EP0836599A1 - Isochromans 1,6-disubstitues destines au traitement des cephalees de type migraine - Google Patents

Isochromans 1,6-disubstitues destines au traitement des cephalees de type migraine

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Publication number
EP0836599A1
EP0836599A1 EP96921264A EP96921264A EP0836599A1 EP 0836599 A1 EP0836599 A1 EP 0836599A1 EP 96921264 A EP96921264 A EP 96921264A EP 96921264 A EP96921264 A EP 96921264A EP 0836599 A1 EP0836599 A1 EP 0836599A1
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EP
European Patent Office
Prior art keywords
ethyl
defined above
isochroman
alkyl
piperazinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96921264A
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German (de)
English (en)
Inventor
Michael D. Ennis
Ruth E. Tenbrink
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Pharmacia and Upjohn Co
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Pharmacia and Upjohn Co
Upjohn Co
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Publication date
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Publication of EP0836599A1 publication Critical patent/EP0836599A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to isochroman-alkyl-piperazinyl/piperidinyl-aryl compounds useful for the treatment of headaches, especially migraine and cluster headaches, as analgesics, and also useful as antipsychotics and for the treatment of other CNS and/or cardiovascular disorders.
  • Chromans also known as 1-benzopyrans, where the oxygen atom is attached to the aromatic ring
  • isochromans also known as 2-benzopyrans, where the oxygen atom is not attached to the aromatic ring
  • aryl- piperazines or 4-arylpiperidines
  • European Patent 300,908 discloses (1- benzopyran)]-alkyl-(piperazinyl or aminopiperidine)-aryls useful as antiarrythmics and anti-fibrillatory agents.
  • the compounds of this invention require -alk l- piperazinyl (or piperidinyl)-aryl at carbon 1 of a 2-benzopyran ring and also require substitution at the 6-position of the isochroman which are useful for the treatment
  • this invention do not permit oxygen substitution on the aromatic ring of the isochroman, thioisochroman, benzoxepin, or benzothiepin ring system for their usefulness in CNS and cardiovascular disorders.
  • isochroman-, isothiochroman-, 2-benzoxepin-, and -2- benzothiepin-alkyloxyethanols as being useful for preparing the above compounds. More specifically 7,8-dimethoxybenzoxepines are disclosed as are l-[(6,7- dimethoxyisochroman)alkyl]-4-(aryl)piperazines. Further disclosed are 2- benzoxepine-alkyl-piperazine(aminopiperidine)-aryls, 2-benzothiepins and 2- benzoxepines all requiring an oxygen atom as a substituent on the aromatic ring and useful for the same purposes. Dutch Patent 8,001,981 discloses l-(2-chlorophenyl)-4-[2-(l,3,4,5-tetrahydro-
  • International Patent Publication WO 88/08424 discloses isochromans-alkyl- piperazinyl (or aminopiperidinyl)-aryls, with the requirement that oxygen be present on the aromatic ring of the isochroman, useful in the treatment of head injury, spinal trauma, and stroke.
  • International Patent Publication WO 90/15056 and US Patent 5,140,040 disclose isochromans, tetralins, and dihydroanaphthalenes substituted with various alkyl amines for the treatment of glaucoma, depression, hypertension, congestive heart failure and vascular spastic conditions.
  • US Patent 4,994,486 discloses isochroman-alkyl-amines for treating psychoses, Parkinson's disease, and addictive behavior.
  • Japanese Patent 61083180 discloses isochroman-alkyl-(alkyl)amines as antiulcer agents.
  • European Patent 404,197 discloses isochroman-alkyl-piperazine-alkyl-keto (alcohol)-aryls with bronchodilator and antiallergy activity.
  • Japanese Patent 51125287 J 52083846 discloses isochroman-alkyl- amines(piperazine) with antidepressive, analgesic, diuretic, antiinflammatory, and anti-asthma activity.
