MXPA01003846A - 1,2-disubstituted cyclopropanes - Google Patents

Abstract

Compounds of Formula (I), wherein the substituents are as described in the specification or pharmaceutically acceptable salts or stereochemically isomeric forms thereof, useful for treating diseases related to calcium imbalance and metabolism.

Description

CICLOPROPANOS 1,2-DISUSTITUTE RECIPROCAL REFERENCE TO RELATED REQUESTS This application claims the priority of United States Provisional Application Series No. 60 / 104,132, filed on October 14, 1998, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION This invention relates to novel cyclopropane derivatives, pharmaceutical compositions containing them and methods of using them. The compounds of the invention bind to the calcium detector receptor and, thus, are useful in the treatment of diseases related to calcium imbalance and metabolism.

BACKGROUND OF THE INVENTION Known cyclopropane derivatives include secondary and tertiary cyclopropyl methylamines described in Teotino, U. M .; Della Bella, D .; Gandini, A .; Benelli, G., J. Med. Chem. 1967, Vol. 10, p. 1091 as monoamine oxidase inhibitors; and cyclopropyl-methylguanidines described in Borne, R. F .; Forrester, M. L .; Waters, I. W., J. Med. Chem. Vol. 20, p. 771 - * - ß-te ^ ri-MMlMÍ-Íl- (1977) as useful in the treatment of hypertension. GB 1, 086,191 describes certain phenyl cyclopropane derivatives. Extracellular calcium can exert effects on different cellular functions as described in Nemeth et al., 11 Cell Calcium 319, 1990. The function of extracellular calcium in parafollicular and parathyroid cells is described in Nemeth, et al., 11 Cell Calcium 323, 1990. PCT / US93 / 01642 (WO 94/18959); PCT / US95 / 13704 (WO 96/12697) and PCT / US92 / 07175 (WO 93/04373) describe compounds that are described as modulators of the inorganic ion receptor activity, such as by simulating or blocking the effect of extracellular calcium on a calcium receptor on the cell surface.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to compounds of formula I: wherein R1 is unsubstituted aryl; or aryl substituted with at least one substituent selected from the group consisting of C-t-Cd alkyl, cycloalkyl, halogen, haloalkyl, nitro and C? -C6 alkoxy; R 2 is phenyl substituted with at least one substituent selected from Ci-Cß alkyl, cycloalkyl, haloalkyl, chloro, fluoro, iodo, C 6 alkoxy, alkylthio, arylthio, alkylsulfone, arylsulfone, hydroxy, hydroxyalkyl, -COOR 7 and CON ( R8) 2; unsubstituted heteroaryl or heteroaryl substituted with at least one substituent selected from C-Cß alkyl, cycloalkyl, haloalkyl, chlorine, fluorine and iodine; R3 is hydrogen, C-i-Ce alkyl or geminal dialkyl of C-i-Cß; R 4 is hydrogen, CON (R 9) 2, SO 2 N (R 10) 2, COR 11 or COOR 12; R5, R6, R7, R8, R9, R10, R11 and R12 are independently selected from hydrogen or alkyl; and n is 1; or a pharmaceutically acceptable salt or stereochemically isomeric form thereof. The compounds of formula I bind to the calcium receptor and, thus, are useful in the treatment of diseases related to calcium imbalance and metabolism. These diseases include hyperparathyroidism, osteoporosis, Paget's disease, malignant hypercalcemia, hypertension and renal osteodystrophy. The present invention also relates to pharmaceutical compositions containing one or more of the compounds of formula I, and methods for the treatment of disorders related to calcium imbalance such as, for example, hyperparathyroidism, osteoporosis, and the like.

