WO2000029380A1 - Derives de tetrahydro-isoquinoleine en tant qu'antagonistes lhrh - Google Patents

Derives de tetrahydro-isoquinoleine en tant qu'antagonistes lhrh Download PDF

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Publication number
WO2000029380A1
WO2000029380A1 PCT/US1999/026584 US9926584W WO0029380A1 WO 2000029380 A1 WO2000029380 A1 WO 2000029380A1 US 9926584 W US9926584 W US 9926584W WO 0029380 A1 WO0029380 A1 WO 0029380A1
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Prior art keywords
tetrahydro
amino
diphenylheptane
propionyl
fluorophenyl
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PCT/US1999/026584
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English (en)
Inventor
Fortuna Haviv
Wesley J. Dwight
Bradley W. Crawford
Rolf E. Swenson
Milan Bruncko
Michele A. Kaminski
Lisa M. Frey
John Demattei
Jonathan Greer
Original Assignee
Abbott Laboratories
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Priority claimed from US09/191,511 external-priority patent/US5981521A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to PCT/US1999/026584 priority Critical patent/WO2000029380A1/fr
Priority to CA002351187A priority patent/CA2351187A1/fr
Priority to EP99961631A priority patent/EP1129076A1/fr
Priority to JP2000582367A priority patent/JP2002529534A/ja
Publication of WO2000029380A1 publication Critical patent/WO2000029380A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel tetrahydroisoquinoline derivatives having activity as luteinizing hormone releasing hormone (LHRH) antagonists.
  • 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 prostate hypertrophy, and in vitro fertilization.
  • LHRH released from the hypothalamus binds to a receptor on the pituitary gland causing the release of gonadotropin hormones.
  • the ongoing system of feedback plays a major role in regulating the synthesis of the steroidal reproductive hormones from the gonads, ie. estrogen and progesterone in females and testosterone in males. Consequently, controlling the pulsatile release of LHRH provides an avenue for the design of novel compounds useful in treating various conditions related to dysfunction of the reproductive cycle and hormone dependent diseases.
  • Synthetic analogs evidencing activity in modulating LHRH secretion typically comprise peptides of naturally-occurring or non-naturally occurring amino acid residues.
  • Peptide LHRH antagonists characterized by substitution of the nitrogen atom of at least one amide bond are described in U.S. Pat. o. 5,110,904, and U.S. Pat. No. 5,502,035.
  • Truncated peptide compounds developed as a series of smaller peptide analogs also exhibit biological activity and afford the added advantage of possibly improving oral bioavailability.
  • "Pseudo" peptide compounds see for example U.S. Pat. No. 5,140,009, are recognized LHRH antagonists. Reduced-size pentapeptides LHRH antagonists are described in pending U.S. Application Ser. No. 132,999.
  • Pending application U.S. Ser. No. 133,055 discloses heptapeptide analogs which provide active compounds truncated from the C-terminus of a decapeptide antagonist sequence.
  • Non-peptide heterocyclic reproductive hormone regulators have been reported in the literature, see for example, WO 95/29900 and WO 97/21704.
  • Macrolide LHRH antagonists are described in the pending U.S. Application Ser. No. 049,963; see also pending U.S. Application Ser. No. 140,805.
  • European Patent EP 0712845 discloses amine compounds exhibiting LHRH receptor antagonist activity; see also European Patent EP 0187700.
  • the non-peptide LHRH antagonists of the present invention comprise tetrahydro- isoquinoline derivatives not previously described by the prior art.
  • the compounds are useful in the treating a variety of sex hormone related conditions including precocious puberty, benign prostatic hyperplasia, breast and ovarian tumors, prostate tumors, cryptorchidism, hirsutism in women, gastric motility disorders, dysmenorrhea and endometriosis.
  • the present invention relates to a compound having the formula:
  • R 2 is selected from the group consisting of: (a) alkyl,
  • R 4 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • R 6 and R are independently selected from the group consisting of:
  • R is hydrogen and R 7 is a group of the formula -COR 8 , wherein R 8 is selected from the group consisting of: (a) alkyl,
  • X and Y are independently selected from the group consisting of:
  • W and Z are independently selected from the group consisting of: (a) hydrogen,
  • N-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 LHRH antagonists.
  • 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.
  • the invention in another aspect, relates to a process of preparing a compound of the invention comprising treating a diphenyl-substituted aminoalkanol with an activated carboxylic acid to obtain an N-substituted aminoalkanol, oxidizing alcohol moiety of the N-substituted aminoalkanol to an aldehyde moiety, and alkylating the aldehyde moiety with a tetrahydroisoquinoline ring to afford a tetrahydroisoquinoline derivative of formula (I).
  • Another aspect of the invention relates to pharmaceutical compositions which are useful as LHRH antagonists and modulating levels of sex hormones in mammals.
  • Yet another aspect of the invention relates to a method of modulating levels of sex hormones in male and female mammals comprising admininstering to a host in need of such treatment a therapeutically effective amount of an LHRH compound of the invention.
  • alkyl and lower alkyl 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.
  • lower alkyl examples include, but are not limited to, methyl, ethyl, w-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2- methylpentyl, 2,2-dimethylpropyl, w-hexyl, w-octyl, H-nonyl, H-decyl, and the like.
  • alkoxy refers to a lower alkyl group of one to three carbons, as defined above, which is bonded to an oxygen atom in an ether linkage.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, w-pentyloxy, t-butoxy, n- octyloxy and the like.
  • This alkoxy radical can also contain a ring which includes, but is not limited to, a five or six atom ring composed of carbons, and up to one or two heteroatoms such as nitrogen, oxygen, or sulfur.
  • alkoxy carbonyl refers to an alkoxy group as described above wherein an oxygen atom is linked to the parent molecular moiety via a carbonyl group.
  • cyclic ring refers to hydrocarbon chain of one to four carbon atoms carbon-carbon bonded to ⁇ , ⁇ -adjacent carbons on the parent molecular moiety or respectively linked by an ether linkage at the - or ⁇ - carbon, for example, acetonido.
  • cycloalkyl refers to a 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 the like.
  • the cyclic group may be optionally substituted with, for example, alkyl, alkoxy, cyano, hydroxy, halogen, trifluoromethyl, amino, or N-substituted aminoalkyl.
  • the cycloalkyl may be carbon-carbon bonded directly to the parent molecular moiety or linked to the parent molecule via an appended substituent.
  • aryl refers to a mono-, fused bicyclic or fused tricyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, indenyl and the like.
  • aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, indenyl and the like.
  • bicyclic aryl as used herein includes naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • tricyclic aryl as used herein includes anthracenyl, phenanthrenyl, biphenylenyl, fluorenyl, and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, N-substituted aminoalkyl, alkenyloxy, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and alkylamido.
  • Substituents also include methylenedioxy and ethylenedioxy.
  • substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
  • Aryl and substituted aryl groups may be carbon-carbon bonded directly to the parent molecular moiety or linked to the parent molecule via an appended substituent.
  • aryloxy 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.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur, or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms, one nitrogen and one sulfur atom, or one nitrogen and one oxygen atom.
  • the 5-membered ring has 0-2 double bonds and the 6- and 7-membered ring have 0-3 double bonds.
  • the nitrogen heteroatoms can be optionally quaternized.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, decahydroquinolyl, benzofuryl or benzothienyl, imidazopyridyl, pyrrolopyridyl and the like).
