclopropanecarboxylic acid (trα«_*-TR18) (360 mg, 2.0 mmol) in anh. CH₂C1 (20 ml) dicyclocarbodiimide (DCC) (454 mg, 2.2 mmol), (S)-l-ρhenylethylamine (255 mg, 2.1 mmol) and a catalytic amount of N,N-dimethylaminepyridine (DMAP) were added. The reaction mixture was stirred for 20 h at room temperature. The formed precipitate was removed by filtration. Separation of the diastereomeric amides was achieved by silica gel chromatography (pentane/Et₂O 1:1). For further purification the diastereomers were recrystallized from ethyl acetate/pentane ((-)-TR1351) and Et₂O/pentane ((+)-TR1352). The amides were isolated as white crystalline solids. Data for (-)-TR1351: (Yield: 172 mg, 35 %) Mp 149 °C (ethyl acetate); [α]_D ²⁰ - 182.3. 1H NMR (CDC1₃) δ 1.41-1.51 (1 H, m, CHx), 1-44 (3 H, d, J= 6.9 Hz, CH₃), 1.91-1.99 (1 H, m, CHAH_B), 2.21 (ddd, J= 7.4 Hz, J= 7.4 Hz, J= 20.7 Hz, 1 H, CH_AH_B), 5.09-5.19 (1 H, m, CH), 6.21 (1 H, d, J= 6.1 Hz, NH), 7.21-7.38 (10 H, m, aromatic); ¹³C NMR (CDC1₃) δ 18.4 (dt, J= 11.4 Hz, CH_AH_B), 21.8 (q, CH₃), 31.0 (dd, J= 11.4 Hz, CH_X), 49.3 (d, CH), 80.5 (ds, J= 225.1 Hz, CF), 124.0 (dd, J= 6.4 Hz, aromatic), 126.2 (d, aromatic), 127.3 (d, aromatic), 127.9 (d, aromatic), 128.5 (d, aromatic), 128.6 (d, aromatic), 138.2 (ds, J- 21.6 Hz, aromatic), 143.3 (s, aromatic), 165.4 (s, CO); ¹⁹F NMR (CDCI₃) δ -190.87 (m); MS m/z (%) 283 (3), 263 (4), 248 (6), 220 (2), 207 (4), 179 (31), 161 (11), 159 (13), 145 (12), 135 (7), 115 (42), 105 (100), 91 (11), 77 (28), 62 (4), 51 (7); IR (KBr) v 3304 (s), 3063 (w), 3028 (w), 3004 (w), 2974 (w), 2929 (w), 2870 (w), 1668 (m), 1642 (s), 1543 (s), 1496 (w), 1452 (m), 1430 (w), 1386 (m), 1321 (m), 1281 (w), 1225 (s), 1111 (w), 1078 (w), 1032 (w), 1006 (w), 997 (w), 979 (m), 919 (w), 890 (m), 847 (w), 796 (w), 756 (s), 696 (s); Anal. (C₁₈H₁₈FNO). The structure of (~)-TR1351 was confirmed by X-ray structural analysis.

Analogous to a procedure described in reference (-)-TR1351 (126 mg, 0.445 mmol) was dissolved at 4 °C in a mixture consisting of Ac₂O (3.7 ml) and AcOH (0.6 ml). To this solution NaNO₂ (0.68 g, 9.8 mmol) was added. The reaction mixture stirred for 17-18 h at 4 °C. After warming to room temperature the reaction mixture was poured into H₂O (10 ml). The aqueous phase was extratced with CH₂C1₂ (75 ml). The combined organic layers were washed with 5% Na₂CO₃ and H₂O (25 ml) and dried (Na₂SO₄). Complete conversion of the amide was detected by GC. All volatiles were removed under vacuum. The residue was dissolved in 1,4-dioxane (10 ml) and refiuxed for 20 h. All volatiles were removed under vacuum. The obtained residue was dissolved in methanol (10 ml). KOH (250 mg, 4.45 mmol) was added. After 8 h at room temperature the reaction mixture was concentrated and H₂O (15 ml) was added. The aqueous phase was extracted with CH2CI2 (20 ml) and then acidified with cone. HCI to pH 1. The aqueous phase was extracted with CH₂CI2 (100 ml). The combined organic phases were dried (Na₂SO₄) and all volatiles were removed under vacuum. After recrystallization from CH₂Cl₂/ρentane (1_),25)-TS10 was isolated as white powder. (Yield: 63 mg, 79 %) Data for (1_?,2_?)-TS10: [α]_D ²⁰ - 292.9.

Analogous to the general procedure for Curtius degradation, (1R,2R)-TS18 was synthesized using (-)-TSlO (71 mg, 0.394 mmol). After silica gel chromatography (cyclohexane/ethyl acetate 6:1) (1R,2R)-TS18 were isolated as a white. (Yield: 14 mg, 14 %) Analysis by chiral GC revealed an enantiomeric excess of > 98 %. Data for (1R,2R)-TS18: α_D ²⁰: - 89.3°.