In another aspect, the claimed invention refers to intermediates of formula: wherein R1, R2 and R3 are as defined above, and one of R5 and R6 is alkyl and the other is hydrogen, or R5 and R6 are alkyl.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term alkyl, alone or in combination, refers to straight chain, cyclic and branched alkyl groups. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl, t-butyl, and the like, preferably C 1 -C 2 alkyl. Alkoxy radicals are oxygen ethers formed from the straight or branched chain alkyl groups described above, and Ci-Cß alkoxy is preferred. The term "aryl", as used herein, alone or in combination with other terms, indicates aromatic hydrocarbon groupsSuch as phenyl or naphthyl, more particularly preferred is phenyl and cyclic heteroaromatic groups ("heteroaryls") such as furan, pyridine, thiophene and pyrrole, preferably the cyclic heteroaromatic group is a 5- or 6-membered ring, wherein the heteroatom is at least one of N, S or O, more preferred is a heteroatom. With respect to substituents, the term independently means that when more than one of said substituents is possible, said substituents may be identical or different from each other. The term halogen defines fluorine, chlorine, bromine and iodine. When the compounds of formula I contain a basic portion, acid addition salts can be prepared. Examples of suitable acids forming said salts include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic, cyclohexansulfamic, salicylic, 2-phenoxybenzoic or 2-acetoxybenzoic, and the like. Said salts can be obtained by known methods which consist of reacting the free base of the compounds of formula I with the acid, and isolating the salt. The stereochemistry of cyclopropane is cis or trans, preferably trans, and the absolute stereochemistry at the stereogenic center identified in formula I by an asterisk is R or S, preferably R. The term stereochemically isomeric forms, as used herein , defines the different isomeric forms that the compounds of formula I may possess. Unless otherwise mentioned or indicated, the chemical designation of the compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all the diastereomers and / or enantiomers of the basic molecular structure. It is intended that all stereochemically isomeric forms of the compounds of formula I, in pure form or in admixture with one another, be embraced within the scope of the present invention, and can be obtained using conventional means. The present invention is directed to compounds of formula I: wherein R1 is unsubstituted aryl; or aryl substituted with at least one substituent selected from the group consisting of C -? - C6 alkyl, cycloalkyl, halogen, haloalkyl, nitro and alkoxy; R 2 is phenyl substituted with at least one substituent selected from C 1 -C 6 alkyl, cycloalkyl, haloalkyl, chlorine, fluorine, iodine, CrC 6 alkoxy, alkylthio, alkylsulfone, arylsulfone, hydroxy, hydroxyalkyl, -COOR 7 and CON (R 8) 2; R3 is hydrogen, C? -C6 alkyl or geminal dialkyl of C -? - C6; R 4 is hydrogen, CON (R 9) 2, SO 2 N (R 10) 2, COR 11 or COOR 12; R5, R6, R7, R8, R9, R10, R11 and R12 are independently selected from hydrogen or alkyl; and n is 1; or a pharmaceutically acceptable salt or stereochemically isomeric form thereof. Of particular interest are the compounds wherein R 1 is unsubstituted aryl or aryl substituted with halogen or C 1 -C 6 alkyl; R2 is unsubstituted pyridyl, pyridyl substituted with at least one of CI-CT alkyl, cycloalkyl, haloalkyl, chloro, fluorine or iodine, or phenyl substituted with at least one substituent selected from C -? - C6 alkyl, cycloalkyl , halogenoalkyl, chlorine, fluorine, iodine, Ci-Cβ alkoxy, alkylthio, alkylsulfone, arylsulfone, hydroxy, hydroxyalkyl, -COOR7 and CON (R8) 2; the stereochemistry in the cyclopropane is trans, preferably the absolute configuration R, R; R3 is alkyl, preferably methyl, and R4 is hydrogen, CON (R9) 2, COR11 or COOR12, preferably hydrogen. More preferred are the compounds of formula I, wherein R 1 is phenyl or thiophene or unsubstituted phenyl or thiophene substituted with halogen or C 1 -C 6 alkyl; R 3 is phenyl substituted with C 1 -C 6 alkyl, chloro, fluoro, iodo or C 1 -C 6 alkoxy. In particularly preferred compounds, R 1 is thiophene or unsubstituted phenyl, and R 2 is phenyl substituted with C 1 -C 6 alkoxy. The absolute stereochemistry is more preferably RRR. In a particularly preferred embodiment, the compound of formula I is N - ((R, R) -2-phenylcyclopropanylmethyl) -1- (R) - (3-methoxyphenyl) ethylamine, represented by formula IA: IA The compounds of formula I are prepared as described in Schemes 1-6.

SCHEME 1 SAW wherein R1, R3, R5 and R6 are as defined above, and R2 is as described above for R2, except that R2 is not phenyl substituted with at least one substituent selected from alkylsulfone, arylsulfone, -COOR7 and -CON (R8) 2.

SCHEME 1 b wherein R1, R3, R4, R5 and R6 are as defined above, and R2"is phenyl substituted with at least one substituent selected from alkylsulfone, arylsulfone, -COOR7 and -CON (R8) 2. As described in Scheme 1 above, the styrene of formula II, a known compound or compound prepared by known methods, is reacted with an alkyl diazoacetate, a known compound or compound prepared by known methods, at reflux in an inert high boiling solvent , such as xylene, to produce the corresponding compound of formula III, which is then selectively saponified, for example, with a metal hydroxide, such as potassium or sodium hydroxide to form the corresponding compound of formula IV. compound of formula III is separated into its cis and trans components by known methods {Org Syn. Coll. Vol. VI 1988, 913) The compound of formula IV is converted to the corresponding salt of formula VI by reaction, preferably at room temperature with a compound of formula Va, in a polar aprotic solvent, such as acetonitrile and a coupling agent such as dicyclohexylcarbodiimide (Aust. J. Chem. 1984, 37, 1709). The compound of formula VI is reduced to the corresponding compound of formula I with a reducing agent, such as with BH3 in tetrahydrofuran (THF), or with lithium or sodium borohydride, followed by the addition of chlorotrimethylsilane, at elevated temperatures in the 50 ° C scale until reflux. Alternatively, as described in scheme Ib, a compound of formula IV can be reduced to the corresponding primary alcohol of formula VII with a reducing agent such as BH3, preferably at room temperature. The compound of formula VII can be converted to the corresponding compound of formula Ib by displacement reaction, such as a Mitsunobu reaction, with a compound of formula Vb.

SCHEME 2a wherein R2 is as defined above for R2, except that R2 'is not phenyl substituted with at least one substituent selected from alkylsulfone, arylsulfone, -COOR7 and -CON (R8) 2; R3 is hydrogen or alkyl of The intermediates of formula Ve are prepared as described in scheme 2a. A compound of formula VIII, a known compound or compound prepared by known methods, is converted to the corresponding compound of formula IX by heating with hydroxylamine in a polar solvent such as ethanol, preferably at about 60 to 80 ° C. The compound of formula IX is reduced, preferably at room temperature, to the corresponding compound of formula Ve, preferably by reaction with hydrogen gas and a catalyst such as palladium, in a polar solvent such as methanol.

SCHEME 2b To the wherein R2 is as defined above, and R3 'is C6 alkyl. The intermediates of formula Vd are prepared as described in scheme 2b. A compound of formula X is reacted with a carbon nucleophile such as methyl magnesium bromide in a non-polar aprotic solvent, such as diethyl ether to form the corresponding compound of formula XI. The compound of formula XI is reacted with an azide liberating agent, such as diphenylphosphoryl azide, in a non-polar solvent such as toluene to form the corresponding compound of formula XII. The compound of formula XII is reduced to the amine, preferably by reaction with hydrogen gas and a catalyst such as palladium in a polar solvent such as ethanol, to form the corresponding intermediate of formula Vd.