  • German Patent DE 2,624,693 and Great England Patent GB 1552004 discloses isochroman-alkyl-amines including aryl piperazines as analgesics, hypotensives, antidepressants, diuretics, antiinflammatories, muscle relaxants, and vasodilators.
  • the compounds differ from the compounds of this invention in that oxygen substitution is required on the isochroman aromatic ring.
  • Japanese Patent 57159713 discloses isochroman- and tetralin-(no alkyl spacer )-piperazine-aryls as antiallergics.
  • the compounds of this invention require at least one carbon as a linker.
  • US Patents 3,549,656 and 3,467,675 and Belgium Patent 678,035 disclose phthalan-, isochroman-, and isochromen-alkylene-amines for the treatment of depression.
  • European Patent 458,387 and US Patent 5,137,911 disclose isochroman- alkylene-piperazme-alkylene-aryls useful as blood platelet aggregation inhibitors, as intracellular calcium antagonists, and for treating cardiac dysrhythmias, angina pectoris, stroke, and myocardial infarction.
  • German Patent DE 3,409,612 discloses dimethoxyisochroman- and benzoxepine-alkyl-amino-alkyls for prophylaxis of coronary heart disease or hypertension.
  • Japanese Patent 6 1083180 discloses isochroman-alkyl-amines useful for treating ulcers.
  • European Patent 457,686 discloses phthalan and indane alkyl aminopiperidinyl ureas or carbamates for the treatment of stress, pain, and schizophrenia.
  • J. Med. Chem., 25(1), 75-81 (1982) discloses 6,7-dimethoxyisochroman-alkyl- piperazinyl-aryl type compounds which have hypotensive activity.
  • WO 95/18118 discloses racemic l-(4-methoxyphenyl)-4-[2-(6-aminocarbonylisochroman-l-yl)-ethylpiperazine (EXAMPLE 138) and l-(4-methoxyphenyl)-4-[2-(6-methylaminocarbonylisochroman- l-yl)-ethylpiperazine (EXAMPLE 139).
  • W j ⁇ is a nitrogen (-N-) or carbon (-CH-) atom
  • R ⁇ is as defined above, (R) -CO-O-Q j ⁇ where Q 1-2 is defined below; (IV) R 2 is defined the same as R j , R 2 can be the same or different than R ⁇
  • (e) is -H, C r C 6 alkyl, -CFg or -CH 2 - ⁇ ,
  • n 2 is as defined above and - ⁇ is optionally substituted with one or two:
  • n 7 is as defined above and - ⁇ is optionally substituted with one or two:
  • Ql-1 and Ql-2 cannot both be selected from: -H,
  • aromatic bicyclic amines of the formula (ABA) are also disclosed.
  • W is a nitrogen (-N-) or carbon (-CH-) atom
  • n 7 is 0 thru 4 and where - ⁇ is optionally substituted with one or two:
  • R j (4) -NR j . 3A R j . 3B where R . 3A and R . 3 B are as defined above, (J) -CO-R j j where R j is as defined above; (IN) R 2 is defined the same as R j , R 2 can be the same or different than R j ; and pharmaceutically acceptable salts thereof.
  • the invention consists of novel compounds, 1,6-disubstituted isochroman (I) and a small group of aromatic bicyclic amines (ABA) which are previously generically disclosed in International Publication WO 95/18118 (PCT/US94/13284) with a unique spectrum of activity, highly active against vascular headaches especially migraine and cluster headaches.
  • the processes used to produce the novel compounds of the claimed invention are known to those skilled in the art. By starting with the appropriate starting materials and organizing the process steps in a particular order (using protective groups where necessary) the novel compounds of the invention are produced. The process of each step of the invention is known to those skilled in the art.
  • CHART A describes the construction of the 6-bromoisochroman (VI), which is a useful intermediate for many of the 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA).