Analogous to the general procedure for deprotection with THF/HC1, (1__,2__)- TS25 was synthesized using (1R,2R)-TS18 (29 mg, 0.155 mmol). After recrystallization from methanol/Et₂O (1__,2R)-TS25 was isolated as white solid. (Yield: 17 mg, 58 %) Data for (1R,2R)-TS25: α_D ²⁰ -70.9 (MeOH).

Example 20: Preparation and characterization of (ltS^t,2<S^t)-(+)-2-Fluoro-2- phenylcyclopropylamine Hydrochloride

To a solution of trαn,,-(±)-(2-Fluoro-2-phenyl)cyclopropanecarboxylic acid (trans-TR18) (360 mg, 2.0 mmol) in anh. CH₂C1₂ (20 ml) dicyclocarbodiimide (DCC) (454 mg, 2.2 mmol), 0_ l-phenylethylamine (255 mg, 2.1 mmol) and a catalytic amount of N,N-dimethylaminepyridine (DMAP) were added. The reaction mixture was stirred for 20 h at room temperature. The formed precipitate was removed by filtration. Separation of the diastereomeric amides was achieved by silica gel chromatography (pentane/Et₂O 1:1). For further purification the diastereomers were recrystallized from ethyl acetate/pentane ((-)-TR1351) and Et₂O/pentane ((+)-TR1352). The amides were isolated as white crystalline solids. Data for (+)-TR1352: (Yield: 175 mg, 35 %) Mp 133 °C (ethyl acetate); [α]_D ²⁰ +146.5; 1H ΝMR (CDC1₃) δ 1.50 (3 H, d, J= 6.9 Hz, CH₃), 1.53 (ddm, J= 7.2 Hz, J = 10.5 Hz, 1 H, CHx), 1.98-2.06 (1 H, dm,J= 7.9 Hz, CH_AH_B), 2.21 (1 H, ddd, J= 7.4 Hz, J= 7.9 Hz, J= 20.5 Hz, CH_AH_B), 5.14-5.27 (1 H, m, CH), 6.05 (1 H, d, J= 6.2 Hz, H), 7.20-7.38 (10 H, m, aromatic); ¹³C ΝMR (CDCI₃) δ 18.4 (dt, 7= 11.4 Hz, CH_AHB), 21.7 (q, CH₃), 31.0 (dd, J= 12.7 Hz, CHx), 49.1 (d, CH), 80.6 (ds, J= 223.8 Hz, CF), 124.1 (dd, J= 7.6 Hz, aromatic), 126.1 (d, aromatic), 127.3 (d, aromatic), 128.0 (d, aromatic), 128.5 (d, aromatic), 128.6 (d, aromatic), 138.0 (ds, J = 21.6 Hz, aromatic), 143.0 (s, aromatic), 165.6 (s, CO); ¹⁹F ΝMR (CDC1₃) δ -189.69 (m); MS m/z (%) 283 (3), 263 (3), 248 (5), 220 (2), 207 (3), 179 (34), 161 (14), 159 (13), 145 (7), 143 (9), 135 (14), 120 (5), 115 (39), 105 (100), 91 (8), 77 (28), 62 (4), 51 (7); IR (KBr) v 3292 (s), 3069 (w), 3041 (w), 2971 (w), 2925 (w), 1648 (s), 1550 (s), 1495 (w), 1450 (m), 1430 (w), 1385 (s), 1320 (w), 1251 (w), 1232 (m), 1134 (w), 1115 (w), 1075 (w), 1037 (w), 1024 (w), 1001 (w), 982 (w), 893 (m), 845 (w), 802 (w), 759 (m), 743 (w), 698 (m), 670 (w); Anal. (C₁₈H₁₈FNO).

Anologous to the method described above, (1R,2R)-TS5 was synthesized using (+)-TR1352 (306 mg, 1.08 mmol). After recrystallization from CH₂Cl₂/pentane (1R,2R)-TS5 was isolated as white powder. (Yield: 100 mg, 51 %) Data for (1R,2R)-TS5: [α]_D ²⁰ +293.5.

Analogous to the general procedure for Curtius degradation, (\S,2S)-TS12 was synthesized using (+)-TS5 (96 mg, 0.531 mmol). After silica gel chromatography (cyclohexane/ethyl acetate 6:1) (\S,2S)-TS12 were isolated as a white. (Yield: 46 mg, 35 %) Analysis by chiral GC revealed an enantiomeric excess of > 98 %. Data for (IS,2S)-TS12: α_D ²⁰: + 89.9°.