SCHEME 3 wherein R 3 is as defined above, and X is a leaving group such as halogen, oxygen or nitrogen. Intermediates of formula Vf are prepared as described in scheme 3. A primary amine of formula Ve, a known compound or compound prepared by known methods, is protected with a group such as phthalimide to form the corresponding compound of formula XIII. The methyl ether of the compound of formula XIII is removed with a Lewis acid, preferably BBr3 in a non-polar solvent such as methylene chloride, to form the corresponding phenol of formula XIV. The phenol of formula XIV is alkylated with an alkylating agent such as alkyl halide, an alkyl tosylate or an alkyl mesylate in the presence of a base, preferably NaH, to form the corresponding compound of formula XV. The compound of formula XV can be deprotected, for example, with hydrazine in refluxing alcohol, preferably ethanol, to form the corresponding primary amine of formula Vf.

SCHEME 4 wherein the substituents are as defined above, except that when R2 is phenyl substituted with hydroxyl or hydroxyalkyl, the hydroxyl group is protected first with a protecting group such as a t-butyldimethylsilyl group. The compounds of formula I, wherein R 4 is different from H (le), can be synthesized as shown in scheme 4, by treating the compound of formula Ib with an appropriate acylation or alkylating agent in the presence of a non-nucleophilic base, such as triethylamine or Hunig's base.

SCHEME S wherein R3 is as described above, and Q is alkyl or aryl. The starting materials of formula Vf and Vg can be obtained as shown above in scheme V. A compound of formula XIII can be demethylated with BBr3, to form the corresponding compound of formula XVI. A compound of formula XVI can be acylated with an agent such as dimethylcarbamic chloride to produce a corresponding compound of formula XVII. The compound of formula XVII can be heated, for example, in diphenyl ether to reflux, to form the corresponding thiocarbamate of formula XVIII (Synthesis 1992, 112). The compound of formula XVIII can be hydrolyzed or saponified with aqueous acid or aqueous base, such as hydrochloric acid or sodium hydroxide, to form the corresponding compound of formula XIX. The compound of formula XIX can be alkylated, for example, with an alkyl halide, or arylated (J. Org. Chem 1995, 60, 7144) to the corresponding compound of formula XX. The compound of formula XX can be deprotected with a reagent such as hydrazine to produce the corresponding compound of formula Vf, which can be converted to the cyclopropane product of formula I by any of the methods described above. Alternatively, the compound of formula XX can be oxidized to the corresponding sulfone of formula XXI with an oxidation agent such as metachloroperoxybenzoic acid (mCPBA) (Helv, Chim Acta 1984, 67, 1316). The compound of formula XX can be deprotected with a reagent such as hydrazine to produce the corresponding compound of formula Vg, which can be converted to the cyclopropane of formula I by the method of scheme Ib.

SCHEME 6 wherein R3 and R8 are as defined above, and R7 'is alkyl. As described in scheme 6 above, a compound of formula XXIV, a known compound or compound prepared by known methods, can be converted to the corresponding ester of formula XXV (Chem. Comm. 1990, 426). The compound of formula XXV can be converted to the compound of formula XXVI by a method such as acid hydrolysis with a reagent such as aqueous HCl, at elevated temperature, near reflux. A compound of formula XXVI can be converted to a corresponding compound of formula Vh by deprotection with a reagent such as hydrazine in a polar solvent such as ethanol at temperatures near the reflux of ethanol. In alternative form, a compound of formula XXVI can be converted to a corresponding acid chloride of formula XXVII by reaction with a reagent such as thionyl chloride in an inert solvent such as methylene chloride, at room temperature or at a lower temperature. The compound of formula XXVII can be converted to a corresponding ester of formula XXVIII with an alcohol, such as 2- (dimethylamino) ethanol, by reaction at room temperature or a lower temperature. The compound of formula XXVIII can be deprotected to a compound of formula Vi by a known method such as reaction with ammonia in a polar solvent such as ethanol, at temperatures near the reflux of ethanol. Alternatively, a compound of formula XXVII may be aminated and deprotected to a compound of formula Vj by a known method such as reaction with dimethylamine in an inert solvent such as methylene chloride, at room temperature or at a lower temperature.

Activity of calcium detection receptors in vitro and in vivo The in vitro potency is measured by calcium mobilization in a fluorescence test using transfected HEK 293 cells to express the same calcium detector receptor present in the human parathyroid gland. In this test, agonists and antagonists of the calcium detector receptors are detected. The test is carried out in a 96-well plate format with the use of FLIPR (fluorescent imaging plate reader; Molecular Devices, Sunnyvale, CA). The HEK 293 cell medium is replaced with the FLUO-3AM fluorescence dye and Pluronic detergent in test pH regulator for FLIPR. The cells are incubated for 60 minutes (in the dark, at room temperature), then washed with a pH regulator, and placed in the FLIPR. Images are collected by FLIPR in the absence of the test compound, then in the presence of the test compound (at 25 M), and then after the addition of a calcium challenge (at 1 mM). In the agonist test, the difference between the maximum and minimum fluorescence values is measured after the addition of the test compound. The shocks have a change in fluorescence greater than or equal to 50% of that observed with a calcium standard at 1 mM. In the antagonist test, the difference between the maximum and minimum fluorescence values is measured after the addition of the calcium challenge. When compared to the challenge in the absence of the test compound, the shocks reduce the fluorescence by at least 50%. In vivo activity is measured by the suppression of parathyroid hormone (PTH) by test compounds in a rat model. The compound is orally administered using 0.5% Tween 80 in distilled water as a carrier, with a volume of approximately 10 ml / kg of body weight. Blood samples are obtained at 15 minutes (and 4 hours, if required) for post-oral dosing. Serum PTH levels are determined with an immunoradiometric test.

