MXPA01004792A - Tetrahydroisoquinoline derivatives as lhrh antagonists - Google Patents

Abstract

Tetrahydroisoquinoline derivatives of formula (I):or a pharmaceutically acceptable salt, ester, or prodrug thereof, having activity as an LHRH antagonist, as well as pharmaceutical compositions containing the same, and methods for their use and preparation.

Description

DERIVATIVES OF TETRAHIDROISOQUINOLI NA AS ANTAGONISTS OF LHRH TECHNICAL FIELD OF THE INVENTION The present invention relates to novel tetrahydroisoquinoline derivatives having activity as luteinizing hormone releasing hormone (LHRH) antagonists. In particular, the invention relates to pharmaceuticals containing these compounds, a process for making them, as well as a method for treating various hormone-dependent diseases, including prostate cancer, endometriosis, uterine fibroids, precocious puberty, benign prostatic hypertrophy and fertilization. in vitro BACKGROUND OF THE INVENTION The hormones gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), regulate fundamental reproductive processes, such as ovarian release and maturation of gametes. LHRH released from the hypothalamus binds to a receptor in the pituitary gland, causing the release of gonadotropin hormones. The ongoing system of feedback plays a greater role in regulating the synthesis of steroidal reproductive hormones of the gonads, ie, estrogen and progesterone in females and testosterone in males. Accordingly, controlling the pulsatile release of LHRL provides a pathway for the design of novel compounds useful for treating various conditions related to reproductive cycle dysfunction and hormone-dependent diseases. The mammalian hormone, natural that releases LH RL isolated and purified from porcine and human hypothalamus, has been characterized by having the sequence: (pyro) Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly -NH2 as described in AV Schally, Science, 202: 6 (1978). Substitutions and derivations of amino acyl residues have been developed to achieve novel compounds useful for treating various disorders related to mammalian reproductive systems. Some derivatives of natural compounds have been shown to exhibit activity as LHRH agonists or as LHRH antagonists. Synthetic analogs that demonstrate activity to modulate LHRH secretion, usually comprise peptides from amino acid residues that occur naturally or do not occur naturally. Peptide LHRH antagonists characterized by substitution of the nitrogen atom of at least one amide bond are described in U.S. Pat. 5, 11.1904 and U.S. Patent No. 5, 502.035. Truncated peptide compounds developed as a series of smaller peptide analogs also exhibit biological activity and provide the additional advantage of possibly improving oral bioavailability. "Pseudo" peptide compounds, see for example U.S. Pat. 5, 140, 009, are recognized LHRH antagonists. LHRH antagonists of reduced size pentapeptides are described in the pending US application. do not. 1 32, 999. The pending US application is. do not. 1 33,055 discloses heptapeptide analogs, which provide truncated C-terminal active compounds of a decapeptide antagonist sequence. Regulators of reproductive, heterocyclic, non-peptide hormones have been reported in the literature, see for example, WO 95/29900 and WO 97/21 704. Macrolide LHRH antagonists are described in the pending US application Ser. do not. 049,963; See also the pending US application. do not. 140,805. European patent EP 0712845 discloses amine compounds that exhibit LHRH receptor antagonist activity; see also European patent EP 01 87700. Non-peptide LHRH antagonists of the present invention comprise tetrahydro-isoquinoline derivatives not previously described by the prior art. The compounds are useful for treating a variety of conditions related to sex hormones including precocious puberty, benign prostatic hyperplasia, breast and ovarian tumors, prostate tumors, cryptorchidism, hirsutism in women, gastric mobility disorders, dysmenorrhea and endometriosis.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention relates to a compound having the formula: (I) or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein: /, m and n are each independently 1, 2, 3 or 4; p is 1 or 2; R ^ is selected from the group consisting of: (a) alkyl, (b) cycloalkyl, (c) aryl, (d) cyano, (e) - (CH2) qR, wherein q is 0 to 1 0, (f) ) -cycloalkyl-R5, and (g) -aryl-R5; R 2 is selected from the group consisting of: (a) alkyl, (b) hydrogen, (c) alkoxycarbonyl, (d) hydroxymethyl and (e) - (CH 2) q-R 4, wherein q is 0 to 1 0; R 4 is selected from the group consisting of: (a) alkyl, (b) alkoxy, (c) aryl, (d) aryloxy, (e) cyano, (f) cycloalkyl, (g) hydroxy, (h) halogen, ( i) phthalimido, (j) -cycloalkyl-R5, (k) -aryl-Rs, and (I) -NR6R7; R5 is selected from the group consisting of: (a) alkyl, (b) alkoxy, (c) cyano, (d) hydroxy, (e) halogen, (f) trifluoromethyl, and (g) - (CH2) q-NR6R7 , where q is 0 to 10; R 6 and 7 are independently selected from the group consisting of: (a) hydrogen, (b) alkyl, (c) cycloalkyl, and (d) aryl, or R 6 is hydrogen and R 7 is a group of the formula -COR 8, wherein R8 is selected from the group consisting of: (a) alkyl, (b) aryl, and (c) heterocycle; X and Y are independently selected from the group consisting of: (a) hydrogen, (b) halogen, (c) alkoxy, (d) alkyl, and (e) trifluoromethyl; and W and Z are independently selected from the group consisting of: (a) hydrogen, (b) hydroxy, (c) alkyl, (d) alkoxy, (e) alkoxycarbonyl, (f) nitro, (g)? / - acyl , (h) halogen, and (i) trifluoromethyl, or W and Z taken together form a cyclic ring.

The compounds of the invention bind to LHRH receptors and are effective LH RH antagonists. The compounds within the scope of the invention are effective in the treatment of prostate cancer, endometriosis, precocious puberty and other types of diseases, which are related to sex hormones. In another aspect, the invention relates to a process for preparing a compound of the invention comprising treating a diphenyl-substituted aminoalkanol with an activated carboxylic acid to obtain a? / - substituted aminoalkanol, oxidizing the alcohol moiety of the? / - substituted aminoalkanol. to a portion of aldehyde, and alkylating the aldehyde portion with a tetrahydroisoquinoline ring to provide a tetrahydroisoquinoline derivative of formula (I). Another aspect of the invention relates to pharmaceutical compositions, which are useful as LHRH antagonists and modulate sex hormone levels in mammals. Yet another aspect of the invention relates to a method for modulating sex hormone levels in male and female mammals, which comprises administering to a host in need of such treatment, a therapeutically effective amount of an LHRH compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION The terms "alkyl" and "lower alkyl", as used in the presene, refer to straight or branched chain alkyl radicals, containing from 1 to 10 carbon atoms, sometimes represented as Cx. -Cy-alkyl, where x and y respectively represent the minimum and maximum number of carbon atoms in the alkyl radical. Examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, n-octyl, n-nonyl, n-decyl and the like. The term "alkoxy", as used herein, refers to a lower alkyl group of one to three carbons, as defined above, which is attached to an oxygen atom in an ether bond. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-pentyloxy, t-butoxy, n-octyloxy and the like. This alkoxy radical can also contain a ring, which includes but is not limited to, a ring of five or six atoms composed of carbons, and up to one or two heteroatoms, such as, nitrogen, oxygen or sulfur. The term "alkoxycarbonyl", as used herein, refers to an alkoxy group, as described above, wherein an oxygen atom is linked to the parent molecular moiety via a carbonyl group. The term "cyclic ring", as used herein, refers to saturated monocyclic hydrocarbon groups, having from three to six carbon atoms in the ring, including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. and similar. The cyclic group can be optionally substituted with, for example, alkyl, alkoxy, cyano, hydroxy, halogen, trifluoromethyl, amino or aminoalkyl? -substituted. The cycloalkyl can be attached carbon-carbon directly to the parent molecular moiety or can be bound to the parent molecule via an attached substituent. The term "aryl", as used herein, refers to a carbocyclic, mono-, bicyclic, fused or tricyclic fused ring system, having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, indenyl and the like. The term "bicyclic aryl", as used herein, includes naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. The term "tricyclic aryl," as used herein, includes anthracenyl, phenanthrenyl, biphenylenyl, fluorenyl, and the like. The aryl groups (including bicyclic and tricyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, aminoalkyl? -substituted, alkenyloxy, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and alkylamido. Substituents also include methylenedioxy and ethylenedioxy. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl. The substituted aryl and aryl groups can be carbon-carbon attached directly to the parent molecular moiety or can be linked to the parent molecule via an attached substituent. The term "aryloxy", as used herein, refers to an aryl group as described above, wherein the aryl group is linked to the parent molecular moiety via an oxygen atom in an ether linkage.

The terms "heterocyclic ring" or "heterocyclic" or "heterocycle", as used herein, refers to any 3 or 4 member ring, containing a heteroatom selected from oxygen, nitrogen and sulfur, or a ring of 5. , 6 or 7 members containing one, two or three nitrogen atoms, a nitrogen and a sulfur atom, or a nitrogen and an oxygen atom. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered ring has 0-3 double bonds. The nitrogen heteroatoms can optionally be quaternized. The term "heterocyclic" also includes bicyclic groups, in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or other heterocyclic ring (e.g., indoiyl, quinolyl, isoquinolin, tetrahydroquinolyl, decahydroquinolyl, benzofuryl or benzothienyl, imidazopyridyl, pyrrolopyridyl and the like). The term "heterocyclic" also includes tricyclic groups, in which any of the above heterocyclic rings is fused to two benzene rings or two cyclohexane rings or two other heterocyclic rings (eg, carbazolyl, iminodibenzyl and the like). Heterocyclics include: azetidinyl; benzimidazolyl; 1,4-benzodioxanyl, 1,3-benzodioxolyl; dioxanil; dioxolanílo; Furyl homopiperidinyl; imidazolyl; imidazolinyl; Midazolidinyl; imidazopyridyl; iminodibenzyl; indolinyl; indolyl; isoquinolinyl; isothiazolidinyl; isothiazolyl; isoxazolidinyl; isoxazolyl; morpholinyl; naphthyridinyl; oxazolydinyl; oxazolyl; piperazinyl; piperidinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrrolidinyl; pyrrolindinylpyridyl; pyrrolinyl; pyrrolopyridyl; pyrrolyl; quinolinyl; tetrahydrofuranyl; tetrahydropyranyl; thiazolidinyl; thiazolyl; and thienyl. The heterocycles can be unsubstituted, monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (= O), alkylimino (R * N = where R * is a lower alkyl group), amino,? / - substituted aminoalkyl, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO3H and lower alkyl. In addition, heterocycles containing nitrogen can be? / - protected.

The term "hydroxymethyl", as used herein, refers to a lower alkyl of one to ten carbon atoms substituted on one or more carbon atoms with a hydroxy group. The term "? -acyl", as used herein, refers to a? / - substituted aminoalkyl group, wherein the nitrogen atom is linked to the parent molecular moiety via a carbonyl group. The term "α-substituted aminoalkyl" refers to an amino group substituted with one, two or three lower alkyl groups of one to ten carbons, for example, ethylamino, butylamino and the like. Amino groups that are substituted with two or three lower alkyl groups as defined above include, for example, diethylamino, methyl propylamino and the like. Lower alkyl groups are optionally substituted with, for example, alkoxy, aryl, substituted aryl, carbonyl, cycloalkyl, hydroxy, halogen or amino. Exemplary γ-acyl groups include, but are not limited to, methylcarbamoyl, 1-cyclopentyl ethylcarbamoyl, and the like. The term "pharmaceutically acceptable salts", as used herein, refers to those carboxylate salts, esters and prodrugs of the compound of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and similar, coextensive with a reasonable risk / benefit ratio, and effective for the intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Pharmaceutically acceptable salts are well known in the art and refer to addition salts of inorganic and organic acid, relatively non-toxic, of the compound of the present invention. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), which is incorporated herein by reference. The salts can be prepared in situ during the isolation and final purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of non-toxic, pharmaceutically acceptable acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids, such as, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art, such as, ion exchange. Other pharmaceutically acceptable salts include salts of adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, guconate, hem isulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectonate, persulfate , 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Further pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. The term "pharmaceutically acceptable esters", as used herein, refers to non-toxic esters of the compounds of this invention. Examples of pharmaceutically acceptable esters include alkanoyl esters of C ^ to C6, wherein the alkanoyl group is a straight or branched chain. The esters of the compounds of the present invention can be prepared according to conventional methods. The term "pharmaceutically acceptable prodrugs", as used herein, refers to those prodrugs of the compounds of the present invention, which are, within the scope of sound medical judgment, suitable for use in contact with human tissues. and lower animals without undue toxicity, irritation, allergic response and the like, coextensive with a reasonable risk / benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to produce the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (Promedications as novel delivery systems), vol. 14 of A. C. S. Symposium Series, and in Edward B. Roche, ed. , Bioreversible Carriers in Druq Pesian (Bio-reversible carriers in drug design), American Pharmaceutical Association and Pergamon Press, 1987, both incorporated herein by reference.

Where appropriate, the prodrugs of derivatives of compounds of the present invention can be prepared by any suitable method. For those compounds in which the promedicamento portion is an amino acid or peptide functionality, the condensation of the amino group with amino acids and peptides, can be carried out according to conventional condensation methods, such as, the azide method, the anh method Mixed acid hydride, the DCC (dicyclohexylcarbodiimide) method, the active ester method (p-nitrophenyl ester method,? / - hydrosuccinic acid imide ester method, cyanomethyl ester method and the like), the K reactive reagent method, Woodward, the method of DCC-HOBT (1-hydroxybenzotriazole) and the like. Classical methods for amino acid condensation reactions are described in M. Bodansky, Y.S. Klausner and M.A. Ondetti, Peptide Svnthesis (Peptide Synthesis), Second Edition, NY, 1976, which is incorporated herein by reference. There may be numerous asymmetric centers in the compounds of the present invention. Unless otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof. Accordingly, whenever a link is represented by a wavy line, it is intended that a mixture of stereo-orientations or an individual isomers of assigned or unassigned orientation may be present.

Preferred Modality The preferred compounds of the invention are those compounds of formula (I), wherein / is 2, m is 3, n is 3 and p is 1. Additional preferred compounds of the invention are compounds represented by the formula (I), wherein Ri is selected from the group consisting of alkyl, cycloalkyl and - (CH2) qR, wherein q is 0 to 10, and R is a group of the formula -NR6R7, wherein R6 and R7 are each independently selected from hydrogen, alkyl and cycloalkyl. Preferred compounds of the invention also include compounds of formula (I), wherein R 2 is selected from the group consisting of hydrogen and methyl. Other preferred compounds of the invention are those compounds represented by the formula (I), wherein X and Y are independently selected from the group consisting of hydrogen and halogen. Additional preferred compounds of the invention are compounds of formula (I), wherein W and Z are independently selected from the group consisting of hydrogen and methoxy. The most preferred compounds of the invention are those compounds as represented by formula (I), wherein R 1 is selected from the group consisting of methyl, cyclopropyl, cyclobutyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, N- [cyclopropylmethyl-butyl butyl and? - [bis-cyclopropylmethyl] -aminobutyl. Representative compounds within the scope of the invention are selected from the group consisting of:. { R, S) 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinolinyl) hydrochloride) ] -4,4-diphenylheptane; . { R) 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrahydro-1-methyl-6, 7- hydrochloride di methoxy isoquinolyl) - 4,4-diphenyl heptane; (S) 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrah id ro-1-met il-6, 7- hydrochloride dim ethoxy isoquinoline il)] - 4, 4-diphenyl hepta no; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxyisoquinone hydrochloride inyl)] - 4, 4-diphenyl hepta no; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1-ethyl-6,7-d methoxy isoquinolinyl)] - 4,4-diphenylhepta no; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 -i-sopropyl-6,7-di methoxy isoquinol hydrochloride) inulyl)] - 4, 4-dif in i I heptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-phenyl-6,7-dimethoxyisoquinolinyl)] - 4 hydrochloride 4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-cyclopentyl-6,7-dimethoxyisoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-cyclobutyl-6,7-dimethoxy-psoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fiuorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1-cyclohexyl-6,7-dimethoxyolyaquinolinyl) - 4,4-diphenylheptane; 7 - [? / - (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-cyanomethyl-6,7-dimethoxyisoquinolinyl)] - 4,4- hydrochloride diphenylheptane; 7 - [? / - (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1-methoxymethyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane; 7 - [/ V-3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-benzyloxymethyl-6,7-dimethoxyisoquinolinyl)] - 4 hydrochloride 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1 - (p-methoxy) phenyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane; Dihydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2,3,4-tetrahydro-1- (4-aminophenyl) -6,7-dimethoxyisoquinolinyl] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [4 - (? / - isopropyl-amino) phenyl] dihydrochloride ] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1-benzyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane; Hydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1, 2,3,4-tetrahydro-1- (4-chlorobenzyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1- (4-methoxybenzyl) -6,7-d! Hydrochloride methoxysoloquinolin)) - 4,4-diphenyl heptane; Hydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-phenethyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; Dihydrochloride of 7- [A / -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2,3,4-tetrahydro-1- (4-aminobenzyl) -6,7-dimethoxy-psoquinolyl) - 4,4-d-phenylheptane; 7 - [? / - 3- (4-f luorofenyl) prop ion il] a-1 - [? / - (1, 2, 3, 4-tetrahydro-1-aminomethyl-6,7-dimethoxyisoquinolinyl dihydrochloride] )] - 4,4-diphenylheptane; Dihydrochloride 7- [? -3- (4-f luorof in i I) own ni l] a mino- 1 - [? / - (1, 2, 3,4-tetrahydro-1 - (? / - isopropyl-aminomethyl-6,7- dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - (4-hydroxychloride -? / - phthalimido-butyl) -6,7-dimethoxyisoquinolinyl] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - dihydrochloride] (1, 2,3,4-tetrah id ro-1 - (4-am i nobutyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenyl heptane; Dihydrochloride of 7 - [? / - 3- ( 4-f luorofenyl) propioni l] am ino- 1 - [? / - (1, 2, 3, 4-tetrahydro-1 - [4 - (? / - isopropyl-amino) butyl] -6,7-dimethoxyisoquinolinyl )] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [4-dihydrochloride] (? / - cyclopropyl-methylamino-6,7-d-methoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (dihydrochloride 1, 2, 3,4-tetrahydro-1 - [4 - (? / - cyclobutyl-amino) butyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - [4-? - isobutyl-amino) butyl] dihydrochloride - 6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [4 - (? / - isopentyl-amino) butyl dihydrochloride ] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [4 - (? / - aifa-methyl) dihydrochloride -benzylamino) butyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [4- (?,? / - d / cyclopropyl) dihydrochloride] -methylamino) butyl] -6,7-dimethoxy isoquinol in i l)] - 4, 4-dif in ilheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - [4 - (? /,? / - dimethyl- dihydrochloride amino) butyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1 - [4 -? / - acetylamino) butyl] -6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane; Hydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [4 - (? / - nicotinyl-amino) butyl] -6,7-dimethoxyisoquinolinyl )] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [4- (? -phthalimido-methyl] cyclohexyl- hydrochloride- 6, 7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (4-amynethyl-cyclohexyl) -6 dihydrochloride, 7-dimethoxy isoquinol inyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino- 1 - [? / - (1, 2, 3,4-tet rah id ro-1 - (4-? - isopropi lami- n- dihydrochloride m ethyl) hexyl-6,7-dimethoxyisoquininoinyl)] - 4,4-diphenylheptane; Hydrochloride of 7- [A / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (4-? - phthalimido-methyl) phenyl-6 , 7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (4-aminomethyl-phenyl) -6,7- dihydrochloride dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; Dihydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - (4 -? / - isopropyl-non-methyl) phenyl-6, 7-di methoxy isoquinol I i)) - 4, 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - (4 -? / - cyclobutyl-non-methyl) dihydrochloride) f eni I-6, 7-di methoxy isoquinol i nyl)] - 4, 4-diphenylheptane; 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? - dihydrochloride - (, 2,3,4-tetrahydro-1 - (4- / V-cyclopropyl-methylaminomethyl) phenyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane; Dihydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2,3,4-tetrahydro-1 - (4 -? / - bicyclopropyl-methylaminomethyl) phenyl-6,7-di methoxy isoquinolyl I) - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - (4? -acetylamide) hydrochloride -methyl) phenyl-6,7-dimethoxy-psoquinolinyl)] - 4,4-diphenylheptane; "7 - [/ V-3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dihydroxyisoquinolinyl) hydrochloride] -4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methylisoquinolinyl)] - 4 Hydrochloride , 4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dioxaIan hydrochloride -isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl) hydrochloride -6,7-dioxan-isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / 3- (4-fluorophenyl) propionyl] l] amino- 1 - [? / - (1, 2, 3, 4-tetrahydro-1-methyl-6-methoxy-isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [?] Hydrochloride - (1, 2,3,4-tetrahydro-1-methyl-7-methoxy-isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-f luorofenyl) propionyl hydrochloride] am ino- 1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-7-chloro-isoquinolinyl)] - 4,4-diphenylheptane; Hydrochloride d e 7 - [?? - 3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1, 2,3,4-tetrahydro-1-methyl-7-fluoro-isoquinolinyl)] - 4.4 -diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1-methyl-7-nitro-isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1, 2,3,4-tetrahydro-1-methyl-7-acetylamino-isoquinolinyl)] - 4 hydrochloride 4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dichloro-isoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6-chloro-7-fluoroisoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-diacetoxy-isoquininoinyl) hydrochloride] - 4,4-diphenyl heptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1, 2,3,4-tetrahydro-1-methyl-6-bromo-7- hydrochloride methoxyisoquinolinyl)] - 4,4-diphenolheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1-methyl-6-fluoro-7-methoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6-methoxy-7-bromo- hydrochloride isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1,6-dimethyl-7-methoxy-isoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6-carbomethoxy-7-methoxyisoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-cyclobutyl-6-bromo-7-methoxy-isoquinolinyl) hydrochloride) ] -4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1,3-dimethyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-3-methyl-6,7-dimethoxy-isoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [/ V-3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1,1-dimethyl-6,7-dimethoxyisoquinoliniI) hydrochloride] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl) amino-1 - [? / - (1, 2,3,4-tetrahydro-1,3-dimethyl-7-methoxy-isoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-7,8-dimethoxy-1 H-2 hydrochloride -benzazepinyl)] - 4,4-diphenyl hepta no; 6 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-6,7-methoxy-isoquinolinyl) hydrochloride] - 3, 3-diphenylhexane; 8 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-6,7-di-methoxy-isoquinolinyl) hydrochloride) ] -5,5-diphenyloctane; Hydrochloride of 8- [? -3- (4-fluorophenyl) acetyl] amino-1 - [? - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinolinyl) - 5,5-diphenyloctane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1, 2,3,4-tetrahydro-1-methyl-7-methoxy-3-methoxycarbonyl isoquinolinyl) hydrochloride) ] -4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-3- (2-hydroxyethyl-aminocarbonyl) -1-methyl- hydrochloride 7-methoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro- (3-hydroxypropyl-aminocarbonyl) -1-methyl-7- hydrochloride methoxy isoquinol inyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-3- (4-hydroxybutyl-aminocarbonyl) -1- hydrochloride methyl-7-methoxyisoquinolyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-7-methoxy-3- (2- (2) hydrochloride ? -pyrrolidinyl) ethylaminocarbonyl) isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-3-hydroxy-methyl-7-rnetoxyisoquinolini hydrochloride! )] - 4,4-diphenyl heptane; 7 - [? / - 3- (phenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinoline il) hydrochloride) -4,4-diphenyl heptane; Hydrochloride of 7- [A / -3- (3, 4-dichlorophenyl) propioni l] am ino- 1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxy isoquinolinyl) ] -4,4-diphenylheptane; 7 - [? / -3- (3,4-difluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / - 3- (3-Fluoro-4-chloro-phenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrah idro-1-methyl-6I 7- hydrochloride dimethoxy-isoquinolinyl)] - 4,4-diphenyl heptane; Hydrochloride 7- [? -3- (4-fluoro-3-chloro-phene) propionyl] amino-1 - [? - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinolinyl)] - 4,4-diphenylheptane; Hydrochloride of 7 - [? / 3- (3,4-di methoxy in i) propioni l] a mino- 1 - [N- (1, 2, 3, 4-tetrahydro-1-methyl-6, 7 -dimethoxyisoquinolinyl)] - 4,4-diphenyl heptane; 7 - [? / -3- (4-methoxyphenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinolinyl)] - 4 hydrochloride 4-diphenylheptane; 7 - [? / - 3- (4-chlorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) acetyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / 3- (4-fluorofenii) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1- (3-? - phthalimido-propyl) -6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (3-aminopropyl) -6,7-di methoxy hydrochloride] isoquinol inyl)] - 4,4-diphenyl heptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1, 2, 3,4-tetrahydro-1 - [3 -? / - (bis-cyclobutyl-amino) -propyl dihydrochloride] ] -6,7-di methoxyisoquinolin yl)] - 4, 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - [3 -? / - (bis-cyclopropyl-methylamino) propyl dihydrochloride ] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenyl heptane; Dihydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2, 3,4-tetrahydro-1 - [3 -? / - (dimethylamino) -propyl] -6,7-dimethoxy isoquinolinyl) - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tet rah id ro-1 - [3-? - (isopropyl) dihydrochloride ) propyl] -6,7-dimethoxy isoquinolyl ni]] - 4,4-diphenylheptane; Hydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - (5 -? / - phthalimido-pentyl) -6,7-dimethoxyisoquinolinyl) ] -4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1, 2, 3,4-tetrahydro-1 - (5-aminopentyl) -6 dihydrochloride, 7-dimethoxy-5-ylquinolyl] - 4,4-diphenylheptane; 7 - [/ V-3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [5- / V- (biscyclobutyl-amino) pentyl dihydrochloride ] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [5 -? / - (bis-cyclopropyl-methylamino) dihydrochloride ) pentyl] -6,7-dimethoxyisoquinoylnl)] - 4,4-diphenyl heptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - [5 -? / - (d-methylamino) dihydrochloride] -pentyl] -6,7-dimethoxyisoquinolinyl]] - 4,4-diphenylheptane; Dihydrochloride 7- [? -3- (4-f luorof en il) propioni l] a mino- 1 - [? / - (1, 2, 3,4-tetrahydro-1 - [5 -? / - (isopropylamino) -pentyl] -6 , 7-d-methoxyisoquinoline (I)) -4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-cyclobutyl-6-fluoro-7-methoxyisoquinolinyl) hydrochloride] -4,4-diphenyl heptane; Hydrochloride of 7 - [? / - 3- (4-fluorophenyl) propion iljam ino- 1 - [? / - (1, 2, 3,4-tetrahydro-1 - (4 -? / - phthalimidobutyl) -6-methyl -7-methoxyisoquinolinii)] - 4,4-diphenylheptane; Dihydrochloride of 7 - [? / - 3- (4-f luorophenyl) prop ioni l] am i no- 1 - [? - (1, 2, 3, 4-tetrahydro-1- (4-aminobutyl) -6-methyl-7-methoxyisoquinolinyl) - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (4-A / -isopropylamino-butyl) -6-dihydrochloride -methyl-7-methoxyisoquinolinyl)] - 4,4-diphenylheptane; and 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-cyclobutyl-6-methyl-7-methoxyisoquinolinyl) hydrochloride] -4,4-diphenylheptane; Effects and utilities of LHRH antagonists In the practice of the method of the invention, a therapeutically effective amount of a compound of the invention or a pharmaceutical composition containing the same, is administered to the human or animal in need of, or desires, such treatment. The compound can be used in pure form or, where such forms exist, in the form of a pharmaceutically acceptable salt, ester or prodrug. By a "therapeutically effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat the target disorder, at a reasonable risk / benefit ratio applicable to any medical treatment, which is administered in such amounts and over a period of time. as necessary to obtain the desired therapeutic effect. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The therapeutically effective, specific dose level for any particular patient will depend on a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the administration time, route of administration and rate of excretion of the specific compound employed; the duration of the treatment; medications used in combination or coincident with the specific compound used; and similar factors well known in the medical arts. For example, it is within the skill of the art to start the doses of the compound at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. The total daily dose of the compound of this invention administered to a human or lower animal, can vary from about 0.1 to about 100 mg / kg / day or for topical administration from about 0.1 to about 10% in cream, ointment or other topical formulation, or for rectal or vaginal administration from about 10 to about 500 mg per dose in a suitable vehicle. For oral administration purposes, the doses may be in the range of from about 1 to about 1000 mg / kg / day or, more preferably, from about 10 to about 20 mg / kg / day. If desired, the effective daily dose can be divided into multiple doses for administration purposes; consequently, single dose compositions may contain such amounts or submultiples thereof, as to form the daily dose.

The compounds and pharmaceutical compositions of the invention can be administered by a variety of routes, depending on the specific end use. Exemplary methods of administration include, but are not limited to, orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, typically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray. The term "parenteral", as used herein, refers to modes of administration, which include infusion and intravenous, intramuscular, intraperitoneal, intracisternal, subcutaneous and intraarticular injection. The pharmaceutical compositions of the present invention comprise a compound of the invention in combination with a pharmaceutically acceptable carrier or excipient. The term "pharmaceutically acceptable carrier" refers to a solid, semi-solid or liquid, non-toxic filler, diluent, encapsulating material or formulation aid of any type. The pharmaceutical compositions of this invention for parenteral injection include sterile, pharmaceutically acceptable non-aqueous solutions or aqueous dispersions, suspensions or emulsions., as well as sterile powders for reconstitution in sterile injectable solutions or dispersions, just before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as, olive oil) and injectable organic esters, such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain auxiliaries such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutane, phenol, sorbic acid and the like. It may also be desirable to include sotonic agents, such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved by the inclusion of agents, which delay absorption, such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of drug absorption then depends on its rate of dissolution which, in turn, may depend on the crystal size and crystalline form. Alternatively, the delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the medicament in an oily vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by trapping the drug in liposomes or microemulsions, which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium just before to be used.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic, c) humectants, such as glycerol, d) disintegrating agents, such as, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as, kaolin and bentonite clay, and i) lubricants, such as, talc, calcium stearate, magnesium stearate, poly solid ethylene glycols and sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type can also be used as fillings in soft and hard filled gelatin capsules, using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The active compounds may also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example tableting lubricants and other tableting aids, such as magensium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Optionally, it may contain opacifying agents and may also be of a composition so that it only releases the active ingredient (s), or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of inlay compositions, which may be used, include polymeric substances and waxes. The active compounds may also be in microencapsulated form, if appropriate, with one or more aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, tiger nut, corn, olive, castor bean and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluents, the oral compositions may also include auxiliaries, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and flavoring agents. The suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye. Compositions for topical administration, including those for inhalation, can be prepared as a dry powder, which can be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredient in finely divided form can be used in admixture with an inert, pharmaceutically acceptable carrier of larger size, comprising particles having a size, for example, up to 1 00 micrometers in diameter. Suitable inert carriers include sugars, such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 microns. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. Alternatively, the composition can be pressurized and contain a compressed gas, such as nitrogen or a liquefied gas propellant. The liquefied propellant medium, and indeed the total composition, is preferably such that the active ingredient does not dissolve therein in any substantial degree. The pressurized composition may also contain an active surface agent. The surface active agent may be an active, nonionic, liquid or solid surface active agent, or it may be an active, anionic, solid surface agent. It is preferred to use the active, anionic, solid surface agent in the form of a sodium salt. Preferably, compositions for rectal or vaginal administration are suppositories, which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which They are solid at room temperature but liquid at body temperature, and therefore, they melt in the rectum or vaginal cavity and release the active compound. The therapeutically effective amount of the compound can also be administered in the form of liposomes. As is known in the art, liposomes are generically derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals, which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in the form of liposomes may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. , 1976, p. 33 et seq.

Synthetic Methods The process for preparing compounds of the invention can be better understood in connection with the following Schemes 1-5. To describe the processes and the Examples that follow, certain abbreviations are used to describe reagents and methods commonly used in the process. Where the abbreviations are used herein, they replace the following: DBU for 1,8-diazabicyclo [5.4.0] undec-7-ene; DMAP for 4-dimethylaminopyridine, DMF for dimethylformamide; EDC for 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; HOBt for 1-hydroxybenzotriazole hydrate; LAH for lithium aluminum hydride; OMe for methoxy; PCC for pyridinium chlorochromate; and TH F for tetrahydrofuran. As summarized below and as further described herein in accordance with the Examples, Schemes 1-5 illustrate the processes within the scope of the invention. Scheme 1 describes the general method for preparing the tetrahydroisoquinoline derivatives of the general formula (I), which is followed by more preferred syntheses made in accordance with Schemes 2-5. The tetrahydroisoquinoline derivatives are prepared from a substituted aminoalkanol, wherein a single carbon of the alkyl chain is disubstituted with an aryl portion, preferably a phenyl group. The procedures for obtaining the aminoalkanol are readily investigated by those skilled in the art from methods previously described, for example, EP 0712845 for the preparation of 6-amino-4,4-diphenylhexanol. The exemplary synthesis of the diphenyl-substituted aminoalkanol is illustrated more particularly and further detailed in Schemes 2-5 and in the Examples. As illustrated by Scheme 1, Step (i) represents the N-substitution of the amino portion by acylating the nitrogen of the amino group or by coupling with an activated carboxylic acid. The oxidation of PCC or Swern from the alcohol to the aldehyde is shown in Step (ii). Alkylation of an isoquinoline ring as depicted in Step (iii) provides the tetrahydroisoquinoline derivative. Alternatively, a reactive group leaving R is prepared from the alcohol, Step (ii-a), which is alkylated with the isoquinoline ring or the hydroiodide salt of the isoquinoline portion depicted in Step (ii). to) . R9 is selected from the group consisting of halide and mesylate. The variables /, m, n, p, W, X, Y, Z, R ^ and R2 described in Scheme 1 are as defined in claim 1. R3 is selected from hydroxy, halo or an aryl ring substituted with a group that removes electrons to obtain an activated ester as illustrated by Scheme 1 below.