Analogous to the general procedure for deprotection with THF/HC1, (\S,2S)- TS15 was synthesized using (\S,2S)-TS12 (40 mg, 0.159 mmol). After recrystallization from methanol/Et₂O (lS^^-TSlδ was isolated as white solid. (Yield: 26 mg, 87 %) Data for (IS,2S)-TS15: α_D ²⁰ +70.2 (MeOH).

Example 21 : Tyramine Oxidase Activity

Tyramine oxidase, purchased from Sigma, is sold as a flavin-containing amine oxidase (EC: 1.4.3.4). However, the properties of this enzyme are quite different from the properties of flavin-containing monoamine oxidases previously reported by many researchers. Wouters et al. suspected that the Sigma tyramine oxidase is a copper-containing amine oxidase on the basis of spectral characteristics, molecular weight and inhibition profile. The absence of inhibition of the enzyme by clorglyline and (R)-deprenyl was confirmed whereas the enzyme was strongly inhibited by semicarbazide (data not shown). Activity of this enzyme is also decreased in the presence of diethyldithiocarbamate, which is a strong copper ion chelating agent. All of the results obtained in this study also strongly suggest that this enzyme is a copper-containing amine oxidase. The ultraviolet spectrum of the tyramine oxidase from Sigma displayed a maximum at 410 nm and a shoulder at around 470-480 nm, and addition of phenylhydrazide (4 μM) to the enzyme solution resulted in an increase of an absorption peak at 435 nm. All copper-containing amine oxidases have a peak around 480 nm in the visible spectrum, and amine oxidases containing topa quinone react with phenylhydrazine to produce an absorption band at 430-440 nm. These results suggest that the Sigma tyramine oxidase is a copper/topa quinone type amine oxidase.

The enzyme activity was measured spectrophotometrically at 31°C by the modified method of Houslay (Houslay, M.D. et al, Biochem. J, 1973, 135, 735- 750) using 0.5 mL of standard reaction mixture containing 0.6 mM benzylamine, 0.1 M potassium phosphate buffer (pH 7.2), 6% dimethylsulfoxide and tyramine oxidase. The reaction was monitored at 250 nm, the maximun absorption wavelength of benzaldehyde. The enzyme activity was calculated by using 13,800 M^"1 cm^" as an extinction coefficient of benzaldehyde at 250 nm. One unit of the enzyme oxidizes 1 μmol of benzylamine to benzaldehyde per 1 minute. Protein concentration was determined by the method of Bradford using bovine serum albumin as a standard (Bradford, M.M. Anal. Biochem, 1976, 72, 248-254).

The inhibition of tyramine oxidase as a function of concentrations of compunds of the invention were investigated and IC₅₀ values (inhibitor concentration at 50% remaining activity) were calculated graphically from the inhibition curves (Figure 1). The IC_SQ values are summarized in Table 1.

Table 1. IC_.o values and inhibition type for 2-fluoro-l-phenylcyclopropylamines and methylamines.

Compound Isomer type ^a IC₅₀ (mM) Inhibition type

3a trans 0.012+-0.001 non competitive

3b cis 0.66+-0.21 nd

4 trans 0.020+-0.006 irreversible

5 trans nd nd

Semicarbazide - 0.0067+-0.0002 nd a Relative configuration of fluorine and the chain amine function, nd, Not determined.

Compounds 3 a and 4 were both strong inhibitors of tyramine oxidase and had comparable activity. Interestingly, inhibition by compound 3b, the eώ-isomer of 3a, was lower, showing that the configuration of fluorine may be important for inhibitory activity.

To investigate the type of inhibition, reversible or irreversible, the compound 3a and 4 were assessed by the previously described method of Kitz and Wilson. As the results show, the hydrazide 4 resulted in time- and concentration-dependent loss of activity. This result indicates that compound 4 functions as a typical irreversible inhibitor of the enzyme, with lower activity than semicarbazide, the classic inhibitor (Table 1). No time- and concentration-dependent inactivation by compound 3a was observed. However, further kinetic analysis on 3 a showed that inhibition of tyramine oxidase by compound 3a was non-competitive, indicating that the enzyme has a separate binding site for this compound.

The inhibition of tyramine oxidase as a function of varying oncentrations of other compounds of the invention was also examined. The inhibition curves are shown in FIGs. 2 and 3. The results are shown below in Table 2.

Table 2. IC50 values and inhibition type for 2-fluoro-2-phenylcyclopropylamines and methylamines.

Compound Isomer type IC₅0 (mM) Inhibition type la trans 0.035+-0.006 competitive lb cis ^a 0.033+-0.007 nd 6a cis ^b 0.0036+-0.0015 competitive

6b trans 0.19+-0.09 nd

7a cis 1.24+-0.06 nd

7b trans ni nd

8a cis 0.49+-0.09 nd

8b trans ni nd

9a cis ^b ni nd

9b trans ^b ni nd

" Relative configuration of the phenyl group and the amine-containing side chain. ^b Relative configuration of fluorine and the amine-containing side chain, ni, No inhibition detected at mM concentration, nd, Not determined.