PICTURE Not all compounds were tested in each of the studies. A script that fills the space for a particular compound indicates that the compound was not tested in that study. Table 1 includes those compounds in which the stereochemistry is not controlled. Each entry represents a mixture of cis and trans cyclopropanes (R, S; S, R; R, R; S, S) with absolute configuration R, when R3 = CH3. Table 2 includes compounds that are trans in cyclopropane (R, R; S, S) with the absolute configuration R in the benzylamine position, or without stereochemistry in benzylamine. Table 3 includes compounds with the absolute stereochemistry R, R in the cyclopropane, and a mixture of stereochemistry in the benzylamine position. Table 4 includes compounds with the absolute configuration R, R, R. Table 5 includes substituted compounds in the amine. Table 6 includes compound IA and all other stereoisomers. Table 7 includes compounds not included in some of the six previous tables. Table 8 includes stereoisomers of compound number 20. The in vitro data in Table 1 correspond to the percentage of activation of the calcium detector receptor against the baseline. The in vitro data in Tables 2 to 7 are expressed as a CS50, where the potency is 50% the standard potency of calcium, and the unit is μM. The in vivo data represent the percentage of PTH in blood serum against vehicle at 30 mg / kg of the test compound, where the levels were measured after 15 minutes.

TABLE 1 Table 2, R3 = H or CH3 trans substitutions in cyclopropane TABLE 2 R1 R2 R3 in vitro In vivo MS (MHH 2-PIRIDYL 3-CH3OPh CH3 6.5-282 (M +) 3-PYRIDYL 3-CH3OPh CH3 37.1-284 4-PIRIDYL 3-CH3OPh CH3 > 25 - 282 (M +) 2-CH3Ph 3-CH3OPh CH3 8.8 -95.8 296 3-CH3Ph 3-CH3OPh CH3 9.5 -98.2 296 2-CF3Ph 3-CH3OPh CH3 52.2 -34.7 350 3-CF3Ph 3-CH3OPh CH3 13.5 +4.2 350 4-CF3Ph 3-CH3OPh CH3 > 25 -14.4 350 2-FPh 3-CH3OPh CH3 5.0 -94.8 300 2-FPh, 3-CH3OPh CH3 11.3 -83.9 299 (M +) DIASTEREO MERO UNO 2-FPh, 3-CH3OPh CH3 9.6 -89.2 299 (M +) DIASTEREO MERO UNO 3-FPh 3-CH3OPh CH3 11.0 -95.2 300 3-FPh, 3-CH3OPh CH3 10.9 -78.7 299 (M +) DIASTEREO MERO UNO 2-FPh, 3-CH3OPh CH3 9.3 -93.4 299 (M +) DIASTEREO MERO UNO 4-FPh 3-CH3OPh CH3 13.5 -55.0 300 2,6-diFPh 3-CH3OPh CH3 11.9 -85.4 318 2-TIENYL 3-CH3OPh CH3 7.1 -89.0 288 3-TIENYL 3-CH3OPh CH3 3.4 - 288 2- (N-METHYL-3-CH3OPh CH3 7.8-285 PIRROLO) Ph 2-PIRIDYL H > 25 +72.0 239 Ph 3-PYRIDILO H > 25 +87.8 239 Ph 4-PYRIDILO H > 25 +70.1 239 Ph 3-CH3OPh H > 25 -26.5 268 2,5-diMePh 3-CH3OPh CH3 12.4 -13.5 310 2,5-diMePh 3-CH3OPh CH3 > 25 -47.6 310 2,4- (NO 2) 2Ph 3-CH 3OPh CH 3 > 25 - 372 2- (5-CI-thienyl) 3-CH3OPh CH3 -15.4 322 2- (5-CH3- 3-CH3OPh CH3 -34.2 302 thienyl) 2- (4-Br-thienyl) 3-CH3OPh CH3 -24.8 366/368 2- (3-CH3- 3-CH3OPh CH3 -51.0 302 thienyl) TABLE 3 # Y R3 in vitro in vivo MS (MH +) 39 CF3O CH3 - 0.0 336 40 CH3 CH3 > 25 -51.2 266 41 CF3 CH3 > 25 -21.4 320 42 CH2CH3 CH3 > 25 -78.9 280 43 CH3O CH2CH3 > 25 -6.3 296 44 CH3O gem- (CH3) 2 > 25 -25.8 296 45 F CH3 > 25 -19.6 270 46 Cl CH3 > 25 -15.9 286 47 3.4 - (- OCH2O-) CH3 > 25 -67.3 296 TABLE 4 # W in vitro in vivo MS (MH +) 48 H 8.7 -41.7 268 49 CH3 5.0 -83.6 282 50 CH2CH3 11.9 -57.0 296 51 CH (CH3) 2 > 25 -7.3 310 52 c-PENTILO 12.2 26.6 336 TABLE 5 # Z in vitro in vivo MS (M +) 3 CH3 > 25 -6.4 323 7 OCH2CH (CH3) 2 > 25 -5.3 381 8 CH2NH (t-BOC) > 25 -12.7 439 (MH +) Table 6 Absolute stereochemistry in 1, 2 and 3 TABLE 6 3 in vitro in vivo MS (MH +) R R R 5.0 -83.6 282 S S R 12.9 -42.1 282 S R R 11.2 0.0 282 R S R 17.6 0.0 282 R R S > 25 -40.1 282 S S S > 25 -11.7 282 R S S > 25 -38.8 282 S R S > 25 -61.8 282 TABLE 7 # In vitro structure / l V / V? MS (MH +) Table 8 Absolute stereochemistry in 1, 2 and 3 TABLE 8 # 1 2 3 ln \ ín vivo MS (MH +) 71 s S R -78.7 300 72 R R R -93.4 300 73 - - R -52.5 300 74 - - R -2.6 300 75 s S -0.9 300 76 R R S +16.8 300 77 - - S +2.1 300 78 - - S +21.4 300 To prepare the pharmaceutical compositions of this invention, one or more compounds or salts thereof, such as the active ingredient, are intimately mixed with a pharmaceutical pharmaceutical carrier with conventional pharmaceutical combination techniques, of which the carrier can take a wide variety of forms, depending on the form of preparation desired for administration, for example, oral or parenteral. In the preparation of the compositions in oral dosage form, any of the usual pharmaceutical media can be used. Thus, for liquid oral preparations such as, for example, suspensions, elixirs and solutions, suitable vehicles and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like; for solid oral preparations such as, for example, powders, capsules and tablets, vehicles and suitable additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously used. If desired, the tablets may be coated with sugar or coated with an enteric layer by standard techniques. For parenteral preparations, the vehicle will usually comprise sterile water, although other ingredients may be included, for example, for purposes such as facilitating solubility or for preservation. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents, and the like may be used. The pharmaceutical compositions herein will preferably contain per dosage unit, eg, tablet, capsule, powder, injection, teaspoonful, and the like, of about 10 to 1000 mg of the active ingredient, although other unit dosages may be used. In the therapeutic use for the treatment of disorders related to calcium imbalance and metabolism in mammals, the compounds of this invention can be administered in an amount of about 0.3 to 30 mg / kg three times per day orally, and particularly preferably from 1 to 10 mg / kg preferably three times per day. In addition, the compounds can be administered by injection at 0.1 to 10 mg / kg per day. The determination of optimal dosages for a particular situation is within the capabilities of the formulators. To illustrate the invention, the following examples are included. These examples do not limit it. It means that they illustrate and suggest a method for putting the invention into practice. Although there are other methods for practicing this invention, it is considered that such methods are within the scope of this invention.

