WO2005007614A1 - Inhibiteurs d'oxydase de monoamine - Google Patents

Inhibiteurs d'oxydase de monoamine Download PDF

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WO2005007614A1
WO2005007614A1 PCT/US2004/021505 US2004021505W WO2005007614A1 WO 2005007614 A1 WO2005007614 A1 WO 2005007614A1 US 2004021505 W US2004021505 W US 2004021505W WO 2005007614 A1 WO2005007614 A1 WO 2005007614A1
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aromatic
nmr
mmol
oxidase
trans
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PCT/US2004/021505
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English (en)
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Kenneth L. Kirk
Shinichi Yoshida
Gunter Haufe
Oliver G. J. Meyer
Thomas C. Rosen
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The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services 6011
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Publication of WO2005007614A1 publication Critical patent/WO2005007614A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/40—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing only non-condensed rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/36—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • 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.
  • MAO Monoamine oxidases
  • neurotransmitters such as 5-hydroxytryptamine, dopamine, and noradrenaline.
  • 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.
  • 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)
  • SSAO semicarbazide-sensitive amine oxidases
  • 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 example of an 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.
  • irreversible inhibitor includes tranylcypromine
  • 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.
  • 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.
  • E is an electron donating group
  • z is an integer from 0 to
  • 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.
  • 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.
  • electron donating group can include halogens, alkyls, amides, carboxylic acids, amines, hydroxyl, and ether.
  • electron withdrawing group can include carboxyl, ester, carboxamide, cyano, nitro, and trifluoromethyl.
  • alkyl includes linear or branched alkyl chains having from one to 4 (i.e. C ⁇ - C 4 or methyl to butyl) carbon atoms.
  • Alkyl includes alkanes, alkenes and alkynes.
  • halogen includes fluoro, chloro, bromo, or iodo.
  • pharmaceutically acceptable salt thereof includes an acid addition salt or a base salt.
  • 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).
  • E is an electron donating group
  • z is an integer from 0 to
  • 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.
  • E is a halogen. In another embodiment, E is fluorine.
  • z is 0. In another embodiment, z is 1. In another embodiment, z is 2. In another embodiment, z is 3.
  • X is an electron donating group.
  • X is a halogen, such as fluorine, chlorine, bromine, or iodine.
  • X is fluorine or chlorine.
  • X is an alkoxy group.
  • X is a methoxy group.
  • Y is wherein E is fluorine
  • X is either fluorine, or chlorine.
  • X, Y, E, and z not specifically excluded herein can be utilized in compounds of the invention.
  • compounds of the invention can have either a cis or trans configuration at any relevant carbon atom.
  • compounds of the invention can have either an R or an S configuration at chiral carbons.
  • 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
  • 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.
  • 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
  • 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).
  • 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).
  • the cyclopropylamines 5a and 5b can be prepared from the carboxylic esters 19a and 19b. (Scheme 5).
  • 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.
  • 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.
  • 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.
  • compounds are used in methods of inhibiting at least one monoamine oxidase.
  • compounds are used in inhibiting monoamine oxidases, such as a copper-containing amine oxidase, a flavin-containing amine oxidase, or some combination thereof.
  • compounds are used to inhibit monoamine oxidase A, monoamine oxidase B, tyramine oxidase or some combination thereof.
  • compounds are used in methods of inhibiting monoamine oxidase A while inhibiting another monoamine oxidase to a lesser degree.
  • 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.
  • 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
  • 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.
  • CAOs also referred to as semicarbazide-sensitive amine oxidases, SSAOs
  • SSAOs semicarbazide-sensitive amine oxidases
  • 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.
  • 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.
  • the compositions can contain microcrystalline cellulose, starch, magnesium stearate and lactose or other excipients, binders, extenders, disintegrants, diluents, and lubricants known in the art.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 %).
  • 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.
  • Example 5 Preparation and characterization of tr ⁇ _--(2-Fluoro-2- phenylcyclopropyD-methylamine Hydrochloride (7a).
  • the trans methylamine 7a was synthesized from tr ⁇ 7M-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 %).
  • 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.
  • 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 %).
  • 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 %).
  • Example 10 Preparation and characterization of czs- ⁇ -Fluoro-l- phenylcyclopropyD-methylamine (3b)
  • the c ⁇ -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%).