Compound 6a was a very potent inhibitor, having an IC₅₀ value 10 times lower than the values for the non-fluorinated compounds la (tranylcypromine) and its cis- isomer lb. In contrast, the other diastereomer 6b is less active by more than one order of magnitude compared to 6a and about two times less active compared to la or lb. This observation may have mechanistic implications as discussed below. Looking to the homologues of 6a and 6b it becomes obvious that the trans- methylamine 7a is about three orders of magnitude and the trαrcs-ethylamine 8a is about two orders of magnitude less active compared to 6a. The coπesponding cis- isomers 7b and 8b did not show any inhibition in the millimolar scale (FIG. 4). These results suggest that the presence of free amino group, directly bonded to the cyclopropane ring, and a fluorine atom in the cts-configuration relative to the amine are structural features that increase tyramine oxidase inhibition

The compounds 3 a, 4 and 6a are non-competitive, irreversible and competitive inhibitors for tyramine oxidase, respectively. In addition, compound la is a reversible and competitive inhibitor for tyramine oxidase. A comparison of the activities of la, lb, 6a, and 6b, all competitive inhibitors, indicated that the presence of fluorine had a strong influence on activity, depending on its relative configuration with the amine function. Thus, a cz^'s-relationship of fluorine and amino group (6a) greatly enhances activity whereas fluorine trans to the amine (6b) substantially decreases activity.

As noted above, copper-dependent amine oxidases are efficiently inhibited by chelating compounds. With this in mind, it is intriguing to consider the facility with which C-F bonds can intreact with metal ions. Thus, we would like to suggest that certain of our fluorinated cyclopropylamines can co-ordinate to the copper center of tyramine oxidase, thereby offering an explanation for why these are more active inhibitors than the non-fluorinated parent compounds. The following shows the effect of stereochemistry on the chelation of copper ion in the active center, and relative order of activity.

_P

_NH2

6a 1a ^{1 b} 6b

Such co-ordination of course is absent in both of the non-fluorinated tranylcypromines la and lb, a fact that could explain the almost equal inhibitory activities of these isomers. A question remains as to why the trans fluorinated isomer 6b has substantially decreased inhibitory activity. Decreased electron density of the amino group due to the electronegativity of fluorine may contribute to lower interaction of the amino group with the enzyme. An additional factor to note is the fact that fluorine in this position would also disfavor ring opening of the cyclopropane ring to form the ammonium ion, although this should not influence reversible competitive inhibition.

All homologous (fluoro-phenylcyclopropyl)alkyl amines 7a, 8a and 3b with cz^'s-configuration of fluorine and the aminoalkyl groups are much less active compared to 6a (FIG. 3). This could support the involvement of chelation. The corresponding trans-compounds 7b and 8b were even less active, showing no activity at millimolar concentrations. Deamination occurs before ring-opening and enzyme inactivation.

Example 22: Inhibition of Tyramine oxidase activity by para-substituted compounds of the invention

Microbial tyramine oxidase was purchased from Sigma, and was dissolved in 25 mM potassium phosphate (pH 7.2). Protein concentration was measured by the method of Bradford. The activity of tyramine oxidase was measured spectrophotometrically using benzylamine as a substrate as shown in Example 21 above. A number of other compounds of the invention were also screened for tyramine oxidase inhibition. The activity of microbial tyramine oxidase was measured in the presence of different concentrations of the inhibitor. IC₅₀ values (inhibitor concentration at 50%) remaining activity) were calculated graphically from the inhibition curves obtained (FIG. 5). The results are shown in Table 3.

Table 3. IC50 values and inhibition type for compounds. Compound isomer type IC50 (mM) inhibition type la trans ^a 0.035+-0.006 competitive

6a cis 0.0028+-0.0009 competitive

13a cis ^b 0.0081+-0.0016 competitive

14a • b CIS 0.0037+-0.0003 competitive

15a cis ^b 0.00039+-0.00017 competitive

" Relative configuration of the phenyl group and the amine-containing side chain. ^b Relative configuration of fluorine and the amine-containing side chain.

As shown in FIG. 5 and Table 3, non-fluorinated phenylcyclopropylamines, compound la (tranylcypromine) and lb, were both inhibitors of tyramine oxidase and had comparable activity. The inhibition was changed by the introduction of a fluorine atom to the 2-position of phenylcyclopropylamines, because compound 12a had a 10-fold higher inhibitory than tranylcypromine, whereas no difference in the inhibitory between 12b and lb was observed. The p -substitution of ez^'._ -isomer (relative configuration of fluorine to amino group) of 2-fluoro-2-cyclopropylamine (12a) resulted in the change of their inhibitory against tyramine oxidase. Compound 13a (p-F) had a 2.9-fold lower inhibitory than non-j! substituted compound (12a). T ep-Cl substituent reduced the inhibition by only 1.3-fold. However, compound 5a had 7.2-fold higher inhibitory than compound 12a. In addition, these p- substituted compounds did not show time- and concentration-dependent inhibition, indicating that the inhibition manner on tyramine oxidase is reversible. Kinetic analysis clearly showed that these compounds are competitive inhibitors (FIG. 6).