Scheme 1 The following Schemes 2-5 further describe methods for preparing compounds within the scope of general formula (I). In particular, Scheme 2 represents a process for preparing a compound of formula (I I) starting with the condensation of dipheniacetaldehyde and acrylonitrile, and followed by additional chemical transformations well known in the art. Scheme 3 involves a coupling reaction of an aryl substituted arylaminine with a carboxylic acid, followed by cyclization to form a tetraisoquinoline portion, which is a suitable intermediate for alkylating compound 7, 8 or 9 of Scheme 2 A compound of the formula (III) is prepared from 4,4-diphenyl-formylbutyronitrile, as illustrated in Scheme 4. Scheme 5 represents a process for preparing a compound of the general formula (IV) via a reaction of Wittig of 4,4-diphenyl-5-formyl-pentanenitrile followed by conventional chemical steps. The variables R ^ R2, W, X, Y and Z described in the schemes are the groups defined in claim 1. The group R3 is selected from hydroxy, halo or an aryl ring substituted with a group that removes electrons, to obtain an activated ester.

Scheme 2 The condensation of diphenylacetaldehyde and acrylonitrile is carried out in the presence of base to provide a 4, 4-diphenyl-formylbutyronitrile 1_. The aldehyde is converted to an α, β-unsaturated 6-cyano-4,4-diphenyl ester via the Wittig reaction. Hydrogenation of 2 in the presence of 10% Pd / C provides compound 3. Treating ester 3 with lithium aluminum hydride reduces the ester as well as the cyano portion to form a 4,4-diphenyl-substituted aminoalkanol 4. The acylation of compound 4 with an acid or acid halide of formula 5, gives a? / - acyl-4,4-diphenyl-aminoalkanol 6. Swern's oxidation of compound 6 oxidizes the alcohol portion to an aldehyde of compound 7. Reductive alkylation of a tetrahydroisoquinoline with compound 7 in the presence of sodium cyanoborane provides the tetrahydroisoquinoline derivative of formula (II).

Alternatively, the displacement of the alcohol portion with a halide in compound 8 is obtained by the Mitsunobu reaction of compound 6. Treatment of compound 6 with methanesulfonyl chloride results in displacement of hydroxy with a mesylate portion to forming the compound 9. Direct alkylation of the tetrahydroisoquinoline portion with the compound 8 or the compound 9, provides the tetrahydroquinoline derivative (II).

Scheme 3 The condensation of aryl-substituted aryl-alkyl-amide with an activated carboxylic acid V \, forms an amide of formula 1_2. Treatment of compound 1_2 with oxaiyl chloride gives compound 13. Treatment of compound! _3 with acid and FeCI3 forms compound 1_4. Compound 14 is decarboxylated to provide compound 15. The reduction of 15. with sodium cyanoborohydride provides an isoquinoline intermediate of formula (A). Another known method for forming the isoquinoline ring (A) is by cyclization of compound 12. with POCI3 to give compound 15. Reacting compound j_5 with sodium cyanoborane yields the isoquinoline derivative (A). Optionally, the isoquinoline ring with hydroiodic acid provides a hydroiodide salt of the isoquinoline ring.

Scheme 4 The Wittig reaction of 4,4-diphenyl-formylbutyronitrile followed by acid hydrolysis of 1 6 with HCl gives the aldehyde 1 7. Treatment of Y7_ with lithium aluminum hydride reduces the portions of cyano and aldehyde to the amine and hydroxy moieties, respectively, yielding compound 18. The? / - substitution of 1_8 with an activated carboxylic acid of formula 5 of Scheme 1, provides a compound of formula 1_9. The α / - mesylation of compound 9 in the presence of methanesulfonyl chloride yields 20. The direct alkylation of 20 results in a compound of formula (11).

Scheme 5 The Wittig reaction of 17 provides an α, β-unsaturated ester 2 The hydrogenation of the α, β-unsaturated double bond forms 22 .. The compound 22 is reduced to compound 23 with lithium aluminum hydride to the amino alcohol, which is? / - substituted with an acyl group to form a compound of formula 24. Direct alkylation of a hydroiodide salt of tetraisoquinoline with mesylate 25, provides a compound of formula (IV).

Scheme 2 Scheme 2 (continued) Scheme 3 Scheme 4 (Compound 5, Scheme 2) Scheme 5 The above Schemes 1-5 will be better understood in relation to the Examples, which are intended to be an illustration and not a limitation on the scope of the invention. The following Examples further describe compounds prepared according to the invention. Modification of the described embodiments to achieve additional compounds having LHRH antagonist activity will be apparent to those skilled in the art. Such substitution, modification and change are within the competence of the scope and limitations of the present invention, and do not depart from the spirit of the invention.

EXAMPLES Example 1 (R.S.) 7-R / V-3- (4-fluorophenyl) propionipamino-1-r? / - (1 .2.3.4-tetrahydro-1-methyl-6,7-dimethoxyisoquin lin hydrochloride il) 1-4.4-dif in ilheptane Step 1: 4.4-diphenyl-4-formylbutyryltrile (Compound 1. Scheme 2) To a stirred solution of diphenylacetaldehyde (11.0 ml) and acrylonitrile (4.5 ml) in dioxane (125 ml), 1,8-diazabicyclo was added [5.4.0] undec-7-ene (DBU) (10.5 ml). The solution was heated under reflux overnight and then concentrated in vacuo. The residue was purified by a column of silica gel, levigating with (95: 5) hexane / ethyl acetate. The desired product (8.1 g) was obtained as colorless crystals, mp 80-82 ° C; MS showed (M + NH4) + @ 267; 1 H-NMR (CDCl 3, d): 2.05-2.1 5 (m, 2 H), 2.65-2.75 (m, 2 H), 7.1 1 -7.45 (m, 10 H), 9.80 (s, 1 H); Anal. Caled for C1 7H1 5NO: C, 81.90; H, 6.60; N, 5.61. Found: C, 81.83; H, 6.64; N, 5.65.

Step 2: Ethyl 6-cyano-4,4-diphenyl-hex-2-enoate (Compound 2, Scheme 21) A mixture of 4,4-diphenyl-4-formy-butyronitrile (8.04 g) and (carbethoxymethylene) triphenylphosphorane was heated ( 20.85 g) in toluene (200 ml) under reflux for 3 days The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography to give the desired product as a yellow-orange oil (12.10. g): MS showed (M + NH4) + @ 337; 1 H-NMR (CDCI3, d): 1.25-1.32 (t, 3H), 2.10-2.1 8 (m, 2H), 2.65-2.75 (m, 2H), 4.15-4.23 (q, 2H), 5.60-5.66 (d, 1 H), 7.05-7.75 (m, 1 1 H).

Step 3: Ethyl 6-cyano-4,4-diphenyl-hexanoate (Compound 3. Scheme 2) A solution of ethyl 6-cyano-4,4-diphenyl-hex-2-enoate (22.06 g) in ethanol ( 500 ml) was hydrogenated in the presence of 10% Pd / C (2.2 g) under 4 atmospheres of pressure for 17 h. The catalyst was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, levigating with (95: 5) hexane / ethyl acetate. The desired product (19.49 g) was obtained as a colorless oil: MS showed (M + NH4) + @ 339; 1 H-NMR (CDCl 3, d): 1.20-1.25 (t, 3H), 1.95-2.06 (m, 4H), 2.38-2.52 (m, 4H), 4.03-4.12 (m, 2H) , 7.10-7.36 (m, 10H).

Step 4: 7-amino-4,4-diphenylheptan-1 -o! (Compound 4, Scheme 2) To a solution of ethyl 6-cyano-4,4-diphenyl-hexanoate (5.476 g) in anhydrous THF (95 ml) was added lithium aluminum hydride in the form of portions (LAH) (1,686 g). A large gas emission was observed. The mixture was stirred at rt (room temperature) for 1.5 h. The reaction mixture was quenched by careful addition of water (4.5 ml), followed by 1 N NaOH (4.5 ml) and additional water (15 ml). The mixture was stirred at rt for 10 min and then filtered and the solid was washed three times with THF. The organic filtrates were combined, dried (Na2SO4) and concentrated to give the desired product as a solid foam (4.56 g): MS showed (M + H) + @ 284; 1 H-NMR (CDCl 3, d): 1 .05-1 .3 (m, 4H), 2.0-2.20 (m, 4H), 2.30-2.42 (t, 2H), 2.82-3.0 (t, 2H), 3.0-3.25 (m, 2H), 3.50-3.65 (t, 2H), 5.10-5.20 (broad m, 1 H), 6.86-7.36 (m, 14H).

Step 5 7-f? / - 3- (4-fluorophenyl) propioninamino-4,4-diphenylheptan-1 -ol (Compound 6. Scheme 2) To an ice-cold, stirred solution of 7-amino-4,4 -diphenylheptan-1 -ol (4.14 g) in methylene chloride / DMF solution (9.5: 0.5) (42 ml), 4-fluorophenyl propionic acid (2.70 g) was added (Compound 5, Scheme 29 followed by hydrate of 1 - hydroxybenzotriazole (HOBt) (2.38 g), triethylamine (5.0 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) (3.36 g) The reaction mixture was stirred at rt overnight and then diluted with Methylene chloride (150 ml) The solution was washed first with water and then with brine The organic phase was dried (Na2SO) and concentrated in vacuo The residue was purified by a silica gel column using ethyl acetate / hexane (1: 1) This produced the desired compound as an amorphous solid (2.1 g): MS showed (M + H) + @ 434; 1 H-NMR (CDCl 3, d): 1.05-1 .28 (m, 4H), 1 .7-1 .8 (m, 1 H), 2.0-2.2 (m, 4H), 2.3-2.4 (t, 2H), 2.85 -2.92 (m, 2H), 3.08-3.2 (q, 2H), 3.5-3.6 (q, 2H), 5.3-5.35 (m, 1 H), 6.85-7.30 (m, 14H).

Step 7-f? / - 3- (4-f luorof in i I) own nillam i no-4, 4-dif enyl hepta n-1 -al (Compound 7, Scheme 2) To a stirred paste of silica gel (2.03 g) and celite (2.02 g) in methylene chloride (80 ml), pyridinium chlorochromate (PCC) (2.06 g) was added, followed by a dropwise addition of a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] amino-4,4-d-phenylheptan-1-ol (2085 g) in methylene chloride (30 ml). The reaction mixture was stirred at rt for 3.5 h and then diluted with anhydrous ether (50 ml) and stirred for 10 min. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The brown residue was dissolved in ethyl acetate and the solution was washed with solutions of sodium bicarbonate, water and brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo. The desired product was obtained as a heavy oil (1.7 g): MS showed (M + H) + @ 432 and (M + NH4) + @ 449; 1 H-NMR (CDCl 3, d): 1 .05-1 .1 8 (m, 2 H), 1 .95-2.08 (m, 2 H), 2.1 -2.2 (t, 2 H), 2.3-2.5 (m, 4 H ), 2.8-3.0 (t, 2H), 3.08-3.20 (q, 2H), 5.08-5.20 (m, 1 H), 6.87-7.35 (m, 14H), 9.6 (s, 1 H).

Step 7: (R, S) 7-fA / -3- (4-fluorophenyl) propionyl-amino-1-f? / - hydrochloride (1, 2, 3, 4-tetrahydro-1-methyl-6,7 -dimethoxy isoquinol i nyl) 1-4,4-diphen-I-hetano (Compound II, Scheme 2) To a solution of 7 - [? / 3- (4-fluoropheni!) propionyl] amino-4,4-diphenylheptan -1-al (0.796 g) in methanol (30 ml) was added (R, S) 1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinoline (0.658 g) followed by sodium cyanoborohydride. (0.235 g) and three drops of acetic acid. The mixture was stirred at rt overnight and then concentrated in vacuo. The residue was treated with ethyl acetate and washed with solutions of sodium bicarbonate and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, levigating with a gradient of hexane / ethyl acetate. The desired product was obtained as a viscous oil (0.30 g): MS showed (M + H) + @ 623; 1 H-NMR (CDCl 3, d): 1.06-1.3 (m, 7H), 2.0-2.18 (m, 4H), 2.30-2.40 (t, 2H), 2.40-2.85 (m, 6H), 2.85 -2.98 (t, 2H), 3.10-3.20 (q, 2H), 3.6-3.7 (m, 1 H), 3.8-3.88 (two s, 6H), 6.45 (s, 1 H), 6.55 (s, 1 H), 6.88-6.97 (m, 2H), 7.08-7.32 (m, 12H). This compound was treated with methanolic HCl, the solution was concentrated in vacuo and the residue was dissolved in acetonitrile / water (1: 1) and lyophilized to give (R, S) 7- [? -3- (4'-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-di-methoxy-isoquinolinyl)] - 4,4-diphenylheptane: mp 1 13-1 15 ° C; IR (KBr)? 3400, 3300, 2950, 1750 c "1; Anal Caled for C40H47N2O3F HCI H2O: C, 70.93; H, 7.44; N, 4.13; Found: C, 71.04; H, 7.32; N, 3.91.

Example 2 (R) 7-r Hydrochloride? -3- (4-fluorophenyl) propionill-1 -r? - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinolinyl) 1-4,4-diphenylheptane Step 1: 7-r? / -3- (4-fluorophenyl) propionyl] amino-4 iodide , 4-diphenyl-heptyl (Compound 8, Scheme 2) To a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptan-1-ol (0.78 g) in toluene ( 40 ml), methyltriphenoxyphosphonium iodide (0.93 g) was added and the mixture was stirred at rt for 2 h. The reaction mixture was washed with sodium bicarbonate solutions and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, yielding the desired compound (0.9.12 g) as a semi-solid compound: 1 H-NMR (CDCl 3, d): 1.05-1.2 (m, 2H) , 1 .32-1.5 (m, 2H), 1 .96-2.05 (m, 2H), 2.1 -2.2 (m, 2H), 2.32-2.4 (t, 2H), 2.85-2.95 (t, 2H) ), 3.05-3.20 (m, 4H), 5.02-5.12 (m, 1 H), 6.88-7.35 (m, 14H).

Step 2: (R) 7-R? / - 3- (4-fluorophenyl) propioniHamino-1 -r / V- (1 .2.3.4-tetrahydro-1-methyl-6,7-dimethoxyisoquinol inyl) Hydrochloride 1- 4.4-diphenyl heptane (Compound II, Scheme 2) To a solution of 7 - [/ V-3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptyl iodide (0.912 g) in dioxane (30 ml) , was added. { R) 1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinoline (0.33 g) followed by a solution of potassium carbonate (0.230 g) in water (2 ml). The mixture was heated at 70 ° C for 34 h and then cooled to rt and diluted with ethyl acetate. The organic phase was washed twice with brine, dried (Na2SO) and concentrated in vacuo. The residue was purified using silica gel column chromatography, levigating with ethyl acetate / methanol (95: 5). The desired product. { R) 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1,2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisocyanolinyl) hydrochloride] 4,4-diphenolheptane (0.693 g) was obtained as a dry foam: [α] 25 D = -11.0 ° (c = 1, EtOH): MS showed (M + H) + @ 623; 1 H-NMR (CDCl 3, d): 1.06-1.32 (, 7H), 2.03-2.18 (m, 4H), 2.32.3.0 (m, 10H), 3.10-3.20 (q, 2H), 3.60-3.72 (m, 1H), 3.82-3.88 (two s, 6H), 6.48 (s, 1H), 6.53 (s, 1H), 6.87-6.97 (t, 2H), 7.08-7.30 (m, 12H). This compound was treated with methanol / HCl solution and the solvent was removed in vacuo. The residue was dissolved in acetonitrile / water (1: 1) and lyophilized to give the hydrochloride salt of the desired product: mp 113-115 ° C; IR (KBr)? 3400, 3300, 2950, 1750 crn "1; Anal Caled for C40H47N2O3F? CI: C, 72.87; H, 7.33; N, 4.24; Found: C, 72.61; H, 7.33; N, 4.13; Example 3 (S) 7-R? / - 3- (4-fluorophenyl) propioniHamino-1-r? / - (1,2,3,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinolyl) -hydrochloride ) 1-4,4-diphenylheptane The procedure described in Example 2 was used, but replacing (S) 1,2,3,4-tetrahydro-1-methyl-4,5-dimethoxyisoquinoline per. { R) 1,2,3,4-tetrahydro-1-methyl-4,5-dimethoxy-isoquinoline. After purification by chromatography, the desired product (S) was obtained: 7- [N-3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro- 1-methyl-6,7-dimethoxyisoquinoIinyl)] - 4,4-diphenylheptane as a dry foam: [a] = + 12.8 ° (c = 1, EtOH): MS showed (M + H) + @ 623; 1 H-NMR (CDCl 3, d): 1.1 (m, 2 H), 1.22-1.32 (m, 5 H), 2.05-2.18 (m, 4 H), 2.38-2.45 (t, 2 H), 2.50-2.82 (m, 5 H) ), 2.90-2.95 (t, 2H), 2.95-3.08 (m, 1H), 3.10-3.22 (q, 2H), 3.72-3.82 (m, 1H), 3.82-3.90 (s, 6H), 5.5-5.65 (broad m, 1H), 6.50 (s, 1H), 6.58 (s, 1 H), 6.88-6.97 (t, 2H), 7.08-7.32 (m, 12H). This compound was treated with methanol / HCl solution and the solvent was removed in vacuo. The residue was dissolved in acetonitrile / water (1: 1) and lyophilized to give the hydrochloride salt of the desired product: mp 13-1 15 ° C; IR (KBr)? 3400, 3300, 2950, 1750 cnT1; Anal. Caled for C40H47N2O3F HCl: C, 72.87; H, 7.33; N, 4.24; Found: C, 72.24; H, 7.1 8; N, 4.18.

Example 4 Hydrochloride of 7-T? / - 3- (4-fluorophenyl) propionyl-1-T Vd, 2.3.4-tetrahydro-1-cyclopropyl-6,7-di methoxy isoquinol in i 1) 1-4, 4- dif enil heptane Step 1: F? / - 2- (3,4-dimethoxyphenyl) etiH-cyclopropylcarboxylamide (Compound 12, Scheme 3) To a solution of 3,4-dimethoxyphenethylamine (5.0 g) in methylene chloride (100 ml), cooled to 0 ° C, cyclopropylcarbonyl chloride (2.5 ml) was slowly added followed by triethylamine (7 ml) and 4-dimethylaminopyridine (DMAP) (0.173 g). The reaction mixture was stirred at rt for 2 h and then washed with solutions of sodium bicarbonate, 0.5 M citric acid and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was crystallized from ethyl acetate to yield the desired product (4.98 g) as a yellow powder: MS showed (M + H) + @ 250; 1H-NMR (CDCl 3, d): 0.68-0.78 (m, 2H), 0.93-1.0 (m, 2H), 1.222-1.35 (m, 1 H), 2.73-2.82 (t, 2H) ), 3.48-3.57 (q, 2H), 3.88 (two s, 6H), 5.68 (broad s, 1 H), 6.72-6.87 (m, 3H).

Step 2: 3,4-dihydro-1-cyclopropyl-6,7-dimethoxyisoquinoline (Compound 15, Scheme 3) To a solution of [2- (3,4-dimethoxyphenyl) ethyl] cyclopropylcarboxylamide (4.9713 g) in toluene (200 ml) POCI3 (10 ml) was added. The mixture was heated under reflux with stirring under nitrogen for 2 h, cooled to rt, emptied on ice, basified to pH 10 with 1 M NaOH and extracted three times with ethyl acetate. The organic phase was washed with brine, dried (Na2SO) and concentrated in vacuo to give the desired product as a colored hard foam: MS showed (M + H) + @ 232; 1 H-NMR (CDCl 3, d): 1.48-1.59 (m, 2H), 1.95-2.05 (m, 2H), 2.30-2.41 (m, 1 H), 2.96-3.07 (t, 2H). ), 2.82-3.92 (m, 2H), 3.98 (s, 3H), 4.03 (s, 3H), 6.85 (s, 1 H), 7.45 (s, 1 H).

Step 3: 1, 2, 3, 4-tetrah id ro-1-cyclopropyl-6,7-di methoxyisoquinoline (Compound A, Scheme 3) To a stirred solution of 3,4-dihydro-1-cyclopropyl-6,7-dimethoxyisoquinoline (3.9318 g) in methanol (100 ml) was added under nitrogen NaCNBH3 (1.28 g), in the presence of three drops of acetic acid. The mixture was stirred at rt for 2 and then concentrated in vacuo and the residue taken up in ethyl acetate and washed with solutions of sodium bicarbonate and brine. The organic phase was dried and concentrated in vacuo to give the desired product as a tan solid: MS showed (M + H) + @ 234; 1 H-NMR (CDCl 3, d): 0.3-0.41 (m, 1 H), 0.5-0.65 (m, 2H), 0.77-0.9 (m, 1 H), 1 .02-1. 16 (m, 1 H), 2.25 (broad s, 1 H), 2.6-2.75 (m, 1 H), 2.85-3.08 (m, 2H), 3.28-3.36 (m, 1 H), 3.88 (two s) , 6H), 6.60 (s, 1 H), 7.08 (s, 1 H).

Step 4: 1, 2,3,4-Tetrahydro-1-cyclopropyl-6,7-dimethoxyisoquinoline hydroiodide To a solution of 1,2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxyisoquinoline ( 0.802 g) in ethanol (10 ml) cooled to 0 ° C, a solution of 57% Hl (0.5 ml) was added dropwise. The ice bath was stirred and the solution was stirred at rt for 20 min in the dark. To the bright orange solution was added ether (250 ml) and the mixture was stirred for 10 min. The light yellow precipitate was filtered and dried under vacuum under P2O5 to give the desired salt (0.958 g).

Step 5: 7-f? -3- (4-fluorophenyl) propioninamino-1 - [α / - (1, 2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxyisoquinolinyl) -1,4,4-diphenylheptane (Compound II, Scheme 2 ) To a solution of 7-amino-4,4-diphenylheptan-1-ol (1.04 g) (Compound 6, Scheme 2) in methylene chloride (10 ml), methanesulfonyl chloride (0.22 ml) was added at 0 ° C, followed by triethylamine (0.5 ml). The solution was stirred at 0CC for 30 min. The reaction mixture was washed with 0.5 N citric acid, water and brine. The organic phase was dried and concentrated in vacuo to give the desired product as an oil (1.010 g). This was used in the next step without further purification. To a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptyl mesilate (1.35 g) (Compound 9, Scheme 2) in acetonitrile (25 ml), was added in the dark hydroiodide of 1, 2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxy-isoquinoline (0.958 g) and triethylamine (2 ml). The mixture was kept in the dark and heated under reflux overnight. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The foamy residue was purified by silica gel column chromatography, levigating with methylene chloride / methanol (98: 2). This produced 7 - [? / - 3-84-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrah idro-1-cyclopropyl-6,7-dirnetoxy-isoquinolinyl)] - 4,4-diphenylheptane (0.47 g): MS showed (M + H) + @ 649; H-NMR (CDCl 3, d): 0.22-0.3 (m, 1 H), 0.5-0.6 (m, 1 H), 0.92-1.25 (m, 3H), 1 .98-2.07 (m, 4H) , 2.3-2.42 (m, 2H), 2.42-2.95 (m, 12H), 3.08-3.3 (m, 3H), 3.83 (s, 6H), 6.53 (s, 1 H), 6.6 (s, 1 H) , 6.86-6.98 (m, 2H), 7.07-7.3 (m, 12H). This compound was dissolved in methanol / HCl, the solution was concentrated in vacuo and the residue was dissolved in acetonitrile / water (1: 1) to give 7 - [/ / 3- (4-fluorophenyl) propionyl] amino-hydrochloride. 1 - [? / - (1, 2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane (0.470 g): mp 122-129 ° C; I R (CHCI3)? 3300, 2942, 1646 cm "1; Anal Caled for C42H49N2O3F HCI: C, 73.61; H, 7.35; N, 4.09; Found: C, 73.73; H, 7.21; N, 3.86.

Example 5 7-R? / -3- (4-fluorophenyl) propionipamino-1 -r? / - (1, 2,3,4-tetrahydro-1-ethyl-6,7-dimethoxyisoqui nolin il hydrochloride) l-4,4-diphenyl heptane 1, 2,3,4-tetrahydro-1-ethyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in Example 4 for 1, 2, 3, 4-tetrah idro-1-cyclopropyl-6,7-dimethoxyisoquinolone, but replacing the first step of propionyl chloride with cyclopropylcarbonyl chloride. 1, 2,3,4-Tetrahydro-1-ethyl-6,7-dimethoxyisoquinoline (0.195 g) was reacted with 7-f? / 3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptan- 1 -al (0.41 82 g) in the presence of sodium cyanoborohydride, as described in Example 1, to give the desired product 7 - [? / 3- (4-fluorophenyl) propionyl] amin or-1 - [? / - (1, 2, 3, 4-tetrahydro-1 -eti 1-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane as a glassy residue (0.0685 g): MS showed (M + H) + @ 637; 1 H-NMR (CDCl 3, d): 0.85-0.93 (t, 3H), 1.05-1.08 (m, 4H), 1.55-1.75 (m, 4H), 2.0-2.17 (m , 4H), 2.3-2.40 (t, 2H), 2.40-2.55 (m, 4H), 2.87-2.93 (t, 2H), 2.97-3.31 (m, 3 H), 3.93 (s, 6H), 6.47 ( s, 1 H), 6.53 (s, 1 H), 6.86-6.98 (t, 2H), 7.08-7.30 (m, 12H). The hydrochloride salt of the desired product was prepared as described in Example 1, to give 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [N-. { 1, 2, 3, 4-tetrah idro-1 -eti I-6, 7-dimethoxyisoquinolinyl)] - 4, 4-dif in iheptane: mp 98-105 ° C; IR (CHCI3)? 3300, 2942, 1646 crn-1; Anal. Caled for C41 H49N2O3F HCI: C, 73.13; H, 7.48; N, 4.16; Found: C, 77.21; H, 7.79; N, 4.35.

Example 6 Hydrochloride of 7-f? -3- (4-fluorophenyl) propioninamino-1 -r? - (1, 2,3,4-tetrahydro-1-isopropyl-6,7-dimethoxyisoquinoline and Dl-4, 4-diphenyl heptane) 1, 2,3,4-tetrahydro-1-isopropyl-6,7 was prepared dimethoxyisoquinoline by a procedure analogous to that described in Example 4 for 1, 2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxy-isoquinoline, but substituent in the first step isobutyryl chloride by cyclopropylcarbonyl chloride. 1, 2, 3,4-tetrahydro-1-isopropyl-6,7-dimethoxyisoquinoline was reacted with 7 - [? / 3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptan-1 - al, in the presence of sodium cyanoborohydride, as described in Example 1, to give the desired product as glassy residue (0.135 g): MS showed (M + H) + @ 651; 1H-NMR (CDCl3, d): 0.8-0.88 (d, 3H), 0.92-1.02 (d, 3H), 1.02-1.20 (m, 3H), 1.52-1.70 ( m, 2H), 1 .7-1 .9 (m, 1 H), 1 .97-2.2 (m, 4H), 2.3-2.50 (m, 4H), 2.50-2.72 (m, 2H), 2.85- 2.96 (m, 3H), 3.02-3.20 (m, 3H), 3.8-3.9 (two s, 6H), 5.08 (broad s, 1 H), 6.43 (s, 1 H), 6.53 (s, 1 H) , 6.9-6.97 (m, 2H), 7.05-7.32 (m, 12H). The hydrochloride salt was prepared as in Example 1 to give 7 - [/ / 3- (4-fluorophenyl) propionyl] -1- [/ / - (1, 2.3, 4-) hydrochloride tetrahydro-1-isopropyl-6,7-dimethoxyisoquinoliniI) - 4,4-diphenylheptane; mp 96-103 ° C; IR (CHCI3)? 3350, 2950, 1650, 1510 cm-1.

Example 7 7-R? / - 3- (4-fluorophenyl) propionipamino-1-r? / - (1, 2,3,4-tetrahydro- 1 -f eni-6,7-dimethoxyisoquiol hydrochloride nil) l-4,4-diphen I I heptane 1, 2,3,4-Tetrahydro-1-phenyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in Example 4 for 1, 2,3,4-tetrahydro-1-cyclopropyl-6. , 7-dimethoxyisoquinoline, but replacing in the first step benzoyl chloride with cyclopropylcarbonyl chloride. 1, 2,3,4-tetrahydro-1-phenyl-6,7-dimethoxyisoquinolinyl was reacted with 7 - [γ / 3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptan-1 -al in the presence of sodium cyanoborohydride, as described in example 1 to give the desired product as glassy residue: MS showed (M + H) + @ 685; 1 H-NMR (CDCl 3, d): 1 .0-1 .2 (m, 4 H), 1 .65-1 .75 (m, 1 H), 1 .95-2.05 (m, 2 H), 2.06- 2.15 (m, 1 H), 2.15-2.25 (m, 1 H), 2.32-2.36 (t, 2H), 2.36-2.45 (m, 2H), 2.62-2.70 (m, 1 H), 2.85-2.95 ( m, 4H), 3.08-3.17 (q, 2H), 3.58 (s, 3H), 3.83 (s, 3H), 4.36 (s, 1 H), 5.01 (broad t, 1 H), 6.13 (s, 1 H), 6.58 (s, 1 H), 6.88-6.94 (m, 2H), 7.06-7.33 (m, 17H); IR (CHCl3)? 3300, 2950, 1645, 1505 crn-1. The hydrochloride salt was prepared as in Example 1 to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 hydrochloride phenyl-6I7-d-methoxyisoquinolinyl) - 4,4-diphenyl heptane: mp 1 17-120 ° C; Anal. Caled for C45H49N2O3F? CI 0.5H2O: C, 74.0; H, 7.30; N, 3.83; Found: C, 73.14; H, 6.74; N, 3.71.

Example 8 7-f? / - 3- (4-fluorophenyl) propionamino-1-f? / - (1, 2,3,4-tetrahydro-1-cyclopentyl-6,7-dimethoxy isoquinol inyl) Hydrochloride l-4, 4-dif in i I heptane 1, 2,3,4-Tetrahydro-1-cyclopentyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in Example 4 for 1, 2, 3, 4-tetrahydro-1-cyclopropyl-6, 7-d methoxy isoquinolone, but replacing in the first step cyclopentylcarbonyl chloride with cyclopropylcarbonyl chloride. 1, 2,3,4-Tetrahydro-1-cyclopentyl-6,7-dimethoxyisoquinoline was reacted with 7 - [? / 3- (4-fluorophenyl) propionyl] -amino-4,4-diphenylheptan- 1 -al, in the presence of sodium cyanoborohydride as described in Example 1, to give the desired product as a solid foam: MS showed (M + H) + @ 677; 1 H-NMR (CDCl 3, d 1 .05-1 .72 (m, 12 H), 1.75-2.1 7 (m, 6 H), 2.28-2.56 (broad m, 5 H), 2.65-2.85 (m, 2 H) , 2.85-2.96 (t, 2H), 3.10-3.35 (m, 3H), 3.78-3.88 (two s, 6H), 6.42 (s, 1 H), 6.52 (s, 1 H), 6.88-6.98 (m , 2H), 7.05-7.30 (m, 12H); IR (KBr)? 3450, 2950, 1650, 1510 cm "1. The hydrochloride salt was prepared as in Example 1 to give 7 - [? / - hydrochloride. 3- (4-fluorophenyl) propionyl] amino-1 - [V- (1, 2,3,4-tetrahydro-1-cyclopentyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 92 ° C (dec); Anal. Caled for C44H53N2O3F? CI .5H2O: C, 73.1 5; H, 7.67; N, 3.87; Found: C, 73.45; H, 7.78; N, 3.87.

Example 9 Hydrochloride of 7-f? / - 3- (4-fluorophenyl) propionamino-1-f? / - (1 .2.3.4- tetrahydro-1-cyclobutyl-6,7-dimethoxyisoquinoline iM-4, 4-dif in I I heptane 1, 2,3,4-tetrahydro-1-cyclobutyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1, 2, 3, 4-tetrah idro-1-cyclopropyl-6,7-dimethoxy-isoquinol ina, but replacing in the first step cyclobutylcarbonyl chloride with cyclopropylcarbonyl chloride. The 1,2,3,4-tetrahydro-1-cyclobutyl-6,7-dimethoxyisoquinoline was reacted with 7 - [/ V-3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptan-1 -al , in the presence of sodium cyanoborohydride as described in example 1, to give the desired product as a solid foam: MS showed (M + H) + @ 663; 1 H-NMR (CDCl 3, d): 1.05-1.28 (m, 4H), 1.62-2.18 (m, 10H), 2.30-2.62 (m, 6H), 2.65-2.82 (m, 2H), 2.83-2.95 (t , 2H), 3.02-3.25 (m, 4H), 3.80-3.88 (two s, 6H), 6.45 (s, 1H), 6.53 (s, 1H), 6.88-6.98 (m, 2H), 7.08-7.32 ( m, 12H); IR (KBr)? 3415, 2937.1646, 1510 crn-1. The hydrochloride salt was prepared as in Example 1 to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1 hydrochloride -cyclobutyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane: mp 112-121 ° C (dec); Anal. Caled for C43H51N2O3F HCl 2H2O: C, 72.88; H, 6.99; N, 3.46; Found: C, 72.56; H, 7.38; N, 3.83.

Example 10 7-f? / 3- (4-fluorophenyl) propionyl-amino-1-fA / - (1, 2,3,4-tetrahydro-1-cyclohexyl-6,7-dimethoxyisoquinoliniM-4.4-diphenylheptane hydrochloride 1,2,3,4-Tetrahydro-1-hexyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in Example 4 for 1,2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxyisoquinol, but replacing in the first step 2-methoxyacetyl chloride with cyclopropylcarbonyl chloride. The 1,2,3,4-tetrahydro-1-cyclohexyl-6,7-dimethoxyisoquinoline was reacted with 7 - [? / 3- (4-f luorofenyl) propionyl] -amino-4,4-diphenylheptan- 1-a, in the presence of sodium cyanoborohydride as described in Example 1, to give the desired product as a solid foam: MS showed (M + H) + @ 691; 1 H-NMR (CDCl 3, d): 0.8-1.3 (m, 8H), 1.3-1.8 (m, 7H), 1.85-2.2 (m, 5H), 2.3-2.45 (m, 5H), 2.5-2.75 (m , 2H), 2.84-3.0 (m, 3H), 3.03-3.2 (q, 2H), 3.83 (two s, 6H), 5.06 (broad s, 1H); 6.39 (s, 1H), 6.53 (s, 1H), 6.87-6.98 (m, 2H), 7.08-7.32 (m, 12H); IR (KBr)? 3415, 2937, 1646, 1510 cm'1. The hydrochloride salt was prepared as in Example 1 to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1 hydrochloride -cyclohexyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 104 ° C; Anal. Caled for C45H55N2O3F HCl: C, 74.30; H, 7.75; N, 3.85; Found: C, 73.86; H, 7.83; N, 3.63.