  • 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 (for example, carbazolyl, iminodibenzyl and the like).
  • Heterocyclics include: azetidinyl; benzimidazolyl; 1 ,4-benzodioxanyl; 1,3-benzodioxolyl; benzoxazolyl; benzothiazolyl; benzothienyl; carbazolyl; dihydropyranyl; dihydrofuranyl; dioxanyl; dioxolanyl; furyl; homopiperidinyl; imidazolyl; imidazolinyl; imidazolidinyl; imidazopyridyl; iminodibenzyl; indolinyl; indolyl; isoquinolinyl; isothiazolidinyl; isothiazolyl; isoxazolidinyl; isoxazolyl; morpholinyl; naphthyridinyl; oxazolidinyl; oxazolyl; piperazinyl; piperidinyl; pyrany
  • nitrogen containing heterocycles can be N-protected.
  • hydroxymethyl refers to a lower alkyl of one to ten carbon atoms substituted at one or more carbon atoms with a hydroxy group.
  • N-acyl refers to an N-substituted aminoalkyl group wherein the nitrogen atom is linked to the parent molecular moiety via a carbonyl group.
  • N-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 which are substituted with two or three lower alkyl groups as defined above, include for example, diethylamino, methyl propylamino, and the like.
  • the lower alkyl groups are optionally substituted with, for example, alkoxy, aryl, substituted aryl, carbonyl, cycloalkyl, hydroxy, halogen or amino.
  • exemplary N-acyl groups include, but are not limited to, methylcarbamoyl, 1-cyclopentyl ethylcarbamoyl, and the like.
  • pharmaceutically acceptable salts 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 with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their 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 the relatively non-toxic, inorganic and organic acid addition salts of the compound of the present invention. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in L Pharmaceutical Sciences.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • suitable organic acid examples include 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.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, pers
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • esters refers to non-toxic esters of the compounds of this invention.
  • examples of pharmaceutically acceptable esters include C, to C 6 alkanoyl esters wherein the alkanoyl group is a straight or branched chain.
  • Esters of the compounds of the present invention may be prepared according to conventional methods.
  • prodrugs 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 the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and N. Stella, Pro-drugs as Novel Delivery Systems. Vol. 14 of the A.C.S. Symposium Series, and in Edward B.
  • prodrugs of derivatives of compounds of the present invention may be prepared by any suitable method.
  • the condensation of the amino group with amino acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodiimide) method, the active ester method (p-nitrophenyl ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBT (1-hydroxybenzotriazole) method and the like.
  • Classical methods for amino acid condensation reactions are described in M. Bodansky, Y.S. Klausner and M.A. Ondetti, Peptide Synthesis. Second Edition,
  • asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplate the various stereoisomers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy line, it is intended that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation may be present.
  • Preferred compounds of the invention are those compounds of formula (I) wherein / is 2, m is 3, n is 3, snap 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 -(CH 2 ) 9 -R 4 , wherein q is 0 to 10, and is a group of the formula -NR ⁇ R 7 , wherein R f , and R 7 are each independently selected from hydrogen, alkyl, and cycloalkyl.
  • Preferred compounds of the invention are also include compounds of formula (I) wherein R 2 is selected from the group consisting of hydrogen and methyl.
  • 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 more preferred compounds of the invention are those compounds as represented by formula (I) wherein Ri is selected from the group consisting of methyl, cyclopropyl, cyclobutyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, N-[cyclopropylmethyl]aminobutyl, and N-
  • 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 desiring, such treatment.
  • the compound may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • a "therapeutically effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat the targeted disorder, at a reasonable benefit risk ratio applicable to any medical treatment, which is administered in such quantities and over such a period of time as is necessary to obtain the desired therapeutic effect. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon 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 time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to 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 may range 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.
  • doses may be in the range of from about 1 to about 100 mg/kg/day or, more preferably, of from about 10 to about 20 mg/kg/day.
  • the effective daily dose may be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof as make up the daily dose.
  • compositions of the invention may 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, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intracisternal, subcutaneous and intraarticular injection and infusion.
  • compositions of the present invention comprise a compound of the invention in combination with a pharmaceutically acceptable carrier or excipient.
  • pharmaceutically acceptable carrier refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • compositions of this invention for parenteral injection include pharmaceutically acceptable sterile nonaqueous solutions or aqueous dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous 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.
  • 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 adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • agents which delay absorption such as aluminum monostearate and gelatin.
  • the rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon 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 entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping 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-retaining 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 prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-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
  • compositions of a similar type may also be employed as fillers 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 can also be in micro-encapsulated 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, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed 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, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • 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,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • suspending agents 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 may be prepared as a dry powder which may be pressurized or non-pressurized.
  • the active ingredient in finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter.
  • suitable inert carriers include sugars such as lactose.
  • 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 micrometers.
  • 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 admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquified gas propellant.
  • a compressed gas such as nitrogen or a liquified gas propellant.
  • the liquified propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent.
  • the pressurized composition may also contain a surface active agent.
  • the surface active agent may be a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of a sodium salt.
  • compositions for rectal or vaginal administration are preferably 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 are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore 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.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that 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 liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form 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.
  • Schemes 1-5 illustrate processes within the scope of the invention.
  • Scheme 1 describes the general method for preparing tetrahydroisoquinoline derivatives of the general formula (I), which is followed by more preferred syntheses carried out 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 moiety, preferably a phenyl group.
  • Step (i) represents the N-substitution of the amino moiety by acylating the nitrogen of the amino group or by coupling with an activated carboxylic acid.
  • PCC or Swern oxidation of the alcohol to the aldehyde is shown in Step (ii).
  • Alkylation of an isoquinoline ring as represented by Step (iii) affords the tetrahydroisoquinoline derivative.
  • a reactive leaving group R 9 is prepared from the alcohol, Step (ii-a), which is alkylated with the isoquinoline ring or the hydroiodide salt of the isoquinoline moiety represented in Step (iii-a).
  • R 9 is selected from the group consisting of halide and mesylate.
  • R 3 is selected from hydroxy, halo, or an aryl ring substituted with an electron withdrawing group to obtain an activated ester as illustrated by Scheme 1 below.
  • Schemes 2-5 further describe methods of preparing compounds within the scope of the general formula (I).
  • Scheme 2 represents a process for preparing a compound of formula (II) starting with the condensation of diphenylacetaldehyde and acrylonitrile and followed by additional chemical transformations well known in the art.
  • Scheme 3 involves a coupling reaction of an aryl-substituted (aryl)alkylamine with a carboxylic acid, followed by cyclization to form a tetraisoquinoline moiety which is an intermediate suitable for alkylating compound 7, 8, or 9 of Scheme 2.
  • a compound of the formula (III) is prepared from
  • Scheme 5 represents a process for preparing a compound of general formula (IV) via a Wittig reaction of 4,4-diphenyl-5-formyl- pentanonitrile followed by conventional chemical steps.
  • the variables Rj, R 2 , W, X, Y, and Z described in the schemes are the groups defined in Claim 1.
  • the group R 3 is selected from hydroxy, halo, or an aryl ring substituted with an electron withdrawing group to obtain an activated ester.
  • N-acylation of compound 4 with an acid or acid halide of formula 5 affords an N-acyl-4,4-diphenyl-amino- alkanol 6.