These results suggest that the ^-substituted electron-donating group maybe important for the improvement of inhibition. On the other hand, ^-substitution had no effect on the inhibition of the tr o_'-isomer of 2-fluoro-2-phenylcyclopropylamine (12b). Tyramine oxidase was not inhibited by (R,R)-enantiomer of 2-fluoro-2- phenylcuclopropylamine ((R,R)-2a) under the condition used in this study. However, the (<S,ιS)-enantiomer ((S,S)-2a) strongly inhibited tyramine oxidase.

Table 4 shows data for the inhibition of tyramine oxidase for all of the compounds tested as measured above. Table 4: IC₅₀ values and inhibition type for compounds.

SCA = semicarbazide; ni = no inhibition detected in millimolar concentration;, nd = not determined

Example 23: Inhibition of monoamine oxidase A and monoamine oxidase B by compounds of the invention

A stock solution of the human liver mitochondrial outer membrane monoamine oxidase A and B, expressed in the methylotrophic yeast Pichia pastoris, were kindly gifted from Professor D. Edmondson's laboratory, University of Atlanta, Georgia.

Prior to use, the enzyme stock solution was passed through gel-filtration column (PD 10 desalting column, Amersham Biosciences) preequilibrated with 50 mM K phosphate (pH 7.2) containing 0.8% octyl-glucoside. The activity of MAOA activity was measured spectrometrically at 25°C by the modified method of Li et al. Protein Expr. Prof. 2002, 24 154-162 using 0.7 mL of standard reaction mixture containing 1 mM kynuramine hydrobromide, 50 mM potassium phosphate buffer (pH 7.2), 0.5% Triton XI 00 (reduced), 6% dimethylsulfoxide and MAOA. The reaction was monitored at 316 nm, the maximum absorption wavelength of 4- hydroxyquinoline. The enzyme activity was calculated by using 12,300 M^"1 cm^"1 as extinction coefficient of 4-hydroxyquinoline at 316 nm. One unit of the enzyme oxidizes 1 μmol of kynuramine to 4-hydroxyquinoline per 1 minute.

The activity of MAOB activity was also measured spectrometrically at 25°C by the modified method of Houslay and Tipton, (Houslay, M.D. et al. Biochem. J, 1973, 135, 735-750) using 0.7 mL of standard reaction mixture containing 1 mM benzylamine, 0.1 M potassium phosphate buffer (pH 7.2), 6% dimethylsulfoxide and MAOB. The reaction was monitored at 250 nm, the maximum absorption wavelength of benzaldehyde. The enzyme activity was calculated by using 13,800 M^"1 cm^"1 as extinction coefficient of benzylamine at 250 nm. One unit of the enzyme oxidizes 1 μmol of benzylamine to benzaldehyde per 1 minute. Protein concentration was determined by the method of Bradford (Bradford, M.M., Anal. Biochem, 1976, 72, 248-254) using bovine serum albumin as a standard.

The compounds to be tested were dissolved in DMSO and diluted with the same solvent to give the appropriate concentration. The solution was immediately divided into several vials and wrapped with aluminum foil. These vials were stocked in ice-bath until use for inhibition experiments. Inhibition experiments were carried out as follows; the different concentrations of inhibitor were added to the reaction mixture described above (without substrate), and allowed to stand for 10 minutes at 10°C. The reaction was started by the addition of substrate stock, and monitored the time course of the absorption increase of the reaction product as described above.

IC50 values (inhibitor concentration at 50%) remaining activity) were calculated graphically from the inhibition curves obtained. The IC₅₀ values are summarized in Table 5. Table 5. IC₅₀ values and inhibition type for fluorinated phenylcyclopropylamine analogues. j Isomer MAOA MAOB Compound . r type ICso (mM) mhibition type ^c IC50 (mM) Inhibition type ^c la trans^a 0.020+-0.000 irreversible 0.019+-0.000 irreversible lb cis ^a nd ^d nd 0.43+-0.28 ^' nd