Example 11 7-f? / - 3- (4-fluorophenyl) propioninamino-1-IA / - (1, 2,3,4-tetrahydro-1-cyanomethyl-6,7-dimethoxyisoquinolinyl) 1-4,4-diphenylheptane hydrochloride 1, 2,3,4-tetrahydro-1-cyanomethylene-6,7-dimethoxyisoquinolone was reacted with 7 - [γ / 3- (4-fluorophenyl) propioni I] am i no-4, 4- diphenylheptan-1-al, in the presence of sodium cyanoborohydride, as described in example 1, to give the desired product as a clear film: MS showed (M + H) + @ 648; 1 H-NMR (CDCl 3, d): 1.08-1.3 (m, 4H), 2.02-2.12 (m, 2H), 2.12-2.25 (m, 2H), 2.32-2.40 (5, 2H), 2.45-2.80 (m , 7H), 2.85-3.0 (m, 3H), 3.06-3.2 (m, 2H), 3.75-3.85 (m, 7H), 5.38 (broad m, 1H), 6.75 (d, 2H), 6.88-6.95 ( m, 2H), 7.10-7.30 (m, 12H); IR (CHCI3)? 3400, 2939, 2240, 1650, 1510 cm "1. The hydrochloride salt was prepared as in example 1, to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1- [? / - (1,2,3,4-tetrahydro-1-cyanomethyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 106-114 ° C; Anal Caled for C41H46N3O3F HCl: C, 71.97; 6.92, N, 6.14, input: C, 71.82, H, 6.86, N, 5.95.

Example 12 7-f? / - 3- (4-fluorophenyl) propionamino-1-r? / - (1,2,3,4-tetrahydro-1-methoxymethyl-6,7-dimethoxyisoquinolinyl) 1-4 hydrochloride 4-diphenylheptane I ^ .S ^ -tetrahydro-l-methoxymethyl-e-dimethoxyisoquinoline was prepared by a procedure analogous to that described in Example 4 for 1,2,3,4-tetrahydro-1-cyclopropylo-6,7-dimethoxy-isoquinol. noli na, but replacing in the first step 2-methoxyacetyl chloride with cyclopropylcarbonyl chloride. The 1,2,3,4-tetrahydro-1-methoxymethyl-6,7-dimethoxyisoquinoline was reacted with 7 - [γ / 3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptan-1-al , in the presence of sodium cyanoborohydride, as described in example 1, to give the desired product as a clear film: MS showed (M + H) + @ 653; 1 H-NMR (CDCl 3, d): 1.1-1.3 (m, 2H), 1.4-1.7 (broad m, 3H), 2.0-2.22 (m, 4H), 2.45-2.57 (t, 2H), 2.75-3.0 ( m, 5H), 3.15-3.28 (m, 4H), 3.37 (broad s, 3H), 3.5-3.65 (m, 2H), 3.65-3.8 (broad m, 1H), 3.8-3.88 (two s, 6H) , 3.98-4.10 (broad m, 1H), 6.45 (s, 1H), 6.59 (s, 1H), 6.88-6.97 (t, 2H), 7.10-7.30 (m, 12H); IR (KBr)? 3331, 2937, 2240, 1646, 1510 cm "1. The hydrochloride salt was prepared as in Example 1, to give 7 - [? / -3- (4-fluorophenyl) propionyljam ino- 1- [? / - (1,2,3,4-tetrahydro-1-methoxymethyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 102-1 1 ° C (dec); Anal Caled for C41 H50N2O4F 2HCI : C, 67.75; H, 7.21 N, 3.85; Found: C, 67.39; H, 6.78; N, 4.22.

Example 13 7-f? / - 3- (4-fluorophenyl) propionamino-1-f? Hydrochloride? - (1, 2,3,4-tetrahydro-1-benzyloxymethyl-6,7-dimethoxyisoquinolinyl) 1-4,4-diphenylheptane 1, 2,3,4-Tetrahydro-1-benzyloxymethyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in step 4 of example 4, but replacing 1, 2,3,4-tetrahydro-1 - benzyloxymethyl-6,7-dimethoxyisoquinoline for 1, 2,3,4-tetrahydro-1-cyclopropyl-6,7-di methoxyisoquinolone. The hydroiodide of 1,2,3,4-tetrahydro-1-benzyloxymethyl-6,7-dimethoxyisoquinoline was reacted with 7 - [? / -3- (4-fluorophenyl) propionyl] amino-4,4-d mesylate Phenylheptyl as described in step 5 of example 4, to give the desired product as a clear film: MS showed (M + H) + @ 730; 1 H-NMR (CDCl 3, d): 1.05-1.33 (m, 4H), 1.98-2.20 (m, 4H), 2.3-2.38 (t, 2H), 2.38-2.8 (m, 5H) , 3.0-3.2 (m, 3H), 3.48-3.60 (m, 1 H), 3.72 (m, 2H), 3.75 (s, 3H), 3.83 (s, 3H), 4.43-4.55 (q, 2H), 5.28 (broad s, 1 H), 6.53 (s, 1 H), 6.58 (s, 1 H), 6.85-6.95 (m, 2H), 7.05-7.34 (m, 17H). The hydrochloride salt was prepared as in Example 4, to give 7 - [? / 3- (4-fluorophenii) propionyl] amino-1 - [? / - (1, 2,3, 4-tetrahydroxy) hydrochloride. 1-benzyloxymethyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane: mp 1 18-133 ° C (dec); IR (MIC)? 3330, 2950, 1650, 1510 ern "1; Anal Caled for C47H53N2O4F HCI.1 .25H2O: C, 71.64; H, 7.22; N, 3.55; Found: C, 71.85; H, 7.09; N, 3.69.

Example 14 Hydrochloride of 7-r? / - 3- (4-fluorophenyl) propionipamino-1 -r? / - (1,2,3,4-tetrahydro-1- (4-methoxyphenyl-6,7-dimethoxyisoquinolinyl ) l-4.4-diphenylheptane 1, 2,3,4-Tetrahydro-1- (4-methoxyphenyl) -6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in Example 7, for 1, 2,3,4-tetrahydro-1 - phenyl-6,7-di-methoxyisoquinoline, but replacing in the first step 4-methoxybenzoic acid with benzoic acid. The 1, 2, 3, 4-tetrah idro-1 - (4-methoxy in il) -6,7-dimethoxyisoquinolone was reacted with 7- [? -3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptanal, in the presence of sodium cyanoborohydride, as described in example 1, to give the desired product as a clear film: MS showed (M + H ) + @ 715; 1 H-NMR (CDCl 3, d): 1 .0-1 .2 (m, 3 H), 1 .65-1.78 (m, 2 H), 1 .93-2.26 (m, 4 H), 2.3-2.48 (m , 4H); 2.6-2.75 (m, 1 H), 2.82-2.97 (m, 4H), 3.06-3.18 (q, 2H), 3.6 (s, 3H), 3.83 (s, 3H), 4.33 (broad s, 1 H) , 5.07 (broad m, 1 H), 6.12 (s, 1 H), 6.57 (s, 1 H), 6.78-6.98 (m, 4H), 7.05-7.32 (m, 14H); IR (movie)? 3300, 2950, 1650, 1510 cm "1. The hydrochloride salt was prepared as in example 4, to give 7 - [? / -3- (4-f luorofenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrah id ro-1 - (4-methoxyphenyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 14-120 ° C; Anal Caled for C46H51 N2O4F HCl.0.5 H2O: C, 72.66; H, 7.20; N, 3.68; found: C, 72.33; H, 6.82; N, 3.50.

Example 15 7-γ / - 3- (4-fluorophenyl) propionamino-1-fα / - (1, 2, 3,4-tetrahydro- 1- (4-aminophenyl) -6.7 dihydrochloride -di methoxy isoqu i no I inil) 1-4.4-d phenyl heptane 1, 2,3,4-Tetrahydro-1- (4-nitrophenyl) -6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in Example 7 for 1, 2,3,4-tetrahydro-1 phenyl-6,7-dimethoxyisoquinoline, but replacing in the first step 4-nitrobenzoic acid with benzoic acid. 1, 2,3,4-tetrahydro-1- (4-nitrophenyl) -6,7-dimethoxyisoquinoline was reacted with 7 - [? / 3- (4-fluorophenyl) propionyl] amino-4.4 -diphenylheptanal, in the presence of sodium cyanoborohydride as described in example 1, to give 7 - [? / -3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4 -tetrahydro-1- (4-nitrophenyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane, as a solid: MS showed (M + H) + @ 730; 1 H-NMR (CDCl 3, d): 0.97-1.2 (m, 4H), 1.666-1.77 (m, 1 H), 1.93-2.12 (m, 2H), 2.18-2.48 (m , 6H), 2.6-2.75 (m, 1 H), 2.8-3.0 (m, 4H), 3.03-3.16 (q, 2H), 3.59 (s, 3H), 3.85 (s, 3H), 4.48 (s, 1 H), 5.0-5.08 (m, 1 H), 6.04 (s, 1 H), 6.6 (s), 1 H), 6.87-6.96 (m, 2H), 7.03-7.3 (m, 12H), 7.33-7.38 (d, 2H). This compound was dissolved in methanol and hydrogenated in the presence of 10% Pd / C. under 4 atm of hydrogen gas pressure for 21 h. The crude product was purified by preparative HPLC to give 7- [? -3- (4-fluorophenyl) propionyl] -amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (4-aminophenyl) -6,7-dimethoxyisoquinolinyl]] - 4, 4-diphenylheptane as a yellow solid: MS showed (M + H) + @ 700. 1 H-NMR (CDCl 3, d): 0.96-1.l 8 (m, 4H), 1.63-1.8 (m, 1 H), 1 .93-2.26 (m, 4H), 2.26-2.50 (m, 4H), 2.6-2.74 (m, 1 H), 2.82-2.95 (m, 4H), 3.03-3.18 (m, 2H) , 3.62 (s, 3H), 3.83 (s, 3H), 4.26 (broad s, 1 H), 5.05-5.15 (m, 1 H), 6.18 (s, 1 H), 6.55 (s, 1 H), 6.56-6.64 (d, 2H), 6.87-7.0 (m, 4H), 7.06-7.30 (m, 12H). The dihydrochloride salt was prepared as in example 4, to give 7 - [? / - 3- (4-f luorof in I) propioni l] amyl- 1 - [? / - (1, 2) hydrochloride. , 3, 4-tetrah id ro-1 - (4-amino) f in i 1-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 168-175 ° C; IR (KBr)? 3269, 2578, 1635, 1612, 1510 cm "1.

Example 16 7-f? / - 3- (4-fluorophenyl) propionyl-1-f? / - (1, 2,3, 4- tetrahydro-1 -r4 - (? / - isopropylamino) phenin dihydrochloride 6, 7-di methoxy isoqu i noli ni D1-4, 4- diphenylheptane To a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2,3,4-tetrahydro-1- (4-aminophenyl) -6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane (0. 168 g) in methanol (10 ml), acetone was added ( 0.2 ml) followed by sodium cyanoborohydride (0.031 g) and three drops of acetic acid. The mixture was stirred under nitrogen overnight, and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with solutions of sodium bicarbonate and brine. The organic phase was dried (Na2SO) and concentrated in vacuo. The crude product was purified by preparative HPLC to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2,3,4-tetrahydro-1 - [4 - (? / - isopropylamino) phenyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; Ms showed (M + H) + @ 742; 1 H-NMR (CDCl 3, d): 0.98-1.16 (broad m, 4H), 1.16-1.24 (d, 6H), 1.26 (m, 1H), 1.65-1.83 (broad m, 1H), 1.93-2.25 (m , 5H), 2.26-2.50 (m, 4H), 2.6-2.75 (m, 1H), 2.8-2.97 (m, 4H), 3.04-3.18 (m, 2H), 3.61 (s, 3H), 3.83 (s) , 3H), 4.28 (extended, 1H), 5.0-5.10 (wide m, 1H), 6.19 (s, 1H), 6.44-6.53 (d, 2H), 6.56 (s, 1H), 6.85-6.97 (t , 4H), 7.03-7.30 (m, 12H). The dihydrochloride salt was prepared as in Example 4 to give 7 - [/ V-3- (4-fluorophenyl) propionyl] amino-1 - [α- (1,2,3,4-tetrahydro-1- dihydrochloride [4 - (? / - isopropylamino) phenyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 153-161 ° C; IR (KBr)? 3275, 2934, 2588, 2459, 1653, 1510 cm "1.

Example 17 7-R? / - 3- (4-fluorophenyl) propionylamino-1-f? / - (1.2.3.4- tetrahydro-1-benzyl-6,7-dimethoxy-isoquinolinyl) 1-4.4-diphenylheptane hydrochloride 1,2,3,4-Tetrahydro-1-benzyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in Example 7 for 1,2,3,4-tetrahydro-1-phenyl-6,7 -dimethoxy-isoquinoline, but replacing in the first step phenylacetyl chloride with benzoyl chloride. The 1,2,3,4-tetrahydro-1-benzyl-6,7-dimethoxyisoquinoline was reacted with 7 - [γ- 3- (4-fluorophenyl) propionyl] amino-4,4-diphenyleptanal, in the presence of sodium cyanoborohydride as described in Example 1, to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? - (1,2,3,4-tetrahydro-1-benzyl- 6,7-dimethoxyisoquinolinyl)] - 4,4-d-phenylheptane as a film; MS showed (M + H) + @ 699; 1 H-NMR (CDCl 3, d): 1.0-1.22 (m, 4H), 1.62-1.92 (broad m, 1H), 1.92-2.15 (m, 4H), 2.3-2.4 (t, 2H), 2.4-2.84 ( m, 5H), 2.84-2.95 (t, 2H), 3.0-3.2 (m, 4H), 3.5 (s, 3H), 3.6-3.7 (broad t, 1H), 3.82 (s, 3H), 5.08 (wide) s, 1H), 5.83 (s, 1H), 6.53 (s, 1H), 6.87-7.03 (m, 4H), 7.08-7.33 (m, 15H). The hydrochloride salt was prepared as in Example 4, to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-) hydrochloride 1-benzyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 94-98 ° C; Anal. Caled for C46H5? N2O3F HCl 0.75 H2O: C, 73.67; H, 7.32; N, 3.73; Found: C, 73.71; H, 6.96; N, 3.57.

Example 18 Hydrochloride of 7-f? / - 3- (4-fluorophenyl) propionamino-1-f? / - (1,2,3,4-tetrahydro-1- (4-chlorobenzyl) -6, 7-di methoxy-5-quinolyl) -1,4,4-dif in ilheptane 1,2,3,4-tetrahydro-1- (4-chloro) benzyl-6,7-dimethoxyisoquinoline was prepared by analogous procedure to that described in Example 17 for 1,2,3,4-tetrahydro-1 -benzyl-6,7-dimethoxyisoquinoline, but replacing in the first step (4-chlorophenyl) acetyl chloride with phenylacetyl chloride. The 1,2,3,4-tetrahydro-1- (4-chlorobenzyl) -6,7-dimethoxyisoquinoline was reacted with 7 - [? / 3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptan -1-al, in the presence of sodium cyanoborohydride as described in example 1, to give 7 - [γ / 3- (4-fluorophenyl) propionyl] amino-1 - [α / - (1, 2, 3,4-tetrahydro-1- (4-chlorobenzyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-dif in ilheptane as a film: MS showed (M + H) + @ 733; 1H-NMR (CDCI3, d): 1.02-1.28 (broad m, 3H), 1.52-1.74 (broad m, 5H), 1.89-2.12 (broad m, 3H), 2.3-2.85 (broad m, 7H), 2.85 -2.95 (t, 2H), 3.04-3.22 (m, 2H), 3.72-3.88 (m, 1 H), 3.76 (s, 3H), 3.93 (s, 3H), 5.95 (broad s, 1 H), 6.54 (s, 1 H), 6.87-7.0 (m, 4H), 7.05-7.32 (m, 14H). The hydrochloride salt was prepared as in Example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 hydrochloride - (4-chlorobenzyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 88-96 ° C.

Example 19 7-R? / - 3- (4-fluorophenyl) propionamino-1-f hydrochloride? - (1, 2,3,4-tetrahydro-1- (4-methoxy benzyl) -6,7-dimethoxyisoquinolini 1) 1-4.4-dif in heptane 1, 2,3,4-Tetrahydro-1- (4-methoxybenzyl) -6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in Example 17 for 1 ^. S ^ -tetrahydro-1-benzyl-e ^ -dimethoxyisoquinoline, but replacing in the first step (4-methoxyphenyl) acetyl chloride with phenylacetyl chloride. The 1, 2, 3, 4-tetrahydro-1 - (4-methoxybenzyl) -6,7-di methoxyisoquinolone was reacted with 7 - [? / 3- (4-fluorophenyl) propionyl] amino- 4,4-diphenylheptanal, in the presence of sodium cyanoborohydride as described in example 1, to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [N-. { 1, 2, 3, 4-tetrah idro-1- (4-methoxybenzyl) -6,7-dimethoxyisoquinoline (I)) - 4,4-diphenylheptane as a film: MS showed (M + H) + @ 729; 1 H-NMR (CDCl 3, d): 1 .0-1 .22 (m, 4 H), 1 .91 -2.10 (m, 4 H), 2.3-2.4 (m, 2 H), 2.4-2.85 (m, 6 H) ), 2.85-2.94 (t, 2H), 2.94-3.2 (m, 5H), 3.51 -3.67 (m, 1 H), 3.55 (s, 3H), 3.76 (s, 3H), 3.82 (s, 3H) , 1 H, (broad s, 5.13), 5.92 (s, 1 H), 6.52 (s, 1H), 6.75-6.97 (m, 6H), 7.07-7.30 (m, 12H); IR (MIC)? 3300, 2950, 1650, 1510 cm "1. The hydrochloride salt was prepared as in example 4, to give 7 - [? - 3- (4-fluorophenyl) propionyl] amino-1 - [? - (1,2 , 3,4-tetrahydro-1- (4-methoxybenzyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 100-108 ° C.

Example 20 7-R? / - 3- (4-fluorophenyl) propioniHamino-1-F? / - (1, 2.3.4-tetrahydro-1-phenethyl-6,7-dimethoxy-1-ynylinolinyl) 1-4 hydrochloride 4-diphenylheptane 1,2,3,4-Tetrahydro-1-phenethyl-6,7-dimethoxy-isoquinoline was prepared by a procedure analogous to that described in example 17 for 1,2,3,4-tetrahydro-1-phenethyl-6, 7-dimethoxy-isoquinoline. It was reacted with 1,2,3,4-tetrahydro-1-phenethyl-6,7-dimethoxyisoquinoline with 7 - [α-3- (4-f luorof in yl) propionyl] amino-4,4-diphenylheptanal, in the presence of sodium cyanoborohydride as described in example 1, to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1,2,3,4- tetrahydro-1-phenethyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane as a film: MS showed (M + H) + @ 713; 1H-NMR (CDCI3> d): 1.06-1.3 (broad m, 4H), 1.8-2.25 (m, 4H), 2.25-2.53 (m, 4H), 2.53-2.78 (m, 4H), 2.83-2.93 (t, 2H), 2.98-3.19 (m, 3H), 3.34-3.43 (broad m, 1H), 3.64-3.72 (t, 1H), 3.79 (s, 3H), 3.84 (s, 3H), 3.87 ( s, 1H), 3.94 (s, 1H), 4.99 (broad s, 1H), 6.43 (s, 1H), 6.53 (s, 1H), 7.87-7.98 (q, 2H), 7.04-7.35 (m, 17H ). The hydrochloride salt was prepared as in example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrahydro-1 hydrochloride -phenethyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphen-ilheptane: mp 97-1 02 ° C.

Example 21 Dihydrochloride of 7-rA -3- (4-fluorophenyl) propioniHamino-1 -r / V- (1, 2, 3,4-tetrahydro-1- (4-aminobenzyl) -6,7-dimethoxyisoquinolinyl) 1-4.4- diphenylheptane 1, 2,3,4-tetrahydro-1- (4-nitrobenzyl) -6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 17, for 1, 2,3,4-tetrahydro-1 - benzyl-6,7-dimethoxyisoquinoline, but replacing in the first step (4-nitrophenyl) acetyl chloride for phenacetyl chloride. 1, 2,3,4-Tetrahydro-1- (4-nitrobenzyl) -6,7-dimethoxy isoquinoline was reacted with 7 - [? / 3- (4-f luorofenyl) propionyl] amino-4, 4 -diphenylheptanal, in the presence of sodium cyanoborohydride, as described in example 1 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4 -tetrahydro-1 - (4-nitrobenzyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane as a film: MS showed (M + H) + @ 744. A solution of 7 - [? / - (4 -fluorophenyl) propionyl] amino-1 - [α / - (1, 2,3,4-tetrahydro-1 - (p-nitro) -benzyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane in Methanol was hydrogenated in the presence of 10% Pd / C under 4 atm of hydrogen gas pressure. The product was purified by preparative HPLC to give 7 - [/ V-3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro-1- (4-aminobenzyl) - 6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane as a film: MS showed (M + H) + @ 714. The hydrochloride salt was prepared as in example 4 to give 7 - [? / - 3 dihydrochloride - (4-fluorophenyl) propionyl] amino-1 - [α / - (1, 2,3,4-tetrahydro-1- (4-aminobenzyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 138-149 ° C.

EXAMPLE 22 7-R? / -3- (4-fluorophenyl) propionylamino-1-r? / - (1, 2,3,4-tetrahydro-1-aminomethyl-6,7-dimethoxyisoquinolinyl) 1-4.4-diphenylheptane dihydrochloride Step 1: 1, 2,3,4-tetrahydro-1 -? / - (phthalimidomethyl) -6,7-dimethoxyisoquinoline To a mixture of 3,4-dimethoxyphenethylamine (5 g) and phthalimidoglycine (5.5 g) in methylene chloride (500 ml) and DMF (30 ml), HOBt (4.8 g) was added followed by triethylamine (11 ml) and EDCI (6.82 g). The reaction mixture was stirred at rt under nitrogen overnight and then concentrated in vacuo. Ethyl acetate was added to the residue and the mixture was washed with sodium bicarbonate solution. The precipitate was filtered and dried to give [α / - 283,4, -dimethoxyphenyl) ethyl] - / V- (phthalimido) acetyl amide (8.8 g): MS showed (M + H) + @ 369.

Step 2: 3,4-dihydro-1 -? / - (phthalimidomethyl) -6,7-dimethoxyisoquinolone To a stirred suspension of [? / 2- (3,4-dimethoxyphenyl) ethyl] -? - (phthalimido) acetyl amide (7.35 g) in toluene, POCI3 (29.6 g) was added. The mixture was heated under reflux overnight, then cooled to 0 ° C and basified with 4N NaOH to pH 10. The organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The toluene and ethyl acetate extracts were combined, washed with brine, dried (Na2SO) and concentrated in vacuo. The solid residue was purified by a column of silica gel, levigating with methylene chloride / methanol (98: 2) to give as a yellow foam 3,4-dihydro-1 -? / - (phthalimidomethyl) -6,7- di-methoxyisoquinoline (5,176 g): MS showed (M + H) + @ 351; 1 H-NMR (CDCl 3, d): 2.58-2.68 (t, 2H), 3.57-3.67 (t, 2H), 3.92 (two s, 6H), 4.92 (s, 2H), 6.7 (s, 1 H) , 7.07 (s, 1 H), 7.68-7.76 (q, 2H), 7.83-7.92 (q, 2H).

Step 3: 1, 2,3,4-tetrahydro-1 -? / - (phthalimidomethyl) -6,7-dimethoxyisoquinoline To a solution of 3,4-dihydro-1 -? - (phthalimidomethyl) -6,7-dimethoxyisoquinoline (4.8 g) in methanol (250 ml), sodium cyanoborohydride (1.033 g) was added. The pH of the solution was adjusted to 5 by the addition of a few drops of acetic acid. The mixture was stirred under nitrogen at rt for 2 h and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed with sodium bicarbonate solutions and brine, dried and concentrated again under vacuum. The residue was purified by a column of silica gel, levigating with methylene chloride / methanol (95: 5) to give 1, 2,3,4-tetrahydro-1 - / V- (phthalimidomethyl) -6,7-dimethoxyisoquinoline (2.26 g): MS showed (M + H) + @ 353; 1 H-NMR (CDCl 3, d): 1.92 (broad s, 1 H), 2.64-2.75 (m, 2 H), 2.92-3.01 (m, 1 H), 3.25-3.38 (m, 1 H), 3.81 -3.92 (m, 1 H), 3.85 (s, 3H), 3.89 (m, 3H), 4.02-4.12 (m, 1 H), 4.24-4.32 (two d, 1 H), 6.6 (s, 1 H) ), 6.76 (s, 1 H), 7.62-7.76 (q, 2H), 7.82-7.9 (q, 2H).

Step 4: 7-f? -3- (4-fluorophenyl) propioninamino-1-f? - (1, 2,3,4-tetrahydro-1 -? / - (phthalimidomethyl) -6,7-dimethoxyisoquinolinyl hydrochloride) 1-4.4-diphenylheptane 1,2,3,4-tetrahydro-1 -? / - (phthalimidohethyl) -6,7-dimethoxyisoquinoline was reductively alkylated with 7 - [? / -3-84-fluorophenyl) propionyl] amino -4,4-diphenylheptan-1-al, in the presence of sodium cyanoborohydride using the procedure described in Example 1. After work-up and chromatographic purification, 7 - [? / - 3- (4-f luorofenil ) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1 -? - (phthalimidomethyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed ( M + H) + @ 768; 1 H-NMR (CDCl 3, d): 0.71-1.13 (m, 3H), 1.56-2.04 (m, 5H), 2.1-2.55 (m, 5H), 2.61-2.85 (m, 2H), 2.85-2.98 (t , 2H), 2.98-3.42 (m, 3H), 3.62-3.75 (dd, 1H), 3.85-3.95 (dd, 1H), 3.82 (s, 3H), 3.86 (s, 3H), 3.95-4.12 (q , 1H), 5.73-5.82 (broad m, 1H), 6.57 (s, 1H), 6.63 (s, 1H), 6.78-6.98 (m, 6H), 7.04-7.13 (m, 8H). The hydrochloride salt was prepared as in Example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1- hydrochloride ? / - (phthalimidomethyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 114-121 ° C (dec); IR (MIC)? 3250, 2943, 1771, 1712, 1671, 1510 cm "1; Anal Caled for C48H5oN3O5F HCl: C, 71.67; H, 6.41; N, 5.22; Found: C, 71.42; H, 6.21; N, 5.38; Step 5: 7 - [? / - 3- (4-fluorophenyl) propioninamino-1-f? / - (1,2,3,4-tetrahydro-1-amomethyl-6,7-dimethoxyisoquinone dihydrochloride) ) 1-4, 4-diphenylheptane To a stirred solution of 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1 -? / - (phthalimidomethyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane (0.33 g) in ethanol (3 ml), hydrazine hydrate (2 ml) was added and the mixture was heated under reflux for 90 min. The solvent and excess reagent were removed in vacuo and to the residue 2N HCl (2.5 ml) was added. The mixture was stirred at rt for 2 h and then concentrated in vacuo. The residue was purified by preparative HPLC to give 7 - [α / 3- (4-fluorophenyl) propionyl] amino- 1 - [W1, 2, 3, 4-tetrahydro-1-amyl not 1-6,7-dimethoxyisoquinolyl)] - 4,4-d-phenylheptane (0.150 g) as a white foam: MS showed (M + H) + @ 768; H-NMR (CDCl 3, d): 1 .0-1 .3 (m, 4H), 1.94-2.24 (m, 7H), 2.32-2.79 (m, 6H), 2.79-2.97 (m, 4H), 2.97 -3.28 (m, 3H), 3.35-3.43 (t, 1 H), 3.8 (s, 3H), 3.84 (s, 3H), 5.68-5.78 (broad t, 1 H), 6.49 (s, 1 H) , 6.54 (s, 1 H), 6.86-6.97 (t, 2H), 7.08-7.32 (m, 12H). The hydrochloride salt was prepared as in Example 4 to give dihydrochloride of 7- [3- (4- (4-f luorof eni) propion il] am ino- 1 - [? / - (1, 2, 3, 4-tetrah idro-1-a-min-omethyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenyl-heptane: mp 1 10-1 16 ° C; Anal. Caled for C40H48N3O3F 2HCI: C, 67.60; H, 7.09; N, 5.91; found: C, 65.20; H, 7.12; N, 5.53.

Example 23 7-R? / - 3- (4-fluorophenyl) propionp-1-r? / - (1, 2, 3,4-tetrahydro-1 - (? / - isopropylaminomethyl-6,7-d methoxy isoquid dihydrochloride i nolin 1) 1-4, 4- diphenylheptane To a solution of 7 - [? / 3- (4-fluorophenyl) propionl] -1 - [? / - (1,2, 3,4-tetrahydro-1-aminomethyl-6-l7-dimethoxyisoquinolinyl)] - 4 , 4-diphenylheptane (0.030 g) in methanol (2 ml), acetone (0.3 ml), sodium cyanoborohydride (0.004 g) and three drops of acetic acid were added. The mixture was stirred at rt under nitrogen for 2 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with sodium bicarbonate solutions and brine, dried (Na 2 SO 4) and again concentrated in vacuo. The residue was purified by preparative HPLC to give 7 - [? / 3- (4-fluorophen-yl) propionyl] -1 - [? / - (1, 2, 3, 4-tetrahydro-1 - (? / -isopropyl ami nom ethyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 680; 1H-NMR (CDCIs, d): 1.0-0.32 (m , 10H), 1 .97-2.32 (m, 6H), 1 .98-2.54 (m, 4H), 2.6-3.18 (m, 9H), 3.2-3.35 (m, 1 H), 3.55-3.68 (m , 1 H), 3.77 (s, 3 H), 3.83 (s, 3 H), 6.49 (s, 1 H), 6.42 (s, 1 H), 6.52 (s, 1 H), 6.86-6.97 (t, 2H) ), 7.08-7.32 (m, 12H); IR (CHCl3)? 3280, 2946, 1647, 1510 cm "1. The hydrochloride salt was prepared as in Example 4 to give dihydrochloride of 7 - [? / - 3- (4-fluoropheni) own nor l] -1 - [/ V- (1, 2, 3, 4-tetrah idro-1 - (? -propyl-aminomethyl-6,7-d¡methoxyisoquinolinyl)] - 4,4- diphenylheptane: mp 14122 ° C; Anal Caled for C43H54N3O3F'2HCI: C, 68.60; H, 7.50; N, 5.58, found: C, 65.69; H, 7.30; N, 5.16.

Example 24 Dihydrochloride 7-f? -3- (4-fluorophenyl) propioniHamino-1 -f? - (1 .2. 3,4-tetrahydro-1 - (? / - phthalimidobutyl) -6,7-dimethoxyisoquinolinyl) -1,4-diphenylheptane The procedure described in Example 22 was used for 1, 2,3,4-tetrahydro-1 -? / - (phthalimido-methyl) -6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane, but substituting 5- ? / - phthalimidopentanoic for N-phthalimidoglicini. After silica gel column chromatography, the desired product was obtained 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? - (1, 2,3,4-tetrahydro-1- (4-phthalimidobutyl) -6,7-dimethoxyisoquinolinyl] - 4,4-diphenylheptane: MS showed (M + H) + @ 810; 1 H-NMR (CDCl 3, d): 1.05-1.23 (m, 4H), 1.32-1.49 (q, 2H), 1.50-1.76 (m, 4H), 1.96-2.2 (m, 4H), 2.28-2.50 (m , 5H), 2.52-2.76 (m, 2H), 2.84-2.94 (t, 2H), 2.94-3.07 (m, 1H), 3.07-3.23 (m, 2H), 3.23-3.33 (m, 1H), 3.6 -3.7 (t, 2H), 3.80 (s, 3H), 3.83 (s, 3H), 5.30-5.43 (broad t, 1H), 6.46 (s, 1H), 6.50 (s, 1H), 6.84-6.95 ( m, 2H), 7.04-7.27 (m, 12H), 7.64-7.83 (m, 4H); IR (MIC)? 3280, 2939, 1770, 1712, 1670, 1653, 1510 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 dihydrochloride - [? - (1,2, 3, 4-tetrah id ro-1- (4 -? / - phthalmido-butyl) -6,7-d methoxy isoquinol ini l)] - 4, 4 -diphenylheptane: mp 112-128 ° C; Anal Caled for C5iH56N3O5F HCl: C, 72.37; H, 6.79; N, 4.96; Found: C, 72.81; H, 7.01; N, 4.67; Example 25 7-Rα / 3- (4-fluorophenyl) propionin-1-f / V- (1,2,3,4-tetrahydro-1- (4-aminobutyl) -6,7-dimethoxyisoquinol dihydrochloride in i M-4.4-dif in ilheptano The synthetic procedure described in Example 22 was adopted for cutting the phthalimido group. After workup and purification of propane HPLC, the desired product was obtained 7 - [? / 3- (4-fluorophenyl) propioniI] -1 - [? / - (1, 2,3) 4-tetrahydro-1- ( 4-aminobutyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 680; 1H NMR (CDCl 3, d): 1.04-1.29 (m, 4H), 1.31-1.76 (m, 7H), 1.94-2.20 (m, 4H), 2.30-2.42 (t, 2H), 2.42-2.53 (q , 2H), 2.58-2.81 (m, 6H), 2.822.94 (t, 2H), 2.98-3.18 (m, 3H), 3.34-3.43 (m, 1H), 3.83 (s, 6H), 5.54-5.67 (m, 1H), 6.47 (s, 1H), 6.2 (s, 1H), 6.87-6.96 (m, 2H), 7.07-7.30 (m, 12H). The hydrochloride salt was prepared as in example 4 to give 7 - [α-3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1- ( 4-aminobutyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 112-118 ° C; IR (KBr)? 3410, 2936.2835, 1646, 1510 cm "1; Anal Caled for C43H54N3O3F 2HCI 1.5H2O: C, 66.22; H, 7.62; N, 5.38; Found: C, 65.89; H, 7.46; N, 5.21; Example 26 7-f? / - 3- (4-fluorophenyl) propionin-1-f? / - dihydrochloride (1,2,3,4-tetrahydro-1-4- (N-? So propi lam i nobutill-6,7- dimetoxiisoqui noli n 1) 1-4, 4-dif in i I heptane To a solution of 7 - [? / - (3- (4-fluorophenyl) propionyl] 1 - [? / - (1, 2,3,4-tetrahydro-1- (4-aminobutyl) -6,7-dimethoxyisoquinol Nil)] - 4,4-diphenylheptane (0.0586 g) in methanol (2 ml), acetone (0.3 ml), sodium cyanoborohydride (0.007 g) and a drop of acetic acid were added. The mixture was stirred at rt under nitrogen for 2 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with sodium bicarbonate solutions and brine, dried (Na2SO4) and again concentrated in vacuo. The residue was purified by preparative HPLC to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1- [4- (? / -isopropyI-aminobutyl] -6,7-dimethoxyisoquinolinyl)] - 4, 4-dif in ilheptane: MS showed (M + H) + @ 722; 1 H-NMR (CDCl 3, d): 1.05 (s, 3H), 1.07 (s, 3H), 1.07-1.22 (m, 4H), 1.3-1.76 (m, 6H), 1.95-2.22 (m, 5H), 2.3-2.50 (m, 5H), 2.52- 2.86 (m, 5H) ), 2.86-2.95 (t, 2H), 2.95-3.08 (m, 1H), 3.08-3.18 (q, 2H), 3.28-3.37 (m, 1H), 3.83 (s, 6H), 5.32-5.42 (s) , 1H), 6.48 (s, 1H), 6.52 (s, 1H), 6.82-6.97 (m, 2H), 7.04-7.29 (m, 12H); IR (CHCl3)? 3299, 2934, 2832, 1669, 1648 1510 cm'1 The hydrochloride salt was prepared as in example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1,2,3,4 -tetrahydro-1- (4 - (? - isopropylaminobutyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 118-128 ° C.