  • 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 trar ⁇ -isomer 4 was obtained by crystallization from ethanol. (Yield 0.13 g, 45%).
  • Example 12 Preparation and characterization of tr ⁇ H_ , -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 NaNO 2 (0.93 L) was slowly added dropwise. The reaction mixture was stirred for an additional 40 minutes at the same temperature.
  • 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 CH 2 Cl 2 /pentane at -20 °C cz_--MN4 was isolated as colorless, crystalline solid. (Yield: 167 mg, 93 %) Data for cis-MN4: Mp
  • 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.
  • 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.
  • trans-TR105 was synthesized using tr ⁇ z till_-TR102 (191 mg, 0.96 mmol). After silica gel chromatography (cyclohexane/ethyl acetate 10:1) tr ⁇ zw-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); !
  • czs-MN ⁇ 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 CH2Cl 2 /pentane cw-MN8 was isolated as colorless, crystalline solid.
  • Example 16 Preparation and characterization of tr ⁇ ,_-(+)-2-Fluoro-2-(4- chlorophenvDcyclopropylamme Hydrochloride (14b) Analogous to the general procedure for Curtius degradation, trans-TRlll was synthesized using tr ⁇ «_--MN9 (190 mg, 0.89 mmol) (tr ⁇ n5-2-(4-Chloro-phenyl)- 2-fluoro-cyclopropanecarboxylic acid- prepared as is example 18 for the preparation of TR110, with 4-methylstyrene is utilized).
  • Example 17 Preparation and characterization of ct_ ⁇ -( ⁇ )-2-Fluoro-2-(4- methylphenyDcyclopropylamine Hydrochloride (15a) To an ice cooled solution of 4-methylstyrene (9.45 g, 80.0 mmol) in anhydrous CH 2 C1 2 (80 ml), Et 3 N-3HF (40 ml, 244 mmol) and N-Bromosuccinimide j
  • TR121 was obtained as a colorless oil which contained 4 % of the regioisomeric terminale bromofluoride (TR121b).
  • TR121b regioisomeric terminale bromofluoride
  • the reaction mixture was diluted with CH 2 C1 (150 ml) and washed with saturated NaCO 3 and H 2 O (300 ml).
  • the organic phases were dried (MgSO 4 ) 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.
  • 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.
  • Example 18 Preparation and characterization of tr ⁇ n.--(+)-2-Fluoro-2-(4- methylphenvDcyclopropylamine Hydrochloride (15b) To an ice cooled solution of 4-methylstyrene (9.45 g, 80.0 mmol) in anhydrous CH 2 C1 2 (80 ml), Et 3 N-3HF (40 ml, 244 mmol) and N-Bromosuccinimide ( ⁇ BS) (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 ⁇ H 4 OH.
  • 4-methylstyrene 9.45 g, 80.0 mmol
  • Et 3 N-3HF 40 ml, 244 mmol
  • ⁇ BS N-Bromosuccinimide
  • the reaction mixture was diluted with CH 2 CI 2 (150 ml) and washed with saturated NaCO 3 and H 2 O (300 ml).
  • the organic phases were dried (MgSO 4 ) 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 2 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.
  • trans-TR112 Analogous to the general procedure for hydrolysis with KOH, tr ⁇ «_--TR112 was synthesized using trans-TRH (524 mg, 2.32 mmol). After recrystallization from CH 2 Cl 2 /pentane (1:4) trans-TR112 was isolated as white, amorphous solid.
  • tr ⁇ ra,_-TR114 Analogous to the general procedure for Curtius degradation, tr ⁇ ra,_-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.
  • trans- TR119 was synthesized using trans-TR114 (53 mg, 0.263 mmol). After recrystallization from methanol/Et 2 O trans-TR119 was isolated as white solid.
  • Tyramine oxidase purchased from Sigma, is sold as a flavin-containing amine oxidase (EC: 1.4.3.4).
  • EC: 1.4.3.4 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).
  • 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 ⁇ mol 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).
  • Compound 6a was a very potent inhibitor, having an IC 50 value 10 times lower than the values for the non-fluorinated compounds la (tranylcypromine) and its cis- isomer lb.
  • 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 tr ⁇ rcs-ethylamine 8a is about two orders of magnitude less active compared to 6a.