EXAMPLE 1 N fR.R) -2-phenylcyclopropanylmethyl) -1- (RM3-mTtoxyphenyl) tthylamine (a) (N) -hydroxysuccinimide (O) -diazoacetate (3.5 g, 19.1 mmol) in 75 ml of CH2Cl2 was dropwise added to a solution of (R) - (3-methoxyphenyl) ethylamine (3.0 g, 20.1 mmoles) and triethylamine (4.0 ml, 28.7 mmol) in 125 ml of CH 2 Cl 2 at 0 ° C under an N 2 atmosphere. This was stirred for 0.5 hour, then an ice bath was removed, and stirred for 1.5 hours at room temperature. The solvent was removed, and cleaned on silica. 3.4 g of (R) - (3-methoxyphenyl) ethyl diazoacetamide (15.7 mmol, 82%) were obtained. NMR (1H, CDCl 3) 7.30 (t, 1 H, J = 8.5), 6.85 (m, 3H), 5.1 (br m, 1 H), 3.79 (s, 3 H), 1.48 (d, 3 H, J = 8.5). (b) Diazoacetamide (312 mg, 1.4 mmol) in 10 ml of dichloroethane was added dropwise to styrene (1.4 ml, 12 mmol) and rhodium acetate dimer (5 mg, 0.011 mmol, 1 mol%) at room temperature. environment, and exposed to the atmosphere. This was stirred at room temperature overnight and then heated to 70 ° C for 2 hours. The solvent was removed and cleaned on silica. 181 mg (0.61 mmol, 44%) of the cyclopropylamide was obtained as a mixture of four diastereomers (14.7: 8.8: 1.4: 1). MS (GC / MS) m / z 295 (M +). (c) Cyclopropane (164 mg, 0.56 mmol) was dissolved in 16 ml of THF, cooled to 0 ° C and borane-THF (1.0 M solution, 2.24 mmol) was added via syringe. This was refluxed overnight, then cooled to 0 ° C, and 2 ml of HCl was added to 6 N. This was stirred for 2 hours, THF was removed, and then 9 ml of saturated aqueous Na 2 CO 3 was added. . This was extracted with 2 X 7 mL of CH2Cl2 and 5 mL of ethyl acetate. The organic extracts were combined, diluted with 12 ml of ether, and washed with brine. The organic extracts were dried (Na2SO4), filtered, and the solvent was removed. 156 mg (0.56 mmole, 99%) of N - ((R, R) -2-phenylcyclopropanylmethyl) -1- (R) - (3-methoxyphenyl) ethylamine were obtained. MS (Cl) m / z 282 (MH +). Compounds 1, 2, 3, 4, 5, 6, 7 and 8 of Table 1 were prepared analogously to Example 1.

EXAMPLE 2 N - ((R.R) -2-phenylcyclopropanylmethyl) -1- (R) - (3-methoxy-phenyl) ethylamine (a) Fra.ns-2-phenylcyclopropanecarboxylic acid (4.7 g, 29 mmoles) to the enantiomer (R, R) with dehydroabietylamine (8.5 g, 29.8 mmoles), as reported in J. Med. Chem. 1972, 15, 1187. The amine salt (3.5 g, 7.8 mmoles, 54% of the acid R, R).

Melting point 168.5-170 ° C (lit 174.0-174.5 ° C); [or -75.6 (lit-80.2). (b) The (R, R) -2-phenylcyclopropanecarboxylic acid (7.5 g, 46 mmol) and (R) -3-methoxyphenyl) ethylamine (9.5 g, 63 mmol) were converted to the amide by the method reported in Aust. J. Chem. 1984, 37, 1709. Recrystallization from acetone / hexane afforded 7.55 g (25.5 mmol, 56%) of the amide [1 R- [1a (R *), 2b]] - 2-phenyl- N- (1- (3-methoxyphenyl) ethyl) cyclopropanecarboxamide. Melting point 149.5-150.0 ° C. A second crop produced 1.59 g (5.4 mmol, 12%) of the amide. Melting point 148.0-149.5 ° C. (c) [1R- [1a (R *), 2b]] - 2-phenyl-N- (1- (3-methoxyphenyl) ethyl) cyclopropanecarboxamide (13.6 g, 46 mmol) was dissolved in 320 ml of THF, and it was cooled to 0 ° C, under N2. BH3 »THF (164 mL, 164 mmol) was added dropwise. After concluding the addition, the solution was heated to reflux overnight. The solution was cooled to 0 ° C and 165 mL of 6 N HCl was carefully added. This was stirred exposed to the atmosphere for two hours. The THF was removed in vacuo. The aqueous residue was basified to pH 9 with Na 2 C 3 solution and extracted with 5 X 100 ml of CH 2 Cl 2. The combined extracts were washed with 100 ml of water and 100 ml of water / brine 1: 1. The organic extracts were dried (Na 2 SO), filtered, and the solvent was removed. 13 g (46 mmol, 99%) of N - ((R, R) -2-phenylcyclopropanylmethyl) -1- (R) - (3-methoxyphenyl) ethylamine were obtained. NMR (1H, CDCl 3) 7.3-6.73 (m, 9H), 3.8 (m, 4H), 2.50 (d, 2H, J = 8), 1.64 (m, 1 H), 1.22 (d, 3H, J = 8), 1.0-0.75 (m, 3H). MS (Cl) m / z 282 (MH +).