Example 27 7-R / V-3- (4-fluorophenyl) propionipamino-1-r? / - (1,2,3,4-tetrahydro-1-f4 - (? / - cyclopropyl) methylamino) dihydrochloride -6.7-dimethoxy isoquinol in i 1) 1-4,4-diphenylheptane The procedure described in Example 26 was used, but replacing cyclopropane-carboxaldehyde in place of acetone. After purification using silica gel column chromatography, 7 - [γ / 3- (4-fluorophenyl) propionyl] -1 - [α / - (1,2,3,4-tetrahydro-1 - [4 -? / - (Cyclopropylmethylamino) butyl-6,7-dimethoxyisoquinolinyl)] - 4, 4-dif eniheptane: MS showed (M + H) + @ 734: 1 H-NMR (CDCl 3, d): 0.1-0.2 (m, 2H), 0.43-0.60 (m, 2H), 0.86-1.05 (m, 1H), 1.05-1.3 (m, 4H), 1.3-1.7 (m, 6H), 1.093-2.22 (m, 4H), 2.33-2.80 (m, 10H), 2.84-2.95 (5, 2H), 2.95-3.21 (m, 3H), 3.23- 3.52 (m, 3H), 3.82-3.87 (two s, 6H) ), 5.7-5.80 (broad t, 1H), 3.48 (s, 2H), 3. 51 (s, 1H), 6.87-6.98 (t, 2H), 7.08-7.32 (m, 12H). The hydrochloride salt was prepared as in example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2, 3, 4-tetrah idro-1 dihydrochloride - [4 - (? - Cyclopropyl-methylamino) butyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 112-120 ° C; IR (KBr)? 3422, 2939, 2590, 1655, 1510 cm'1; Anal. Caled for C47H60N3O3F-2HCI: C, 69.96; H, 7.74; N, 5.21; Found: C, 68.41; H, 7.92; N, 5.18.

Example 28 7-f? / - 3- (4-fluorophenyl) propionp-1-fA / - (1,2,3,4-tetrahydro-1- (4- (A / -cyclobutylamino) butyl) -6-dihydrochloride , 7-d-methoxyisoquinol! Nl) l-4,4-diphenylheptane The procedure described in example 26 was used, but replacing cyclobutanone with acetone. After purification of the product using silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1- [- (1,2,3,4-tetrahydro-1 was obtained - [4 - (/ V-cyclobutylamido) butyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenium heptane: MS showed (M + H) + @ 734; 1 H-NMR (CDCl 3, d): 1.05-1.54 (m, 6H), 1.54-1.96 (m, 7H), 1.96-2.31 (m, 8H), 2.32-2.83 (m, 10H), 2.85-2.97 (t , 2H), 3.03-3.23 (3.3-3.51 (m, 1H), 3.58-3.68 (m, 1H), 3.83 (s, 3H), 3.86 (s, 3H), 4.35 (broad m, 1H), 6.0 ( t, 1H), 6.51 (s, 1H), 6.54 (s, 1H), 7.07-7.32 (m, 12H), IR (KBr)? 3421, 2942, 2742, 1641, 1510 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [/ V- (1,2,3,4-tetrahydro-1- [4 - (? butyl] -6,7-di methoxy isoquinolin I)] - 4,4-dipheniiheptane: mp 121-128 ° C; Anal Caled for C47H6oN3O3F-2HCI: C, 69.96; H, 7.74; N, 5.21; Found: C, 68.76; H, 7.97; N, 5.11; EXAMPLE 29 7-R? / 3- (4-fluorophenyl) propionyl-1-r? / - (1.2.3.4-tetrahydro-1- [4 - (? / - isobutyl-amino) butyne-6,7-dimethoxyisoquinolinyl dihydrochloride ) 1-4.4-diphenylheptane The procedure described in Example 26 was used, but replacing isobutyraldehyde with acetone. After preparation and purification by silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? - (1,2,3,4-tetrahydro-1 - [4 - (/ V-Isobutylamino) butyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 736: 1 H-NMR (CDCl 3, d): 0.82-1.0 (m, 1H), 1.0-1.1 (dd, 6H), 1.1-1.53 (m, 4H), 1.73-1.9 (m, 4H), 1.9-2.38 (m, 8H), 2.45-2.62 (m, 2H) , 2.62-2.87 (m, 4H), 2.87-3.55 (m, 10H), 3.84 (s, 3H), 3.86 (s, 3H), 4.1 (broad s, 1H), 6.51 (s, 1H), 6.55 ( s, 1H), 6.84-6.98 (m, 2H), 7.03-7.29 (m, 12H); IR (KBr)? 3421, 2950, 1650, 1510 cm "1. The hydrochloride salt was prepared as in example 4 to give dihydrochloride of 7 - [/ V-3- (4-f luorofenyl) propionyl] -1 - [? / - (1,2,3,4-tetrah-idro-1- [4 - (α-isobutylamido) butyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 114-128 ° C; for C47H62N3O3F-2HCI: C, 69.78; H, 7.97; N, 5.10; Found: C, 68.25; H, 8.06; N, 5.06.

Example 30 7-f? / -3- (4-fluorophenyl) propionamino-1-f? / - (1.2.3.4- tetrahydro-1- (4 -? / - isopentylamino) butyl] -6.7 dihydrochloride -di methoxyisoqui nolin i 1) 1-4,4-diphenylheotan The procedure described in Example 26 was used, but replacing isovaleryl aldehyde with acetone. After preparation and purification by silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro) was obtained -1- [4 - (? / - isopentylamino) butyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 750; 1 H-NMR (CDCl 3, d): 0.86-0.94 (d, 6H), 0.93-0.98 (m, 1 H), 1.05-1.33 (m, 4H), 1.33-1.95 ( m, 8H), 1.95-2.25 (broad m, 6H), 2.45-2.58 (m, 2H), 2.58-3.4 (broad m, 1 1 H), 3.38-3.53 (m, 1 H), 3.67- 3.8 (m, 1 H), 3.84 (s, 3H), 3.86 (s, 3H), 4.02-4.1 2 (m, 1 H), 6.54 (s, 2H), 6.7-6.78 (broad t, 1 H) , 6.84-6.96 (m, 2H), 7.0-7.29 (m, 12H); IR (KBr)? 3421, 2950, 1650, 1510 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (dihydrochloride 1, 2,3,4-tetrahydro-1 - [4 - (? / - isopentylamino) butyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 1 18-132 ° C; Anal. Caled for C48H69N3O3F-2HCI: C, 70.05; H, 8.08; N, 5.1 1; Found: C, 68.53; H, 8.46; N, 5.02.

Example 31 7 - [? / 3- (4-fluorophenyl) propionyl-amino-1-f? / - (1,2,3,4-tetrahydro-1- (4 - (? / - alpha-methyl) dihydrochloride -benzylamine) butyl-6,7-dimethoxyisoquinolinyl) 1-4,4-diphenylheptane The procedure described in Example 26 was used, but replacing acetophenone with acetone. After preparation and purification by silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro- 1- (4 - (? / - alpha-methyl-benzyl) aminobutyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 784; 1 H-NMR (CDCl 3, d): 1.02-1.29 (broad m, 4H), 1.29-1.78 (m, 8H), 1.94-1.77 (m, 15H), 2.93-2.97 (t, 2H), 2.97-3.23 ( m, 3H), 3.40 (broad m, 1H), 3.72-3.85 (m, 1H), 3.83 (s, 6H), 6.44 (d, 1H), 6.51 (s, 1H), 6.87-6.98 (t, 2H) ), 7.08-7.42 (m, 19H); IR (KBr)? 3430, 2938, 2594, 1654, 1510 cm "1. The dihydrochloride salt was prepared as in example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - ( 1,2,3,4-tetrahydro-1- (4 - (? / - alpha-methyl-benzylamino-butyl)) - 6,7-dimethoxyisoquinolinyl)] - 4,4-d-phenylheptane: mp 120-132 ° C; Anal Caled for C51H62N3O3F-2HCI: C, 71.48; H, 7.53; N, 4.90; Found: C, 70.11; H, 7.69; N, 4.85; Example 32 7-R / V-3- (4-fluorophenyl) propionipamino-1-r? / - (1.2.3.4- tetrahydro-1 -f4 - (? /,? / - d -cyclopropyl-methylamino) butyl dihydrochloride -6.7- dimethoxyisoquinolinyl) 1-4,4-diphenylheptane The procedure described in Example 26 was used, but replacing a large excess of cyclopropyl aldehyde with acetone. After preparation and silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1- (4 - (?,? / - dicyclopropyl-methylamino) butyl] -6,7-dimethoxyisoquinoline il)] - 4, 4-dif in ilheptane: MS showed (M + H) + @ 788; 1 H-NMR (CDCl 3, d) : 0.03-0.17 (q, 4H), 0.45-0.55 (m, 4H), 0.8-0.95 (m, 2H), 1.05-1.22 (m, 4H), 1.22-1.75 (m, 6H), 1.95-2.2 ( m, 4H), 2.3-2.5 (m, 9H), 2.53-2.77 (m, 4H), 2.83-2.99 (t, 2H), 2.93-3.02 (m, 1H), 3.02-3.19 (q, 2H), 3.26-3.36 (m, 1H), 3.83 (s, 6H), 5.23 (broad s, 1H), 6.47 (s, 1H), 6.51 (s, 1H), 6.87-6.97 (m, 2H), 7.05-7.29 (m, 12H), 3.72-3.85 (m, 1H), 3.83 (s, 6H), 6.44 (d, 1H), 6.51 (s, 1H), 6.87-6.98 (t, 2H), 7.08-7.42 (ni , 19H); IR (KBr)? 3423, 2938, 2595, 1657, 1510 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [? / 3- (4-fluorophenyl) dihydrochloride) propioniI] amino-1 - [? / - (1, 2,3,4-tetrah id ro-1- (4 -? /,? / - d iciclopropi l-meti lami) buti 1-6,7-dimethoxyisoquinolinil )] - 4,4-diphenylheptane: mp 118-130 ° C; Anal. Caled for C51H66N3O3F-2HCI: C, 71.14; H, 7.96; N, 4.88; Found: C, 70.68; H, 8.14; N, 4.73.

Example 33 7-R? / -3- (4-fluorophenyl-1-propionyl-1-r? / - (1, 2.3.4-tetrahydro-1-y4 - (? /,? / - dimethylamino) butyl1-6 dihydrochloride , 7-dimethoxy isoquinol ini 1) 1-4, 4- diphenylheptane The procedure described in example 26 was used, but replacing a large excess of 37% formaldehyde with acetone. After preparation and purification by silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [/ V- (1,2,3,4-tetrahydro-1 - (4 - (? /,? / - dimethylamino) butyl-6,7-dimethoxyisoquinolinyl] - 4,4-diphenylheptane: MS showed (M + H) + @ 708; 1H-NMR (CDCl3, d) : 1.05-1.28 (m, 4H), 1.3-1.77 (m, 6H), 1.96-2.18 (m, 5H), 2.23 (s, 6H), 2.25-250 (m, 5H), 2.53-2.77 (m, 3H), 2.84-2.95 (t, 2H), 2.84-2.95 (t, 2H), 2.95-3.08 (m, 1H), 3.08-3.19 (q, 2H), 3.28-3.39 (m, 1H), 3.83 ( two s, 6H), 5.30 (broad s, 1 H), 6.47 (s, 1 H), 6.51 (s, 1 H), 6.87-6.97 (m, 2H), 7.05-7.30 (m, 12H); (MIC)? 3598, 2938, 2583, 2423, 1654, 151 8 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [? / - 3- (4-f luorofenyl) propioni I ] - 1 - [? / - (1, 2, 3, 4-tetrah idro-1 - (4 -? /,? / - d imeti la mino) buty I-6,7-dimethoxyisoquinolinyl)] - 4.4 -diphenylheptane: mp 16-1 34 ° C; Anal Caled for C45H58N3? 3F 2HCI: C, 69.22; H, 7.74; N, 5.38; Found: C, 68.82, H, 7.93; N, 5.27.

Example 34 Hydrochloride 7-f? -3- (4-fluorophenyl) propionyl-amino-1 -f? - (1, 2,3,4-tetrahydro-1 - (4 -? / - acetylamino) butyl) -6,7-dimethoxyisoquinolinyl) 1-4.4- diphenylheptane To a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro-1- (4-amino-butyl) -6,7 -dimethoxyisoquinolinyl)] - 4,4-diphenylheptane (0.157 g) in methylene chloride (10 ml), acetic anhydride (1 ml) and? , / V-diisopropylethylamine (1 ml). The solution was stirred at rt overnight and then emptied into a separatory funnel and washed with brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography, to give the desired product 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - (4 -? / - acetylamino) butyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane (0.084 g): MS showed (M + H) + @ 722; 1 H-NMR (CDCl 3, d): 1 .02-1 .33 (broad m, 4H), 1 .33-1 .79 (6H, m), 1.97 (3H, s), 1 .96- 2.2 (5H, broad m), 2.43-2.58 (2H, m), 2.63-3.0 (5H, m), 3.0-3.37 (m, 6H), 3.84 (s, 6H), 5.3 (s, 2H), 6.43 (s, 1 H), 6.56 (s, 1 H), 6.84-6.98 (m, 2H), 7.04-7.28 (m, 12H). The hydrochloride salt was prepared as in Example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2,3,4-tetrahydro-1 - (4 -? / - acetylamino) butyl) -6,7-dimethoxyisoquinolinyl] - 4,4-diphenylheptane: mp 1 15-128 ° C; Anal. Caled for C45H56N3O4F HCl: c, 71.27; H, 7.58; N, 5.54; Found: C, 69.53; H, 7.68; N, 5.41.

Example 35 Hydrochloride of 7-f? / - 3- (4-fluorophenyl) propioninamino-1 -r? / - (1, 2,3,4-tetrahydro-1 - (4? -nicotin-lamino) butyl-6.7 -dimethoxyisoquinolinyl) 1-4.4- diphenylheptane To a solution of 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (4-amino) butyl-6,7 -dimethoxyquinolinyl)] - 4,4-diphenylheptane (0.206 g) in methylene chloride (10 ml), nicotinic acid (0.402 g) was added, followed by HOBt (0.4775 g), triethylamine (0.8 ml) and EDCI (0.069 g) ). The mixture was stirred at rt under nitrogen for two days and then washed with solutions of sodium bicarbonate and brine. The organic phase was dried (Na2SO) and concentrated in vacuo to give a dry brown foam. This residue was purified by a column of silica gel to produce 7 - [/ / 3- (4-fluorophenyl) propionyl] amino-1 - [/ / - (1, 2,3,4-tetrahydro-1 - ( 4 - (? / - nicotinylamino) butyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane (0.2 g): MS showed (M + H) + @ 785; 1 H-NMR (CDCl 3, d): 1 .05-1 .24 (broad m, 2H), 1.5-1.84 (wide m, 6H), 1 .97-2.18 (m, 5H), 2.34-2.8 (broad m, 6H), 2.80-2.98 ( m, 3H), 3.0-3.64 (broad m, 7H), 3.83 (s, 3H), 3.89 (s, 3H), 5.29 (s, 2H), 6.43 (s, 1H), 6.54 (s, 1H), 6.83-7.0 (m, 2H), 7.0-7.28 (m, 12H), 7.30-7.37 (m, 1H), 8.5 (broad m, 1H), 8.6 (broad d, 1H), 9.18 (broad s, 1H); IR (MIC)? 3370, 2959, 2934, 2908, 2837, 1600, 1585, 1521 cm. "1 The hydrochloride salt was prepared as in Example 4 to give 7 - [? / - 3- (4-dihydrochloride. -fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1 - (4- / V-nicotynylamino) butyl] -6,7-dimethoxyisoquinolinyl)] - 4 , 4-diphen-ilheptane: mp 124-133 ° C.

Example 36 Hydrochloride of 7-f? / - 3- (4-f luorofenyl) pro pion i Hamin o- 1-ÍA- (1, 2,3,4-tetrahydro-1-f4 - (? / - phthalimido-metipcyclohexyl- 6.7-dimethoxyisoquinolinyl) 1-4.4- diphenylheptane Step 1:? / - f (3,4-dimethoxy) phenylethyl-4 - (? / - phthalimidomethyl-8-cyclohexylcarbonyl amide) To a stirred solution of 3,4-dimethoxyphenylethylamine (3.6224 g) in methylene chloride (100 ml), trans- 4 - (/ V-fatalimidomethyl) cyclohexanecarboxylic acid (6.3224 g), followed by HOBt (2.9731 g), triethyleamine (4.1 ml) and EDCI (4.2175 g) The reaction mixture was stirred at rt overnight and then washed with Sodium bicarbonate and brine solutions The organic phase was dried over Na2SO4 and concentrated in vacuo The residue obtained was crystallized from ethyl acetate to give? / - [(3,4-dimethoxy) phenylethyl] - (4) -? / - phthalimido-methyl) cyclohexyl-carbonyl amide (5.5 g): MS showed (M + H) + @ 451; 1H-NMR (d6DMSO, d): 0.85-1.06 (broad q, 2H), 1.08-1.38 (broad q, 2H), 1.54-1.76 (broad d, 5H), 1.94-2.09 (m, 1H), 2.55-2.66 (t, 2H), 3.14-3.24 (q, 2H), 3.37-3.50 (d, 2H), 3.70 (s, 3H), 3.72 (s, 3H), 6.63-6.70 (dd, 1H), 6.77 (d, 1H), 6.8-6.88 (d, 1H), 7.66-7.74 (t, 1H) , 7.80-7.93 ( m, 3H).

Step 2: 3,4-dihydro-1-f4 - (? / - phthalimidomethylcyclohexyl) 1-6,7-dimethoxyisoquinoline To a stirred solution of? / - [(3,4-dimethoxy) phenylethyl] -4- (A / Phthalimidomethyl) -cyclohexylcarbonyl amie (4.3178 g) in benzene (200 ml), POCI3 (10 ml) was added and the mixture was heated under reflux for 4 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with solutions of sodium bicarbonate and brine. The organic phase was dried (Na2SO) and concentrated in vacuo. The residue was purified by silica gel column chromatography, levigating with methylene chloride / methanol (9: 1) to give 3,4-dihydro-1 - [(4-phthalimidomethyl) cyclohexyl] -6,7-dimethoxyisoquinoline (2.05 g): MS showed (M + H) + @ 433; 1 H-NMR (CDCl 3, d): 1.13-1.32 (broad q, 2H), 1.47-1.68 (broad q, 2H), 1.82-2.05 (broad t, 5H), 2.6-2.7 (t, 2H), 2.77- 2.93 (broad t, 1H), 3.57-3.72 (m, 4H), 3.94 (s, 3H), 3.96 (s, 3H), 6.71 (s, 1H), 7.03 (s, 1H), 7.67-7.77 (m , 2H), 7.8-7.92 (m, 2H).

Step 1.2.3.4-tetrahydro-1-f4 - (? / - phthalimidomethyl) cyclohexyH-6.7-dimethoxyisoquinoline To a stirred solution of 3,4-dihydro-1 - [(4- / V-phthalimidomethyl) cyclohexyl] -6.7 dimethoxyisoquinoline (2.05 g) in methanol (50 m), sodium cyanoborohydride (0.3276 g) was added followed by three drops of acetic acid. The mixture was stirred at rt for 4 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with solutions of sodium bicarbonate and brine. The organic phase was dried (Na2SO) and concentrated in vacuo. The residue was purified by silica gel column chromatography, levigating with methylene chloride / methanol (98: 2) to give 1, 2,3,4-tetrahydro-1- [4 - (? / - phthalimidomethyl) -cyclohexyl] -6,7-dimethoxyisoquinoline: MS showed (M + H) + @ 435; 1 H-NMR (CDCl 3, d): 0.91-1.24 (m, 3H), 1.32-1.52 (m, 2H), 1.52-1.92 (broad m, 7H), 2.52-2.63 (td, 1H), 2.67-2.82 ( m, 1H), 2.84-2.97 (m, 1H), 3.19-3.30 (m, 1H), 3.50-3.58 (d, 2H), 3.87 (s, 6H), 6.56 (s, 1H), 6.61 (s, 1H), 7.68-7.76 (m, 2H), 7.8-7.88 (m, 2H).

Step 4: 7-r? / - 3- (4-fluorophenyl) propionylamino-1-F? / - (1,2,3,4-tetrahydro-1- (4 - (? / - phthalimidomethyl) cyclohexyl hydrochloride) 6,7-dimethoxyisoquinolinyl) 1-4,4-diphenylheptane To a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptan-1-al (0.5051 g) in methanol ( 50 ml), 1,2,3,4-tetrahydro-1- [4 - (/ V-phthalimidomethyl) cyclohexyl] -6,7-dimethoxyisoquinoline (0.5077 g) was added, followed by sodium cyanoborohydride (0.811 g) and three drops of acetic acid The mixture was stirred under nitrogen at rt for 2 h.The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed with sodium bicarbonate solutions and brine The organic phase was dried and concentrated (Na2SO4) in vacuo The residue was purified by silica gel column chromatography to give 7 - [/ / 3- (4-fluorophenyl) propionyl] amino-1 - [γ- (1, 2). , 3,4-tetrahydro-1- [4 - (? / - phthalimidomethyl] -cyclohexyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 850; 1H-NMR ( C DCI3, d): 0.8-1.23 (broad m, 6H), 1.32-1.83 (broad m, 6H), 1.91-2.2 (m, 6H), 2.25-2.72 (m, 7H), 2.82-2.97 (t, 2H) ), 2.97-3.23 (m, 3H), 3.79 (s, 3H), 3.83 (s, 3H), 3.83-3.89 (m, 1H), 5.07 (broad t, 1H), 6.86-6.99 (m, 2H) , 7.03-7.32 (m, 12H), 7.65-7.75 (m, 2H), 7.79-7.89 (m, -2H); IR (KBr)? 3397, 2929, 2852, 1772, 1714, 1653, 1509 cm. "The hydrochloride salt was prepared as in Example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1- hydrochloride [? / - (1,2,3, 4-tetrahydro-1 - [4- { N -phthalimidomethyl] -cyclohexyl-6,7-dimethoxyisoquinolyl)] - 4,4-diphenylheptane: mp 108-121 ° C; Anal Caled for C54H6oN3O5F HCl: C, 73.16; H, 6.94; N, 4.74; found: C, 66.33; H, 6.39; N, 5.86.

Example 37 7-f? -3- (4-fluorophenyl) propionin-1-f? / - (1, 2,3,4-tetrahydro-1- (4-aminomethyl-cyclohexyl) -6,7-dimethoxy-isoquinolinyl) 1-4,4-dihydrochloride -diphenylheptane To a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,34-tetrahydro-1- (4 -? / - phthalimidomethylcyclohexyl) -6,7- dimethoxyisoquinolinyl)] - 4,4-diphenylheptane (0.795 g) in ethanol (10 ml), hydrazine hydrate (2 ml) was added and the mixture was heated under reflux for 2 h. Methanolic HCl (5 ml) was added, the mixture it was stirred at rt for 10 min and the precipitate was filtered The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC to give 7 - [/ V-3- (4-fluorophenyl) propioniI] -1- [? - (1, 2,3,4-tetrahydro-1- (4-aminomethyl) cyclohexyl-6,7-dimethoxyisoquinolyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 720. The salt of hydrochloride was prepared as in example 4 to give dihydrochloride of 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1-) (4-am i nomet il) cyclohexy 1-6, 7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane.

Example 38 7- [omega] -3- (4-fluorophenyl) proponyl-1-f? / - (1, 2,3,4-tetrahydro-1- (4 -? / - (isopropylaminomethyl) dihydrochloride ) cyclohexyl-6,7-dimethoxyisoquinoline 1) 1-4,4-diphenylheptane To a stirred solution of 7 - [/ V-3 (4-fluorofenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1- (4-aminomethyl) cyclohexyl- 6,7-dimethoxy-1-trichloro-1-yl)] - 4,4-diphenylheptane (0.80 g) in methanol (10 ml), acetone (1 ml), sodium cyanoborohydride (0.0157 g) and three drops of acid were added. acetic. The mixture was stirred under nitrogen at rt for 2 h and concentrated in vacuo to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro- 1- (4- / V-isopropylaminomethyl) cyclohexyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenyl heptane (0.125 g): MS showed (M + H) + @ 762; 1 H-NMR (CDCl 3, d): 0.77-1.31 (m, 6H), 1.26 (d, 6H), 1.31-1.3 (broad m, 4H), 1.73-1.90 (broad t, 2H), 1.9-2.22 (m , 6H), 2.3-2.8 (m, 10H), 2.8-2.92 (t, 2H), 2.92-3.23 (m, 4H), 3.82 (s, 3H), 3.83 (s, 3H), 5.29 (broad t, 1H), 6.4 (s, 1H), 6.54 (s, 1H), 6.87-6.98 (t, 2H), 7.03-7.30 (m, 12H); IR (KBr)? 3400, 2950, 1740, 1510 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1-dihydrochloride 2,3,4-tetrahydro-1- (4 -? / - isopropylamomethyl) cyclohexyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane (0.115 g): mp 114-122 ° C; Anal. Caled for C49H64N3O3F 2HCI: C, 70.49; H, 7.97; N, 5.03; Found: C, 70.73; H; 7.86; N, 5.17; Example 39 Hydrochloride of 7-r? / - 3- (4-fluorophenyl) propionyl-1? -f? / - (1, 2, 3,4-tetrahydro-1 - (4 -? / - phthalimidomethyl) phenyl-6,7- dimethoxy isoquinol ini l) l-4,4-diphenyl heptane Step 1:? / - f (314-dimethoxyphenyl) etn (4-A / -phthalimidomethyl) benzoyl amide The procedure described in Experiment 36 was used, but substituting (4 -? / - phthalimidomethyl) benzoic acid for trans- (4 -? / - phthalimidomethyl) cyclohexanecarboxylic acid in step 1, to give N- [. { 3,4-dimethoxyphenyl) ethyl] (4 -? / - phthalimidomethyl) benzoyl amide: MS showed (M + H) + @ 445; 1 H-NMR (d6DMSO, d): 2.73-2.85 (m, 2H), 3.37-3.53 (m, 2H), 3.73 (s, 6H), 4.83 (s, 2H), 6.7-6.77 (dd, 1 H ), 6.8-6.9 (m, 2H), 7.37-7.44 (d, 1 H), 7.45-7.60 (m, 1 H), 7.76-7.98 (m, 6H), 8.6 (broad t, 1 H).

Step 2: 3,4-dihydro-1 -r4-? Phthalimidomethyl) phenin-6,7-dimethoxyisoquinoline.] - [3,4-Dimethoxyphenyl) ethyl] - (4 -? / - phthalimidomethyl) benzoyl amide was reacted with POCI3, using the same conditions as described in experiment 36 , step 2, to give 3,4-dihydro-1 - [4 -? / - phthalimidomethyl) phenyl] -6,7-dimethoxyisoquinoline: MS showed (M + H) + @ 427; 1 H-NMR (CDCl 3, d): 2.64-2.74 (m, 2H), 3.72 (s, 3H), 3.74-3.83 (m, 2H), 3.94 (s, 3H), 4.91 (s, 2H), 6.74. -6.79 (d, 2H), 7.43-7.50 (d, 2H), 7.5-7.6 (d, 2H), 7.68-7.77 (m, 2H), 7.82-7.91 (m, 2H).

Step 3: 1.2.3.4tetrahydro-1-r (4 -? - phthalimidomethyl) phenyl-6,7-dimethoxyisoquinoline 3,4-dithyro-1 - [(4 -? / - phthalimidomethyl) phenyl] -6 , 7-Di methoxy isoquinol inil, was treated with sodium cyanoborohydride, using the same conditions as described in experiment 36, step 3, to produce 1, 2,3,4-tetrahydro-1 - [(4 -? phthalimidomethyl) phenyl] -6,7-dimethoxyisoquinoline: MS showed (M + H) + @ 429; ? -NMR (CDCI3, d): 2.35 (broad s, 1H), 2.68-2.80 (m, 1H), 2.82-3.04 (m, 2H), 3.09-3.20 (m, 1H), 3.63 (s, 3H) , 3.87 (s, 3H), 4.84 (s, 2H), 5.04 (s, 1H), 6.22 (s, 1H), 6.62 (s, 1H), 7.11-7.22 (d, 2H), 7.33-7.42 (d , 2H), 7.65-7.75 (m, 2H), 7.8-7.88 (m, 2H).

Step 4: 7-rA / -3- (4-fluorophenyl) propionpamino-1 - [? / - (1,2,3,4-tetrahydro-1- (4-A / -phthalimidomethyl) phenol hydrochloride l-6,7-dimethoxyisoquinolinyl) -1,4,4-diphenylheptane 1, 2,3,4-tetrahydro-1- [4 - (? / - phthalimidomethyl) phenyl] -6,7-dimethoxyisoquinoline was reacted with 7- [A / -3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptan-1-al, in the presence of sodium cyanoborohydride, using the same conditions described in experiment 36, step 4, to give 7 - [? / - 3- (4-fluorophenyl) propionl] amino-1 - [N-. { 1,2,3,4-tetrahydro-1- (4- / V-phthalimidomethyl) phenyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenyl heptane: MS showed (M + H) + @ 844; 1 H-NMR (CDCl 3, d). 0.94-1.25 (broad m, 4H), 1.57-1.78 (broad m, 2H), 1.89-2.48 (m, 8H), 2.56-2.77 (m, 1H), 2.77-3.0 (m, 4H), 3.02-3.20 (broad m, 2H), 3.58 (s, 3H), 3.83 (s, 3H), 4.36 (broad m, 1H), 4.77-4.92 (q, 2H), 6.10 (s, 1H),), 6.56 (s) , 1H), 6.82-6.96 (m, 2H), 7.0-7.4 (m, 16H), 7.67-7.76 (m, 4H), 7.77-7.88 (m, 2H); IR (KBr)? 3308, 3055, 2939, 1769, 1716, 1668, 1510 cm "1. The hydrochloride salt was prepared as in example 4, to give 7- [N-3-. {4-fluorophenyl) propionyl] amino hydrochloride -1 - [? / - (1, 2,3,4-tetrahydro-1- (4 -? / - phthalimidomethyl) phenyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphen-ilheptane: mp 114-128 ° C (dec); Anal Caled for C54H54N3O5F HCl: c, 73.66; H, 6.30; N, 4.77; Found: C, 72.21; H, 6.37; N, 4.67; Example 40 7-R? / - 3- (4-fluorophenyl) propionyl1-1 - ['? / - (1,2,3,4-tetrahydro-1- (4-aminomethylphenyl) -6,7-dimethoxyisoquinolinyl dihydrochloride ) l-4,4-diphen-ilheptane To a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1- (4 - (? / - phthalimidomethyl) phenyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane (0.265 g) in ethanol (10 ml), methyl hydrazine (1 ml) was added and the solution was stirred at rt for 15 min and then refluxed for 1 h The reaction mixture was concentrated in vacuo and the residue was taken up in ethyl acetate.The solution was washed with sodium bicarbonate solutions and brine, dried (Na2SO4) and again concentrated in vacuo to give 7- [ ? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2, 3, 4-tetrahydro-1- (4-a min ometilf eni I) -6,7-dim ethoxyisoquinol inyl)] - 4,4-diphenylheptane as solid foam: MS showed (M + H) + @ 714; 1 H-NMR (CDCl 3, d): 0.97-1.2 (m, 4 H), 1.56-1.92 (m, 3 H), 1.93-2.27 (m, 4 H), 2.28-2.48 (m, 4 H), 2.6-2.78 (m , 1H), 2.82-2.98 (m, 4H), 3.03-3.17 (q, 2H), 3.60 (s, 3H), 3.84 (s, 3H), 3.88 (s, 2H), 4.38 (s, 1H), 5.23 (broad t, 1H); 6.14 (s, 1H), 6.58 (s, 1H), 6.84-6.96 (m, 2H), 7.03-7.30 (m, 16H). The hydrochloride salt was prepared as in example 4 to give 7 - [γ- 3- (4-fluorophenyl) propionyl] amino-1 - [α- (1,2,3,4-tetrahydro-1- (dihydrochloride 4-aminomethyl) phenyl-6,7-dimethoxyisoquinoline il)] - 4, 4-dif in ilheptane: mp 126-134 ° C (dec); Anal. Caled for C46H52N3? 3F 2HCI 2H2O: C, 67.14; H, 7.10; N, 5.10; Found: C, 67.11; H.7.11; N, 5.16.