  • VI 6-bromoisochroman
  • II 3-bromophenethanol
  • III isochroman ester
  • Standard hydrolysis using lithium hydroxide in THF-water provides the acid (TV), which can be coupled to a variety of substituted arylpiperazines or 4-arylpiperidines to give the amides (V).
  • the arylpiperazine moiety carries the R j and R 2 substituents. It is preferred that the desired R j and R 2 substituents be on the aryl group prior to the production of the amide (V).
  • the starting R j and R 2 aryl groups are known to those skilled in the art or can be readily prepared by known methods from known compounds. Many of the arylpiperazine moieties are commercially available or known in the chemical literature. Those that are not commercially available or known can readily be prepared as illustrated in CHARTS Q and R. These amides are reduced using borane to provide the bromoisochromans (VI).
  • CHART B describes the conversion of the 6-bromoisochroman (VI) into the corresponding 6-amide and 6-ester analogs. Conversion of the aryl bromide to the primary amide is accomplished via metal-halogen exchange using t-butyl lithium and quenching the resulting aryl anion with trimethylsilylisocyanate, see J. Med. Chem., 36, 2208 (1993).
  • the aryl anion can also be treated with gaseous carbon dioxide, followed by treatment with oxalyl chloride in DMF and subsequent reaction with amines to provide the amides (LX) directly.
  • the 6- bromoisochroman (VI) can be reacted with carbon monoxide in the presence of palladium (II) acetate, 1,3-bisdiphenylphosphinopropane, d ⁇ sopropylamine, and hexamethyldisilazane in solvents such as DMF to give the amide (VII).
  • palladium catalysts such as in situ prepared palladium(O) with organophosphines, or pre-prepared palladium(O) phosphine catalysts can be utilized.
  • the amide (VII) can be converted into either substituted amides (LX) or esters (X) via the bis-BOC derivative (VIII) using the procedure described in J. Org.
  • the 6-bromoisochroman (VI) can be converted to N-methyl substituted amides (LX) directly by using either methylamine or N-methylformamide in place of hexamethyldisilazsane in the palladium-mediated reaction described above (see EXAMPLES 5 and 6).
  • other patterns of N-substitution can be obtained by using other primary or secondary amines in place of hexamethyldisilasane in the palladium-mediated reaction described above.
  • CHART C describes the enzymatic resolution of racemic (II).
  • Mixing (II) with an enzyme such as the lipase derived from Pseudomonas cepacia in aqueous buffer (preferred pH 5-8) results in selective hydrolysis of the (-)-ester to give the (-)-acid (XI). It is preferred to carry out this reaction at room temperature (20-35°) using 5- 20% by weight of the enzyme. The reaction is monitored by known means of removing an aliquot, acidifying, and examining by HPLC. When the reaction is complete, the products (XI), the (-)-acid, and (XII), the (+)-ester are recovered and separated by acid/base extractive techniques well-known by those skilled in the art.
  • These optically-active compounds can be used when appropriate in any of the illustrated Charts to prepare optically pure versions of the described compounds.
  • This iterative process optimizes the overall yield of the desired (-)-isochroman-l-yl-acetic acid (XI).
  • Suitable bases for this racemization are those with pKa's greater than 11, preferably greater than 12.
  • Operable bases include alkali metal amide bases, alkali metal alkoxides, and alkali metal carbonates which can all induce this racemization. It is preferred that the base be alkali metal amide bases or alkali metal alkoxides; it is more preferred that the base be the alkali metal alkoxides, such as sodium or potassium i-butoxide or ethoxide.
  • the reaction is quenched with a proton donor. Virtually any proton donor is operable, for example even water will quench the reaction. However, operationally water is not preferred. Usually the proton donor is an acid.
  • Treatment of the aryl bromide (VI) with trimethylsilylacetylene in the presence of palladium (II) acetate, copper(I) iodide, and triethylamine provides the acetylenic isochroman (XIII).
  • a palladium catalyst preferably palladium (II) acetate
  • 1,3-bisdiphenylphosphinopropane and diisopropylamine in ah organic solvent such as dimethylformamide gives (XVI).