3a trans 0.32+-0.01 nd 0.024+-0.001 irreversible

3b cis ^b nd nd 0.48+-0.23 nd

4 - 0.73+-0.15 nd 0.19+-0.02 irreversible

5 trans ^b 0.0031+-0.0001 irreversible 0.42+-0.19 nd

6a cis 0.012+-0.001 irreversible 0.0064+-0.0001 irreversible

6b trans 0.065+-0.042 nd 0.019+-0.001 irreversible

7a cis ^b nd nd nd nd

7b trans ^b nd nd nd nd

8a cis ^b 0.041+-0.002 competitive 0.19+-0.01 nd

8b trans ^b nd nd nd nd

13a cis ^b 0.0036+-0.0002 irreversible 0.0049+-0.0001 irreversible

13b trans ^b 0.27+-0.07 nd 0.010+-0.000 irreversible

14a cis ^b 0.0016+-0.0000 irreversible 0.00037+-0.0001 irreversible

14b trans ^b 0.089+-0.009 nd 0.0048+-0.0001 irreversible

15a cis ^b 0.013+-0.000 nd 0.013+-0.000 irreversible

15b trans ^b 0.23+-0.12 nd 0.030+-0.001 irreversible

Deprenyl - nd nd 0.0006+-0.0001 nd

Clorgylin. » _ 0.00013+- nd 0.0030+-0.0012 nd 0.00001

a Relative configuration of aromatic ring and amine-containing side chain. ^b Relative configuration of fluorine and amine-containing side chain. ^c hihibition type was determined by the observation of time- and concentration-dependent inactivation of MAOA and B in the presence of the inhibitor. The incubation of MAOB with an inhibitor was carried out at 4°C in the 0.1 mL of 0.1 M potassium phosphate (pH 7.2) containing 11.2 μg of enzyme, 6% of dimethylsulfoxide and different concentration of an inhibitor. Aliquots (20 μL) were taken out periodically from the mixture, and diluted with 0.68 mL of assay solution. The increase of absorbance at 250 nm was monitored as described in Experimental Section. For the condition of MAOA incubation was described in the legend of Figure 6. ^d Not determined.

As already known, MAOA and B were strongly and selectively inhibited by clorgyline and R-(-)-deprenyl, respectively. In addition, MAOA was inhibited by the trazω-series (relative configuration of amine to aromatic ring) of 2-fluoro-2- phenylcyclopropylamine, whereas the cw -series are generally not good inhibitors of MAOA. Inhibition of MAOA by compound 6a, 13a, 14a and 15a was shown to be stronger than that by non-fluorinated compound la (tranylcypromine). These results indicate that the introduction of fluorine may be important to increase the inhibition for MAOA. Furthermore, the ^-substitution of the aromatic ring of 2-fluoro-2- phenylcyclopropylamines clearly improved the inhibition of MAOA. The introduction of an electron withdrawing group (Cl, F) increased the activity of the MAOA inhibition by a factor of 7.5 for Cl and 3.3 for F (Table 5) for example. The methyl group (+ 1 substituent) slightly decreased the activity. The introduction of p- substituents was more effective on the trans -series (relative configuration to aromatic ring to amine) of 2-fiuoro-2phenylcyclopropylamine than cz^'s-series (FIG.

7).

MAOB was also inhibited by 2-fluoro-2-phenylcyclopropylamines (FIGs. 8a and 8b). Interestingly, in contrast to the results of MAOA, the fluorinated analogues (6b, 13b, 14b and 15b) were strong inhibitors of MAOB although compound lb had no inhibitory on MAOB (FIG. 8b). hi addition, the introduction ofp-chlorine to both trans- and cz^'s-isomers is most effective on the inhibition of MAOB, as it was for MAOA. This suggests that there are differences in the mechanisms of copper-containing and flavin-containing enzymes. Furthermore, these results also suggest the differences in the catalytic mechanism of MAOA and B. MAOA is known to exhibit different substrate and inhibitory binding specificities than MAOB even though the two enzymes exhibit the same covalent flavin binding site and approximately 70% sequence homology. MAOA is specific for the bulkier substrates such as serotonin, whereas substrates such as dopamine and benzylamine are more specific for MAOB.

No inhibition of MAOA and B by 2-fluoro-2-phenylcyclopropyl methylamines (7a, 7b) and ethylamine (8b) were observed. One exception is compound 8a which was a weak inhibitor for both enzymes (FIG. 9).

As shown in Figure 5, 2-fluoro-l-phenycyclopropylamine (5) was found to be a good specific inhibitor for MAOA , not for MAOB. In the presence of compound 5, the activity of MAOB slightly increased. 2-Fluoro-l- phenylcyclopropyl methylamine (3a) was an inhibitor for MAOB.

To obtain further information on the inhibition of MAOA and B by the compounds of the invention, the time- and concentration-dependent inhibition experiments were carried out by using the previously described method of Kitz and Wilson. Due to unstability of MAO, especially A type, the incubation of MAO with inhibitors was carried out at 4°C. Addition of compound 5 resulted in the time- and concentration-dependent inactivation of MAOA (FIG. 10a). See results for MAO-B in FIG. 10b. However, it should be noted that the relative activity did not show the exponential decrease at each concentration of inhibitor. One reason for this is thought to be unstability of the compound 5.