Example 41 7-f? / - 3- (4-fluorophenyl) propionyl-1-f? / - (1, 2,3,4-tetrahydro-1- (4 -? / - isopropylaminomethyl) phenyl-6 dihydrochloride, 7-dimethoxyisoquinolin i 1) 1-4, 4-diphen-ilheptane To a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1- (4-aminomethyl) phenyl-6 , 7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane (0.102 g) in methanol (15 ml), acetone (0.010 ml), sodium cyanoborohydride (0.010 g) and three drops of acetic acid were added. The reaction mixture was stirred at rt for 3 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with solutions of sodium bicarbonate and brine. The residue was taken up in ethyl acetate and washed with solutions of sodium bicarbonate and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by a silica gel column to give 7 - [/ / 3- (4-fluorophenyl) propionyl] -1 - [/ / - (1,2,3,4-tetrahydro-1- (4 -? / - isopropylaminomethyl) phenyl-6,7-dimethoxyisoquinollnyl)] - 4,4-diphen-ilheptane (0.045 g); (M + H) + @ 756; 1 H-NMR (CDCl 3, d): 0.9-1.1 (broad m, 2H), 1.13-1.31 (wide m, 3H), 1.33-1.47 (d, 6H), 1.76-2.22 (broad m, 4H), 2.35- 2.58 (m, 2H), 2.70-2.93 (extended m, 6H), 2.98-3.13 (wide m, 2H), 3.13-3.42 (wide m, 3H), 3.58 (s, 3H), 3.86 (s, 3H) , 4.03 (s, 2H), 4.94 (broad m, 1H), 6.09 (s, 1H), 6.63 (s, 1H), 6.84-6.97 (m, 2H), 7.03-7.37 (m, 14H), 7.42- 7.52 (d, 2H). The hydrochloride salt was prepared as in Example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro-1- dihydrochloride (4 -? / - isopropylaminomethyl) phenyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane: mp 128-139 ° C (dec.); Anal. Caled for C4gH58N3? 3F2HCI H2O: C, 69.48; H, 7.37; N, 4.96; Found: C, 69.44; H, 7.39; N, 4.94.

Example 42 7-R / \ / 3- (4-fluorophenyl) propionyl-1-fA / - (1, 2,3,4-tetrahydro-1- (4 -? / - cyclobutylaminomethyl) phenyl dihydrochloride 6,7-dimethoxyisoquinolinyl) 1-4,4-diphenylheptane To a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro-1- (4-aminomethyl) phenyl-6,7- dimethoxyisoquinolinyl)] - 4,4-diphenylheptane (0.10 g) in methanol (15 ml), cyclobutanone (0.0108 g), sodium cyanoborohydride (0.0097 g) and three drops of acetic acid were added. The reaction mixture was stirred at rt for 3 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with solutions of sodium bicarbonate and brine. The organic phase was dried (Na2SO) and concentrated in vacuo. The residue was purified by a silica gel column to yield 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1- ( 4 -? - cyclobutylaminomethyl) phenyl-6,7-dimethoxyisoquinolinyl) - 4,4-dipheniiheptane (0.020 g); (M + H) + @ 768; 1 H-NMR (CDCl 3, d): 0.75-1.32 (broad m, 7H), 1.52-2.21 (m, 6H), 2.21-2.38 (m, 2H), 2.38-2.97 (m, 8H), 2.97-3.21 ( m, 2H), 3.21-3.44 (m, 2H), 3.58 (s, 3H), 3.58-3.74 (m, 1H), 3.87 (s, 3H), 3.92 (s, 2H), 5.3 (s, 1H) , 6.04 (s, 1H), 6.62 (s, 1H), 6.84-6.98 (m, 2H), 7.0-7.52 (m, 16H). The hydrochloride salt was prepared as in Example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro-1- dihydrochloride (4 -? - cyclobutylaminomethyl) phenyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane: mp 121-133 ° C; Anal. Caled for CsoHssNsOsF ^ HCI HzO: C, 69.91; H, 7.27; N, 4.89; Found: C, 69.82; H, 7.24; N, 4.87.

Example 43 7- [A / -3- (4-fluorophenyl) propionyl-1-fA / - (1, 2.3.4-tetrahydro-1 (4 -? / - cyclopropyl-methylaminomethyl) phenyl-6,7- dihydrochloride dimethoxyisoquinolinyl) 1-4.4- diphenylheptane The procedure described in example 42 was used, but replacing cyclopropylcarboxaldehyde with cyclobutanone. After preparation and purification of silica gel column, 7- [N-3-. { 4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1- (4 -? / - cyclopropylmethyl aminemethyl) f eniI-6,7-di methoxy isoquinoline)] -4, 4-dif in ilheptane: MS showed (M + H) + @ 768; 1 H-NMR (CDCl 3, d): 0.07-0.22 (m, 2H), 0.45-0.6 (m, 2H), 0.92-1.24 (m, 5H), 1.6 (m, 1H), 2.0-2.28 (m, 2H ), 2.29-2.49 (m, 5H), 2.5-2.77 (m, 3H), 2.82-3.0 (t, 4H), 01-3.18 (q, 2H), 3.6 (s, 3H), 3.85 (s, 3H) ), 3.91 (s, 2H), 4.19 (broad s, 2H), 4.39 (s, 1H), 5.4 (t, 1H), 6.11 (s, 1H), 6.58 (s, 1H), 6.85-6.97 (t , 2H), 7.0-7.34 (m, 16H). The hydrochloride salt was prepared as in Example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] -1- [? / - (1,2,3,4-tetrahydrohydrochloride) dihydrochloride. 1- (4 -? - cyclopropi I methylamino non-methyl) phenyl-6,7-d methoxy isoquinol inyl)] - 4,4-diphen-ilheptane: mp 124-136 ° C; Anal. Caled for C5oH58N3O3F 2HCI H2O: C, 69.91; H, 7.27; N, 4.89; Found: C, 69.88; H, 7.31; N, 4.88.

Example 44 7-f? / - 3- (4-f luorofenyl) propionyl-1-f? / - (1,2,3,4-tetrahydro-1 • (4 -? / - bis-cyclopropylmethylaminomethyl) dihydrochloride) phenyl-6,7-dimethoxy isoquinol inyl) l-4, 4-diphenylheptane The procedure described in Example 42 was adopted, but using three equivalents of cyclopropylcarboxaldehyde per cyclobutanone. After preparation and silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1- (4 -? / - bis-cyclopropylmethylaminomethyl) phenyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane: MS sample (M + H) + @ 822; 1 H-NMR (CDCl 3, d): 0.25-0.36 (m, 4H), 0.66-0.80 (m, 4H), 1.0-1.18 (m, 6H), 1.66-181 (m, 1H), 1.9-2.22 (m , 3H), 2.29-2.83 (m, 6H), 2.83-3.22 (m, 10H), 3.61 (s, 3H), 3.85 (s, 3H), 4.11-4.33 (m, 2H), 4.62 (broad m, 1H), 5.67 (broad m, 1H), 6.11 (s, 1H), 6.61 (s, 1H), 6.82-6.97 (t, 2H), 7.01-7.37 (m, 14H), 7.37-7.50 (d, H ). The hydrochloride salt was prepared as in Example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1- dihydrochloride (4- / V-bixciclopropilmethylaminomethyl) phenyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 118-134 ° C (dec); Anal. Caled for C54H64N3O3F 2HCI H20: C, 71.30; H, 7.50; N, 4.60; Found: C, 71.08; H, 7.54; N, 4.56.

Example 45 Hydrochloride of 7-f? / - 3- (4-fluorophenyl) propioni 11-1 - \ N- (1 .2, 3, 4-tetrahydro-1 - (4 -? / - acetylaminomethyl) phenyl-6 , 7-dimethoxy isoquinol inyl) 1-4.4-diphenylheptane To a solution of 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro-1- (4-amino-methyl) phenol- 6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane (0.101 g) in methylene chloride (10 ml), acetic anhydride (1 ml) and diisopropylethylamine (1 ml) were added. The reaction mixture was stirred at rt overnight and then emptied into a separatory funnel and washed with solutions of sodium bicarbonate and brine. The organic phase was dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield 7 - [/ V-3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro-1 - (4 - (/ V-acetylaminomethyl) phenyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphen-ilheptane (0.070 g): MS sample (M + H) + @ 756. The hydrochloride salt was prepared as in Example 4, to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - (4 -? / - acetylamino) hydrochloride -methyl) phenyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: mp 1 18-132 ° C (dec); Anal Caled for C48H54N3O4F HCl 0.75H2O: C, 71.53; H, 7.60; N , 5.21, found: C, 71 .1 9; H, 7.08; N, 5. 16.

Example 46 7-f? / - 3- (4-fluorophenyl) propionyl1-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dihydroxyisoquinolinyl) 1-4 hydrochloride 4-difen ilheptane The procedure described in experiment 1 was used, but replacing 1,2,3,4-tetrahydro-1-methyl-6,7-dihydroxyisoquinoline with 1,2,3,4-tetrahydro-1-methyl-6,7- dimethoxyisoquinoline. After preparation and purification by silica gel column chromatography, levigating with methylene chloride / methanol (95: 5), 7- [N-3- (4-f luorofenyl) propionyl] -1- [ ? / - (1,2, 3,4-tetrahydro-1-methyl-6,7-dihydroxyisoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 595; H-NMR (CDCl 3, d): 1.05-1.20 (m, 2H), 1.27 (s, 3H), 1.88-2.19 (m, 7H), 2.33-2.51 (m, 4H), 2.67-2.94 (m, 3H) ), 3.05-3.19 (m, 2H), 3.30 (broad s, 1H), 4.12 (broad s, 1H), 5.37 (t, 1H), 6.28 (t, 1H), 6.53 (s, 1H), 6.59 ( s, 1H), 6.83-6.97 (m, 2H), 7.04-7.30 (m, 12H). The hydrochloride salt was prepared as in example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrahydrate hydrochloride -1-methyl 1-6,7-dihydroxyisoquinolinyl)] - 4,4-diphenylheptane.

Example 47 7-f? / - 3- (4-fluorophenyl) propioniH-1-f? / - (1, 2,3,4-tetrahydro-1-methylisoquinoline i 1) 1-4, 4- Hydrochloride difen ilheptano The procedure described in experiment 1 was used, but replacing 1, 2,3,4-tetrahydro-1-methylisoquinolone with 1, 2,3,4-tetrahydro-1-methylene-6,7- d, methoxy isoquinoline. After preparation and purification by silica gel column chromatography, levigating with methylene chloride / methanol (95: 5), 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [ N-. { 1,2,3,4-tetrahydroxy-1-methyl-soquinolinyl)] - 4,4-d-phen-1-heptane: MS sample (M + H) + @ 563; 1 H-NMR (CDCl 3, d): 1.07-1.17 (m, 2H), 1.18-1.30 (m, 5H), 2.01-2.15 (m, 4H), 2.30-2.38 (t, 2H), 2.42-2.58 (m , 2H), 2.58-2.69 (m, 2H), 2.77-2.98 (m, 4H), 3.09-3.17 (m, 2H), 3.71-3.79 (q, 1H), 5.10 (broad s, 1H), 6.88- 7.29 (m, 18H); IR (KBr)? 3416, 3300, 2939, 1613, 1716, 1509 cm. "1 The hydrochloride salt was prepared as in Example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] -1- [? / - (1, 2,3,4-tetrahydro-1-methylisoquinolinyl) - 4,4-diphenylheptane: mp 83-87 ° C; Anal, caled for C38H43N2OF? CIO.5H2O: C, 72.30; H, 8.27; N, 5.11; Found: C. 72.61; H, 742; N, 4.43.

Example 48 7-f? / - 3- (4-fluorophenyl) propionyl-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dioxalan-isoquinoline) hydrochloride 1-4.4- diphenylheptane The procedure described in experiment 1 was used, but replacing 1,2,3,4-tetrahydro-1-methyl-6,7-dioxalan-isoquinoline with 1,2,3,4-tetrahydro-1-methyl-6, 7-dimethoxyisoquinoline. After preparation and purification by silica gel column chromatography, levigating with ethyl acetate, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2, 3,4-tetrahydro-1-methyl-6,7-dioxalan-isoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 607; 1 H-NMR (CDCl 3, d): 1.08-1.26 (m, 7H), 2.02-2.14 (m, 4H), 2.33-2.38 (t, 2H), 2.38-2.58 (m, 4H), 2.68-2.83 (m , 1H), 2.83-2.94 (m, 3H), 3.10-3.18 (q, 2H), 3.57-3.64 (q, 1H), 5.14 (wide, 1H), 5.88 (s, 2H), 6.48 (s, 1H), 6.51 (s, 1H), 6.89-6.97 (t, 2H), 7.08-7.30 (m, 12H); IR (KBr)? 3420, 3296, 2939, 1643, 1550, 1510, 1482 cm "1. The hydrochloride salt was prepared as in Example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 hydrochloride. - [α / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dioxalan-isoquinol in nyl)] - 4,4-dif eniheptane: mp 91-95 ° C; Anal. Caled for C39H43N2O3F HCl 1.25H2O: c, 70.36; H, 7.30; N, 4.20; Found: C, 70.49; H, 7.00; N, 4.07.

Example 49 7-f? / - 3- (4-fluorophenyl) propionylamino-1? /? - (1.2.3.4- tetrahydro-1-methyl-6,7-dioxan-isoquinolinyl) 1-4,4- hydrochloride difenlheptano The procedure described in experiment 1 was used, but replacing 1,2,3,4-tetrahydro-1-methyl-6,7-dioxan-isoquinoline with 1,2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinoline. After preparation and purification by silica gel column chromatography, levigating with methylene chloride / methanol (95: 5) to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1- [? / - (1,2,3,4-tetrahydro-1-methyl-6,7-dioxan-isoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 621; 1 H-NMR (CDCl 3, d): 1.04-1.328m, 7H), 1.97-2.13 (m, 4H), 2.28-2.59 (m, 6H), 2.61-2.67 (m, 1H), 2.80-2.94 (m, 3H), 3.06-3.65 (m, 1H), 4.22 (s, 4H), 5.04 (broad s, 1H), 6.51 (s, 1H), 6.54 (s, 1H), 6.85-6.97 (t, 2H), 7.06-7.28 (m, 12H); IR (KBr)? 3417, 3312, 2931, 2870, 1644, 1509 crn "1. The hydrochloride salt was prepared as in example 4, to give 7 - [? / -3- (4-fluorophenyl) propionyljam ino- 1- hydrochloride. [? / - (1,2,3,4-tetrah-idro-1 -meti 1-6,7-dioxan-isoquinolinyl)] - 4,4-diphenylheptane, mp 104-109 ° C; Anal Caled for C40H45N2O3F HCl H2O: C, 71.14; H, 7.16; N, 4.14; Found: C, 71.00; H, 7.21; N, 4.01.

Example 50 Hydrochloride of 7-f? / - 3- (4-f luorofenyl) propioni llam i no- 1-f? / - (1,2, 3,4-tetrahydro-1-methyl-6-methoxyisoquinolinyl) 1 -4, 4-dif in ilheptane Step 1: Í? / - 2- (3-methoxyphenyl) ethyl 1acetyl amide (Compound 12, Scheme 3) To a stirred solution of 3-methoxyphenethylamine (3.11 g) in methylene chloride (150 ml) was added under nitrogen, triethylamine (6.0 ml), acetic anhydride (2.1 ml) and DMAP (0.126 g). The mixture was stirred at rt overnight and then washed with solutions of sodium bicarbonate, 1N hydrochloric acid and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo to give [? / 2- (3-methoxyphenyl) ethyl] acetyl amide (3.65 g) as a yellow oil: MS sample (M + H) + @ 194, (M + NH4) + @ 211; 1 H-NMR (CDCl 3, d): 1.94 (s, 3 H), 2.75-2.83 (t, 2 H), 3.45-3.56 (q, 2 H), 3.80 (s, 3 H), 5.64 (broad s, 1 H), 6.72. -6.81 (m, 3H), 7.19-7.28 (m, 1H); IR (KBr)? 3285, 3080, 2935, 1651, 1584, 1490 cm "1.

Step 2: 4,5-dihydro-7-methoxy-9b-methyl-oxazolof2.3-a1isoquinoline-2,3-dione (Compound 14, Scheme 3) To a stirred solution of [A / -2- (3-methoxyphenyl) ethyl ] acetyl amide (3.65 g) in methylene chloride (175 ml), 2M oxalyl chloride solution in methylene chloride (10.4 ml) was added, followed by an addition in the form of FeCl3 portions (3.68 g). The mixture was stirred at rt overnight. To the dark brown mixture was added 2N HCl (150 ml) and stirring was continued for 1 h. The mixture was emptied into a separatory funnel and the layers separated. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give 1- (3-methoxy-phenethyl) -2-chlorooxazolidine-4,5-dione (3.60 g) as a dark brown solid: MS sample (M + H) + @ 248, (M + NH4) + @ 265. This solid was recrystallized from ethyl acetate to give the 7-methoxy isomer (1139 g) as the main product and the 9-methoxy isomer (0.128 g) as the lowest . The spectral data were consistent with the 7-methoxy isomer, 1 H-NMR (CDCl 3, d): 2.84-2.91 (dd, 1H), 3.10-3.20 (m, 1H), 3.48-3.56 (m, 1H), 3.81 ( s, 3H), 4.51-4.58 (dq, 1H), 6.65 (d, 1H), 6.85-6.89 (dd, 1H), 7.2-7.25 (d, 1H); IR (KBr)? 33423, 2921, 1806, 1737 cm "1; mp 135-136 ° C; Anal Caled for C13H13NO4: C, 63.15; H, 5.29; N, 5.66; Found: C, 63.01; H, 5.27; N, 5.62; Step 3: 3,4-dihydro-6-methoxy-1-methylisoquinoline (Compound 15, Scheme 31 To a stirred paste of 4,5-dihydro-7-methoxy-9b-methyl-oxazolo [2,3-a] so-quinoline 2,3-dione (2.27 g) in methanol (100 ml), H 2 SO 4 (2 ml) was added and the mixture was heated at 75 ° C overnight and then concentrated in vacuo. ethyl acetate and water The organic phase was washed twice with 2N HCl The aqueous extracts were combined and basified with NaOH solution to pH 11.0 and extracted with chloroform three times The organic extracts were combined, dried (MgSO) and concentrated in vacuo to give 3,4-dihydro-6-methoxy-1-methylisoquinoline as a brown oil (1.503 g): MS sample (M + H) + @ 176; 1 H-NMR (CDCl 3, d): 2.36 (t, 3H), 2.65-2.73 (t, 2H), 3.59-3.69 (dt, 2H), 3.85 (s, 3H), 6.68-6.72 (d, 1H), 6.72-6.82 (dd, 1H), 7.4-7.46 (d, 1H); IR (MIC)? 2937, 2834, 1627, 1569 cm "1.

Step 4: 1, 2,3,4-tetrahydro-6-methoxy-1-methylisoquinoline (Compound A, Scheme 3) To a stirred solution of 3,4-dihydro-6-methoxy-1-methylisoquinolinyl (1.503 g) in methanol (100 ml) was added sodium cyanoborohydride (1078 g). The pH of the solution was adjusted to pH 4-5 by the addition of a few drops of acetic acid. The reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was partitioned between ethyl acetate and sodium bicarbonate solution. The aqueous phase was washed three times with ethyl acetate. The organic extracts were combined and washed with brine, dried (MgSO) 4 and concentrated in vacuo to give 1,2,3,4-tetrahydro-6-methoxy-1-methylisoquinoline (1.48 g) as brown oil. : MS shows (M + H) + @ 178; 1 H-NMR (CDCl 3 1 d): 1.60-1.67 (d, 3H), 2.87-3.0 (m, 1H), 3.02-3.17 (m, 1H), 3.19-3.30 (m, 1H), 3.40-3.52 (m, 1H), 3.79 (s, 3H), 3.31-4.41 (m, 1H), 5.10 (broad s, 1H), 6.63-6.68 (d, 1H), 6.77-6.82 (dd, 1H), 7.05-7.10 (d , 1 HOUR). 1,2,3,4-Tetrahydro-6-methoxy-1-methylisoquinoline was reacted with 7- [A / -3-84-fluoro-phenyl) propionyl] amino-4,4-diphenylheptan-1-al , in the presence of sodium cyanoborohydride using the procedure described in Example 1. After preparation and purification by silica gel column chromatography, 7 - [γ / 3- (4-fluorophenyl) propionyl] was obtained] am? no-1 - [? / - (1,2,3, 4-tetrah id ro-1 -met i I -6-methoxy-quinolinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 593; H-NMR (CDCl 3, d): 1.05-1.27 (m, 5H), 1.57-1.76 (m, 2H), 2.0-2.15 (m, 4H), 2.29-2.39 (t, 2H), 2.39-2.66 (m , 4H), 2.70-2.96 (m, 4H), 3.07-3.18 (q, 2H), 3.62-3.72 (q, 1H), 3.78 (s, 3H), 5.05 (broad t, 1H), 6.57-6.60 ( d, 1H), 6.67-6.83 (dd, 1H), 6.87-6.97 (m, 3H), 7.06-7.30 (m, 12H); IR (MIC)? 3296, 2943, 1644, 1509 cm "1. The hydrochloride salt was prepared as in example 4, to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - hydrochloride { 1, 2,3,4-tetrahydro-1-methyl-6-methoxy-isoquinolinyl)] - 4,4-diphenylheptane.

Example 51 7-f? / - 3- (4-fluorophenyl) propionyl-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-7-methoxy-isoquinolinyl) l-4,4- hydrochloride diphenylheptane The procedure described in experiment 50 was used, but replacing 1,2,3,4-tetrahydro-7-methoxyisoquinoline with 1,2,3,4-tetrahydro-6-methoxyisoquinoline. After preparation and purification by silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro) was obtained -1-methyl-7-methoxy-isoquinolyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 593; 1H-NMR (CDCI, d): 1.08-1.30 (m, 7H), 2.02-2.16 (m, 4H), 2.31-2.38 (t, 2H), 2.40-2.62 (m, 4H), 2.70-2.80 (m , 1H), 2.86-2.97 (m, 3H), 3.09-3.18 (q, 2H), 3.64-3.72 (q, 1H), 3.78 (s, 3H), 5.14 (broad s, 1H), 6.56 (d, 1H), 6.67-6.72 (dd, 1H), 6.88-7.0 (m, 3H, m), 7.07-7.3Í (12H, m); IR (MIC)? 3296, 2944, 1644, 1509 cm. "1 The hydrochloride salt was prepared as in Example 4, to give 7 - [? / -3- (4-fluorophenyl) propionyl] -1- [A / - ( 1,2,3,4-tetrahydro-1-methyl-7-m-ethoxy isoqui no I init)] - 4, 4-dif in heptane.

Example 52 7-f? / - 3- (4-fluorophenyl) propionin-1-f? / - (1,2,3,4-tetrahydro-1-methyl-7-chloro-isoquinolinyl) l-4,4 hydrochloride diphenyl hepta not The procedure described in experiment 50 was used, but replacing 1, 2,3,4-tetrahydro-isoquinolinyl-1-methyl-7-chloroisoquinoline with 1,2,3,4-tetrahydroisoquinolinyl-1-methyl-6-methoxyisoquinoline. After preparation and purification by silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro -1-methyl-7-chloro-isoquinollnyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 597; 1 H-NMR (CDCl 3, d): 1.05-1.25 (m, 7H), 2.00-2.12 (m, 4H), 2.3-2.37 (t, 2H), 2.37-2.60 (m, 4H), 2.70-2.82 (m , 1H), 2.82-2.93 (m, 3H), 3.09-3.17 (q, 2H), 3.60-3.68 (m, 1H), 5.02 (broad s, 1H), 6.88-7.00 (m, 3H), 7.02- 7.29 (m, 14H); IR (MIC)? 3423, 3300, 2940, 1642, 1509 cm. "1 The hydrochloride salt was prepared as in example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] -1 - [? / - hydrochloride. (1, 2,3,4-tetrahydro-1-methyl-7-chloroisoquinolinyl)] - 4,4-diphenylheptane: mp 84-88 ° C; Anal Caled for C38H42N2OFCI HCl 1.25H2O: C, 69.55; H, 6.98; N, 4.26; Found: C, 69.49; H, 6.97; N, 4.22.

Example 53 Hydrochloride of 7-fA / -3- (4-fluorophenyl) propionyl1-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-7-fluoro-isoquinolinyl) I-4,4 -diphenyl heptane The procedure described in experiment 50 was used, but substituting 1, 2,3,4-tetrahydro-1-methyl-7-fluoroisoquinoline for 1,2,3,4-tetrahydro-1-methyl-6-methoxyisoquinoline. After preparation and purification by silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro -1-methyl-7-fluoroisoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 581; 1 H-NMR (CDCl 3, d): 1.05-1.29 (m, 7H), 1.98-2.15 (m, 4H), 2.29-2.37 (t, 2H), 2.37-2.62 (m, 4H), 2.70-2.80 (m , 1H), 2.84-2.93 (m, 3H), 3.08-3.17 (q, 2H), 3.62-3.70 (q, 1H), 5.16 (broad s, 1H), 6.67-6.72 (dd, 1H), 6.75- 6.82 (td, 1H), 6.88-6.95 (t, 2H), 6.95-7.02 (m, 1H), 7.05-7.20 (m, 8H), 7.20-7.28 (t, 4H); IR (MIC)? 3291, 3086, 2943, 1643, 1552, 1509, 1500 cm'1. The hydrochloride salt was prepared as in Example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1- hydrochloride methyl-7-fluoroisoquinolinyl)] - 4,4-diphenylheptane: mp 80-84 ° C; Anal. Caled for C38H42N2OF2 HCl H2O: C, 71.85; H, 7.13; N, 4.40; Found: C, 71.44; H, 7.08; N, 4.24.

Example 54 7-f? / - 3- (4-fluorophenyl) propionyl-1? F - / - (1,2,3,4-tetrahydro-1-methyl-7-nitro-isoquinolinyl) 1-4 hydrochloride 4-difen ilheptane The procedure described in experiment 50 was used, but replacing 1,2,3,4-tetrahydro-1-methyl-7-nitroisoquinoline with 1,2,3,4-tetrahydro-1-methyl-6-methoxyisoquinoline. After preparation and purification by silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrah) was obtained id ro-1-methyl-7-nitro-isoquinolinyl)] - 4,4-dipheniiheptane: MS sample (M + H) + @ 608; 1 H-NMR (CDCl 3, d): 1.08-1.32 (m, 7H), 2.0-2.18 (m, 4H), 2.32-2.42 (m, 2H), 2.42-2.57 (m, 2H), 2.58-2.68 (broad m, 1H); 2.68-2.97 (t, 4H), 3.08-3.18 (q, 2H), 3.73-3.82 (m, 1H), 5.18 (broad m, 1H), 6.88-6.97 (m, 2H), 7.07-7.30 (m, 13H), 7.88-7.98 (m, 2H); IR (MIC)? 3297, 3086, 2943, 1645, 1552 c '1. The hydrochloride salt was prepared as in example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] -1 - [? / - hydrochloride (1, 2,3,4-tetrahydro-1-methyI-7-nitro-isoquinolinyl)] - 4,4-diphenylheptane.

Example 55 7-f? / - 3- (4-fluorophenyl) propionyl-amino-1-f? / - (1,2,3,4-tetrahydro-1-methyl-7-acetylamino-isoquinolinyl) 1-4 hydrochloride 4-diphenylheptane A solution of 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-,. V tetrahydro-1-methyl-7-nitro-isoquinolinyl)] -4,4-diphenylheptane (0.060 g) in ethyl acetate (10 ml), was hydrogenated in the presence of 10% Pd / C (0.030 g) to give 7 - [? / 3- (4-fluorophenyl) propionyl ] -1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-7-aminoisoquinolinyl)] - 4,4-diphenylheptane (0.057 g). A solution of this amine in methylene chloride (10 ml) was treated with triethylamine (0.021 ml), acetic anhydride (0.01 0 ml) and catalytic amount of DMAP "and stirred at rt overnight. It was diluted with methylene chloride and the organic phase was washed three times with sodium bicarbonate solutions and brine., dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2,3,4-tetrahydro-1-methyl-7-acetylaminoisoquinolinyl) - 4,4-diphenylheptane (0.025 g): MS sample (M + H) + @ 620. The hydrochloride salt was prepared as in Example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [/ V- (1, 2,3,4-tetrahydro-1-methyl-7-acetylamino-isoquinolinyl hydrochloride )] - 4,4-diphenylheptane: mp 1 14 ° C; Anal. Caled for C40H46N3OF HCM .75H2O: C, 69.85; H, 7.40; N, 6. 1 0; Found: C, 70.01; H, 7.49; N, 5.90.

Example 56 Hydrochloride of 7-f? / - 3- (4-fluorophenyl) propionyl-1? F - / - C1, 2.3.4-tetrahydro-1 methyl-6,7-dichloro-isoquinoline 1) -4, 4-diphenylheptane The procedure described in experiment 50 was used, but replacing 1, 2,3,4-tetrahydro-1-methyl-6,7-dichloroisoquinoline with 1, 2,3,4-tetrahydroisoquinoline-1-methyl-6- methoxy isoquinoline. After preparation and purification by silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro- 1-methyl-6,7-dichioro-isoquinolinyl] - 4,4-diphenylheptane: MS sample (M + H) + @ 631: 1 H-NMR (CDCl 3, d): 1.08-1.18 (m, 2H) , 1.18-1.32 (m, 5H), 2.02-2.14 (m, 4H), 2.32-2.40 (t, 2H), 2.4-2.64 (m, 4H), 2.70-2.81 (m, 1 H), 2.86-2.95 (m, 3H), 3.10-3.19 (q ", 2H), 3.62-3.71 (q, 1H), 5.23 (broad s, 1H), 6.89-6.97 (t, 2H), 7.07-7.30 (m, 14H); IR (KBr)? 3431, 2932, 1642, 1509 cm "1. The hydrochloride salt was prepared as in Example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1 hydrochloride -methyl-6,7-dichloroisoquinolinyl)] - 4,4-diphenylheptane.

Example 57 Hydrochloride of 7-f? / - 3- (4-fluorophenyl) propionin-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-6-chloro-7-fluoroisoquinolinyl) 1-4.4-diphenylheptane The procedure described in experiment 50 was used, but replacing 1,2,3,4-tetrahydro-1-methyl-6-chloro-7-fluoroisoquinoline with 1,2,3,4-tetrahydro-1-methyl-6-methoxyisoquinoline. After preparation and purification by silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrah) was obtained idro-1-methyl-6-chloro-7-fluoroisoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 615; 1 H-NMR (CDCl 3, d): 0.97-1.29 (m, 7H), 1.91-2.07 (m, 4H), 2.22-2.57 (m, 6H), 2.60-2.71 (m, 1H), 2.71-2.85 (m, 3H), 3.0-3.11 (q, 2H), 3.50-3.61 (m, 1H), 5.02 (broad m, 1H), 6.7-6.74 (d, 1H), 6.81-6.89 (t, 2H), 6.97-7.22 (m, 13H); IR (KBr)? 3285, 2942, 1642, 1509 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [/ / 3- (4-fluorophenyl) propionyl] -1 - [/ V- (1.2 , 3,4-tetrahydro-1-methyl-6-chloro-7-fluoroisoquinolinyl) - 4,4-diphenylheptane: mp 97-99 ° C; Anal Caled for C38H41N2OCIF2 HCl 3H2O: C, 68.65; H, 6.32; N, 4.21; Found: C, 68.29; H, 6.65; N, 3.96.

Example 58 7-γ / - 3- (4-fluorophenyl) propionyl-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-diacetoxy-isoquinolinyl) 1-4 hydrochloride 4-difeni I heptane A solution of methylene chloride of the dihydroxy compound (0.250 g), obtained from experiment 46, was treated with acetic anhydride, triethylamine and DMAP at rt overnight. After preparation and purification by silica gel column chromatography, 7 - [/ V-3- (4-fluorophenyl) propionyl] -1- [/ - (1,2, 3, 4-tetrahydro) was obtained. -1-methyl-6,7-diacetoxyisoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 679; 1 H-NMR (CDCl 3, d): 1.08-1.32 (m, 7H), 2.0-2.16 (m, 4H), 2.32-2.38 (t, 2H), 2.38-2.55 (m, 2H), 2.55-2.64 (m , 2H), 2.72-2.83 (m, 1H), 2.85-2.95 (m, 3H), 3.07-3.18 (q, 2H), 3.66-3.74 (q, 1H), 5.28 (broad s, 1H), 6.79- 6.98 (m, 2H), 7.07-7.40 (m, 14H); IR (KBr)? 3403, 2939, 1769, 1509 cm "1.