  • Hydrogenation of (XVI) by standard techniques known to those skilled in the art provides the saturated species (XVII).
  • CHART G describes the preparation of isochromans bearing a 6-acyl substituent such as an acid, an ester, a ketone, or an oxime.
  • Palladium- mediated carbonylation of the aryl bromide (TV) in the presence of an alcohol generates the corresponding esters (X) via conditions well-documented in the literature.
  • palladium-mediated cross-coupling of (VI) with enol-ethers gives rise to ketones (XXTV) following standard acidic hydrolysis of the enol-ether intermediate.
  • CHART H describes the preparation of the sulfonamides (XXVII) and the sulfones (XXLX).
  • Treatment of the aryl bromide (VI) with t-butyl lithium results in metal-halogen exchange, and the resulting aryl lithium can be quenched with sulfur dioxide to afford the lithium salt (XXVI).
  • This salt is then treated with phosphorous pentachloride and the resulting sulfonyl chloride is mixed with the appropriate amine to generate the corresponding sulfonamide (XXVII).
  • aryl bromide (VI) is converted to the aryl lithium species as described above and quenched with the appropriate disulfide to give the sulfide (XXVIII).
  • CHART I describes the preparation of the sulfones (XXXIN) in which the sulfone moiety is linked to the isochroman nucleus with a methylene tether of 1, 2, or 3 carbon atoms.
  • XXXIN sulfones
  • the carboxylic acids (XXX) can be reduced to the primary alcohols (XXXI) using well- known techniques and reagents such as lithium aluminum hydride or borane.
  • the alcohols (XXXI) can be converted to the corresponding bromides (XXXII) using well- known techniques and reagents such as phosphorous tribromide or carbon tetrabromide and triphenylphosphine.
  • the bromides (XXXII) can be used to alkylate thiols using techniques known to those skilled in the art to provide the sulfides (XXXIII).
  • the sulfides (XXXIII) can be oxidized to the sulfones (XXXTV) by using standard oxidative techniques and reagents such as osmium tetroxide and ⁇ - methylmorpholine ⁇ -oxide.
  • CHART J describes the preparation of the sulfonamides (XXXVII) in which the sulfonamide moiety is linked to the isochroman nucleus with a methylene tether of 1, 2, or 3 carbon atoms.
  • the bromides (XXXII can be treated with sodium sulfite in refluxing 10% aqueous sodium hydroxide solution to provided the sulfonate salts (XXXV).
  • the sulfonate salts are converted to the sulfonyl chlorides (XXXVI) using phosphorous pentachloride and phosphorous oxychloride.
  • Treatment of (XXXVI) with amines ( ⁇ QJ_JQJ_ 2 ) gives the sulfonamides (XXXVII).
  • CHART K describes the preparation of substituted imidazoles and triazoles which are linked to the isochroman nucleus with a methylene tether of 1, 2 or 3 carbon atoms.
  • CHART K when the "X" in the substituent is nitrogen the substituent is a triazole and when the "X" is a carbon atom the substituent is an imidazole.
  • These compounds are obtained by alkylating the appropriate imidazole or triazole with the bromides (XXXII).
  • the imidazoles and triazoles are either commercially available or can be prepared as described in the chemical literature using techniques known to those skilled in the art. In this fashion are obtained the compounds (XXXVIII).
  • CHART L describes the preparation of the oxadiazoles (XL) which are linked to the isochroman nucleus with a methylene tether of 1, 2 or 3 carbon atoms.
  • the requisite oxime amides are prepared from the corresponding nitriles using hydroxylamine hydrochloride and sodium metal in methanol according to the procedure disclosed in J. Med. Chem., 36, 1529 (1993).
  • the nitriles are either commercially available or can be readily prepared as described in the chemical literature using techniques known to those skilled in the art.