  • S wasn oxidation of compound 6 oxidizes the alcohol moiety to an aldehyde of compound 7.
  • Reductive alkylation of a tetrahydroisoquinoline with compound 7 in the presence of sodium cyanoborane affords the tetrahydroisoquinoline derivative of formula (II).
  • displacement of the alcohol moiety with a halide in compound 8 is obtained by Mitsunobu reaction of compound 6.
  • Treatment of compound 6 with methanesulfonyl chloride results in hydroxy displacement with a mesylate moiety to form compound 9.
  • Direct alkylation of the tetrahydroisoquinoline moiety with compound 8 or compound 9 affords the tetrahydroisoquinoline derivative (II).
  • isoquinoline ring (A) Another known method to form isoquinoline ring (A) is by the cyclization of compound 12 with POCl 3 to afford compound 15. Reacting compound L5 with sodium cyanoborane yields the isoquinoline derivative (A).
  • Step 2 Ethyl 6-cyano-4.4-diphenyl-hex-2-enoate (Compound 2, Scheme 2)
  • Step 4 7-Amino-4,4-diphenylheptan-l-ol (Compound 4, Scheme 2)
  • LAH lithium aluminum hydride
  • the reaction mixture was stirred at rt for 1.5 hr.
  • the reaction mixture was quenched by a careful addition of water (4.5 mL), followed by IN 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.
  • Step 7 (R.S) 7-rN-3-(4-Fluorophenvnpropionyllamino-l-rN- ⁇ .2.3.4-tetrahvdro-l-methyl-6.7- dimethoxyisoquinolinv01-4.4-diphenylheptane hydrochloride (Compound II. Scheme 2)
  • Step 1 7-[N-3-(4-Fluorophenyl propionyl "
  • Step 2 (R) 7-rN-3-(4-Fluorophenyl propionyllamino-l-rN-(1.2.3.4-tetrahvdro-l-methyl-6.7-di- methoxyisoquinolinvP "
  • -4,4-diphenylheptane hydrochloride Compound II.
  • Step 1 rN-2-(3,4-Dimethoxyphenyl ethyl "
  • Step 4 1.2.3,4-Tetrahvdro-l-cyclopropyl-6.7-dimethoxyisoquinoline hvdroiodide
  • Step 5 7-rN-3-(4-FluorophenvDpropiony ⁇ amino- 1 -FN-(1 ,2.3.4-tetrahvdro- 1 -cvclopropyl- 6.7-dimethoxyisoquinolinyl)]-4.4-diphenylheptane (Compound II. Scheme 2)
  • l,2,3,4-Tetrahydro-l-ethyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1 ,2,3,4-tetrahydro- l-cyclopropyl-6,7- dimethoxyisoquinoline but substituting in the first step propionyl chloride for cyclopropyl- carbonyl chloride.
  • l,2,3,4-tetrahydro-l-ethyl-6,7-dimethoxyisoquinoline (0.195 g) was reacted with
  • the hydrochloride salt was prepared as in example 1 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4-tetra- hydro-l-isopropyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 96-103 °C; IR (CHC1 3 ) ⁇ 3350, 2950, 1650, 1510 cm "1 .
  • l,2,3,4-Tetrahydro-l-phenyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1,2,3 ,4-tetrahydro- l-cyclopropyl-6,7-dimethoxy- isoquinoline but substituting in the first step benzoyl chloride for cyclopropylcarbonyl chloride.
  • the hydrochloride salt was prepared as in example 1 to give 7-[N-3-(4-fluorophenylpropionyl]amino-l-[N-(l,2,3,4-tetrahydro-l-phenyl-6,7-dimethoxy- isoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 117-120 °C; Anal. Calcd for C45H49 ⁇ 2O 3 F ⁇ CIO.5H 2 O: C, 74.0; H, 7.30; N, 3.83; Found: C, 73.14; H, 6.74; N, 3.71.
  • the hydrochloride salt was prepared as in example 1 to give 7- [N-3 -(4-fluoropheny l)propionyl]- 1 -[N-( 1 ,2,3,4-tetrahydro- 1 -cyclopentyl-6,7-dimethoxyisoquinolinyl)]-4,4- diphenylheptane hydrochloride: mp 92 °C (dec); Anal. Calcd for C 44 H 53 ⁇ O 3 F HCl 0.5H 2 O: C, 73.15; H, 7.67; N, 3.87; Found: C, 73.45; H, 7.78; N, 3.87.
  • l,2,3,4-Tetrahydro-l-cyclobutyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for l,2,3,4-tetrahydro-l-cyclopropyl-6,7-dimethoxy- isoquinoline but substituting in the first step cyclobutylcarbonyl chloride for cyclopropylcarbonyl chloride.
  • the 1 ,2,3 ,4-tetrahydro- 1 -cyclobutyl-6,7-dimethoxyisoquinoline was reacted with
  • the hydrochloride salt was prepared as in example 1 to give 7-[N-3-(4-fluorophenyl- propionyl]- 1 -[N-( 1 ,2,3,4-tetrahydro- 1 -cyclobutyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenyl- heptane hydrochloride: mp 112-121 °C (dec); Anal. Calcd for C 43 H 5 ⁇ 2 O 3 F HCl 2H 2 O: C, 72.88; H, 6.99; N, 3.46; Found: C, 72.56; H, 7.38; N, 3.83.
  • l,2,3,4-Tetrahydro-l-hexyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1 ,2,3,4-tetrahydro- l-cyclopropyl-6,7- dimethoxyisoquinoline but substituting in the first step 2-methoxyacetyl chloride for cyclopropylcarbonyl chloride.
  • the hydrochloride salt was prepared as in example 1 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4-tetrahydro-l-cyclohexyl-6,7-dimethoxy- isoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 104 °C; Anal. Calcd for C 45 H 55 ⁇ 2 O 3 F HCl: C, 74.30; H, 7.75; N, 3.85; Found: C, 73.86; H, 7.83; N, 3.63.
  • the hydrochloride salt was prepared as in example 1 to give 7- [N-3 -(4-fluoropheny l)propionyl] amino- 1 -[N-( 1 ,2,3,4-tetrahydro- 1 -cyanomethyl-6,7-di- methoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 106-114 °C; Anal. Calcd for C 4 ⁇ H 46 ⁇ 3 O 3 F HCl: C, 71.97; H, 6.92; N, 6.14; Found: C, 71.82; H, ; 6.86; N, 5.95.
  • l,2,3,4-Tetrahydro-l-methoxymethyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1,2,3,4-tetrahydro-l-cyclopropyl- 6,7-dimethoxy-isoquinoline but substituting in the first step 2-methoxyacetyl chloride for cyclopropylcarbonyl chloride.
  • the hydrochloride salt was prepared as in example 1 to give 7-[N-3-(4-fluorophenyl)propionyl]- amino- 1 -[N-( 1 ,2,3 ,4-tetrahydro- 1 -methoxymethyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenyl- heptane hydrochloride: mp 102-110 °C (dec); Anal. Calcd for C 4 ⁇ H 50 ⁇ 2 O 4 F-2HCl: C, 67.75; H, 7.21; N, 3.85; Found: C, 67.39; H, 6.78; N, 4.22.