Example 59 Hydrochloride of 7-f? -3- (4-fluorophenyl) propion-1-f? - (1, 2,3,4-tetrahydro-1-methyl-6-bromo-7-methoxyisoquinolinyl) 1-4,4-d-phenylheptane The procedure described in experiment 50 was used, but replacing 1,2,3,4-tetrahydro-1-methyl-6-bromo-7-methoxyisoquinoline with 1,2,3,4-tetrahydro-1-methyl-6- methoxyisoquinoline. After preparation and purification with a silica gel column chromatography, 7 - [α-3- (4-f luorofenyl) propionyl] -1 - [α / - (1,2,3,4) was obtained. -tetrah idro- 1-met i l-6-brom o-7-methoxyisoquinoliniI) - 4,4-diphenyi-heptane: MS sample (M + H) + @ 673; 1 H-NMR (CDCl 3, d): 1.06-1.28 (m, 7H), 2.0-2.12 (m, 4H), 2.3-2.36 (t, 2H), 2.36-2.58 (m, 4H), 2.68-2.77 (m , 1H), 2.82-2.92 (m, 3H), 3.07-3.17 (q, 2H), 3.59-3.67 (q, 1H), 3.84 (s, 3H), 5.04 (broad s, 1H), 6.51 (s, 1H), 6.87-6.94 (t, 1H), 7.05-7.28 (m, 14H); IR (KBr)? 3419, 2936, 1643, 1509 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? - (1, 2, 3, 4-tetrah idro-1-methyl-6-brom or-7-methoxyisoquinolinyl) - 4,4-diphenylheptane: mp 104-108 ° C; Anal Caled for C39H44N2O2BrF HCM.25H2O : C, 64.10; H, 6.55; N, 3.85; Found: C, 63.94; H, 6.55; N, 3.68; Example 60 7-f? / - 3- (4-fluorophenyl) propionin-1-f / V- (1, 2,3,4-tetrahydro-1-methyl-6-fluoro-7-methoxyisoquinolinyl) hydrochloride 1- 4.4-diphenylheptane The procedure described in experiment 50 was used, but replacing 1,2,3,4-tetrahydro-1-methyl-6-fluoro-7-methoxyisoquinine with 1,2,3,4-tetrahydro-1-methyl-6- methoxyisoquinoline. After preparation and purification with silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro -1-methyl-6-fIuoro-7-methoxyisoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 611; 1 H-NMR (CDCl 3, d): 1.08-1.30 (m, 7H), 2.02-2.18 (m, 4H), 2.32-2.40 (t, 2H), 2.40-2.62 (m, 4H), 2.68-2.78 (m , 1H), 2.85-2.95 (m, 3H), 3.10-3.18 (q, 2H), 3.62-3.70 (q, 2H), 3.84 (s, 3H), 5.25 (broad s, 1H), 6.54-6.61 ( d, 1H), 6.72-6.78 (d, 1H), 6.89-6.97 (t, 2H), 7.08-7.31 (m, 12H); IR (MIC)? 3298, 2941, 1644, 1510 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [γ- 3- (4-fluorophenyl) propionyl] -1 - [/ V- (1, 2, 3, 4-tetrahydro-1-methyl-6-f-uoro-7-methoxyisoqui nolyl)] - 4,4-diphenylheptane.

Example 61 7-f? / - 3- (4-fluorophenyl) propionyl1-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-6-methoxy-7-bromo-isoquinolinyl) hydrochloride 4,4-diphenylheptane The procedure described in experiment 50 was used, but replacing 1,2,3,4-tetrahydro-1-methyl-6-methoxy-7-bromoisoquinoline with 1,2,3,4-tetrahydro-1-methyl- 6-methoxyisoquinine After preparation and purification with silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4- tetrahydro-1-methyl-6-methoxy-7-bromoisoqui noli ni l)] - 4, 4-dif in i I heptane: MS sample (M + H) + @ 673; 1 H-NMR (CDCl 3, d): 1.07-1.28 (m, 7H), 2.0-2.12 (m, 4H), 2.30-2.52 (m, 4H), 2.60-2.77 (m, 3H), 2.83-2.94 (m , 3H), 3.07-3.16 (m, 2H), 3.65-3.70 (m, 1H), 3.86 (s, 3H), 5.18 (broad s, 1H), 6.70-6.75 (d, 1H), 6.88-6.96 ( m, 3H), 7.06-7.28 (m, 12H); IR (MIC)? 3293, 2939, 1646, 1509 cm. "1 The hydrochloride salt was prepared as in example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] -1 - [? / - (1) hydrochloride. , 2,3,4-tetrahydro-1-methyl-6-methoxy-7-bromoisoquinolinyl) - 4,4-diphenylheptane.

EXAMPLE 62 Hydrochloride of 7-r? / - 3- (4-fluorophenyl) propionip-1-f? / - (1,2,3,4-tetrahydro-1,6-dimethyl-7-methoxy-isoquinolini01-4, 4-diphenylheptane The procedure described in experiment 50 was used, but replacing 1, 2,3,4-tetrahydro-1,6-dimethyl-7-methoxyisoquinoline with 1,2,3,4-tetrahydro-1-methyl-6-methoxyisoquinoline. After preparation and purification with silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro -1,6-dimethyl-7-methoxyisoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 607; 1 H-NMR (CDCl 3, d): 1.07-1.20 (m, 2H), 1.22-1.38 (m, 5H), 2.01-2.17 (m, 4H), 2.14 (s, 3H), 2.34-2.43 (t, 2H) ), 2.47-2.78 (m, 5H), 2.85-2.94 (t, 2H), 2.94-3.05 (m, 1H), 3.10-3.19 (q, 2H), 3.72-3.78 (m, 1H), 3.78 (s) , 3H), 5.59 (broad s, 1H), 6.42 (s, 1H), 6.81 (s, 1H), 6.87-6.95 (t, 2H), 7.08-7.29 (m, 12H). The hydrochloride salt was prepared as in Example 4 to give 7 - [/ / 3- (4-fluorophenyl) propionyl] -1 - [/ / - (1,2,3,4-tetrahydro-1, 6-dimethyl-7-methoxy-isoquinolinyl)] - 4,4-diphenylheptane.

Example 63 Hydrochloride of 7-f? / - 3- (4-fluorophenyl) propion-p-1-f / V- (1, 2,3,4-tetrahydro-1'-methyl-6-carbomethoxy-7-methoxyisoquinolinyl) 1-4,4-diphen-ilheptane A solution of 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-7-methoxy-6-bromoisoquinoline il)] -4,4-dif-en-yl-heptane (0.10 g) in methanol (25 ml) was treated with complex [1,1'-bis (diphenylphosphino) ferrocene] dichloroplasty (II) with dichloromethane (0.025 g) and lutidine ( 0.032 g), it was heated to 120 ° C under a pressure of 12.65 kg / cm2 of carbon monoxide for 22 h. The catalyst was filtered and the solution was concentrated in vacuo. The residue was purified by silica gel column chromatography, to give 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydroxy) 1-methyl-6-carbomethoxy-7-methoxy isoquinol inyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 651. The hydrochloride salt was prepared as in example 4 to give hydrochloride 7- [? / - 3- (4-f luorofenyl) propionyl] mino- 1 - [? / - (1,2,3,4-tetrahydro-1-methyl-6-carbo methoxy-7-methoxyisoquinolinyl) ] -4,4-diphenylheptane: mp 92 ° C; Anal. Caled for C41H47N2O4FHCI2.5H2O: C, 67.18; H, 6.55; N, 3.82; Found: C, 67.15; H, 6.93; N, 3.62.

Example 64 7-f? / - 3- (4-fluorophenyl) propionipamino-1-f? / - (1,2,3,4-tetrahydro-1-cyclobutyl-6-bromo-7-methoxyisoquinolinyl) -1,4-diphenylheptane hydrochloride The procedure described in Example 50 was used, but replacing 1,2,3,4-tetrahydro-1-cyclobutyl-6-bromo-7-methoxy isoquinoline with 1,2,3,4-tetrahydro- 1-methyl-6-bromo-7-methoxyisoquinoline. After preparation and purification with silica gel column chromatography, 7 - [γ- 3- (4-fluorophenyl) propionyl] -1 - [α / - (1,2,3,4-tetrahydro- 1-cyclobutyl-6-bromo-7-methoxyisoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 713; 1H-NMR (CDCl 3, d): 1.07-1.13 (m, 4H), 1.51-191 (m, 6H), 1.91-21.8 (m, 6H), 2.27-2.58 (m, 6H), 2.60-2.80 (m , 2H), 2.86-3.24 (m, 3H), 3.84 (s, 3H), 5.03 (broad s, 1H), 6.48 (s, 1H), 6.89-6.97 (t, 2H), 7.08-7.30 (m, 13H); IR (MIC)? 3295, 2941, 1644, 1509 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [/ / 3- (4-fluorophenyl) propioniI] -1 - [- - (1, 2, 3, 4-tetrahydro-1-butyl-l-6-b-rom-7-methoxy-isoquinolinyl) - 4,4-diphen-il-heptane.

Example 65 Hydrochloride of 7-f? / - 3- (4-fluorophenyl) propionin-1-f? / - (1, 2,3,4-tetrahydro-1,3-dimethyl-6,7-di methoxy isoquinol inyl) 1 -4,4-diphen-ilheptane The procedure described in Example 50 was used, but replacing 1,2,3,4-tetrahydro-1,3-dimethyl-6,7-dimethoxyisoquinoline with 1,2,3,4-tetrahydro-1-methyl-6- methoxy isoquinoline. After preparation and purification with silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro -1,3-dimethyl-6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane: MS sample (M + H) + @ 637; 1 H-NMR (CDCl 3, d): 0.98-1.34 (m, 8H), 1.54-1.68 (m, 2H), 1.33-2.10 (m, 4H), 2.28-2.40 (m, 4H), 2.28-2.40 (t , 2H), 2.45-2.64 (m, 4H), 2.72-2.94 (q, 2H), 3.60-3.77 (m, 1H), 3.84 (s, 6H), 5.05 (broad s, 1H), 6.52 (s, 1H), 6.57 (s, 1H), 6.86-6.97 (t, 2H), 7.05-7.29 (m, 12H); IR (KBr)? 3414, 2933, 1646, 1509 cm. "1 The hydrochloride salt was prepared as in Example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [?] Hydrochloride. - (1,2,3,4-tetrah id ro- 1, 3-di meti I-6, 7-di methoxy isoquinol I ¡nl)] - 4, 4-dif in ilheptane: mp 97-108 ° C.

Example 66 7-R? / -3- (4-fluorophenyl) propionyl1-1-f? / - (1, 2,3,4-tetrahydro-3-methyl-6,7-dimethoxy-isoquinolinyl) hydrochloride 4,4-diphenylheptane The procedure described in example 50 was used, but replacing 1, 2,3,4-tetrahydro-3-methyl-6,7-dimethoxy-so-quinoline by 1,2,3,4-tetrahydro-1-methyl-6-methoxyisoquinoline. After preparation and purification with silica gel column chromatography, 7 - [γ- 3- (4-fluorophenyl) propionyl] -1 - [α / - (1,2,3,4-tetrahydro- 3-methyl-6,7-dimethoxy-isoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 623; 1 H-NMR (CDCl 3, d): 0.94-1.04 (d, 3H), 1.04-1.30 (m, 4H), 1.98-2.15 (m, 4H), 1.98-2.15 (m, 4H), 2.27-2.60 (m , 5H), 2.76-2.94 (m, 4H), 3.05-3.18 (q, 2H), 3.36-3.59 (m, 2H), 3.83 (s, 6H), 5.03 (broad s, 1H), 6.47 (s, 1H), 6.53 (s, 1H), 6.87-6.98 (m, 2H), 7.06-7.30 (m, 12H); IR (KBr)? 3384, 2934, 1646, 1510 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [/ / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1) hydrochloride. , 2,3,4-tetrahydro-3-methyl-6,7-dimethoxy-isoquinolinyl)] - 4,4-diphenylheptane: mp 87-91 ° C; Anal Caled for C40H47N2O3F HCl H2O: C, 70.93; H, 7.44; N, 4.13; Found: C, 70.49; H, 72.8; N, 3.85.

Example 67 7-f? / - 3- (4-fluorophenyl) propionyl-1-f? / - (1, 2,3,4-tetrahydro-1,1-dimethyl-6,7-dimethoxyisoquinolinyl) hydrochloride 1-4.4- difen ilheptane The procedure described in example 50 was used, but replacing 1, 2, 3, 4-tetrah idro-1,1-dimethyl-6,7-dimethoxyisoquinolinyl by 1,2,3,4-tetrahydro-1-methyl -6-methoxytetra-hydroisoquinoline. After preparation and purification with silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1, 2,3,4-tetrahydro) was obtained -1,1-dimethyl-6,7-dimethoxy-isoquinolinyl] - 4,4-d-phenyl heptane: MS sample (M + H) + @ 637; 1 H-NMR (CDCl 3, d): 1.08-1.23 (m, 4 H), 1.37 (s, 6 H), 2.01-2.12 (m, 2 H), 2.12-2.21 (m, 2 H), 2.31-2.39 (t, 2 H) ), 2.39-2.48 (broad m, 2H), 2.56-2.70 (m, 4H), 2.87-2.95 (t, 2H), 3.10-3.19 (q, 2H), 3.83 (s, 3H), 3.89 (s, 3H), 5.13 (broad s, 1H), 6.51 (s, 1H), 6.72 (s, 1H), 6.89-6.96 (t, 1H), 7.08-7.30 (m, 13H); IR (KBr)? 3388, 2932, 1646, 1510 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] -1 - [? / - (1) hydrochloride. , 2,3,4-tetrahydro-1,3-dimethyl-6,7-dimethoxy-trisolinolinyl) - 4,4-diphenylheptane: mp 104-107 ° C; Anal Caled for C41H49N2O3F HCl 1.25H2O: C , 70.77; H, 7.60; N, 4.20; found: C, 70.76; H, 7.57; N, 3.84.

EXAMPLE 68 Hydrochloride of 7-f? / 3- (4-fluorophenyl) propionH-f? - (1, 2,3,4-tetrahydro-1,3-dimethyl-7-methoxyisoquinoline) ) 1-4, 4-dif in I I heptane The procedure described in example 50 was used, but replacing 1,2,3,4-tetrahydro-1,3-dimethyl-7-methoxyisoquinoline with 1,2,3,4-tetrahydro-1-methyl-6-methoxytetrahydro- isoquinoline. After preparation and purification with silica gel column chromatography, 7 - [γ- 3- (4-fluorophenyl) propionyl] -1 - [α / - (1, 2,3,4-tetrahydro- 1,3-dimethyl-7-methoxy-isoquinolinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 607; IR (KBr)? 3273, 2934, 1616, 1509 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [/ / 3- (4-fluorophenyl) propionyl] amino-1 - [- - (1-hydrochloride. , 2, 3, 4-tetrah id ro-1, 3-dimethyl-7-methoxy-isoquinolinyl) - 4,4-diphenylheptane.

Example 69 Hydrochloride of 7-fA / -3- (4-fluorophenyl) propionin-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-7,8-dimethoxy-1 H- 2-benzazepinyl) l-4, 4-dif in heptane The procedure described in Example 50 was used, but substituting 2,3,4,5-tetrahydro-1-methyl-7,8-dimethoxy-1H-2-benzazepine for 1,2,3,4-tetrahydro-1- methyl-6-methoxy-isoquinoline. After preparation and purification with silica gel column chromatography, 7 - [? / 3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro -1-methyI-7,8-dimethoxy-1 H-2-benzazepinyl)] - 4,4-diphenylheptane: MS sample (M + H) + @ 637; 1 H-NMR (CDCl 3, d): 1.04-1.21 (m, 4H), 1.21-1.35 (broad m, 1H), 1.43-1.52 (d, 3H), 1.52-1.68 (m, 2H), 1.87-1.99 (m. m, 2H), 1.99-2.12 (m, 3H), 2.14-2.46 (m, 3H), 2.68-2.85 (broad m, 1H), 2.85-3.02 (m, 3H), 3.06-3.17 (t, 2H) , 3.18-3.32 (broad m, 1H), 3.80 (s, 3H), 3.84 (s, 3H), 5.48 (broad s, 1H); 6.48 (broad s, 1H), 6.62 (s, 1H), 6.87-6.97 (t, 2H), 7.03-7.30 (m, 12H). The hydrochloride salt was prepared as in Example 4 to give 7 - [/ / 3- (4-fluorophenyl) propionyl] -1 - [/ V- (1, 2,3,4-tetrahydrate) hydrochloride. -1-methyl-7,8-di methoxy-1H-2-benzazepin-yl)] - 4,4-dibenium heptane.

Example 70 Hydrochloride of 6-γ / 3- (4-fluorophenyl) propionyl-amino-1 -f? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-methoxy-isoquinolinyl) l-3, 3-diphenylhexane Step 1: 4,4-diphenyl-6-methoxyhex-5-enonitrile (Compound 1 6, Scheme 4) To a solution of (methoxymethyl) triphenylphosphonium chloride (9.83 g, 28.7 mmol, 1.1 eq.) In anhydrous THF (60 ml), cooled to 0-5 ° C, under nitrogen, a solution of n-butyllithium (1 3.7 ml of 2M solution in pentane) was added dropwise. The reaction mixture was stirred at the same temperature for 1 h. Then a solution of 4,4-diphenyl-4-formylbutyronitrile (Compound 1, Scheme 2) (6.5 g, 26.1 mmol) in THF (20 ml) was added via syringe and stirring was continued for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluted with 3% to 10% ethyl acetate / hexane) to give the desired product as a yellow oil (4.2 g, 58 g. %): 1 H-NM R (CDCl 3, d): 2.06-2.1 7 (m, 2H), 2.81 -2.86 [2.62-2.68] (m, 2H), 3.57 (s, 3H), 4.76 (d, J = 7.3 Hz, 1 H), 5.95 (d, J = 7.3 Hz, 1 H), 7.15-7.42 (m, 10H).

Step 2: 4,4-diphenyl-5-formylpentanonitrile (Compound 17, Scheme 4) To a solution of 4,4-diphenyl-6-methoxyhex-5-enonitrile (4.0 g, 14.4 mmol) in diethyl ether (60 ml), HCl was added (2 ml, 37%). The reaction mixture was stirred at room temperature for 16 h and then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane and filtered through a plug of silica gel to give the desired aldehyde as an oil (3.78 g, 99%): 1 H-NMR (CDCl 3, d): 2.03-2.10 (m, 2H ), 2.56-2.64 (m, 2H), 3.12 (d, J = 3 Hz, 2H), 7.14-7.41 (m, 10H), 9.34 (t, J = 3 Hz, 1H) ~ Anal. Caled for C18H17NO: C, 82.10; H, 6.51; N, 5.32. Found: C, 82.10; H, 7.02; N, 4.78.

Step 3: 6-amino-3,3-diphenylhexan-1-ol (Compound 18, Scheme 4) To a suspension of lithium aluminum hydride (0.57 g, 15 mmol) in anhydrous THF (20 ml) was carefully added in the form of drops a solution of 4, 4-diphenyl-5-formylpentanenitrile (1.96 g, 7.4 mmol) in anhydrous THF (20 ml). The mixture was stirred at rt for 1.5 h. The reaction mixture was quenched by careful addition of 5N NaOH (2.5 ml) followed by water (1.5 ml). The mixture was stirred at room temperature for 10 min, then filtered and the solid was washed twice with diethyl ether. The organic filtrates were combined, dried (Na2SO4) and concentrated to give the desired product as a solid foam (1.60 g, 80%): MS showed (M + H) + @ 270; 1 H-NMR (CDCl 3, d): 1.17-1.34 (m, 2H), 2.12-2.22 (m, 2H), 2.31-2.43 (m, 2H), 2.62-2.74 (m, 2H), 3.30-3.40 (m , 2H), 7.11-7.34 (m, 10H).

Step 4: 6-y? / - 3- (4-fluorophenyl) propionylamino-3,3-diphenylhexan-1-ol (Compound 19, Scheme 4) To a frozen and stirred solution of 6-amino-3,3-diphenylhexan-1-ol (0.54 g, 2 mmol) in methylene chloride solution (10 ml), 3- (4-fluorophenyl) propionic acid (0.37 g, 2.2 mmol) was added, followed by 1-hydroxybenzotriazole hydrate (HOBt) (0.297 g). , 2.2 mmol), triethylamine (0.31 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) (0.422 g, 2.2 mmol). The reaction mixture was stirred at rt overnight and then diluted with methylene chloride (30 ml) and the solution was washed first with water and then with brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by a silica gel column using ethyl acetate / hexane (1: 1), yielding the desired compound as an amorphous solid (0.24 g): MS showed (M + H) + @ 420; 1 H-NMR (CDCl 3, d): 1.10-1.21 (m, 2 H), 2.05-2.12 (m, 2 H), 2.37 (d, 4 H, J = 7, 14 Hz), 2.90 (t, 2 H, J = 7.5 Hz), 3.14 (dd, 2H, J = 7, 13 Hz), 3.41 (t, 2H, J = 7 Hz), 5.29 (bs, 1H), 6.91-7.02 (m, 4H), 7.10-7.30 (m , 10H).

Step 5: 6-Í? / - 3- (4-fluorophenyl) propionylamino-3,3-diphenylhexyl mesylate (Compound 20, Scheme 4) To a solution of 6 - [? / 3- (4-fluorophenyl) propionyl ] amino-3,3-diphenylhexan-1-ol (0.20 g, 0.49 mmol) in methylene chloride (5 ml), methanesulfonyl chloride (0.046 ml) was added at 0 ° C, followed by triethylamine (0.074 ml). The solution was stirred at 0 ° C for 30 min. The reaction mixture was washed with 1 N HCl, water and brine. The organic phase was dried and concentrated in vacuo to give the desired product as an oil (0.227 g, 93%): MS showed (M + H) + @ 498; 1 H-NMR (CDCl 3, d): 1.12-1.22 (m, 2H), 2.06-2.13 (m, 2H), 2.42 (t, 2H, J = 7.5 Hz), 2.56 (t, 2H, J = 7.5 Hz) , 2.87-2.96 (m, 5H), 3.16 (dd, 2H, J = 7.3, 12.2 Hz), 3.94 (t, 2H, j = 7 Hz), 5.39 (bs, 1H), 6.89-6.98 (m, 4H ), 7.09-7.31 (m, 10H): Anal. Caled for C28H32NO4FS: C, 67.58; H, 6.48; N, 2.81; Found: C, 67.80; H, 6.64; N, 2.74. This was used in the next step without further purification.

Step 6: 6-Í? / - 3- (4-fluorophenyl) propionate-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxy hydrochloride) isoquinolinyl) l-3,3-diphenylhexane (Compound III, Scheme 4) 6 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinolinyl)] - 3,3-diphenylhexane using the procedure described in Example 4, but substituting the 6 - [? / 3- (4-) mesylate fluorophenyl) propionyl] amino-3,3-diphenylhexyl per mesylate by 7 - [? / 3- (4-fluorophenyl) propionyl] amino-4,4-diphenylheptyl and hydroiodide of 1, 2,3,4-tetrahydro-1 -methyl-6,7-dimethoxy-isoquinoline by 1-cyclopropyl-4,5-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydroiodide. The obtained residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate / methanol (95: 5)) to give the product as an amorphous solid: MS showed (M + H) + @ 609; 1 H-NMR (CDCl 3, d): 1.11-1.28 (m, 5H), 2.00-2.11 (m, 2H), 2.22-2.28 (m, 1H), 2.35-2.62 (m, 6H), 2.68-3.02 (m , 5H), 3.06-3.24 (m, 2H), 3.81 (s, 3H), 3.82 (s, 3H), 3.88 (q, 1H, J = 7 Hz), 5.95 (bt, 1H), 6.43 (1H, s), 6.49 (1H, s), 6.90-6.97 (2H, m), 7.10-7.29 (12H, m). This compound was treated with methanol / HCl, the solution was concentrated in vacuo and the residue was dissolved in acetonitrile / water (1: 1) and lyophilized to give the hydrochloride salt: IR (MIC)? 3300, 2942, 1646 cm "1; Anal Caled for C39H45N2O3F HCl 0.5H2O: C, 71.59; H, 7.24; N, 4.28; Found: C, 71.35; H, 7.13; N, 4.01.

EXAMPLE 71 8-R / V-3- (4-fluorophenyl) propionylamino-1-f / V- (1, 2,3,4-tetrahydro-1-methyl-4-dimethoxyisoquinoliniDl-d.5-dif hydrochloride eniloctane Step 1: Methyl 7-cyano-5,5-diphenyl-hepty-2-enoate (Compound 21, Scheme 5) A mixture of 4,4-diphenyl-5-formylpentanenitrile (1.87 g, 7.1 mmol) was heated and (carbomethoxymethylene) triphenyl phosphorane (2.85 g, 8.5 mmol) in toluene (50 ml) under reflux for three days. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography to give the desired product as a colorless oil (1.56 g, 69%): MS showed (M + H) + @ 320; 1 H-NMR (CDCl 3, d): 1.97-2.02 (m, 2H), 2.44-2.51 (m, 2H), 3.00 (dd, 2H, J = 1.4, 7.4 Hz), 3.68 (s, 3H), 5.82 ( dt, 1H, J = 1.4, 15.6 Hz), 6.52 (dt, 1H, J = 7.3, 15.6 Hz), 7.10-7.55 (m, 4H), 7.21-7.35 (m, 6H), Anal. Caled for C2? H21NO2: C, 78.97; H, 6.63; N, 4.39; Found: C, 78.68; H, 6.85; N, 4.27.

Step 2: Methyl 7-cyano-5,5-diphenylheptanoate (Compound 22, Scheme To a solution of methyl 7-cyano-5,5-diphenyl-hepty-2-enoate (1.41 g, 4.41 mmol) in MeOH (100 mL) was added Pd / C (0.14 g). The reaction mixture was hydrogenated at 4 atm for 21 h. The catalyst was filtered and the filtrate was evaporated in vacuo. The oily residue (2 g) was purified by silica gel column chromatography (levigating with 15:85 ethyl acetate / hexane mixture) to yield the desired product as a colorless oil (96%): MS showed (M + H) + @ 322; 1 H-NMR (CDCl 3, d): 1.25-1.36 (m, 2H), 1.98-2.13 (m, 4H), 2.26 (t, 2H, J = 7.1 Hz), 2.49-2.58 (m, 2H), 3.65 ( s, 3H), 7.10-7.17 (m, 4H), 7.21-7.36 (m, 6H); IR (MIC)? 2951, 2247, 1735, 1444, 1196 cm "1; Anal Caled for C21H21NO2: C, 78.47; H, 7.21; N, 4.36; Found: C, 78.58; H, 7.12; N, 4.14; Step 3: 8-amino-5,5-diphenylocta-1-ol (Compound 23, Scheme 5) To a solution of methyl 7-cyano-5,5-diphenyl-heptanoate (1.26 g, 3.92 mmol) in anhydrous THF (7 ml), a solution of LAH (7.8 mmol) in anhydrous THF (7.8 ml) was added dropwise. The mixture was stirred at rt for 2 h. The reaction mixture was quenched by the careful addition of 5N NaOH (2.5 mL). The mixture was stirred at rt for 10 min and then filtered. The solid was washed twice with diethyl ether. The organic filtrates were combined, dried (Mg2SO4) and concentrated in vacuo to give the desired product as a solid foam (1.03 g, 88%): MS showed (M + H) + @ 298; 1 H-NMR (CDCl 3, d): 1.00-1.18 (m, 4 H), 1.41-1.57 (m, 2 H), 2.05-2.19 (m, 4 H), 2.62 (t, J = 7 Hz, 2 H), 3.52 ( t, J = 7 Hz, 2H), 7.10-7.36 (m, 10H); IR (MIC)? 3171, 2945, 1597, 1495, 1079 cm "1; Anal.Called for C20H27NO.0.5 H2O: C, 78.38; H, 9.20; N, 4.59; Found: C, 78.92; H, 8.89; N, 4.30.

Step 8-r / V-3- (4-fluorophenol) propionamino-5,5-diphenyloctane-1-ol (Compound 24. Scheme 5) To a chilled and stirred solution of 8-amino-5,5-diphenylocta-1-ol (0.53 g, 1.79 mmol) in methylene chloride solution (5 ml) and DMF (0.5 ml) , 3- (4-fluorophenyl) propionic acid (0.452 g, 2.7 mmol) was added, followed by 1-hydroxybenzotriazole hydrate (HOBt) (0.363 g, 2.7 mmol), triethylamine (0.27 g, 2.7 mmol) and 1 - ( 3-dimethylaminopropy) -3-ethylcarbodiimide (EDC I) (0.518 g, 2.7 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in methanol (50 ml) and a solution of LiOH (1 M, 8 ml) was added and stirred overnight. The volatiles were evaporated, the residue was diluted with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water, 1 M HCl, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (levigating with a gradient from 60% to 100% ethyl acetate / hexane), yielding the desired compound as an amorphous solid: MS showed (M + H) + @ 448; 1 H-NMR (CDCl 3, d): 0.96-1 .1 6 (m, 4H), 1 .37-1 .54 (m, 2H), 2.01 -2.12 (m, 4H), 2.35 (t, J = 7.2 Hz, 2H), 2.90 (t, J) 7.8 Hz, 2H), 3.08-3.17 (m, 2H), 3.56 (t, J = 7 Hz, 2H), 5.16 (bt, 1 H), 6.88-6.97 ( m, 2H), 7.10-7.36 (m, 12H); Anal. Caled for C29H3 FNO2: C, 77.82; H, 7.66; N, 3.13; Found: C, 77.72; h, 7.6; N, 3.15.

Step 6: 8-f? / - 3- (4-fluorophenyl) propionipanam-5-diphenyloctyl mesylate (Compound 25, Scheme 5) To a solution of 8 - [? / 3- (4-fluorophenyl) ) propionyl] amino-5,5-diphenyloctane-1-ol (0.181 g, 0.404 mmol) in methylene chloride (3 ml) was added at 0 ° C methanesulfonyl chloride (0.034 ml), followed by triethylamine (0.085 ml). ml). The solution was stirred at 0 ° C for 30 min. The reaction mixture was washed with water, 1N HCl, water and brine. The organic phase was dried (MgSO) and concentrated in vacuo to give the desired product as an oil (0.201 g, 95%): MS showed (M + H) + @ 526; 1 H-NMR (300 MHz, CDCl 3, d): 1.00-1.17 (m, 4H), 1.62-1.73 (m, 2H), 2.01-2.11 (m, 4H), 2.37 (t, J = 7.2 Hz, 2H) , 2.90 (t, J = 7.8 Hz, 2H), 2.92 (s, 3H), 3.08-3.18 (m, 2H), 4.16 (t, J = 7 Hz, 2H), 5.24 (bt, 1H), 6.89- 6.96 (m, 2H), 7.10-7.29 (m, 12H). This was used in the next step without further purification.

Step 7: 8-f? / - 3- (4-fluorophenyl) propioninamino-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxy isoquinol in 1) 1- 5.5-diphenyloctane 8 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinol Nl)] - 5,5-diphenyloctane using the procedure described in Example 4, but substituting 8 - [? / -3- (4-fluorophenyl) propionii] amino-5,5-d-mesylate. phenyloctyl by 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-4,4-diphenyl-heptyl and hydroiodide of 1-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline by hydroiodide of 1-cyclopropyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. The residue was purified by silica gel column chromatography, using a gradient of (95: 5) ethyl acetate / methanol, to give the desired product as an amorphous solid: MS showed (M + H) + @ 637; 1 H-NMR (CDCl 3, d): 0.94-1.13 (m, 5H), 1.27 (d, J = 6.6 Hz, 3H), 1.46-1.55 (m, 2H), 1.99-2.10 (m, 4H), 2.32 ( t, J = 7.5 Hz, 2H), 2.42-2.60 (m, 3H), 2.67-2.80 (m, 2H), 2.88 (t, J = 8 Hz, 2H), 2.94-3.00 (m, 1H), 3.10 (q, J = 6.8 Hz, 2H), 3.73 (q, 1H, J = 6.6 Hz), 3.82 (s, 6H), 5.08 (bt, 1H), 6.51 (1H, s), 6.54 (1H, s) , 6.88-6.95 (2H, m), 7.08-7.24 (12H, m); IR (MIC)? 3306, 2935, 1653, 1510, 1224 cm "1. This compound was treated with methanol / HCl, the solution was concentrated in vacuo and the residue was dissolved in acetonitrile / water (1.1) and lyophilized to give the hydrochloride of 8- [? -3- (4-fluorophenyl) propionyl] am ino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinolinyl)] - 5, 5-diphenyloctane: Anal Caled for C41 H49N2O3F HCl 1.5H2O: C, 70.31; H, 7.62; N, 4.00; found: C, 70. 1 1; H, 7.57; N, 4.22.

EXAMPLE 72 Hydrochloride of 8-f? / - (4-fluorophenylacetyl) lamino-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-di methoxy isoquinol i nil) 1-5.5-diphenylocta Step 1: 8- (4-fluorophenylacetyl) amino-5,5-diphenyloctane-1-ol To a stirred, stirred solution of 8-amino-5,5-diphenylocta-1 -ol (Compound 23, Scheme 5) (0.437 g, 1.47 mmol) in methylene chloride solution (5 ml) and DMF (0.5 ml) was added 4-fluoro-phenylacetic acid (0.34 g, 2.2 mmol), followed by 1-hydroxybenzotriazole hydrate (HOBt) ( 0.30 g, 2.2 mmol), triethylamine (0.22 g, 2.2 mmol) and 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide (EDCI) (0.422 g, 2.2 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was dissolved in methanol (50 ml) and a solution of LiOH (1 M, 8 ml) was added and stirred overnight. The volatiles were evaporated, the residue was treated with water (10 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic layers were washed with water, 1 M HCl, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (using a gradient from 60% to 100% ethyl acetate in hexane), yielding the desired product as an amorphous solid: MS showed (M + H) + @ 434; 1 H-NMR (CDCl 3, d): 0.91 -1 .17 (m, 4H), 1 .39-1 .51 (m, 2H), 1 .95-2.12 (m, 4H), 3.04-3.16 (m , 2H), 3.45 (s, 2H), 3.52 (t, J = 7 Hz, 2H), 5.50 (bt, 1 H), 6.95-7.36 (m, 14H); Anal. Caled for C28H32FNO2: C, 77.57; H, 7.44; N, 3.23; Found: C, 77.34; H, 7.55; N, 3.1 8.