EXAMPLE 3 N- a? Raps-2- ^ 3-fluorophenyl) cyclopropanlmethyl) -1-fRW3-methoxyphenyl) ethylamine (a) 3-Fluorostyrene (9.7 ml, 82 mmol) and ethyl diazoacetate (8.6 ml, 82 mmol) were reacted by the method reported in Org. Syn. Coll. Vol. VI, 1988, 913. The product was purified on silica. There were obtained 9.4 g of ethyl 2- (3-fluorophenyl) cyclopropane carboxylate (45 mmol, 55%). MS (GC / MS, El) 208 (M +). (b) The trans ester was selectively hydrolyzed from the cis / trans mixture by the method reported in Org. Syn. Coll. Vol. VI, 1988, 913. Recrystallization from hexane afforded 2.5 g (13.9 mmol, 89% trans) of trans-2- (3-fluorophenyl) -cyclopropanecarboxylic acid. (c) The acid / ra 7S-2- (3-fluorophenyl) cyclopropanecarboxylic acid (400 mg, 2. 2 mmol) and (R) -3-methoxyphenyl-ethylamine (280 mg, 1.9 mmol) were converted to the diastereomeric amides by the method reported in Aust. J. Chem. 1984, 37, 1709. 446 mg (1.4 mmol, 75%) of trans-2- (3-fluorophenyl) -N- (1 (R)) - (3-methoxyphenyl) ethyl) cyclopropane carboxamide were obtained. . f MS (GC / MS, EI) 313 (M +). (d) The mixture of diastereomeric amides (550 mg, 1.8 mmol) was reduced to the amines with BH3 * THF (7 ml, 7.0 mmol) in 10 ml of THF After concluding the addition, the solution was heated to reflux overnight. The solution was cooled to 0 ° C, and 7 ml of HCl was added carefully to 6 N. This was stirred exposed to atmosphere f for two hours, and the THF was removed in vacuo. The aqueous residue was basified to pH 9 with Na 2 CO 3 solution and extracted with 3 x 20 ml of CH2Cl2. The combined extracts were washed with 20 ml of water and 20 ml of water / brine 1: 1. The organic extracts were dried (Na2SO4), filtered, and the solvent was removed. 520 mg of N- (frans-2- (3-fluorophenyl) cyclopropanylmethyl) -1- (R) - (3-methoxyphenyl) ethylamine (1.8 mmoles, 99%) as an oil. MS (Cl) m / z 300 (MH +). The compounds 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 and 70 of Tables 2, 6 and 7 were prepared in an analogous manner to example 3.

EXAMPLE 4 N - .. R, R) -2-phenylcyclopropanylmethyl) -1-. 3-methoxyphenin propylamine (a) 3-Ethylacetophenone (10 g, 68 mmol) was added to hydroxylamine hydrochloride (9.5 g, 135 mmol) and pyridine (27.4 mL, 430 mmol) in 100 mL of ethanol, and the mixture was heated to 65 ° C. during the night, under N2. The solvent was removed, the residue was taken up in 60 ml of ether and 20 ml of dichloromethane, and washed with 2 x 25 ml of water, 4 x 25 ml of 10% aqueous copper sulfate, 2 x 25 ml of water and 2 x 25 ml of brine. The organic extracts were dried (Na2SO4), filtered, and the solvent was removed. 10.4 g (75 mmol, 99%) of 3-ethylacetophenone oxime was obtained as an oil. NMR (1 H, CDCl 3) 7.5-7.2 (m, 4H), 2.68 (q, 2H, J = 7.7), 2.33, (s, 3H), 1.27 (t, 3H, J = 7.7). (b) The oxime was reduced to the primary amine by the method reported in Tet. Leu 1990, 31, 4011. The hydrochloride salt was converted to the free amine by exposure to aqueous K2CO3 and isolation of the organic extract with ether / ethyl acetate 1: 1. 8.9 g (60 mmol, 80%) of 1- (3-ethylphenyl) etillamine was obtained as an oil. MS (CI) m / z 150 (MH +). The amine was converted to the amide with (R, R) -trans-2-phenylcyclopropanecarboxylic acid, and then reduced to the amine as described in example 2.

Compounds 39, 40, 41, 42, 43, 44 and 45 of Table 3 were prepared analogously to Example 4.

EXAMPLE 5 N - ((R, R) -2-phenylcyclopropanylmethyl) -1- (R) - (3-ethoxyphenyl) ethylamine (a) (R) -3-methoxyphenyl) ethylamine (10 g, 66 mimols) was converted to phthalimide by the method reported in J. Heterocyclic Chem. 1991, 28, 609. 15.1 g (53 mmol, 81%) were obtained. ) of (R) - (3-methoxyphenyl) ethyl phthalimide as a white solid. GC / MS (El) m / z 281 (M +). (b) The methyl ether of the measure (5 g, 18 mmol) was dissolved in 100 ml of CH 2 Cl, cooled to 0 ° C, and BBr 3 (1.0 M in CH 2 Cl 2, 53 ml, 53 mmol) was added dropwise. The reaction was warmed to room temperature overnight. The reaction was cooled to 0 ° C and 70 mL of water was carefully added, followed by 70 mL of NaOH to 1 N. This was washed with 3 x 100 mL of ethyl acetate, the organic extracts were combined and washed with NaHCO ^ water and brine. The organic extracts were dried (Na2SO4), filtered, and the solvent was evaporated to yield the phenol. 4.5 g (17 mmol, 95%) of the (R) - (3-hydroxyphenyl) ethyl phthalimide was obtained as a white solid. GC / MS (El) m / z 267 (M +).