  • l,2,3,4-Tetrahydro-l-benzyloxymethyl-6,7-dimethoxyisoquinoline hydroiodide was prepared by a procedure analogous to that described in step 4 ofexample 4 but substituting 1 ,2,3,4-tetrahydro- l-benzyloxymethyl-6,7-dimethoxyisoquinoline for 1,2,3,4-tetrahydro-l-cyclopropyl- 6,7-dimethoxyisoquinoline.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl-propionyl)]- amino- 1 -[N-(l ,2,3,4-tetrahydro- 1 -benzyloxymethyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenyl- heptane hydrochloride: mp 118-133 °C (dec); IR (MIC) ⁇ 3330, 2950, 1650, 1510 cm "1 ; Anal. Calcd for C 47 H 53 ⁇ 2 O 4 F' HCl. 1.25 H 2 O: C, 71.64; H, 7.22; N, 3.55; Found: C, 71.85; H, 7.09; N, 3.69.
  • l,2,3,4-Tetrahydro-l-(4-methoxyphenyl)-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 7 for l,2,3,4-tetrahydro-l-phenyl-6,7-di- methoxyisoquinoline, but substituting in the first step 4-methoxybenzoic acid for benzoic acid.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4-tetra- hydro-l-(4-methoxyphenyl)-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 114-120 °C; Anal. Calcd for C 46 H 51 ⁇ 2 O 4 F- HCl. 0.5 H 2 O: C, 72.66; H, 7.20; N, 3.68; Found: C, 72.33; H, 6.82; N, 3.50.
  • the dihydrochloride salt was prepared as in example 4 to give 7- [N-3 -(4-fluoropheny l-propionyl)] - amino- 1 -[N-( 1 ,2,3 ,4-tetrahydro- 1 -(4-amino)phenyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenyl- heptane hydrochloride: mp 168-175 °C; IR (KBr) ⁇ 3269, 2934, 2578, 1635, 1612, 1510 cm "1 .
  • Example 16 7- N-3-(4-Fluorophenyl propionyl1amino-l-rN-(1.2.3.4-tetrahydro-l-r4-(N-iso ⁇ ropylamino ' )- phenyl-6.7-dimethoxyisoquinolinyl) ⁇
  • the dihydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluoro- phenyl-propionyl]amino-l-[N-(l,2,3,4-tetrahydro-l-[4-(N-isopropylamino)phenyl-6,7-di- methoxyisoquinolinyl]-4,4-diphenylheptane dihydrochloride: mp 153-161 °C; IR (KBr) ⁇ 3275, 2934, 2588, 2459, 1653, 1510 cm "1 .
  • l,2,3,4-Tetrahydro-l-benzyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 7 for 1 ,2,3,4-tetrahydro- l-phenyl-6,7-dimethoxy- isoquinoline but substituting in the first step phenylacetyl chloride for benzoyl chloride.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino- 1 -[N-( 1 ,2,3 ,4-tetrahydro- 1 -benzyl-6,7-dimethoxy- isoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 94-98 °C; Anal. Calcd for C 46 H 5 , ⁇ 2 O 3 F ⁇ Cr ⁇ .75 H 2 ⁇ : C, 73.67; H, 7.32; N, 3.73; Found: C, 73.71; H, 6.96; N, 3.57.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l -[N-(l ,2,3,4-tetrahydro- 1 -(4-chlorobenzyl)- 6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 88-96 °C.
  • l,2,3,4-Tetrahydro-l-(4-methoxybenzyl)-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 17 for 1 ,2,3,4-tetrahydro- l-benzyl-6,7-di- methoxyisoquinoline but substituting in the first step (4-methoxyphenyl)acetyl chloride for phenylacetyl chloride.
  • the l,2,3,4-tetrahydro-l-(4-methoxybenzyl)-6,7-dimethoxyisoquinoline was reacted with
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetra- hydro- 1 -(4-methoxybenzyl)-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 100-108 °C.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l, 2,3,4- tetrahydro-l-phenethyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 97-102 °C.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluoro- phenyl)propionyl]- 1 -[N-( 1 ,2,3,4-tetrahydro- 1 -(4-aminobenzyl)-6,7-dimethoxyisoquinolinyl)]- 4,4-diphenylheptane dihydrochloride: mp 138-149 °C.
  • Step 1 1.2,3,4-Tetrahvdro-l-N-(phthalimidomethyl)-6.7-dimethoxyisoquinoline
  • Step 2 3.4-dihydro-l -N-(phthalimidomethyl)-6.7-dimethoxyisoquinoline
  • Step 3 1.2.3.4-tetrahvdro- 1 -N-(phthalimidomethyl)-6.7-dimethoxyisoquinoline
  • Step 4 7- N-3-(4-fluorophenyl)propionyl]amino-l-[N- ⁇ .2.3.4-tetrahvdro-l-N-(phthalimido- methyl)-6,7-dimetho ⁇ yisoquinolinyl)1-4.4-diphenylheptane hydrochloride l,2,3,4-Tetrahydro-l-N-(phthalimidomethyl)-6,7-dimethoxyisoquinoline was reductively alkylated with 7-[N-3-(4-fluorophenyl)propionyl]amino-4,4-diphenylheptan-l-al in the presence of sodium cyanoborohydride using the procedure described in example 1.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-N-(phthalimido- methyl)-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 114-121 °C (dec); IR (MIC) ⁇ 3250, 2943, 1771, 1712, 1671, 1510 cm "1 ; Anal. Calcd for C 48 H 50 ⁇ 3 O 5 F HCl: C, 71.67; H, 6.41 ; N, 5.22; Found: C, 71.42; H, 6.21; N, 5.38.
  • Step 5 7-[N-3-(4-fluorophenvDpropionyl "
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl- propionyl)]amino- 1 -[N-( 1 ,2,3,4-tetrahydro- 1 -aminomethyl-6,7-dimethoxyisoquinolinyl)]-4,4- diphenylheptane dihydrochloride: mp 110-116 °C; Anal. Calcd for C 40 H 48 ⁇ 3 O 3 F2HC1: C, 67.60; H, 7.09; N, 5.91 ; Found: C, 65.20; H, 7.12; N, 5.53.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-(N-iso- propylaminomethyl)-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride: mp 114-122 °C; Anal. Calcd for C 43 H 54 ⁇ 3 O 3 F 2HC1: C, 68.60; H, 7.50; N, 5.58; Found: C, 65.69; H,
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l, 2,3 ,4-tetrahydro- 1 -(4-N-phthalimidobutyl)-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride: mp 112-128 °C; Anal. Calcd for C 5 ⁇ H 56 ⁇ 3 O 5 F HCl: C, 72.37; H, 6.79; N, 4.96; Found: C, 72.81; H, 7.01; N, 4.67.