With the exception of the compound 8a, all inhibitors caused a time- and concentration-dependent inhibition of MAO, indicating that the inhibition type was an irreversible (Table 5). Kinetic analysis of MAOA in the presence of compound 8a showed that the inhibition was competitive (data not shown).

To investigate the enantio-selectivity in the inhibition of MAOA and B, two enantiomers of 2-fluoro-2-phenylcycloropylamine ((R,R)-5a and (S,S)-5a) were used for the assay. Clear differences in the behavior were observed (FIG. 11). The (S,S)-5a was a good inhibitor for both MAO A and B, in contrast of the results for (R,R)-5a.

Example 24: pKa's and Lipophilicities of 2-aryl-2-fluorocvclopropylamines

The p c_a's and lipophilicities of 2-aryl-2-fluorocyclopropylamines were measured to examine how these properties might affect their behavior as amine oxidase inhibitors. Cis- (lb) and trans (la) -tranylcypromine have comparable p _'s of 8.50 and 8.47, respectively. Fluorine substitution lowers the p-___ by about two orders of magnitude in the trans or (Z)-series (compounds with fluorine cis- to the amine side chain-the configuration that leads to active compounds), but all compounds with fluorine trans- to the amine side chain have p c_a's about 0.4 pH units lower than the cw-configured compounds. This may be due to a stereoelectronic effects. The piζ, of trans (i.e. Z-)-2-fluoro-2- phenylcyclopropylamine is 7.41. Therefore, under physiological conditions it would be essentially 50% protonated. Fluorine substitution also leads to increased lipophilicity, which can be an important factor in drug development.

Example 25: Inhibition of Monoaminer Oxidase A and Monoamine Oxidase B by compounds of the invention

Further compounds of the invention were synthesized and their ability to inhibit monoamine oxidase A and monoamine oxidase B were investigated.

The structures of the compounds from Table 6 are shown below.

1-phenylcyclopropylamine (1-PCA) trans-2-fluoro- 1 -phenylcyclopropylamine (5)

cis-2-fluoro-l-phenylcyclopropylamine (5b) cis-2-fluoro-l-para-chloro-phenylcyclopropylamine

trans-2-fluoro-para-chloro- 1 -phenylcyclopropylamine cis-2-fluoro- 1 -para-methoxy- (20b) phenylcyclopropylamine (21a)

trans-2-fluoro- 1 -para-methoxy- phenylcyclopropylamine (21b)

Table 6 shows the results for the inhibition of monoamine oxidase A and monoamine oxidase B by the following compounds. As seen here, trans (i.e. E)-2- fluoro- 1-phenylcyclopropylamine (compound 5 in Table 6 and Table 5 above) was a potent and selective inhibitor of MAO A (IC₅o = 3.1 μM above iri Table 5; and 1.4 μM in Table 6). In contrast the parent compound 1-phenylcyclopropylamine (1- PCA) is a weak and selective inhibitor of MAO B, IC₅₀ = 190 μM, (MAO A inhibition: IC₅₀ = 730 μM).

Furthermore, cw-2-fluoro-l-phenycyclopropylamine (5b) has been found to be a potent and selective MAO A inhibitor, as are cis (Z)- and trans (E)- para-Cl, (20a, 20b) and -OMe (21a, 21b) substituted analogues. Table 6. IC₅₀ values and inhibition type for 2-fluoro-l -phenylcyclopropylamines. MAO A MAO B

„ j Isomer MAOA MAOB Compound _A type IC₅₀ (μM) Inhibition type ^c IC50 (μM) Inhibition type ^c

1-PCA 320 + 10 nc 24 + 1 irreversible

5 trans 1.4 + 0.1 irreversible None^a

5b cis 0.9 + 0.1 irreversible nd^b nd^b

20a trans 0.7 ± 0.1 irreversible nd^b nd

20b cis 0.5 ± 0.1 irreversible 24 + 0 nd^b

21a trans 0.7 + 0.1 irreversible nd nd^b

21b cis 0.6 ± 0.1 irreversible 230 + 0 nd^b aNo inhibition was observed. bCould not be determined.

Example 26: Effects of Stereochemistry on the Activity of Compounds of the

Invention

Because potent inhibition of CAO was seen wherein the fluorine and amino substituent were in a cz^'s-configuration, whereas decreased inhibition was seen if these groups were trans to each other, mechanistically, it may be important to study the gem-difluoro substituted derivatives because they present both situations. This should shed further light on which factor controls the activity. Therefore, gem- difluoro substituted derivatives are being synthesized, and their activity examined. The activity of enantiopure compounds will also be examined in an effort to more fully understand the mechanistic effects of the compounds of the invention.

Since electron donating groups on the aromatic ring increase inhibitory activity towards CAO, derivatives, such aspara-OMe, are being made that have even more electron donating capabilities.