Step 2: 8- (4-fluorophenylacetyl) amino-5,5-diphenylhexyl mesylate To a solution of 8- (4-fluorophenyl) propionylamino-5,5-diphenyloctane-1-ol (0.189 g, 0.436 mmol) in chloride of methylene (3 ml), methanesulfonyl chloride (0.037 ml) was added at 0 ° C, followed by triethylamine (0.91 ml). The solution was stirred at 0 ° C for 30 m in. The reaction mixture was washed with water, 1 N HCl, water and brine. The organic phase was dried (MgSO4) and concentrated in vacuo to give the desired product as an oil (0.198 g, 89% >). This was used in the next step without further purification: MS showed (M + H) + @ 512; 1 H-NMR (CDCl 3, d): 1 .00-1 .14 (m, 4H), 1 .63-1 .71 (m, 2H), 1 .97-2.09 (m, 4H), 2.93 (s) , 3H), 3.1 1 -3.20 (m, 2H), 3.48 (s, 2H), 4.15 (t, J = 7 Hz, 2H), 5.30 (bt, 1 H), 6.98-7.28 (m, 14H).

Step 3: 8-f? / - (4-fluorophenylacetyl) 1 amino-1? -? - (1,2,3,4-tetrahydro-1-methyl-6,7-dimethoxy-1-yquinoline) 1-5.5-diphenyloctane prepared 8 - [? / - (4-fluorophenyl-acetyl)] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinolinyl)] - 5,5-diphenyloctane prepared using the procedure described in Example 4, but substituting 8- (4-fluorophenylacetyl) amino-5,5-diphenylhexyl mesylate for 7 - (? / - 3 -) (4-fluoro-phenyl) propionyl] amino mesylate -4,4-diphenylheptyl and 1-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydroiodide per 1-cyclopropyl-4,5-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydroiodide . The residue was purified by silica gel column chromatography (using a gradient of 100% to 95% ethyl acetate / methanol) to give the desired product as an amorphous solid: MS showed (M + H) + @ 623; 1 H-NMR (CDCl 3, d): 0.94-1.01 (m, 2H), 1.07-1.17 (m, 2H), 1.30 (d, J = 6.7 Hz, 3H), 1.45-1.56 (m, 2H), 1.96- 2.09 (m, 4H), 2.43-2.62 (m, 3H), 2.69-2.86 (m, 2H), 2.97-3.05 (m, 1H), 3.13 (q, J = 6.1 Hz, 2H), 3.45 (s, 2H), 3.77 (q, 1H, J = 6.5 Hz), 3.83 (s, 6H), 5.25 (bt, 1H), 6.51 (1H, s), 6.54 (s, 1H), 6.97-7.04 (2H, m ), 7.07-7.25 (12H, m); IR (MIC)? 3301, 2934, 1648, 1509, 1225, 1033 cm "1. This compound was dissolved in methanol / HCl, the solution was concentrated in vacuo and the residue was dissolved in (1: 1) acetonitrile / water and lyophilized to give - [? / - (4-fluorophenylacetyl)] amino-1 - [? / - (1,2,3,4-tetrah-idro-1-methyl-6,7-dimethoxyisoquinolinyl)] - 5,5-diphenyl-octane: Anal Caled for C40H47N2O3F? CI0.75H2O: C, 71.40; H, 7.41; N, 4.16; Found: C, 71.37; H, 7.31; N, 4.06.

Example 73 7-f? / - 3- (4-fluorophenyl) propionyl-amino-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-7-methoxy-3-methoxycarbonyl isoquinolinyl) hydrochloride 4,4-diphenylheptane Step 1: 3,4-dihydro-7-methoxy-3-methoxycarbonyl-1-methyl-isoquinoline To a solution of? / -acetyl-O-methyltyrosine methyl ester (1.0 g, 39.8 mmol) in dichloromethane anhydrous (350 ml), oxalyl chloride (44 ml, 2M solution) was added. The reaction mixture was stirred for 1 h and then cooled to -10 ° C and its iron trichloride (11) anhydrous (7.75 g, 47.8 mmol) was added in portions. Stirring was continued overnight at room temperature and then the reaction mixture was treated with 2M HCi (100 ml) for 2 h. The organic phase was separated, washed with water and brine, dried (MgSO4) and concentrated in vacuo. Methanol (130 ml) and concentrated sulfuric acid (6 ml) were added to the foaming residue and the reaction was heated to reflux for 8 h. The reaction mixture was concentrated in vacuo, diluted with water (100 ml) and extracted with ethyl acetate (2 x 50 ml). The water layer was basified with ammonium hydroxide at pH > 9 and extracted with dichloromethane (3 x 50 ml). The organic phase was washed with water, brine, dried (MgSO4) and concentrated in vacuo. The dark yellow product (8.7 g) was purified by column chromatography on silica gel, levigating with ethyl acetate / hexane (1: 1) to yield 5.61 g (60%) of the product as a whole: 1 H-NMR ( CDCI3, d): 2.45 (d, J = 2 Hz, 3H), 2.82-3.00 (m, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.19 (qq, J = 2, 6.8 Hz , 1 H), 6.93 (dd, J = 2.7, 7.5 Hz, 1 H), 7.05 (d, J = 2.7 Hz, 1 H), 7.14 (d, J = 7.5 Hz, 1 H): MS showed (M + H) + @ 234; Anal. Caled for C13H15NO3: C, 66.94; H, 6.48; N, 6.00; Found: C, 66.78; H, 6.36; N, 5.96.

Step 2: 1, 2,3,4-tetrahydro-7-methoxy-3-methoxycarbonyl-1-methyl-isoquinoline To a solution of 3,4-dihydro-7-methoxy-3-methoxycarbonyl-1-methyl-isoquinoline ( 2.0 g, 8.57 mmol), obtained from the previous step, in MeOH (150 ml), Pd / C (0.2 g) was added. The reaction mixture was hydrogenated for 21 h at 4 atm of hydrogen pressure. The catalyst was filtered and the filtrate was concentrated in vacuo. The oily residue (2 g) was purified by a column of silica gel, using ethyl acetate / hexane (1: 1) to yield a yellowish oil (94%): IR (MIC)? 3340, 2951, 1739, 1616, 1503, 1436, 1290, 1228, 1035 cm "1; 1 H-NMR (CDCl 3, d): 1.51 (d, J = 6.6 Hz, 3H), 2.75 (broad s, 1H), 289-3.03 (m, 2H), 3.72 (dd, J = 4.5, 11.1 Hz, 1H), 3.79 (s, 6H), 4.14 (q, J = 6.6 Hz, 1H), 6.71-6.75 (m, 2H) , 7.02 (d, J = 7.8 Hz, 1H): MS showed (M + H) + @ 236; Anal.Called for C13H17NO3.HCI: c, 57.46; H, 6.68; N, 5.15; Found: C, 57.42; H, 6.64; N, 5.02.

Step 3: Hydroiodide of 1, 2,3,4-tetrahydro-7-methoxy-3-methoxycarbonyl-1-methyl-isoquinoline To a solution of 1,2,3,4-tetrahydro-7-methoxy-3-methoxycarbonyl-1- methyl isoquinoline (0.526 g, 2.24 mmol) in methanol (10 ml), cooled to 0 ° C, was added in the form of drops, a 57% Hl solution (0.33 ml). The ice bath was stirred and the solution was stirred at rt for 20 min. To the bright orange solution was added ether (100 ml) and the mixture was stirred for 10 min. The light yellow precipitate was filtered and dried under vacuum (P2O5) to give the desired salt (0.736 g).

Step 4: 7-f? / - 3- (4-fluorophenyl) propionamino-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-7-methoxy-3-hydrochloride methoxycarbonyl isoquinolinyl) 1-4,4-diphenylheptane 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1,2,3,4-tetrahydro-1-methyl) hydrochloride was prepared -7-methoxy-3-methoxycarbonyl isoquinolinyl)] - 4,4-diphenylheptane in a manner analogous to Example 4, but substituting 7-methoxy-3-methoxycarboxy or 1-1-methyl-1, 2,3,4-tetrahydroisoquinoline for 1-cyclopropyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydroiodide. The residue was purified by silica gel column chromatography (levigating with a gradient of 100% to 95% ethyl acetate / methanol) to yield an amorphous solid. MS showed (M + H) +: @ 651; IR (MIC)? 3303, 2948, 1734, 1647, 1509, 1222, 1034 cm "1; 1 H-NMR (CDCl 3, d): 1.02-1.20 (m, 4H), 1.23 (d, J = 6.8 Hz, 3H), 1.99-2.06 (m, 4H), 2.35 (t, J = 7.2 Hz, 2H), 2.57-2.68 (m, 2H), 2.81 (dd, J = 15.8, 4.8 Hz, 1H), 2.89 (t, J = 7.8 Hz, 2H), 3.01 (dd, J = q15.8, 8.4 Hz, 1H), 3.12 (q, J = 6.1 Hz, 2H), 3.39-3.45 (m, 1H), 3.63 (s, 3H), 3.70-3.75 (m, 1H), 3.76 (s, 3H), 5.20 (bt, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 2.4, 8.4 Hz, 1H), 6.86-6.95 ( m, 2H), 7.00 (d, J = 8.4, 1H), 7.07-7.25 (12H, m) This compound was dissolved in methane / HCi, the solution was concentrated in vacuo and the residue was dissolved in acetonitrile / water ( 1: 1) and lyophilized to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2,3,4-tetrahydro-1-methyl-7-hydrochloride. methoxy-3-methoxycarbonyl isoquinolinyl)] - 4,4-diphenylheptane: Anal Caled for C41H47N2O4F? CI0.5H2O: C, 70.72; H, 7.09; N, 4.02; Found: C, 70.84; H, 7.19; N, 3.87.

EXAMPLE 74 7-f? / - 3- (4-fluorophenyl) propionate-1-yl? - (1,2,3,4-tetrahydro-3- (2-hydroxyethyl) -carbonyl) hydrochloride 1-methyl-7-methoxyisoquinolinyl) -1,4,4-diphenylheptane 7 - [/ V-3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-7-methoxy-3-methoxycarbonyl isoquinoline)] - was dissolved 4,4-diphenylheptane (72 mg) in DMF (0.5 ml) and ethanolamine (1 ml), and the solution was stirred for 3 days at room temperature. The reaction mixture was concentrated in vacuo to give an oily residue, which was purified by silica gel column chromatography (levigating with a gradient of 100% to 95% dichloromethane / methanol). MS showed (M + H) + @ 680; IR (MIC)? 3304, 2938, 1651, 1510, 1222, 1032 cm "1; 1 H-NMR (CDCl 3, d): 0.95-1.30 (m, 7H), 1.92-2.09 (m, 4H), 2.34-2.53 (m, 4H) , 2.76-3.70 (m, 12H), 3.77 (s, 3H), 5.23 (broad t, 1H), 5.48 (broad t, 1H), 6.57-6.60 (m, 1H), 6.69-6.74 (m, 1H) 6.86-6.95 (m, 2H), 7.07-7.25 (m, 13H) This compound was dissolved in methanol / HCl, the solution was concentrated in vacuo and the residue was dissolved in acetonitrile / water (1: 1) and lyophilized to give 7 - [α-3- (4-fluorophenyl) propionyl] amino-1 - [α / - (1, 2,3,4-tetrahydro-3- (2-hydroxyethylaminocarbonyl) -1- hydrochloride methyl-7-methoxyisoquinolinyl] - 4,4-diphenylheptane; Anal Caled for C42H5oN3O4F HCl: C, 70.42; H, 7.18; N, 5.87; Found: C, 69.96; H, 7.35; N, 5.71; Example 75 Hydrochloride of 7-γ / 3- (4-fluorophenyl) propioni Ha m ino- 1 -f / V- (1, 2,3,4-tetrahydro- (3-h idrox i propi lami nocarbonil) -1 - met i I-7-methoxy isoquinol i nil) l-4,4-diphenylheptane The procedure described in Example 74 was used, but substituting 3-amino-1-propanol for ethanolamine. The residue obtained was purified by silica gel column chromatography (using a gradient of 100% to 95% dichloromethane / methanol) to yield the desired product as an amorphous solid: MS showed (M + H) + @ 694; IR (MIC)? 3296, 2943, 1669, 1510, 1201 cm "1; H-NMR (CDCl 3, d): 0.95-1.37 (m, 7H), 1.50-1.76 (m, 2H), 1.90-2.08 (m, 4H), 2.34 -2.59 (m, 4H), 2.80-3.56 (m, 12H), 3.77 (s, 3H), 5.36 (bs, 2H), 6.58-6.75 (m, 2H), 6.84-6.93 (m, 2H), 7.07 -7.25 (m, 13H) This compound was dissolved in methanol / HCl, the solution was concentrated in vacuo and the residue was dissolved in acetonitrile / water (1: 1) and lyophilized to give 7 - [? / - hydrochloride. 3- (4-f luorof eni i) propioni l] a mino- 1 - [? / - (1,2,3, 4-tetrahydro-3- (3-h id roxi prop i I-amínocarbonil) -1- methyl-7-methoxyisoquinolinyl)] - 4,4-diphenylheptane: Anal.

Caled for C43H52N3O4F HCl: C, 70.71; H, 7.31; N, 5.75; Found: C, 70.40; H, 7.38; N, 5.60.

Example 76 Hydrochloride of 7-r? -3- (4-fluorophenyl) propioninamino-1? F? - (1,2,3,4-tetrahydro-3- (4-hydroxybutylaminocarbonyl) -1-methyl-7-methoxyisoquinolinyl) l- 4.4- diphenylheptane The procedure described in Example 74 was used, but substituting 4-amino-1-butanol for ethanolamine. The crude residue was purified by silica gel column chromatography (levigating with a gradient of 100% to 95% dichloromethane / methanol), to yield the desired product as an amorphous solid: MS showed (M + H) + @ 708; IR (MIC)? 3294, 2938, 1653, 1510, 1221 cm "1; 1H-NMR (CDCI3, d): 0.98-1-50 (m, 11H), 1.92-2.06 (m, 4H), 2.34-2.53 (m, 4H) , 2.80-3.62 (m, 12H), 3.78 (s, 3H), 4.22 (t, J = 8.8 Hz, 1H), 5.39 (broad t, 1H), 5.51 (broad t, 1H), 6.61-6.73 (m , 2H), 6.87-6.95 (m, 2H), 7.02-7.29 (m, 13H) This compound was dissolved in menthol / HCl, the solution was concentrated in vacuo and the residue was dissolved in acetonitrile / water (1: 1). ) and lyophilized to give 7 - [/ / 3- (4-fluorophenyl) propionyl] amino-1 - [/ / - (1,2,3,4-tetrahydro-3- (4-hydroxybutylaminocarbon) hydrochloride. ) -1-methyl-7-methoxyisoquinolinyl)] - 4,4-diphenylheptane; Anal Caled for C44H54N3O4F HCI H2O: C, 70.14; H, 7.49; N, 5.61; Found: C, 69.97; H, 7.51; N, 5.37.

Example 77 7-f? / - 3- (4-fluorophenyl) propionyl-amino-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-7-methoxy-3- (hydrochloride 2 - (? - pyrrolidinyl) ethylaminocarbonyl) isoquinolinyl) -1,4,4-diphenylheptane The procedure described in Example 75 was used, but replacing? / - (2-hydroxyethyl) -pyrrolidine by ethanolamine. The residue was purified by silica gel column chromatography (using a gradient of 100% to 95% dichloromethane / methanol), to yield the product as an amorphous solid: MS showed (M + H) + @ 733; 1 H-NMR (CDCl 3, d): 0.79-1.12 (m, 4 H), 1.36 (d, J = 6.8 Hz, 3 H), 1.75-2.17 (m, 8 H), 2.38-2.58 (m, ~ 9 H), 2.84 -2.95 (m, 5H), 3.08-3.19 (m, 4H), 3.24-3.30 (m, 1H), 3.47 (q, J = 6.8 Hz, 1H), 3.77 (s, 3H), 5.77 (bt, 1H) ), 6.64 (d, J = 3.4 Hz, 1H), 6.70 (dd, J = 3.4, 8.1 Hz, 1H), 6.86-6.95 (m, 2H), 7.03 (d, J = 8.1 Hz, 1H), 7.07 -7.26 (m, 12H). This compound was dissolved in methanol / HCl, the solution was concentrated in vacuo and the residue was dissolved in acetonitrile / water (1: 1) and lyophilized to give 7 - [? / 3- (fluorophenyl) -propionyl] hydrochloride] amino - [? / - (1,2,3,4-tetrahydro-1-methyl-7-methoxy-3- (2 - (? / - pyrrolidinyl) -ethyl-aminocarbonyl) isoquinol inyl)] - 4 , 4-diphenylheptane.

Example 78 7-f? / - 3- (4-fluorophenyl) propioninamino-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-3-hydroxy-methyl-7-methoxyisoquinolinyl) hydrochloride l-4,4-diphenylheptane Step 1: 1.2, 3, 4-tetrahydro-1-methyl-3-hydroxy-1-methyl-3-methoxy isoquinone Ine A solution of 1,2,3,4-tetrahydro-1-methyl-3-methoxycarbonyl -7-methoxyisoquinoline (0.67 g, 2.87 mmol) (described in example 73) in anhydrous tetrahydrofuran (5 ml), a 1M solution of lithium aluminum hydride (5.7 mmol) in anhydrous tetrahydrofuran (5.7 ml) was added dropwise. ). The mixture was stirred at rt for 3 h. The reaction mixture was stirred at room temperature for 10 min and then filtered and the solid was washed twice with diethyl ether. The organic filtrates were combined, dried (MgSO) and concentrated in vacuo to give the desired product as a solid foam (0.486 g, 82%): 1 H-NMR (CDCl 3, d) 1.48 (d, J = 6.3 Hz, 3 H ), 2.46-2.67 (m, 2H), 3.04-3.12 (m, 1H), 3.72 (dd, J = 8.4, 11.1 Hz, 1H), 3.72-3.81 (m, 1H), 3.79 (s, 3H), 4.08 (q, J = 6.3 Hz, 1H), 6.71-6.75 (m, 2H), 7.02 (d, J = 7.8 Hz, 1H): MS showed (M + H) + @ 208.

Step 2: 1, 2,3,4-tetrahydro-1-methyl-3-hydroxymethyl-7-methoxyisoquinoline Hydroiodide To a solution of 1,2,3,4-tetrahydro-1-methyl-3-hydroxymethyl-7- methoxyisoquinoline (0.486 g, 2.3 mmol) in methanol (10 ml), cooled to 0 ° C, was added dropwise a 57% Hl solution (0.34 ml). The ice bath was stirred and the solution was stirred at rt for 20 min. To the bright orange solution was added ether (100 ml) and the mixture was stirred for 10 min. The light yellow precipitate was filtered and dried under vacuum (P205) to give the desired salt.

Step 3: 7-f? / - 3- (4-fluorophenyl) propionylamino-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-3-hydroxymethyl-7-methoxyisoquinoline) ) 1-4.4-diphenylheptane 7 - [? - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1-methyl-3-hydroxymethyl) -7-methoxyisoquinolinium] - 4,4-diphenolheptane using the procedure described in Example 4, but replacing 1,2,3,4-tetrahydro-1-methyl-3-hydroxymethyl hydroiodide. 7-methoxyisoquinoline, from the previous step, by hydroiodide of 1, 2,3,4-tetrahydro-1-cyclopropyl-4,5-dimethoxyisoquinoline. The residue was purified by silica gel column chromatography (levigating with a gradient of 100%) to 95% ethyl acetate / methanol) to yield an amorphous solid: MS showed (M + H) + @ 623; IR (MIC)? 3290, 2929, 1647, 1510, 1222, 1032 cm "1; 1 H-NMR (CDCl 3, d): 0.83-1.18 (m, 4H), 1.41 (broad d, 3H), 2.01-2.11 (m, 4H), 2.43 (t, J = 7.5 Hz, 2H), 2.57-2.78 (m, 3H), 2.92 (t, J = 7.2 Hz, 2H), 3.01 (dd, J = 15.8, 8.4 Hz, 1H), 3.13-3.20 (m, 2H), 3.44-3.72 (m, 2H), 3.77 (s, 3H), 5.75 (bs, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 2.4, 8.4 Hz, 1H), 6.88-6.97 (m, 2H), 7.04 (d, J = 8.4, 1H), 7.08-7.28 (12H, m) This compound was dissolved in methanol / HCl, the solution was concentrated in vacuo and the residue was dissolved in acetonitrile / water (1: 1) to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-hydrochloride. -tetrahydro-1-methyl-3-hydroxymethyl-7-methoxyisoquinoline il)] - 4, 4-dif in ilheptane.

Example 79 The procedure described in Example 1 was used, wherein the appropriate acids were substituted by 3- (4-fluorophenyl) propionic acid. After preparation and chromatographic purification, the following compounds were obtained: (79a) Hydrochloride of 7-fA / -3- (phenyl) propioninamino-1-f? - (1.2.3.4-tetrahydro-1-methyl-6,7-dimethoxyisoquinolinyl) 1-4.4-diphenolheptane: MS showed ( M + H) + @ 605. (79b) 7-f? / - 3- (3,4-dichlorophenyl) p.pionamino-1-f? - (1,2,3,4-tetrahydro-) hydrochloride 1-methyl-6,7-dimethoxyisoquinolinyl) -1,4-diphenylheptane: MS showed (M + H) + @ 675. (79c) 7-Í? / - 3- (3,4-difluorophenyl) propionHamino hydrochloride -1-f? / - (1, 2, 3, 4-tetrah idro- 1 -m et i 1-6, 7-d im ethoxy isoquinol i nil) l-4, 4-dif in ilheptane: MS showed (M + H) + @ 641; mp 96-99 ° C; Anal. Caled for C40H46N2O3F2 HCl 1.25 H20: C, 68.65; H, 7.12; N, 4.00; Found: C, 68.45; H, 7.12; N, 3.99. (79d) 7-f / V-3- (3-fluoro-4-chloro-phenyl) propionyl-amino-1-f / V- (1, 2,3,4-tetrahydro-1-methyl-6,7 hydrochloride -dimethoxy-5-quinolinyl) -1,4,4-diphenolheptane: MS showed (M + H) + @ 658; mp 99-103 ° C; Anal. Caled for C40H46N2O3CIF HCl 1.25H2O: C, 66.65; H, 6.99; N, 3.88; Found: C, 66.96; H, 6.99; N, 3.93. (79e) 7-f? / - 3- (4-Fluoro-3-chloro-phenyl) propionipamino-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-6,7 hydrochloride -dimethoxyisoquinolinium) 1-4,4-diphenylheptane: MS showed (M + H) + @ 658. (79f) 7-f? / - 3- (3,4-dimethoxyphenyl) propionylamino-1- hydrochloride fA / - (1, 2, 3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinolinyl) 1-4,4-diphenyl heptane: MS showed (M + H) + @ 681. (79 g) Hydrochloride 7-f? / - 3- (4-methoxyphenyl) propionylamino-1-f? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinolinyl) 1-4,4-di phenylheptane: MS showed (M + H) + @ 651. (79h) 7-f? / - 3- (4-chlorophenyl) propioniHamino-1-f? / - hydrochloride (1, 2, 3,4-tetrahydrate) -1-methyl-6,7-dimethoxyisoquinolinyl) -1,4,4-diphenylheptane: MS showed (M + H) + @ 640. (79i) 7-fA / -3- (4-fluorophenyl) acetyl hydrochloride llamino-1-fA / - (1.2.3.4-tetrahydro-1-methyl-6,7-d methoxy isoquinol inyl) 1-4.4-dif eni Iheptane: MS showed (M + H) + @ 609.

EXAMPLE 80 Hydrochloride of 7-f? / - 3- (4-fluorophenyl) propionamino-1 -f? / - (1, 2, 3,4-tetrahydro- 1 - (3 -? / - phthalimido propyl) -6, 7-d, methoxy isoquinol, ni 1) 1-4, 4-diphenylheptane The procedure described in example 22 was used, replacing in the first step 4-α / - phthalimidobutyric acid by α / - phthalimidoglycine. After preparation and chromatographic purification, 7- [A / -3- (4-phlorophenyl) propionyl] amino-1 - [α / - (1, 2, 3,4-tetrahydro-1 - (3- ? / - phthalimid or propi I) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 797. The hydrochloride salt was prepared as in Example 4 to give the hydrochloride of 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - (3 -? / - phthalimidopropi) -6,7-dimethoxyisoquinolinyl) )] - 4,4-diphenylheptane.

Example 81 Hydrochloride of 7-fA / -3- (4-fluorophenyl) propioninamino-1 -f? - (1, 2,3,4-tetrahydro-1- (3-aminopropyl) -6,7-dimethoxy-isoquinolinyl) -1,4,4-diphenyl heptane The procedure described in Example 22 was used, but substituting 4 -? / - phthalimidobutyric acid for? / - phthalimidoglycine in step 1. After preparation and chromatography, 7 - [? / 3- (4-fiuorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrah idro-1 - (3-amin. inopropyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 666. The hydrochloride salt was prepared as in Example 4 to give 7 - [? / - 3 hydrochloride - (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - (3-aminopropyl) -6,7-di methoxyquinolquinol)] - 4, 4-dif enylheptane: Anal. Caled for C42H52FN3O3 2HCl 1 .25H2O: C, 66.26; H, 7.48; N, 5.51; Found: C, 66.02; H, 6.96; N, 5.52.

Example 82 Dihydrochloride 7-f? -3- (4-fluorophenyl) propioni pamino-1 -f? / - (1, 2, 3,4-tetrahydro-1 -f3 -? / - (biscyclobutylamino) propyl-6,7-dimethoxy isoquin i nolin i 1) 1-4,4- diphenylheptane The procedure described in Example 28 was used, but using an excess of cyclobutanone in the reductive alkylation step. After preparation and chromatographic purification, 7 - [? / 3- (4-phlorophenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrahydro-1 - [ 3 -? / - (b'-Cyclobutyl) propyl] -6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane: MS showed (M + H) + @ 774. The hydrochloride salt was prepared as in the example 4 to give 7 - [/ / 3- (4-fluorophenyl) propionyl] amino-1 - [di dihydrochloride - (1, 2, 3,4-tetrahydro-1 - [3 -? / - (biscyclobutylamino) propyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: Anal. Caled for C50H6 FN3O3 2HCI H2O: C, 68.01; H, 7.99; N, 4.75; Found: C, 67.37; H, 7.79; N, 4.82.

Example 83 7-fA / -3- (4-fluorophenyl) propionylamino-1-f / V- (1, 2, 3,4-tetrahydrohydrochloride 7-fA / -3- (4-fluorophenyl) propionylamino-1) ) prop i II -6, 7- dimethoxyisoquinolinyl) 1-4,4-diphenylheptane The procedure described in Example 82 was used, but replacing cyclopropylcarboxaldehyde with cyclobutanone. After preparation and chromatographic purification, 7- [A / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrahydro-1 - [3 -? / - (bis-cyclopropylmethyl-amino) propyl] -6,7-dimethoxyisoquinolinyl) - 4,4-diphenylheptane: MS showed (M + H) + @ 775. The hydrochloride salt was prepared as in example 4 to give 7 - [? / - 3- (4-f luorofenyl) pro pion il] amyl- 1 - [? - (1, 2, 3, 4-tetrah idro- 1 - [3-N- (biscyclopropylmethylamino) propyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: Anal. Caled for C5oH64FN3O3-2HCI H2O: C, 68.35; H, 7.97; N, 4.78; Found: C, 68.1 0; H, 7.57; N, 4.83.

Example 84 7-f? / -3- (4-fluorophenyl) propionylamino-1 -fA / - (1, 2, 3,4-tetrahydrohydrochloride) 1 -f 3 -? / - (dimeti lami no) -propiH-6, 7-di methoxy isoquinol i nor 1) 1-4,4-diphenoheptane The procedure described in Example 82 was used, but replacing formaldehyde with cyclobutanone. After preparation and chromatographic purification, 7 - [/ V-3- (4-fluorofenyl-propionyl)] dihydrochloride was obtained at min or- [N- 1, 2, 3, 4-tetrahydro-1 - [3-N- (dimethyl-min) proyl] -6,7-dimethoxy-isoquinolinyl)] - 4,4-dif eniheptane: MS showed (M + H) + @ 693. The hydrochloride salt was prepared as in Example 4 to give 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrahydrohydrochloride] - [3 -? / - (dimethylamino) -propyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane.

Eiem plo 85 Dihydrochloride of 7-f? / - 3- (4-f-lorophenyl) propionyl-lane-1 - [? / - (1, 2, 3,4-tetrahydro-1 -f3-? - (isopropyl propin-6,7-dimethoxyisoquinolinyl) 1-4,4-diphenylheptane The procedure described in Example 82 was used, but replacing acetone with cyclobutanone. After preparation and chromatographic purification, the following was obtained: 7 - [α / - 3- (4-f luorofenyl) propionyl) dihydrochloride min-1 - [N-. { 1, 2, 3, 4-tetrah idro- 1 - [3 -? / - (i so propyl) propi I] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 708. The hydrochloride salt was prepared as in example 4, to give dihydrochloride of 7 - [? / 3- (4-f luorof eni I) propioni l] amino-1 - [? / - (1, 2 , 3,4-tetrahydro-1 - [3 -? / - (isopropyl I) propyl] -6,7-dimethoxy-isoquinol inyl) - 4,4-diphenoheptane.

EXAMPLE 86 7 - [? / - 3- (4-fluorophenyl) propioniHamino-1 -f? / - (1, 2,3,4-tetrahydro-1 - (5 -? / - phthalimidopentyl) -6,7- Hydrochloride dimethoxyisoquinolyl) -1,4,4-diphenylheptane The procedure described in Example 22 was used, but substituting 6 -? / - phthalimido-hexanoic acid for? / - phthalimidoglycine in step 1. After preparation and chromatographic purification, 7 - [? / 3- (4-fluorophenyl) propionii] amino-1 - [? / - (1, 2, 3, 4-tetrahydro-1 - (5- / V-phthalimidopentyl) -6,7-dimethoxyisoquinolinyl] - 4,4-diphen-ilheptane: MS showed (M + H) + @ 824. The hydrochloride salt was prepared as in Example 4 to give hydrochloride of 7%. - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [A - (1, 2, 3,4-tetrahydro-1 - (5 -? / - ftal im id opentyl) -6, 7 -di methoxy isoqu i no i ini l)] - 4, 4-diphenylheptane.

Example 87 7-R? / - 3- (4-fluorophenyl) propionipamino-1-f? / - (1, 2, 3,4-tetrahydro-1- (5-aminopentyl) -6,7-dimethoxyisoquinolinyl dihydrochloride) l-4,4-diphenolheptane The procedure was used in Example 22, by cutting the phthalimido group of 7 - [γ / 3- (4-fluorophenyl) propionyl] amino-1 - [α / - (, 2, 3, 4-tetrahydro-1 - (5 -? / - phthalimidopentyl) -6,7-dimethoxyisoquinolinyl] - 4,4-diphenylheptane. After preparation and chromatographic purification, 7 - [? / - 3- (4-fluorophenyl) propy oni I] ami n o-1 - [? / - (1, 2, 3, 4-tetrahydroxy) was obtained. 1 - (5-amynopentyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 694.

The hydrochloride salt was prepared as in example 4, to give dihydrochloride of 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1, 2,3,4- tetrahydro-1- (5-aminopentyl) -6,7-dimethoxyisoq or inoyl il)] - 4,4-diphenyl heptane: Anal. Caled for C44H56FN3O3 2HCI H2O: C, 67.33; H, 7.70; n, 5.35; Found: C, 67.10; H, 7.24; N, 5.24.

Example 88 7-f? / - 3- (4-fluorophenyl) propionylamino-1-f? / - (1, 2, 3,4-tetrahydro-1-f5-? - (biscyclobutylamino) pentill-6 dihydrochloride , 7-dimethoxyisoquinolinyl) -1,4,4-diphenylheptane The procedure described in Example 82 was used, but substituting 7 - [? / 3- (4-f luoro-f-enyl) propionyljam ino- 1 - [A / - (1, 2, 3, 4-tetrahydro-1 - (5-aminopentyl) -6,7-dimethoxy-isoquinolinyl)] - 4,4-diphenylheptane by 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2 , 3,4-tetrahydro-1- (3-aminopropyl) -6,7-dimethoxy-isoquinolinyl) - 4,4-diphenylheptane. After preparation and chromatographic purification, 7 - [? / - 3- (4-f luorofenil) own ni!] Am ino- 1 - [? / - (1, 2, 3, 4-tetrahydrate) was obtained. -1- [5- / V- (biscyclobutylamino) pentyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 802. The hydrochloride salt was prepared as in example 4, to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [5-? dihydrochloride] / - (biscyclobutylamino) pentyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane.

EXAMPLE 89 7-f? / - 3- (4-fluorophenyl) propionyl-amino-1-f? / - (1, 2,3,4-tetrahydro-1-f 5 -α / - (bis-cyclopropylmethylamino) pentiphenyl dihydrochloride 6,7-dimethoxyisoquinolinyl) 1-4,4-diphenylheptane The procedure described in Example 88 was used, but replacing cyclopropylcarboxaldehyde with cyclobutanone. After preparation and chromatographic purification, 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrah idro- 1 - [5- ? / - (Biscyclopropylmethylamino) pentyl] -6,7-dimethoxyisoquinolyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 802. The hydrochloride salt was prepared as in Example 4 to give dihydrochloride of 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrahydro-1 - [5-N- (bis-cyclopropy-1-methylamino) pe Nethyl] -6,7-di methoxy isoquinolyl)] - 4,4-diphenylheptane: Anal. Caled for C52H68FN3O3-2HCI? 2O: C, 68.55; H, 8.18; N, 4.61; Found: C, 67.87; H; 7.84; N, 4.59.

Example 90 7-γ / - 3- (4-fluorophenyl) propionylamino-1-γ / - (1 .2.3,4-tetrahydro-1 -f5 -? / - (dimethylamino) pentin-6,7- dihydrochloride dimethoxyisoquinolinyl) 1-4,4-diphenylheptane The procedure described in Example 88 was used, but replacing formaldehyde with cyclobutanone. After preparation and chromatographic purification, 7 - [? / 3- (4- fluorofenyl) propionl] amino-1 - [? / - (1, 2, 3, 4-tetrahydrate) was obtained. 1 - [5-? - (d.methylamido) pentyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 722. The hydrochloride salt was prepared as in Example 4, to give 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - [5 -? / - ( dimethylamino) pentyl] -6,7-dimethoxyisoquinolyl)] - 4,4-diphenylheptane.