  • the hydrochloride salt was prepared as in example 4 to give 7- [N-3 -(4-fluoropheny l)propionyl- l-[N-[l,2,3,4-tetrahydro-l-(4-aminobutyl) -6,7-dimethoxyisoquinolinyl)]-4,4-diphenyl heptane dihydrochloride: mp 112-118 °C; IR (KBr) ⁇ 3410, 2936, 2835, 1646, 1510 cm "1 ; Anal. Calcd for C 43 H 54 ⁇ 3 O 3 F 2HCl 1.5H 2 O: C, 66.22; H, 7.62; N, 5.38; Found: C, 65.89; H, 7.46; N, 5.21.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- amino-l-[N-(l,2,3,4-tetrahydro-l-(4-N-isopropylaminobuty)l-6,7-dimethoxyisoquinolinyl)]- 4,4-diphenylheptane: mp 118-128 °C.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-[4-N-(cyclopropyl- methylamino)butyl]-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride: mp 112-120 °C; IR (KBr) ⁇ 3422, 2939, 2590, 1655, 1510 cm "1 ; Anal. Calcd for C 47 H 60 ⁇ 3 O 3 F 2HC1: C, 69.96; H, 7.74; N, 5.21; Found: C, 68.41; H, 7.92; N, 5.18.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- 1 -[N-( 1 ,2,3,4-tetrahydro- 1 -[4-(N-cyclobutylamino)butyl- 6,7-dimethoxyisoquinolinyl)]-4,4- diphenylheptane: mp 121-128 °C; Anal. Calcd for C 47 H 60 ⁇ 3 O 3 F 2HC1: C, 69.96; H, 7.74; N, 5.21 ; Found: C, 68.76; H, 7.97; N, 5.11.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluoro- phenyl)propionyl]- 1 -[N- 1 ,2,3 ,4-tetrahydro- 1 -[4-(N-isobutylamino)butyl-6,7-dimethoxy- isoquinolinyl)]-4,4-diphenylheptane dichlorohydrochloride: mp 114-128 °C; Anal. Calcd for C 47 H 62 ⁇ 3 O 3 F 2HCl: C, 69.78; H, 7.97; N, 5.19; Found: C, 68.25; H, 8.06; N, 5.06.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-N-(l,2,3,4-tetrahydro- 1 -[4-(N-isopentylaminobutyl)-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride: mp 118-132 °C; Anal. Calcd for C 48 H 69 ⁇ 3 O 3 F 2HCl: C, 70.05; H, 8.08; N, 5.11; Found: C, 68.53; H, 8.46; N, 5.02.
  • Example 31 7-[N-3-(4-Fluorophenyf)propionyllamino- 1 -fN-( 1.2,3 ,4-tetrahydro- 1 -
  • the dihydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-amino-l-[N-(l, 2,3,4- tetrahydro-l-(4-(N-alpha-methyl-benzylaminobutyl))-6,7-dimethoxy-isoquinolinyl)]-4,4- diphen lyyllhheeppttaannee:: mmpp 112200--113322 °°CC;; AAnnaall.. ⁇ Calcd for C 5 ⁇ H 62 N 3 O 3 F 2HCl: C, 71.48; H, 7.53; N,
  • Example 32 7-[N-3-(4-Fluorophenyl)propionvnamino-l - N-( ⁇ .2,3, 4-tetrahvdro- 1 -
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4-tetrahydro-l-(4-N,N-dicyclo- propylmethylamino)-butyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride: mp 118-130 °C; Anal. Calcd for C 5 ⁇ H 66 ⁇ 3 O 3 F 2HCl: C, 71.14; H, 7.96; N, 4.88; Found: C, 70.68; H, 8.14; N, 4.73.
  • Example 33 7- [N-3 -(4-FluorophenvDpropionv ⁇ amino- 1 - [N-( 1.2.3.4- tetrahvdro-l-(4-N,N-dimethylamino ' )butyl-6.7-dimethoxyisoquinolinyl ' )l- 4,4-diphenylheptane dihydrochloride
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- l-[N-(l,2,3,4-tetrahydro-l-(4-N,N-dimethylamino)butyl-6,7-dimethoxyisoquinolinyl)]-4,4- diphenylheptane dihydrochloride: mp 116-134 °C; Anal. Calcd for C 45 H 58 ⁇ 3 O 3 F 2HC1: C,
  • the hydrochloride salt was prepared as in example 4 to give 7- [N-3 -(4-fluoropheny l)propiony 1] amino- 1 - [N-( 1 ,2 ,3 ,4-tetrahydro- 1 -(4- N-acetylamino)- butyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 115-128 °C; Anal. Calcd for C 45 H 56 ⁇ 3 O 4 F HCl: C, 71.27; H, 7.58; N, 5.54; Found: C, 69.53; H, 7.68; N, 5.41.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4-tetrahydro-l-(4-N- nicotinylamino)butyl-6,7-dimethoxyisoquinolinyl]-4,4-diphenylheptane dihydrochloride: mp 124-133 °C.
  • Step 1 N-r(3,4-Dimethoxy)phenylethyl]-4-(N-phthalimidomethv ⁇ cyclohexylcarbonyl amide
  • 3,4-dimethoxyphenethylamine 3.6224 g
  • methylene chloride 100 mL
  • trans-4-(N-phthalimidomethyl)cyclohexanecarboxylic acid 6.3224 g
  • HOBt 2.9731 g
  • triethylamine 4.1 mL
  • EDCI 4.2175 g
  • Step 3 1.2.3,4-Tetrahvdro-l- 4-(N-phthalimidomethyl cyclohexyl1-6,7-dimethoxyisoquinoline
  • methanol 50 mL
  • sodium cyanoborohydride 0.3276 g
  • Step 4 7-rN-3-(4-FluorophenvDpropionv ⁇ amino- 1 - ⁇ N-( 1.2.3.4-tetrahvdro- 1 -(4-N- phthalimidomethyl -cvclohexyl-6.7-dimethoxyisoquinolinyl)]-4.4-diphenylheptane hydrochloride
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4- tetrahydro-l-(4-N-phthalimidomethyl)cyclohexyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenyl- heptane hydrochloride: mp 108-121 °C; Anal. Calcd for C 54 H 60 ⁇ 3 O 5 F ⁇ C1: C, 73.16; H, 6.94; N, 4.74; Found: C, 66.33; H, 6.39; N, 5.86.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- 1 -[N-( 1 ,2,3,4-tetrahydro- 1 -(4-aminomethyl)cyclohexyl- 6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4- tetrahydro- 1 -(4-(N-isopropylaminomethyl)cyclohexyl-6,7-dimethoxyisoquinolinyl)]- 4,4-diphenylheptane dihydrochloride (0.115 g): mp 114-122 °C; Anal. Calcd for C ⁇ HM ⁇ S O S F ⁇ HCI: C, 70.49; H, 7.97; ⁇ , 5.03; Found: C, 70.73; H, 7.86; ⁇ , 5.17.