NMR (CDC) 7.78 (m, 2H), 7.66 (m, 2H, 7.20 (t, 1H, J = 8.0), 7.08 (m, 2H), 6.79 (m, 1 H), 5.53 (q, 1 H, J = 7.5), 1.91 (d, 3H, J = 7.5) 9 (c) Phenol (500 mg, 1.9 mmol) was dissolved in 100 ml of acetone, K2CO3 (517 mg, 3.7 mmol) was added, followed by iodoethane (0.2 ml, 2.2 mmol), and the mixture was stirred at 60 ° C for 24 hours, water was added, and the mixture was washed with 3 x 100 ml ether.The combined organic extracts were washed with 1 N NaOH. N and water, and then dried (Na ?SO ^.) The solution was filtered and the solvent was removed, 350 mg Jfe (1.2 mol, 63%) of (R) - (3-ethoxyphenyl) ethyl phthalimide was obtained as a oil 10 GC / MS (El) m / z 295 (M +). (d) Imide (350 mg, 1.2 mmol) was dissolved in 40 ml of ethanol, hydrazine (0.3 ml, 9.7 mmol) was added, and the The mixture was heated to reflux for 3 hours.The stirring was continued overnight at room temperature The solid was filtered and then the solvent was evaporated to produce the product 178 mg (1.1 mmol, 90%) of (R) -3- (ethoxyphenyl) ethylamine were obtained as a pale yellow oil. MS (Cl) m / z 166 (MH +). The amine was converted to the amide with (R, R) -2-phenylcyclopropanecarboxylic acid, and then reduced to the amine using the method of example 2. Compounds 48, 49, 50, 51 and 52 were prepared analogously to the amine. example 5 EXAMPLE 6 N- (R.R) -2-phenolcyclopropanylmethyl) -N-methylcarbamoyl-1- (R) -3-methoxyphenyl-O-ethyl amine N - ((R, R) -2-phenylcyclopropanylmethyl) -1- (R) - (3-methoxyphenyl) ethylamine (150 mg, 0.53 mmoles) was dissolved in 7 ml of CH2Cl2. DMAP (65 mg, 0.53 mmol) and methyl chloroformate (0.05 mL, 0.64 mmol) were added, and the mixture was stirred overnight at room temperature. The organic mixture was diluted with 10 ml of solvent, washed with 3 x 10 ml of 10% aqueous HCl and 10 ml of water. The organic extracts were dried (Na 2 SO), filtered, and the solvent was removed in vacuo. Everything was cleaned on silica. 119 mg (0.35 mmol, 66%) of N - ((R, R) -2-phenylcyclopropanylmethyl) -N-methylcarbamoyl-1- (R) - (3-methoxyphenyl) ethylamine was obtained as an oil. GC / MS (El) m / z 339 (M +). Compounds 53, 54, 55, 56, 57 and 58 of the table were prepared analogously to example 6.

EXAMPLE 7 N-R R.R) -2-Phenylcyclopropanylmethyl) -1- (3-chlorophenyl) ethylamine 3-Chloroacetophenone was reduced to the primary amine using the method described in J. Med. Chem. 1990, 33, 1910. The amine, without further purification, was converted to the amide with (R, R) -2-phenylcyclopropanecarboxylic acid, and reduced to the amine using the method described in Example 2. MS (Cl) m / z 286. Compounds 46 and 47 of Table 3 were prepared analogously to Example 7.

EXAMPLE 8 N - ((RR) -2-phenylcyclopropylmethyl) -2-. { 3-methoxyphenylpropylamine Ethyl 3-methoxybenzoate (10 g, 56 mmol) was dissolved in 55 ml of ether, cooled to -78 ° C, and treated with 55 ml of methylmagnesium bromide at 3.0 M in ether. The reaction was warmed to room temperature, stirred overnight, and the excess reagent was quenched by the addition of water and 6 M H2SO4 to the reaction at 0 ° C. 8.2 g (49 mmol, 89%) of 2- (3-methoxyphenyl) propan-2-ol were obtained as a colorless oil. NMR (1H, CDCl 3): 7.25 (m, 1 H), 7.07 (m, 2H), 6.79 (m, 1 H), 3.80 (s, 3H), 1.56 (s, 6H). Alcohol (8.2 g, 49 mmol) was converted to azide by the method reported in J. Org. Chem. 1993, 58, 5886. 1.8 g (9.4 mmol, 19%) of 2- (3-methoxyphenyl) propylazide were obtained. NMR (1H, CDCl 3): 7.5-6.7 (m, 4H), 3.8 (s, 3H), 1.55 (s, 6H).

The azide (1.8 g, 9.4 mmol) was reduced to the amine with 10% catalytic Pd / C, H2 (2.812 kg / cm2) and 5 ml of concentrated HCl in 75 ml of ethanol. 1.5 g (9.3 mmol, 99%) of 2- (3-methoxyphenyl) propyl-2-amine was obtained as an oil. MS (CI) m / z 166 (MH +). The amine was converted to the amide with (R, R) -2-phenylcyclopropanecarboxylic acid, and then reduced to the amine using the method of example 2.