To the extent that facilitated cyclopropyl ring opening is critical to the mechanism of irreversible inhibition by fluorinated 1 -aryl-2- fluorocyclopropylamines (derivatives of 1-PCA), a second fluorine may increase ring-strain further to provide even more potent inhibitors. These compounds are being synthesized and their activity tested.

The inhibition by 2-fluoro-l -arylcyclopropylamines shows no diastereoselectivity, in that both E- and Z-isomers are potent and selective for the MAO A isoform. The enantioselectivity of this inhibition will be further examined by making the 1R.2R-, 1R.2S-, 1S.2R- and ZS^-enantiomers of 2-fluoro-l - phenylcyclopropyl- amine. The above specification, examples and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention resides in the claims hereinafter appended.

Claims

WE CLAIM:

1. A compound according to the formula

(I) . wherein each X is independently, an electron donating group, or an electron withdrawing group; n is an integer from 0 to 3 and Y is

wherein E is an electron donating group, and z is an integer from 0 to

with the proviso that when Y is

or where the cyclopropyl ring is attached at the carbon substituted with the E , X is not H; or pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein n is an integer from 1 to 3 and wherein X is an electron-donating group.

3. A compound according to claim 2, wherein X is fluorine, chlorine, bromine, or iodine.

4. A compound according to claim 3, wherein X is fluorine.

5. A compound according to claim 1, wherein E is a halogen.

6. A compound according to claim 5, wherein E is fluorine.

7. A compound according to claim 1, wherein the cyclopropyl ring is attached to the phenyl ring at the E substituted position.

8. A compound according to claim 1, wherein the cyclopropyl ring is attached to the phenyl ring at the unsubstituted position.

9. A compound according to claim 1 chosen from:

NH₂. HCI

10. A composition for the inhibition of monoamine oxidase, said composition comprising: a.) at least one pharmaceutically acceptable carrier; and b.) at least one compound according to formula I

(I) wherein each X is independently, an electron donating group, or an electron withdrawing group; n is an integer from 0 to 3 and

Y is

wherein E is an electron donating group, and z is an integer from 0 to

with the proviso that when Y is

or where the cyclopropyl ring is attached at the carbon substituted with the E , X is not H; or pharmaceutically acceptable salts thereof.

11. A composition according to claim 10, wherein n is an integer from 1 to 3, and wherein X is an electron-donating group.

12. A composition according to claim 11, wherein X is fluorine, chlorine, bromine, or iodine.

13. A composition according to claim 12, wherein X is fluorine.

14. A composition according to claim 13, wherein E is a halogen.

15. A composition according to claim 14, wherein E is fluorine.

16. A c composition according to claim 10, wherein the cyclopropyl ring is attached to the phenyl ring at the E substituted position.

17. A composition according to claim 10, wherein the cyclopropyl ring is attached to the phenyl ring at the unsubstituted position.

18. A composition according to claim 1 , wherein the compound of formula I is

19. A method for the inhibition of at least one monoamine oxidase comprising administering an effective amount of a compound of formula I

(I) wherein each X is independently, an electron donating group, or an electron withdrawing group; n is an integer from 0 to 3 and Y is

wherein E is an electron donating group, and z is an integer from 0 to 3 or pharmaceutically acceptable salts thereof.

20. The method of claim 19, wherein said at least one monoamine oxidase is a copper-containing amine oxidase or a flavin-containing amine oxidase.

21. The method of claim 19, wherein said at least one amine oxidase is tyramine oxidase.

22. The method of claim 19, wherein said at least one amine oxidase is monoamine oxidase A.

23. The method of claim 19, wherein said at least one>amine oxidase is monoamine oxidase B.

24. A method according to claim 19, wherein n is an integer from 1 to 3, and wherein X is an electron-donating group.

25. A method according to claim 24, wherein X is fluorine, chlorine, bromine, or iodine.

26. A method according to claim 25, wherein X is fluorine.

27. A method according to claim 26, wherein E is a halogen.

28. A method according to claim 27, wherein E is fluorine.

29. A method according to claim 19, wherein the cyclopropyl ring is attached to the phenyl ring at the E substituted position.

30. A method according to claim 19, wherein the cyclopropyl ring is attached to the phenyl ring at the unsubstituted position.

31. A method according to claim 19, wherein the compound of formula I

.NHBoc -OH j λ _NH₂. HCI

32. A method of inhibiting one amine oxidase while inhibiting another amine oxidase to a lesser degree comprising administering an effective amount of a compound of formula I

(I) wherein X is H, or an electron donating group, and Y is

wherein E is an electron donating group, and z is an integer from 0 to 3 or pharmaceutically acceptable salts thereof.

33. The method according to claim 32, wherein the monoamine oxidase that is inhibited is monoamine oxidase B and the monoamine oxidase that is inhibited to a lesser degree is monoamine oxidase A.