  • Example 39 7-IN-3 -(4-Fluorophenyl)propionyll- 1 - fN-( 1.2.3.4-tetrahvdro- 1 -(4-N-phthalimidomethyl V phenyl-6.7-dimethoxyisoquinolinyl)]-4.4-diphenylheptane hydrochloride
  • Step 1 N-r(3,4-dimethoxyphenyl)ethvn(4-N-phthalimidomethyl')benzoyl amide
  • Step 2 3.4-dihvdro-l - ⁇ -N-phthalimidomethy ⁇ phenyll- ⁇ -dimethoxyisoquinoline
  • Step 3 1.2.3.4-tetrahvdro-l-r(4-N-phthalimidomethyl phenyll-6.7-dimethoxyisoquinoline
  • Step 4 7-rN-3-f4-Fluoro ⁇ henvnpropionyll-l -IN-d .2.3.4-tetrahvdro- 1 -(4-N- phthalimidomethv ⁇ -phenyl-6.7-dimethoxyisoquinolinv ⁇ i-4,4-diphenylheptane hydrochloride 1 ,2,3 ,4-Tetrahydro- 1 -[4-(N-phthalimidomethyl)phenyl]-6,7-dimethoxyisoquinoline was reacted with 7-[N-3-(4-fluorophenyl)propionyl]amino-4,4-diphenylheptan-l-al in the presence of sodium cyanoborohydride, using the same conditions described in experiment 36, step 4, to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4-tetrahydro-
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- 1 -[N-(l ,2,3,4-tetrahydro- 1 -(4-N-phthalimidomethyl)phenyl-6,7-dimethoxyisoquinolinyl)]-4,4- diphenylheptane hydrochloride: mp 114-128 °C (dec); Anal. Calcd for C 5 H 54 ⁇ 3 O 5 FHCl: C, 73.66; H, 6.30; N, 4.77; Found: C, 72.21; H, 6.37; N, 4.67.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4- tetrahydro-l-(4-aminomethyl)phenyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride: mp 126-134 °C (dec); Anal. Calcd for C 46 H 52 ⁇ 3 O 3 F 2HC12H 2 O: C, 67.14; H, 7.10; N, 5.10; Found: C, 67.11; H, 7.11; N, 5.16.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l- [N-(l,2,3,4-tetrahydro-l-(4-N-isopropylaminomethyl)phenyl-6,7-dimethoxyisoquinolinyl)]- 4,4-diphenylheptane dihydrochloride: mp 128-139 °C (dec); Anal. Calcd for C 49 H 58 ⁇ 3 O 3 F 2HC1 H 2 O: C, 69.48; H, 7.37; N, 4.96; Found: C, 69.44; H, 7.39; N, 4.94.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluoro- phenyl)propionyl]- 1 -[N-(l ,2,3,4-tetrahydro- 1 -(4-N-cyclobutylaminomethyl)phenyl-6,7-di- methoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride: mp 121-133 °C; Anal. Calcd for C 50 H 58 ⁇ 3 O 3 F 2HC1 H 2 O: C, 69.91 ; H, 7.27; N. 4.89; Found: C, 69.82; H. 7.24; N, 4.87.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-(4-N-cyclopropylmethylamino- methyl)phenyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride: mp 124-136 °C; Anal. Calcd for C 50 H 58 ⁇ 3 O 3 F 2HC1 ⁇ 2 O: C, 69.91; H, 7.27; N, 4.89; Found: C, 69.88; H, 7.31; N, 4.88.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4- tetrahydro-l-(4-N-biscyclopropylmethylaminomethyl)phenyl-6,7-dimethoxyisoquinolinyl)]- 4,4-diphenylheptane dihydrochloride: mp 118-134 °C (dec); Anal. Calcd for C 54 H 64 ⁇ 3 O 3 F 2HCl H 2 O: C, 71.30; H, 7.50; N, 4.60; Found: C, 71.08; H, 7.54; N, 4.56.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- amino- 1 -[N-( 1 ,2,3 ,4-tetrahydro- 1 -(4-N-acetylaminornethyl)phenyl-6,7-dimethoxyiso- quinolinyl)]-4,4-diphenylheptane hydrochloride: mp 118-132 °C (dec); Anal. Calcd for C 48 H 54 ⁇ 3 O 4 F HCl 0.75H 2 O: C, 71.53; H, 7.60; N, 5.21; Found: C, 71.19; H, 7.08; N, 5.16.
  • Example 46 7-rN-3-(4-Fluorophenvnpropionyll-l-rN-(1.2.3.4-tetrahvdro-l-methyl-6.7- dihydroxyisoquinolinvDl ⁇ -diphenylheptane hydrochloride
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- amino-l-[N-(l,2,3,4-tetrahydro-l-methyl-6,7-dihydroxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l- [N-(l,2,3,4-tetrahydro-l-methylisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 83-87 °C; Anal. Calcd for C 38 H 43 ⁇ 2 OF HCl 0.5H 2 O: C, 72.30; H, 8.27; N, 5.11 ; Found: C, 72.61; H, 7.42; N, 4.43.
  • Example 48 7-rN-3-(4-Fluorophenyl)propionyll- 1 -[N-( 1.2,3 ,4-tetrahydro- 1 -methyl-6.7-dioxalane- isoquinolinylYl-4,4-diphenylheptane hydrochloride
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4-tetrahydro-l-methyl-6,7- dioxalane-isoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 91-95 C; Anal. Calcd for C 39 H 43 ⁇ 2 O 3 F HCl 1.25H 2 O: C, 70.36; H, 7.30; N, 4.20; Found: C, 70.49; H, 7.00; N, 4.07.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluoro- phenyl)propionyl]amino-l -[N-(l ,2,3,4-tetrahydro-l -methyl-6,7-dioxane-isoquinolinyl)]- 4,4-diphenylheptane hydrochloride, mp 104-109 °C; Anal. Calcd for C 40 H 45 ⁇ 2 O 3 F HCl H 2 O: C, 71.14; H, 7.16; N, 4.14; Found: C, 71.00; H, 7.21; N, 4.01.
  • Step 1 rN-2-(3-MethoxyphenvOethyl]acetyl amide (Compound 12. Scheme 3)
  • 3-methoxyphenethylamine 3.11 g
  • methylene chloride 150 mL
  • acetic anhydride 2.1 mL
  • DMAP 0.126 g
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4-tetrahydro-l-methyl-6-methoxy- isoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluoropheny)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-methyl-7- methoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-methyl-7- chloroisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 84-88 °C; Anal. Calcd for
  • the hydrochloride salt was prepared as in example 4 to give 7- [N-3-(4-fluorophenyl)propionyl]- 1 -[N-( 1 ,2,3,4-tetrahydro- 1 -methyl-7-fluoroisoquinolinyl)]-4,4- diphenylheptane hydrochloride: mp 80-84 °C; Anal. Calcd for C 38 H 42 ⁇ 2 OF 2 HCl H 2 O: C, 71.85; H, 7.13; N, 4.40; Found: C, 71.44; H, 7.08; N, 4.24.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-methyl-7- nitroisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-methyl-7-acetylamino- isoquinolinyl)]-4,4-diphenylheptane hydrochlorid: mp 1 14 0C; Anal. Calcd for
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l- [N-(l,2,3,4-tetrahydro-l-methyl-6,7-dichloroisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-methyl-6-chloro-7- fluoroisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 97-99 0C; Anal. Calcd for C 38 H 4 ⁇ 2 OClF 2 HCl 3H 2 O: C, 68.65; H, 6.32; N, 4.21; Found: C, 68.29; H, 6.65; N, 3.96.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l- methyl-6-bromo-7-methoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 104-108 °C; Anal. Calcd for C 39 H 44 N 2 O 2 BrF HCl 1.25H 2 O: C, 64.10; H, 6.55; N, 3.85; Found: C, 63.94; H, 6.55; N, 3.68.