EXAMPLE 9 N (R.R) -2-phenylcyclopropanylmethyl) -1- (R) - (3-methoxyphenyl) ethylamine as the hydrochloride salt Lithium borohydride (14.7 g, 677.0 mmol) was dissolved in 400 mL of THF, and treated with [1R- [1a (R *), 2b]] - 2-phenyl-N- (1- (3-methoxyphenyl) ethyl) cyclopropanecarboxamide (100.0 g, 338.5 mmol). The reaction mixture was heated to 60 ° C, and chlorotrimethylsilane (73.5 g, 677.0 mmol) was added dropwise. After the addition was complete, the solution was heated to reflux for 4 hours. The solution was cooled to room temperature and added to 600 ml of 6 N HCl at 15-20 ° C. The aqueous residue was basified with 265 g of 50% NaOH and extracted with 1 x 600 ml, then 1 x 400 ml of tert-butyl methyl ether (MTBE). The combined extracts were washed with 500 ml of water and 500 ml of brine. The organic extracts were dried (MgSO 4), then cooled to 0 ° C and treated with 18.5 g of gaseous HCl. The white crystalline HCl salt was collected by filtration and washed with 200 ml of MTBE. The product was dried under vacuum to yield 93.6 g (86.9%) of N - ((R, R) -2-phenylcyclopropanylmethyl) -1- (R) - (3-methoxyphenyl) ethylamine as the hydrochloride salt. Melting point: 136.2-137 ° C.

Claims (13)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula: wherein R1 is unsubstituted aryl; or aryl substituted with at least one substituent selected from the group consisting of Ci-Cβ alkyl, cycloalkyl, halogen, halogenoalkyl, nitro and alkoxy; R2 is phenyl substituted with at least one substituent selected from C.sub.1 -C.sub.1 alkyl, cycloalkyl, haloalkyl, chloro, fluoro, iodo, alkoxy, alkylthio, alkylsulfone, arylsulfone, hydroxy, hydroxyalkyl, -COOR7 and CON (R8) 2; unsubstituted heteroaryl or heteroaryl substituted with at least one substituent selected from Ci-Cß alkyl, cycloalkyl, haloalkyl, chloro, fluoro and iodo; R 3 is hydrogen, C 1 -C 6 alkyl or geminal dialkyl of dCe; R 4 is hydrogen, CON (R 9) 2, SO 2 N (R 10) 2, COR 11 or COOR 12; R5, R6, R7, R8, R9, R10, R11 and R12 are independently selected from hydrogen or alkyl; and n is 1; or a pharmaceutically acceptable salt or stereochemically isomeric forms thereof.

2. The compound according to claim 1, further characterized in that R1 is unsubstituted aryl or aryl substituted with 5 halogen or d-Cß alkyl; R 2 is unsubstituted pyridyl, pyridyl substituted with at least one Ci-Cß alkyl, cycloalkyl, haloalkyl, chloro, fluorine or iodine, or phenyl substituted with at least one substituent selected from Ci-Cß alkyl, cycloalkyl, haloalkyl , chlorine, fluorine, iodine, Ci-i alkoxy «Ce, alkylthio, alkylsulfone, arylsulfone, hydroxy, hydroxyalkyl, -COOR7 and 10 CON (R8) 2; R3 is alkyl and R4 is hydrogen, CON (R9) 2, COR11 or COOR12

3. The compound according to claim 2, further characterized in that R3 is methyl and R4 is hydrogen.

4. The compound according to claim 2, further characterized in that R1 is phenyl or thiophene or unsubstituted phenyl or thiophene substituted with halogen or C-i-Cß alkyl; R3 is phenyl substituted with Ci-Cß alkyl, chloro, fluoro, iodo or C?-Β alkoxy.

5. The compound according to claim 4, further characterized in that R1 is unsubstituted phenyl or thiophene, and R2 is phenyl substituted with dCS alkyl, chloro, fluoro, iodo or C6-C6 alkoxy.

6. The compound according to claim 5, further characterized in that R3 is methyl and R4 is hydrogen.

7. The compound according to claim 1, 2-N- ((R, R) -2-phenylcyclopropanylmethyl) -1 - (R) - (3-methoxyphenyl) ethylamine, represented • by the formula: THE

8. - A pharmaceutical composition comprising an effective amount of the compound according to claim 1, and a pharmaceutically acceptable carrier.

9. The use of a compound as claimed in claim 1, in the manufacture of a medicament for treating diseases related to calcium imbalance and metabolism in a host.

10. The use as claimed in claim 9, wherein the disease is hyperparathyroidism.

11. The use as claimed in claim 9, wherein the disease is osteoporosis.

12.- A compound of the formula: Via where R1, R2 and R3 are as described in claim 1, and one of R5 and R6 is alkyl and the other is hydrogen, or R5 and R6 are alkyl.

13. A process for preparing a compound of formula ** wherein R1 is unsubstituted aryl; or aryl substituted with at least one The substituent selected from the group consisting of Ci-Cβ alkyl, cycloalkyl, halogen, haloalkyl and alkoxy; R2 is phenyl substituted with at least one substituent selected from alkyl of d-Cß, cycloalkyl, haloalkyl, chloro, fluoro, iodo, alkoxy, alkylthio, hydroxy, hydroxyalkyl, unsubstituted heteroaryl or heteroaryl substituted with at least one substituent selected C 1 -C 7 alkyl, cycloalkyl, haloalkyl, chlorine, fluorine and iodine; R3 is hydrogen, C1-C6 alkyl or geminal dialkyl of C6C6; R4 is hydrogen, CON (R9) 2, S02N (R10) 2, COR11 or COOR12; R5, R6, R9 R10, R11 and R12 are independently selected from hydrogen or alkyl; and n is 1; or a pharmaceutically acceptable salt or stereochemically isomeric forms thereof, characterized in that it comprises reacting a compound of formula VI: SAW with lithium or sodium borohydride and then adding chlorotrimethylsilane. M » fgum¡S¿¡t¡2esuttti