Example 91 Dihydrochloride of 7-f? / - 3- (4-fluorophenyl) propionillam I no-1 -f? H 1 .2, 3, 4- tetrahydro-1-f5 -? / - (isopropylamino) -pentyl-1 6,7-dimethoxyisoquinolinyl) 1-4,4-diphenylheptane The procedure described in Example 88 was used, but replacing acetone with cyclobutanone. After preparation and chromatographic purification, 7- [A -3- (4-f luorofenil) pro pio was obtained, and Ijam ¡no- 1 - [? / - (1, 2, 3, 4-tetrah idro- 1 - [5-N- (isopropylamine) pentyl] -6,7-dimethoxy-psoquinolinyl]] - 4,4-diphenylheptane: MS showed (M + H) + @ 736. The hydrochloride salt was prepared as in Example 4 to give dihydrocioride of 7 - [? / 3- (4-f! uorophenyl) propionyl] amino-1 - [? - (1, 2, 3,4-tetrahydro-1 - [5-? - (isopropylamino) pentyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane: Anal. Caled for C47H62FN3O3 0.7H2O: C, 75.15; H, 10.33; N, 5.59; Found: C, 74.99; H, 8.34; N, 5.51.

EXAMPLE 92 Hydrochloride of 7-f? / - 3- (4-fluorophenyl) pro pion i II-1-f? / - (1, 2,3,4-tetrahydro-1-cyclobutyl-6-fluoro- 7-methoxyisoquinolinyl) 1-4,4-diphenol hepta not The procedure described in example 9 was used, but replacing 1, 2, 3, 4-tetrah-idro-1-butyl-6-fluoro-7-methoxyisoquinoline by 1,2,3,4-tetrahydro-1-cyclobutyl-6,7-dimethoxy-isoquinoline. After preparation and chromatographic purification, 7 - [/ V-3- (4-fluorophenyl) propionyl] -1 - [? / - (1,2,3,4-tetrahydro-1-cyclobutyl-6-fluoro was obtained. -7-methoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 651; 1 H-NMR (CDCl 3, d): 1.05-1.21 (m, 4H), 1.62-1.90 (m, 5H), 1.90-2.17 (m, 5H), 2.25-2.58 (m, 6H), 2.60-2.76 (m , 2H), 2.84-2.92 (t, 2H), 2.97-3.09 (m, 1H), 3.09-3.20 (m, 3H), 3.81 (s, 3H), 5.11 (broad m, 1H), 6.47-6.53 ( d, 1H), 6.69-6.76 (d, 1H), 6.86-6.95 (t, 2H), 7.05-7.7.29 (m, 12H); IR (MIC)? 3310, 2940, 1630, 1510 cm "1. The hydrochloride salt was prepared as in example 4 to give 7 - [? / -3- (4-fluorophenyl) propionyl] -1 - [? / - (1) hydrochloride. , 2,3,4-tetrahydro-1-cyclobutyl-6-fluoro-7-methoxyisoquinolinyl) - 4,4-diphenylheptane.

Example 93 7-f A / -3- (4-f-lorophenyl) propionylamine ino- 1-f? / - (1.2.3.4-tetrah-idro-1 - (4-N-phthalimidobutyl) -6-methyl-7-methoxy isoquinol inyl) l-4.4-diphen-ilheptane The synthetic procedure described in Example 24 was used, but replacing 1, 2,3 ', 4-tetrahydro-1- (4 -? / - phthalimidobutyl) -6-methyl-7-methoxyisoquinoline, to replace 1, 2.3 , 4-tetrahydro-1- (4 -? - phthalimidobutyl) -6,7-dimethoxyisoquinoline. After preparation and purification with silica gel column chromatography, 7- [A / -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2, 3, 4-tetrahydrate) was obtained. 1- (4 -? / - phthalimido-butyl) -6-methyl-7-methoxy-polyquinolinyl) - 4,4-diphenylheptane: MS showed (M + H) + @ 794; 1 H-NMR (CDCl 3, d): 1.08-1.23 (m, 4 H), 1.38-1.51 (m, 2 H), 1.56-1.79 (m, 5 H), 1.98-2.13 (m, 3 H), 2.14 (s, 3 H) ), 2.29-2.52 (m, 5H), 2.56-2.74 (m, 2H), 2.87-2.93 (t, 2H), 2.95-3.08 (m, 1H), 3.09-3.24 (m, 2H), 3.29-3.37 (m, 1H), 3.61-3.72 (t, 2H), 3.78 (s, 3H), 5.42-5.50 (broad m, 1H), 6.43 (s, 1H), 6.58 (s, 1H), 6.87-6.95 ( t, 2H), 7.07-7.29 (m, 12H); IR (KBr)? 2940, 1755, 1720, 1510 cm "1.

Example 94 7-fV-3- (4-fluoropheni I) propionyl-1-f (? / - (1,2,3,4-tetrahydro-1- (4-aminobutyl) -6-methyl-7-methoxyisoquinolinyl) -4,4-diphenylheptane The synthetic procedure described in Example 22 was used for the erote of the phthalimido group. After preparation and purification with a silica, 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [(? / - (1, 2,3,4-tetrahydro- 1- ( 4-aminobutyl) -6-methyl-7-methoxyisoquinolinyl)] - 4,4-diphenylheptane: MS showed (M + H) + @ 664:? -NMR (CDCl3, d): 1.04-1.28 (m, 4H), 1.34-1.76 (m, 6H), 1.95-2.13 (m, 3H), 2.14 (s, 3H), 2.30-2.41 (m, 3H), 2.41-2.48 (t, 2H), 2.56-2.76 (m, 4H) ), 2.82-2.92 (t, 2H), 2.95-3.22 (m, 6H), 3.32-3.41 (broad q, 1H), 3.27 (s, 3H), 5.65-5.73 (broad t, 1H), 6.41 (s) , 1H), 6.78 (s, 1H), 6.87-6.94 (t, 2H), 7.07-7.28 (m, 12H), IR (KBr)? 3280, 2940, 1630, 1510 cm "1.

Example 95 7-f? / - 3- (4-fluorophenyl) propionylamino-1-f (A / - (1.2.3.4-tetrahydro-1- (4-N-isopropylamino-butyl) -6-methyl-7-methoxyisoquinol ni l) l-4,4-diphen-ilheptane 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [(? / - (1,2,3,4-tetrahydro-1- (4-aminobutyl) -6-methyl-7-methoxyisoquinolinyl )] 4,4-diphenolheptane was reductively alkylated on treatment with acetone and sodium cyanoborohydride as described in Example 26. After preparation and purification with a silica, 7 - [? / - 3- ( 4-fluorophenyl) propionyl] amino-1 - [(? / - [1, 2, 3, 4-tetrah idro-1- (4 -? / - isopropylamino-butyl) -6-methyl-7-methoxyisoquinolinyl) ] -4,4-diphenylheptane: MS showed (M + H) + @ 706: H-NMR (CDCl 3, d): 1.02-1.29 (m, 5H), 1.13-1.16 (d, 6H), 1.33-1.48 ( m, 2H), 1.51-1.75 (m, 4H), 1.94-2.12 (m, 4H), 2.14 (s, 3H), 2.28-2.48 (m, 5H), 2.53-2.71 (m, 4H), 2.83- 3.04 (m, 4H), 3.07-3.18 (broad q, 2H), 3.32-3.42 (m, 1H), 3.77 (s, 3H), 5.52-5.59 (broad t, 1H), 6.41 (s, 1H), 6.78 (s, 1H), 6.88-6.96 (t, 2H), 7.07-7.29 (m, 12H); IR (KBr)? 3280, 2940, 1630, 1510 cm "1.

Example 96 Hydrochloride of 7-r? / - 3- (4-fluorophenyl) propionyl-amino-1-f (? / - (1, 2,3,4-tetrahydro-1-cyclobutyl-6-methyl-7-methoxyisoquinolinyl) 1-4 , 4-diphen-ilheptane The procedure described in Example 92 was used, but replacing 1, 2, 3, 4-tetrahydro-1-cyclobutyl-6-methyl-7-methoxyisoquinol ina by 1, 2,3,4 -tetrahyd o-1-cyclobutyl-6-fluoro-7-methoxyisoquinoline After preparation and purification by a silica gel column, 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 was obtained - [(? / - (1, 2,3,4-tetrahydro-1-cyclobutyl-6-methyl-7-methoxyisoquinoline)] - 4,4-diphen-ilheptane: MS showed (M + H) + @ 647; 1 H-NMR (CDCl 3, d): 1.04-1.22 (m, 4H), 1.62-2.0 (m, 6H), 2.0-2.15 (m, 4H), 2.17 (s, 3H), 2.23-2.58 (m , '6H), 2.61-2.77 (m, 2H), 2.83-2.92 (t, 2H), 2.98-3.08 (m, 1H), 3.08-3.21 (m, 3H), 3.75 (s, 3H), 5.06- 5.10 (broad t, 1H), 6.39 (s, 1H), 6.79 (s, 1H), 6.85-6.96 (t, 2H), 7.05-7.28 (m, 12H); IR (KBr)? 3320, 2940, 1635 , 1510 cm "1. The hydrochloride salt was prepared as in Example 4 to give 7 - [? / 3- (4-f luorofenyl) prop! on! I] am- no - 1 - [(? / - [1, 2, 3, 4-tetrahydro hydrochloride -1-cyclobutyl-6-methyl-7-methoxyisoquinolinyl)] - 4,4-diphenolheptane.

ACTIVITY OF LHRH ANTAGONIST Representative compounds of the present invention were evaluated in vitro for potency against rat pituitary receptor binding LHRH [pKi]. The methods for the assay procedures are described in F. Haviv, et al. J. Med. Chem., 32: 2340-2344 (1989). The pKi values are the negative logarithms of the equilibrium dissociation constant of the particular antagonist test compound for receptor binding. Values normally of 7.0 or greater are indicative of good potency of LHRH antagonist, values of 8.0 or greater being preferred. The leuprolide LHRH agonist, described and claimed in U.S. Pat. No. 4.005, 063, has the structure 5-oxo-Pro1-His2-Trp3-Ser4-Tyr5-D-Leu6-Leu7-Arg8-Pro9-NH Et. The results for the assay of representative compounds within the scope of the invention are summarized in Tables 1-3. The values of pK | for the compounds of formula (I), where / is 2, m is 3, p is 1. X is fluorine, Y is hydrogen, R2 is hydrogen, and W and Z are both -OCH3, as represented by formula (V) below (V) they are described by the corresponding value of n and the substituent R1 in Table 1.

Table 1 Table 1 (continued) Table 1 (continued) Table 1 (continued) Examples 46-71 The values of pK | for compounds of formula (I), wherein / is 2, m is 3, n is 3, X is fluorine, Y is hydrogen and a portion of isoquinoline is denoted by R, as represented below by the formula (VI) : (SAW) they are summarized according to the substituent R in Table 2 below.

Table 2 Table 2 (continued) Table 2 (continued) Examples 72-80 The values of pK | for compounds of formula (I), wherein m is 3, n is 3, p is 1, R is methyl, R 2 is H, W, and Z are both -OCH 3, and the substitution of the primary amine is denoted by R ', as represented below by the formula (Vi l) (VII) are in accordance with the substituent R 'in Table 3 below. Table 3 Table 3 (continued)

Claims (10)

1. A compound that has a formula: (I) or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein: /, m and n are each independently 1, 2, 3 or 4; p is 1 or 2; Ri is selected from the group consisting of: (a) alkyl, (b) cycloalkyl, (c) aryl, (d) cyano, (e) - (CH2) q-R4, wherein q is 0 to 10, (f) ) -cycloalkyl-R5, and (g) -apl-R5; R 2 is selected from the group consisting of: (a) alkyl, (b) hydrogen, (c) alkoxycarbonyl, (d) hydroxymethyl and (e) - (CH 2) q-R, wherein q is 0 to 1 0; R 4 is selected from the group consisting of: (a) alkyl, (b) alkoxy, (c) aryl, (d) aryloxy, (e) cyano, (f) cycloalkyl, (g) hydroxy, (h) halogen, ( i) phthalimido, (j) -cycloalkyl-R5, (k) -aryl-R5, and (I) -NR6R7; R5 is selected from the group consisting of: (a) alkyl, (b) alkoxy, (c) cyano, (d) hydroxy, (e) halogen, (f) trifluoromethyl, and (g) - (CH2) q-NR6R7 , where q is 0 to 10; R 6 and 7 are independently selected from the group consisting of: (a) hydrogen, (b) alkyl, (c) cycloalkyl, and (d) aryl, or R6 is hydrogen and R7 is a group of the formula -COR8, wherein R8 is selected from the group consisting of: (a) alkyl, (b) aryl, and (c) heterocycle; X and Y are independently selected from the group consisting of: (a) hydrogen, (b) halogen, (c) alkoxy, (d) aikyl, and (e) trifluoromethyl; and W and Z are independently selected from the group consisting of: (a) hydrogen, (b) hydroxy, (c) alkyl, (d) alkoxy, (e) alkoxycarbonyl, (f) nitro, (g)? / - acyl , (h) halogen, and (i) trifluoromethy, or W and Z taken together form a cyclic ring.

2. A compound according to claim 1, wherein / is 2, m is 3, n is 3, and p is I.

3. A compound according to claim 1, wherein R ^ is selected from the group consisting of of alkyl, cycloalkyl, and - (CH2) q-R4, wherein q is 0 to 1 0, and R4 is a group of the formula -NR6R7, wherein R6 and R7 are each independently selected from hydrogen, alkyl and cycloalkyl .

4. A compound according to claim 3, wherein R ^ is selected from the group consisting of methyl, cyclopropyl, cyclobutyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, N- [cyclopropylmethyl] -aminobutyl and? / - [bis-cyclopropylmethyl] am. Nobut it.

5. A compound according to claim 1, wherein R2 is selected from the group consisting of hydrogen and methyl.

6. A compound according to claim 1, wherein X and Y are independently selected from the group consisting of hydrogen and halogen.

7. A compound according to claim 1, wherein W and Z are independently selected from the group consisting of hydrogen and methoxy.

8. A compound according to claim 1, selected from the group consisting of:. { R, S) 7 - [? - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrah idro-1-methyl-6,7-dimethoxyisoquinol ini hydrochloride l)] - 4, 4-dif in ilheptane; . { R) 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinol hydrochloride nil)] - 4, 4-dif in i I heptane; (S) 7 - [/ V-3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinolinii hydrochloride )] - 4,4-diphenium heptane; 7 - [? 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxyisoquinolinyl)] - 4,4 hydrochloride -diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-ethyl 1-6, 7-di methoxy hydrochloride isoquinol inyl)] - 4,4-diphenylhepta no; 7 - [? / - 3- (4-fluorophenyl) propionyl] am i non-1 - [? / - (1, 2, 3,4-tetrah idro-1-isopropyl-6,7-dimethoxyisoquinolinyl) hydrochloride) ] -4,4-diphen-ilheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-phenyl-6,7-dimethoxyisoquinolinyl)] - 4 hydrochloride 4-diphenolheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1-cyclopentyl-6,7-dimethoxyisoquinolyl)] - hydrochloride 4,4-diphenyl heptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1-cyclobutyl-6,7-dimethoxyisoquinolinyl)] - 4 hydrochloride 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1- [A / - (1, 2,3,4-tetrahydro-1-cyclohexyl-6,7-dimethoxyisoquinolinyl)] - 4 hydrochloride, 4-diphenylheptane; 7 - [? / - (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1-cyanomethyl-6,7-dimethoxyisoquinolinyl)] - 4,4- hydrochloride diphenylheptane; Hydrochloride of 7 - [? / - (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methoxymethyl-6,7-dimethoxyisoquin-1-inyl)] - 4, 4-difen-ilheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amine-1 - [? / - (1, 2, 3,4-tetrahydro-1 -be ncyloxymethyl-6,7-di methoxy hydrochloride] isoquinol i nor l)] - 4,4-diphen-ilheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - (p-methoxy) phenyl-6,7-dimethoxyisoquinol hydrochloride i ni I)] -4,4-dif in ilheptane; Dihydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrah idro-1 - (4-aminophenyl) -6,7-dimethoxyisoquinolinii)] - 4,4- diphenylhepta no; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrah idro-1 - [4 - (? / - isopropyl-amino) dihydrochloride phenyl] -6,7-di methoxy isoquinol (n!)) - 4,4-diphenylheptane; Hydrochloride of 7- [A / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-benzyl-6,7-dimethoxy! -soquinolinyl) )] - 4,4-diphen-ilheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (4-chlorobenzyl) -6,7-dimethoxyisoquinolinyl hydrochloride) ] -4,4-diphenolheptane; Hydrochloride of 7 - [/ V-3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (4-methoxybenzyl) -6,7-dimethoxyisoquinol ini) l)] - 4, 4-dif in ilheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [/ V- (1, 2,3,4-tetrahydro-1-phenethyl-6,7-dimethoxyisoquinolinyl)] - 4 hydrochloride, 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydrq-1 - (4-aminobenzyl) -6,7-dimethoxyisoqui nol dihydrochloride ni l)] - 4,4-diphen-ilheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-aminomethyl-6,7-dimethoxyisoquinolinyl)] - 4, dihydrochloride 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrah idro-1 - (? -isopropyl-aminomethyl-6,7- dihydrochloride dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; Hydrochloride of 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - (4 -? butyl) -6,7-dimethoxy isoquinol I ini I)] -4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? - dihydrochloride - (1, 2, 3,4-tetrahydro-1- (4-aminobutyl) -6,7-d-methoxy isoq -inolinyl)] - 4,4-diphenylamine; Dihydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2, 3,4-tetrah idro- 1 - [4 - (? / - i so propi la no) but il] -6,7-d¡ methoxy isoquinolin il)] - 4, 4- diphenylheptane; 7 - [? / -3- (4-f luorofenyl) propionyljam- 1 - [? / - (1, 2, 3,4- tetrahydro-1 - [4 - (? / - cyclopropyl-meth) dihydrochloride lamino-6,7-d-methoxy -soquinol l) j-4,4-diphenylheptane; 7 - [? / 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (dihydrochloride 1, 2, 3,4-tetrahydro-1 - [4- (α-cyclobutyl-amino) butyl] -6,7-dimethoxy isoquinoline]) - 4,4-diphenylheptane; Dihydrochloride 7- [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [4 -? / - isobutyl-amino) butyl] -6,7-dimethoxy Soquinolinyl)] - 4,4-diphenylheptane; Dihydrochloride 7- [? -3- (4-f luorophenyl) propioni l] amino-1 - [? - (1, 2, 3,4-tetrah idro-1 - [4 - (? / - isopentyl-amyl) butyl] -6,7-di methoxy isoquinolyl)] - 4, 4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyljam i non-1 - [? / - (1, 2, 3, 4-tetrahydro-1 - [4 - (? / - alpha-methyl- dihydrochloride benzylamino) butyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) prop? Oni) amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - [4 - (? /? / -dicyclopropyl-methylamino) butyl] -6,7-dimethoxy-5-quinolinyl] - 4,4-diphenyl-heptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? - (1, 2, 3,4-tetrahydro-1 - [4 - (? /,? / - d -methyl-amino) -butyl] -6,7-dimethoxy-isoquinolin-1)] - 4,4-diphenylheptane; Hydrochloride of 7 - [? / - 3- (4-f luorofenyl) propioni I] am ino- 1 - [? / - (1, 2, 3,4-tetrah idro- 1 - [4 -? / - acet i l-am i no) butyl] -6,7-dimethoxy isoquinol in i l)] - 4, 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [4 - (? / - nicotinyl-amino) butyl hydrochloride ] -6,7-dimethoxyisoquinolinyl]] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [4 - (? / - phthalimido-methyl] -cyclohexyl hydrochloride] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fi uo rofenyl) propionyl) dihydrochloride mino- 1 - [? / - (1, 2, 3, 4-tetrahydro-1 - (4-ami non-methyl) I-cyclohexyl) -6,7-di methoxy isoquinolinyl) - 4, 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - (4 -? / - isopropylamino-metii) cyclohexyl- dihydrochloride 6, 7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - (4 -? / - phthalimido-methyl) phenyl- hydrochloride 6,7-dimethoxy-isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-f luorofenyl) dihydrochloride itself nil] am i no- 1 - [? / - (1, 2, 3,4-tetrahydro-1- (4-ammonomethyl) phenyI) -6,7-dimethoxyisoquinoline (I)) - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro- 1- (4-? / - i so propi lami- dihydrochloride methyl) phenyl-6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; Dihydrochloride of 7 - [? / 3- (4-A-fluorophenyl) propioni Ijam i non- 1 - [? / - (1, 2,3,4-tetrahydro-1- (4-A-cyclobutylamino-methyl) phenyl-6,7-dimethoxy-isoquinol inyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (4-o-cyclopropyl-methylaminomethyl) phenyl-6-dihydrochloride , 7-dimethoxyisoquinolinyl]] - 4,4-d-phenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1- (4 -? / - bicyclopropyl-methylaminomethyl) phenol dihydrochloride -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [/ V-3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (4 -? / - acetylamino-methyl) phenyl- hydrochloride 6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dihydroxyisoquinolinyl)] - 4 hydrochloride 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1-methylisoquinolinyl)] - 4,4-diphenylheptane hydrochloride; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dioxalan-isoquinolinyl) hydrochloride] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-6,7-dioxan-isoquinolinyl) hydrochloride] - 4,4-diphenylheptane; Hydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-6-methoxy-isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-7-methoxy-isoquinolinyl)] - 4 hydrochloride 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-7-chloro-isoquinolinyl)] - 4 hydrochloride 4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] l] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-7-fluoro-isoquinolinyl) hydrochloride] - 4,4-diphenolheptane; Hydrochloride of 7 - [? / - 3- (4-fluorophenyl) propionyl] amino] -1 - [A / - (1, 2, 3,4-tetrahydro-1-methyl-7-nitro-isoquinolinyl) ] -4,4-d-phenoheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-7-acetylamino-isoquinolinyl)] - 4 hydrochloride 4-diphenylheptane; Hydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methy I-6,7-dichloro-isoq ui nolin il)] - 4, 4-dif in i I hepta no; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6-chloro-7-fluoroisoquinoliniI) hydrochloride] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrah id ro-1-methyl-6,7-diacetoxy-isoqu i no lin i I)] - 4, 4-dif in ilheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrah idro-1-methyl-6-bromo-7-methoxyisoquinol hydrochloride) l)] - 4, 4-dif in i I hepta no; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2,3,4-tetrahydro-1-methyl-6-fluoro-7-methoxyisoquinolinyl)] - 4,4-diphenyl heptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6-methoxy-7-bromo-isoquinoliniI) hydrochloride) ] -4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1,6-dimethyl-7-methoxy-isoquinoliniI) hydrochloride] - 4,4-diphenylheptane; 7 - [? - 3- (4-fluorophenyl) propionii] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-6-carbomethoxy-7-m-ethoxy isoquinol hydrochloride) indole)) - 4,4-diphenylheptane; 7 - [? - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-cyclobutyl-6-bromo-7-methoxy) hydrochloride isoquinolinyl)] - 4,4-diphen-ilheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? - (1,2,3,4-tetrahydro-1,3-dimethyl-6,7-dimethoxyisoquinolinyl)] - 4 hydrochloride , 4-diphenyl heptane; Hydrochloride of 7 - [? / - 3- (4-fluorophenyl) propioni I] am ino- 1 - [? / - (1,2, 3,4-tetrahydro-3-methyl-6,7-dimethoxy-isoquinolinyl )] - 4,4-diphenylheptane; Hydrochloride of 7- [A / -3- (4-fluorophenyl) propionyl] am i no-1 - [? / - (1,2,4,4-tetrahydro-1,1-dimethyl-6,7-dimethoxyisoquinol) Nolinol)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1,3-dimethyl-7-methoxy-isoquinolinyl) hydrochloride] - 4,4-diphenolheptane; 7 - [? - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-7,8-di methoxy- 1 H- hydrochloride 2-benzazepinyl)] - 4, 4-dif in i I heptane; 6 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-methoxy-isoquinolinyl) hydrochloride] - 3,3-diphenylhexane; Hydrochloride of 8 - [? / - 3- (4-f luorofenyl) propioni I] ami no- 1 - [? / - (1,2, 3,4-tetrah idro- 1-methyl-6,7-d i-methoxy-isoqu i noli ni l)] - 5, 5-difeni locta no; 8 - [? / - 3- (4-fluorophenyl) acetyl] amino-1 - [? / - (1,2,3,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinolinyl)] - hydrochloride 5,5-diphenyloctane; 7 - [? / - 3- (4-fluorophenyl) propionyl] am ino-1 - [? / - (1, 2, 3,4-tetrah idro-1-methyl-7-methoxy-3-methoxycarbonyl isoquinolinyl) hydrochloride) ] -4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-3- (2-hydroxyethyl-aminocarbonyl) -1 - hydrochloride methyl-7-methoxyisoquinolinyl)] - 4,4-diphenylheptane; Hydrochloride 7- [? -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro- (3-hydroxypropyl-aminocarbonyl) -1-methyl-7-methoxy isoquinoline )] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-3- (4-h idroxybutyl-am hydrochloride i noca nor l) -1-methyl-7-methoxy isoq ui not I inyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-7-methoxy-3- (2- ( ? -pyrrolidinyl) ethylaminocarbonyl) isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-3-h idroxy-met hydrochloride i-l-7-m-ethoxy isoquinolin il)] - 4, 4-dif in ilheptane; 7 - [? / -3- (phenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinolinyl)] - 4 hydrochloride 4-diphenylheptane; 7 - [? / - 3- (3,4-Dichlorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1-methyl-6,7-di methoxy isoquinide hydrochloride i no lin il)] - 4,4-difen i I hepta no; Hydrochloride of 7 - [? / - 3- (3,4-difluorof in i I) propioni l] a mino- 1 - [N- (1, 2,3,4-tetrahydro-1-methyl-6, 7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (3-Fluoro-4-chloro-phenyl) propionyl] amino-1 - [? / - (1, 2, 3, 4-tetrahydro-1-methyl-6-hydrochloride, 7-d-methoxy-isoquinolinyl)] - 4,4-d-phenyl heptane; H id ruro ruro of 7 - [? / - 3- (4-f I uoro-3-chloro-phenyl) propioni l] am ino- 1 - [? / - (1, 2,3,4-tetrahydro-1 -methyl-6,7-dimethoxy-isoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (3,4-Dimethoxy-enyl) -propionyl] -l- am- 1 - [N- (1, 2, 3, 4-tetrahydro-1-methyl-6,7-dim hydrochloride ethoxy isoquinolinyl)] - 4, 4-dif in ilheptane; 7 - [? / - 3- (4-methoxyphenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-methyl-6,7-dimethoxyisoquinolyl)] - hydrochloride 4,4-diphenylheptane; 7 - [? / - 3- (4-chlorophenyl) propionyl] l] amino- 1 - [? / - (1,2,4,4-tetrahydro-1-methyl-6,7-dimethoxy-isoquinyl hydrochloride nolinyl)] - 4,4-diphenylheptane; 7 - [? - 3- (4-fluorophenyl) acetyl] amino-1 - [? / - (1, 2,3,4-tetrah idro-1-methyl-6,7-dimethoxy-isoquin linyl hydrochloride) ] -4,4-diphenylheptane; Hydrochloride of 7 - [? / 3- (4-fluorophenyl) propionyl] am ino- 1 - [? / - (1,2,3,4-tetrahydro-1- (3 -? / - phthalimido-propyl) -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (3-aminopropyl) -6,7-dimethoxyisoquinolinyl hydrochloride) ] -4,4-diphen-ilheptane; Dihydrochloride of 7- [A / -3- (4-fluorophenyl) propionyl] amino-1 - [? - (1,2,3,4-tetrahydro-1- [3 -? / - (biscyclobutyl-amino) propi I] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- [3 -? / - (bis-cyclopropyl-methylamino) propyl) dihydrochloride ] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphen-ilheptane; Dihydrochloride of 7 - [? / - 3- (4-f luorof eni I) propioni l] a mino- 1 - [? / - (1,2, 3, 4-tetrahydro-1- [3 -? / - ( dimethylamino) -propyl] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - [3 -? / - (isopropyl) propyl] dihydrochloride] -6,7-dimethoxyisoquinolinyl)) - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1- (5-? -phthalimido-pentyl) -6 hydrochloride, 7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrahydro-1 - (5-am and nopenti I) -hydrochloride -6 , 7-di methoxy isoquinolyl]) - 4,4-diphenolheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [5 -? / - (biscyclobutyl-amino) pentihydrochloride L] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino- 1 - [? / - (1, 2, 3,4-tetrahydro-1 - [5 -? / - (bis-cyclopropyl-m-dihydrochloride ethyl ami no) pen ti l] -6, 7-dim ethoxy isoq u ino lin il]] - 4, 4-dif en ilheptano; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [5 -? / - (dimethylamino) -pentyl] dihydrochloride] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1 - [5 -? / - (isopropylamino) -pentyl] dihydrochloride] -6,7-dimethoxyisoquinolinyl)] - 4,4-diphenylheptane; 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? Hydrochloride - (1, 2, 3,4-tetrah idro-1-cid obutil-6-f Ioro-7-methoxy isoquinolyl)) - 4,4-diphen-ilheptane; Hydrochloride of 7 - [? / - 3- (4-f luorof in i I) own níljam ino- 1 - [? / - (1, 2, 3,4-tetrahydro-1 - (4? - phthalimidobutyl) - 6-methyl-7-methoxyisoquinolinyl)] - 4,4-diphenylheptane; Dihydrochloride 7- [? -3- (4-fluorophenyl) propionyl] ami no-1 - [? / - (1, 2, 3,4-tetrah id ro-1 - (4-am i nobutyl) -6-methyl-7-methoxyisoquinolinyl )] - 4, 4-diphenylheptane; 7 - [? / -3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2, 3,4-tetrah idro-1 - (4 -? / - isopropylamide and non-butyl dihydrochloride ) -6-methyl-7-methoxyisoquinolinyl) j-4,4-diphenylheptane; and 7 - [? / - 3- (4-fluorophenyl) propionyl] amino-1 - [? / - (1, 2,3,4-tetrahydro-1-cyclobutyl-6-methyl-7-m-ethoxy isoquinolinyl hydrochloride )] - 4,4-diphen-ilheptane;

9. A process for preparing a compound of formula: (I) or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein /, m, n, p, R ^ R2, W, X, Y and Z represent the groups as defined in claim 1, comprising the steps of: a) treating a diphenyl-substituted aminoalkanoi of the formula: where m and n are as defined above, with a compound of the formula: wherein /, X and Y are as defined above, and R3 is selected from hydroxy, halo or an aryl ring substituted with a group that removes electrons, to obtain a? / - substituted aminoalkanol; (b) oxidizing the alcohol moiety of the α / - substituted aminoalkanol to an aldehyde moiety; and (c) alkylating the aldehyde portion with an isoquinoline ring of the formula: wherein p, R ^ R2, W and Z are as defined above.

10. A compound according to claim 9, wherein Ri is selected from the group consisting of alkyl, cycloalkyl and - (CH2) q-R4, wherein q is 0 to 10, and R4 is a group of the formula -NR6R7, wherein R6 and R7 are each independently selected from hydrogen, alkyl and cycloaikyl. eleven . A compound according to claim 9, wherein X and Y are independently selected from the group consisting of hydrogen and halogen. 12. A compound according to claim 1, wherein the acylating reagent is 3- (4-fluorophenyl) propionic acid. 13. A process for preparing a compound of formula: > or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein /, m, n, p, Rt R2, W, X, Y and Z represent the groups as defined in claim 1, comprising the steps of: (a) ) treating a diphenyl-substituted aminoalkanol of the formula: where m and n are as defined above, with a compound of the formula: wherein /, X and Y are defined above, and R3 is selected from hydroxy, halo or an aryl ring substituted with a group that removes electrons, to obtain an A / -substituted aminoalkanol; (b) preparing a reactive group leaving the alcohol moiety of the α / - substituted aminoalkanol to obtain a compound of the formula: H2N wherein R9 is selected from the group consisting of halide and mesylate; and (c) rent the aminoalkanol? -substituted with an isoquinoline ring of the formula: or the hydroiodide salt thereof, wherein p, R ^ R2, W and Z are as defined above. 14. A compound according to claim 1, wherein Ri is selected from the group consisting of alkyl, cycloalkyl and - (CH2) q-R4, wherein q is 0 to 1 0, and R4 is a group of the formula -NR6R7, wherein R6 and R7 are each independently selected from hydrogen, alkylene and cycloalkyl. 5. A compound according to claim 13, wherein X and Y are independently selected from the group consisting of hydrogen and halogen. 16. A compound according to claim 1, wherein the acylating reagent is 3- (4-fluorophenyl) propionic acid. 17. A pharmaceutical composition for inhibiting the release of luteinizing hormone, comprising a therapeutically effective amount of a compound in accordance with re-excitation 1, and a pharmaceutically acceptable carrier. 18. A pharmaceutical composition for inhibiting the release of luteinizing hormone, comprising a therapeutically effective amount of a compound according to claim 8 and a pharmaceutically acceptable carrier. 19. A method to modulate the release of luteinizing hormone in humans and other mammals in need of such treatment, which comprises administering, to a patient in need thereof, a therapeutically effective amount of a compound according to claim 1. 20. A method for modulating the release of luteinizing hormone in humans and other mammals in need of such treatment, which comprises administering, to a patient in need thereof, a therapeutically effective amount of a compound according to claim 8. SUMMARY The tetrahydroisoquinoline derivatives of formula (I): or a pharmaceutically acceptable salt, ester or prodrug thereof, having activity as an LH RH antagonist, as well as pharmaceutical compositions containing the same and methods for their use and preparation.