  • Example 60 7- ⁇ r N-3-(4-Fluorophenyl)propionyl]-l-[N-(1.2.3.4-tetrahvdro-l-methyl-6-fluoro-7- methoxyisoquinolinyl)]-4.4-diphenylheptane hydrochloride
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- 1 -[N-( 1 ,2,3 ,4-tetrahydro- 1 -methyl-6-fluoro-7-methoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro- l-methyl-6-methoxy-7-bromoisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • Example 62
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l,6-di- methyl-7-methoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl-propionyl)]amino-l-[N-( 1,2,3, 4-tetrahydro-l -methyl-6-carbo- methoxy-7-methoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 92 °C; Anal. Calcd for C 4 ⁇ H 47 ⁇ 2 O 4 F ⁇ C12.5H 2 O: C, 67.18; H, 6.55; N, 3.82; Found: C, 67.15; H, 6.93; N, 3.62.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l- [N-(l,2,3,4-tetrahydro-l-cyclobutyl-6-bromo-7-methoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenylpropionyl)]- amino-l-[N-(l,2,3,4-tetrahydro-l ,3-dimethyl-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 97-108 °C.
  • Example 66
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-3-methyl-6,7- dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 87-91 °C; Anal. Calcd for C 40 H 47 ⁇ 2 O 3 F HC1 H 2 O: C, 70.93; H, 7.44; N, 4.13; Found: C, 70.49; H, 7.28; N, 3.85.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4-tetrahydro-l,3-dimethyl-7-methoxy- isoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(2,3,4,5-tetra- hydro-l-methyl-7,8-dimethoxy-lH-2-benzazepinyl)]-4,4-diphenylheptane hydrochloride.
  • Step 4 6-[N-3-(4-Fluorophenyl)propionyl]amino-3.3-diphenylhexan-l-ol (Compound 19, Scheme 41.
  • Step 5 6-[N-3-(4-Fluorophenyl propionyl]amino-3.3-diphenylhexyl mesylate (Compound 20. Scheme 4).
  • Step 6 6-rN-3-(4-FIuorophenyl)propionyl]arnino-l -[N-(l ,2,3,4-tetrahydro- 1 -methyl-6.7- dimethoxy-isoquinoline ⁇ -S -diphenylhexane hydrochloride (Compound III, Scheme 4)
  • 6-[N-3-(4-Fluorophenyl)propionyl]amino- 1 -[N-( 1 ,2,3 ,4-tetrahydro- 1 -methyl-6,7-dimethoxy- isoquinoline)]-3,3-diphenylhexane hydrochloride was prepared using the procedure described in example 4 but substituting 6-[N-3-(4-fluorophenyl)propionyl]amino-3,3-diphenylhexyl mesylate for 7-[N-3-(4-fluorophenyl)propionyl]amino-4,4-diphenylheptyl mesylate and 1,2,3,4-tetrahydro- l-methyl-6,7-dimethoxy-isoquinoline hydroiodide for l-cyclopropyl-4,5-dimethoxy-l,2,3,4- tetrahydroisoquinoline hydroiodide.
  • Step 1 Methyl 7-cvano-5.5-diphenyl-hept-2-enoate (Compound 21. Scheme 5) A mixture of 4,4-diphenyl-5-formylpentanonitrile (1.87 g, 7.1 mmol) and (carbornethoxymethylene)triphenyl phosphorane (2.85 g, 8.5 mmol) in toluene (50 mL) was heated under reflux for three days.
  • Step 3 8-Amino-5.5-diphenylocta-l-ol (Compound 23. Scheme 5)
  • Step 4 8-rN-3-(4-Fluorophenyl)propionyl]amino-5.5-diphenyloctan-l-ol (Compound 24, Scheme 5)
  • Step 6 8-rN-3-(4-Fluorophenyl)propionyl]amino-5.5-diphenyloctyl mesylate (Compound 25. Scheme 5).
  • Step 7 8-[N-3-(4-Fluorophenyl propionyl]amino-l-[N-(1.2.3.4-tetrahvdro-l-methyl-6.7- dimethoxyisoquinolinvP1-5.5-diphenyloctane (Compound IV.
  • Step 1 8-(4-Fluorophenylacetyl)amino-5.5-diphenyloctan-l-ol To an ice-cold and stirred solution of 8-amino-5,5-diphenylocta-l-ol (Compound 23,
  • Step 2 8-(4-Fluorophenylacetyl)amino-5.5-diphenylhexyl mesylate
  • Step 3 8-rN-(4-FluorophenvIacetyl)lamino-l-[N-(1.2.3,4-tetrahydro-l-methyl-6.7-dimethoxy- isoquinoline 1-5,5-diphenyloctane 8-[N-(4-Fluorophenylacetyl)]amino-l-[N-(l,2,3,4-tetrahydro-l-methyl-6,7-dimethoxy- isoquinoline)]-5,5-diphenyloctane was prepared using the procedure described in example 4 but substituting 8-(4-fluorophenylacetyl)amino-5,5-diphenylhexyl mesylate for 7-[N-3-(4-fluoro- phenyl)propionyl]amino-4,4-diphenylheptyl mesylate and 1 -methyl-6,7-dimethoxy- 1,2,3,4- te
  • Step 1 3.4-Dihvdro-7-methoxy-3-methoxycarbonyl-l-methyl-isoquinoline
  • Step 2 1.2.3.4-Tetrahvdro-7-methoxy-3-methoxycarbonyl-l-methyl-isoquinoline
  • Step 3 1.2.3.4-Tetrahvdro-7-methoxy-3-methoxycarbonyl-l-methyl-isoquinoline hydroiodide To a solution of 1 ,2,3,4-tetrahydro-7-methoxy-3-methoxycarbonyl- 1 -methyl-isoquinoline
  • Step 4 7-rN-3-(4-Fluorophenyl)propionyllamino-l-[N-(l,2,3.4-tetrahvdro-l-methyl-7-methoxy- 3-methoxycarbonylisoquinolinyQ]-4.4-diphenylheptane hydrochloride
  • Step 1 1.2.3.4-Tetrahvdro-l-methyl-3-hydroxymethyl-7-methoxyisoquinoline
  • Step 2 1.2.3,4-Tetrahvdro-l-methyl-3-hvdroxymethyl-7-methoxyisoquinoline hydroiodide
  • methanol 10 mL
  • methanol 10 mL
  • ether 100 mL
  • Example 79 The procedure described in example 1 was used wherein the appropriate acids were substituted for 3 -(4-fluoropheny l)propionic acid. After workup and chromatographic purification the following compounds were obtained:
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino- 1 -[N-( 1 ,2,3,4-tetrahydro- 1 -(3 -N-phthalimidopropyl)- 6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- amino-l-[N-(l,2,3,4-tetrahydro-l-(3-aminopropyl)-6,7-dimethoxyisoquinolinyl)]-4,4-diphenyl- heptane hydrochloride: Anal. Calcd for C 42 H 52 F ⁇ 3 O 3 2HC1 1.25H 2 O: C, 66.26; H, 7.48; N, 5.51; Found: C, 66.02; H, 6.96; N, 5.52.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- amino-l-[N-(l,2,3,4-tetrahydro-l-[3-N-(biscyclobutylamino)propyl]-6,7-dimethoxy- isoquinolinyl)]-4,4-diphenylheptane dihydrochloride: Anal. Calcd for C 5 oH 64 F ⁇ 3 O 3 2HCl H 2 O: C, 68.01; H, 7.99; N, 4.75; Found: C, 67.37; H, 7.79; N, 4.82.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluoro-phenylpropionyl)]- 1 -[N-(l ,2,3,4-tetrahydro- 1 -[3-N-(biscyclopropylmethylamino)propyl]-6,7-dimethoxy- isoquinolinyl)]-4,4-diphenylheptane dihydrochloride: Anal. Calcd for C 50 H 64 F ⁇ 3 O 3 2HC1 H 2 O: C, 68.35; H, 7.97; N, 4.78; Found: C, 68.10; H, 7.57; N, 4.83.