  • the compounds 3 a, 4 and 6a are non-competitive, irreversible and competitive inhibitors for tyramine oxidase, respectively.
  • compound la is a reversible and competitive inhibitor for tyramine oxidase.
  • a cz ' s-relationship of fluorine and amino group (6a) greatly enhances activity whereas fluorine trans to the amine (6b) substantially decreases activity.
  • 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. IC 50 values (inhibitor concentration at 50%) remaining activity) were calculated graphically from the inhibition curves obtained (FIG. 5). The results are shown in Table 3.
  • non-fluorinated phenylcyclopropylamines 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.
  • Table 4 shows data for the inhibition of tyramine oxidase for all of the compounds tested as measured above. Table 4: IC 50 values and inhibition type for compounds.
  • Example 23 Inhibition of monoamine oxidase A and monoamine oxidase B by compounds of the invention
  • 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 ⁇ mol 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 ⁇ mol 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 IC 50 values are summarized in Table 5. Table 5. IC 50 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
  • MAOA and B were strongly and selectively inhibited by clorgyline and R-(-)-deprenyl, respectively.
  • MAOA was inhibited by the traz ⁇ -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).
  • 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.
  • 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.
  • p c a 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.
  • Example 25 Inhibition of Monoaminer Oxidase A and Monoamine Oxidase B by compounds of the invention
  • Table 6 shows the results for the inhibition of monoamine oxidase A and monoamine oxidase B by the following compounds.
  • cw-2-fluoro-l-phenycyclopropylamine 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.

Abstract

L'invention concerne des composés correspondant à la formule (I), leurs sels pharmaceutiquement acceptables, des compositions contenant des composés correspondant à la formule (I), des procédés pour inhiber au moins une oxydase de monoamine tout en inhibant une autre oxydase de monoamine à un degré moins important au moyen d'un composé ayant la formule (I). Chaque X est indépendamment un groupe donneur d'électrons ou un groupe de retrait d'électrons, n est un nombre entier compris entre 0 et 3 et Y est la formule (II), (III), (IV), (V) (VI); E et un groupe donneur d'électrons et z et un nombre entier compris entre 0 et 3, à condition que si Y est formule (VII) ou formule (VIII), dans lesquelles le noyau cyclopropylique est attaché au carbone substitué par E, X n'est pas H; ou son sel pharmaceutiquement acceptable.
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WO2006097817A1 (fr) 2005-03-17 2006-09-21 Pfizer Japan Inc. Derives de n-(n-sulfonylaminomethyl)cyclopropanecarboxamide utilises pour traiter une douleur
WO2007025144A1 (fr) * 2005-08-24 2007-03-01 University Of Illinois - Chicago Agonistes de recepteur 5-ht2c utilises en tant qu'agents anorexigenes
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
JP2013518894A (ja) * 2010-02-04 2013-05-23 ザ・ボード・オブ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・イリノイ ５−ｈｔ（２ｂ）受容体でアンタゴニスト活性を有する高選択性５−ｈｔ（２ｃ）受容体アゴニスト
JP2013525318A (ja) * 2010-04-20 2013-06-20 ウニヴェルシタ・デグリ・ストゥディ・ディ・ローマ・ラ・サピエンツァ ヒストンデメチラーゼｌｓｄ１及び／又はｌｓｄ２の阻害剤としてのトラニルシプロミン誘導体
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
WO2016123164A1 (fr) 2015-01-29 2016-08-04 The Board Of Trustees Of The University Of Illinois Cyclopropylméthanamines utilisées comme agonistes sélectifs des récepteurs 5-ht(2c)
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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JP2013525318A (ja) * 2010-04-20 2013-06-20 ウニヴェルシタ・デグリ・ストゥディ・ディ・ローマ・ラ・サピエンツァ ヒストンデメチラーゼｌｓｄ１及び／又はｌｓｄ２の阻害剤としてのトラニルシプロミン誘導体
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
WO2016123164A1 (fr) 2015-01-29 2016-08-04 The Board Of Trustees Of The University Of Illinois Cyclopropylméthanamines utilisées comme agonistes sélectifs des récepteurs 5-ht(2c)
US10407381B2 (en) 2015-01-29 2019-09-10 The Board Of Trustees Of The University Of Illinois Cyclopropylmethanamines as selective 5-HT(2C) receptor agonists
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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