  • Example 84 Anal. Calcd for C 50 H 64 F ⁇ 3 O 3 2HC1 H 2 O: C, 68.35; H, 7.97; N, 4.78; Found: C, 68.10; H, 7.57; N, 4.83.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- amino-l-[N-(l,2,3,4-tetrahydro-l-[3-N-(dimethylamino)propyl]-6,7-dimethoxyisoquinolinyl)]- 4,4-diphenylheptane dihydrochloride.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- l-[N-(l,2,3,4-tetrahydro-l-[3-N-(isopropyl)-propyl]-6,7-dimethoxyisoquinolinyl)]-4,4- diphenylheptane dihydrochloride.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-(5-N-phthalimidopentyl)- 6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluoro- phenyl)propionyl]-amino-l -[N-(l ,2,3,4-tetrahydro-l -(5-aminopentyl)-6,7-dimethoxyiso- quinolinyl)]-4,4-diphenyl-heptane dihydrochloride: Anal. Calcd for C 4 H 56 F ⁇ O 3 2HCl H 2 O: C, 67.33; H, 7.70; n, 5.35; Found: C, 67.10; H, 7.24; N, 5.24.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]amino-l-[N-(l,2,3,4-tetrahydro-l- [5-N-(biscyclobutylamino)pentyl]-6,7-dimethoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)- propionyl] amino- 1 -[N-( 1 ,2,3 ,4-tetrahydro- 1 -[5-N-(biscyclopropylmethyl-amino)pentyl]-6,7- dimethoxyisoquinolinyl)]-4,4-diphenylheptane dihydrochloride: Anal. Calcd for C 5 2H 68 FN 3 O 3 2HCrH 2 O: C, 68.55; H, 8.18; N, 4.61 ; Found: C, 67.87; H, 7.84; N, 4.59.
  • Example 90 Anal. Calcd for C 5 2H 68 FN 3 O 3 2HCrH 2 O: C, 68.55; H, 8.18; N, 4.61 ; Found: C, 67.87; H, 7.84; N, 4.59.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- amino-l-[N-(l,2,3,4-tetrahydro-l-[5-N-(dimethylamino)pentyl]-6,7-dimethoxyisoquinolinyl)]- 4,4-diphenylheptane dihydrochloride.
  • the hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluorophenyl)propionyl]- amino-l-[N-(l,2,3,4-tetrahydro-l-[5-N-(isopropylamino)pentyl]-6,7-dimethoxyisoquinolinyl)]- 4,4-diphenylheptane dihydrochloride: Anal. Calcd for C 47 H 62 F ⁇ 3 O 3 0.75 H 2 O: C, 75.15; H, 10.33; N, 5.59; Found: C, 74.99; H, 8.34; N, 5.51.
  • hydrochloride salt was prepared as in example 4 to give 7- [N-3 -(4- fluorophenyl)propionyl]-l-[N-(l,2,3,4-tetrahydro-l-cyclobutyl-6-fluoro-7- methoxyisoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • hydrochloride salt was prepared as in example 4 to give 7-[N-3-(4-fluoro- phenyl)propionyl]amino-l-[(N-[l,2,3,4-tetrahydro-l-cyclobutyl-6-methyl-7-methoxy- isoquinolinyl)]-4,4-diphenylheptane hydrochloride.
  • Representative compounds of the present invention were evaluated in vitro for potency against for LHRH rat pituitary receptor binding [pKj ]. Methods for the assay procedures are described in F. Haviv, et al. J. Med. Chem., 32: 2340-2344 (1989).
  • Values of pK] are the negative logarithms of the equilibrium dissociation constant of the particular antagonist test compound for the receptor binding. Typically values of 7.0 or greater are indicative of good LHRH antagonist potency, with values of 8.0 or greater being preferred.
  • Leuprolide LHRH agonist disclosed and claimed in U.S. Pat. No. 4,005, 063, has the structure S-oxo-Pro'-His ⁇ Trp ⁇ Se ⁇ -Ty ⁇ -D-Leu ⁇ Leu'-Arg ⁇ Pro ⁇ NHEt.

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Abstract

L'invention concerne des dérivés de tétrahydro-isoquinoléine de formule (I), ou un sel, un ester pharmaceutiquement acceptables, ou un promédicament de ces derniers, possédant une activité d'antagoniste LHRH, ainsi que des compositions pharmaceutiques les contenant, et des procédés de leur utilisation et préparation.
PCT/US1999/026584 1998-11-13 1999-11-09 Derives de tetrahydro-isoquinoleine en tant qu'antagonistes lhrh WO2000029380A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/US1999/026584 WO2000029380A1 (fr) 1998-11-13 1999-11-09 Derives de tetrahydro-isoquinoleine en tant qu'antagonistes lhrh
CA002351187A CA2351187A1 (fr) 1998-11-13 1999-11-09 Derives de tetrahydro-isoquinoleine en tant qu'antagonistes lhrh
EP99961631A EP1129076A1 (fr) 1998-11-13 1999-11-09 Derives de tetrahydro-isoquinoleine en tant qu'antagonistes lhrh
JP2000582367A JP2002529534A (ja) 1998-11-13 1999-11-09 Ｌｈｒｈ拮抗薬としてのテトラヒドロイソキノリン誘導体

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US09/151,511 1998-09-11
US09/191,511 US5981521A (en) 1998-11-13 1998-11-13 Tetrahydroisoquinoline derivatives as LHRH antagonists
PCT/US1999/026584 WO2000029380A1 (fr) 1998-11-13 1999-11-09 Derives de tetrahydro-isoquinoleine en tant qu'antagonistes lhrh

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100386319C (zh) * 2005-12-05 2008-05-07 中国人民解放军第二军医大学 具有抗生育和抗真菌活性的四氢异喹啉类化合物或其盐类
CN113416140A (zh) * 2021-06-03 2021-09-21 万华化学集团股份有限公司 一种制备2-甲基戊二胺的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0187700A1 (fr) * 1985-01-10 1986-07-16 H. Lundbeck A/S Nouveaux dérivés de l'urée substitués par un groupe aminoalkyle, leurs sels d'addition acides et énantiomères
EP0712845A1 (fr) * 1994-11-21 1996-05-22 Takeda Chemical Industries, Ltd. Dérivés d'amines, leur préparation et utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0187700A1 (fr) * 1985-01-10 1986-07-16 H. Lundbeck A/S Nouveaux dérivés de l'urée substitués par un groupe aminoalkyle, leurs sels d'addition acides et énantiomères
EP0712845A1 (fr) * 1994-11-21 1996-05-22 Takeda Chemical Industries, Ltd. Dérivés d'amines, leur préparation et utilisation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100386319C (zh) * 2005-12-05 2008-05-07 中国人民解放军第二军医大学 具有抗生育和抗真菌活性的四氢异喹啉类化合物或其盐类
CN113416140A (zh) * 2021-06-03 2021-09-21 万华化学集团股份有限公司 一种制备2-甲基戊二胺的方法
CN113416140B (zh) * 2021-06-03 2023-01-13 万华化学集团股份有限公司 一种制备2-甲基戊二胺的方法

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