  • the oxime amides are treated with either sodium hydride or sodium metal and then further treated with the ester (XXXLX) according to the procedure disclosed in J. Med. Chem., 36, 1529 (1993) to give the heterocyclic products (XL).
  • CHART M describes the preparation of mono-(XLII) or di-substituted tetrazoles (XLIII) which are linked to the isochroman nucleus with a methylene tether of 1, 2 or 3 carbon atoms.
  • the bromides (XXXII) are converted to the corresponding nitriles (XLI) via a cyanide displacement reaction known to those skilled in the art.
  • These nitriles are then converted to the mono-substituted tetrazoles (XLII) by the action of sodium azide in a solvent such as N-methyl-2- pyrrolidinone according to the procedure disclosed in J. Med. Chem., 38, 1799 (1995).
  • the mono-substituted tetrazoles are converted to the di-substituted tetrazoles (XLIII) by standard alkylation reactions (R-X, acetonitrile, triethylamine).
  • CHART N describes the preparation of the isomeric triazoles (XLIII) and (XLIN) which are linked to the isochroman nucleus with a methylene tether of 1, 2 or 3 carbon atoms.
  • the nitriles (XLI) can be converted to the imidoesters (XLII) by the action of ethanolic hydrochloric acid according to the procedure disclosed in J. Med. Chem., 38, 1799 (1995).
  • treatment of (XLII) with alkyl hydrazines either commercially available or prepared by means known in the literature
  • a solvent such as ethanol
  • subsequent treatment with formic acid gives a mixture of (XLIII) and (XLIV). This mixture can be separated into its components by standard laboratory techniques such as chromatography or crystallization.
  • CHART O describes the preparation of substituted triazoles and oxadiazoles from primary carboxamides (VII) using methods known to those skilled in the art, see for example, J. Org. Chem., 44, 4160-4164 (1979).
  • X in (0-2) is nitrogen
  • the product is a triazole.
  • X in (0-2) is oxygen
  • the product is a oxadiazole.
  • Treatment of amides (VII) with dimethylamide acetals in non-polar, high boiling solvents such as toluene at 50-100° generates the intermediate (O-l).
  • CHART Q discloses the synthesis of piperazine (Q-3) in which R j is an electron withdrawing substituent ortho or para to the aniline nitrogen of the piperazine.
  • Amine (Q-l) and aryl halide (Q-2) where a fluorine or bromine atom is ortho or para to the electron withdrawing substituent are heated without solvent or in a polar solvent such as water, DMF, dimethylacetamide, or other such solvents with a base (either excess (Q-l) or diisopropylethylamine, potassium carbonate or the like) at elevated temperature (60-200°) to give piperazine (Q-3).
  • CHART R discloses the synthesis of piperazines (R-3). Nitro aryl (R-l) is reduced to aniline (R-2) using hydrogen and a catalyst such as palladium on carbon, Raney nickel, stannous chloride or the like. Alternatively, (R-2) can be purchased commercially. Aniline (R-2) is then heated (about 80 to about 165°) with bis(2- haloethyl)amine hydrochloride with or without added base in solvents such as THF, toluene, ethylene glycol, or chlorobenzene to give piperazine (R-3).
  • CHART S illustrates an the preparation of an important intermediate useful for the preparation of compounds claimed in this patent.
  • the hydroxy amide (S-3) is conveniently prepared from the hydroxy bromide (S-1; see CHART T) either directly via a palladium-mediated amidation reaction (identical to that illustrated in CHART B) or via the intermediacy of an ester (S-2).
  • This ester is readily synthesized from (S-1) via a palladium-based carbonylation reaction known to those skilled in the art as similar to those already described.
  • the conversion of (S-2) to the amide (S-3) is accomplished by treating (S-2) with an alcoholic solution (typically methanol) containing the appropriate amine reagent in a manner similar to that described in J. Org. Chem., 52, 2033-2036 (1987). This reaction can be carried at at room temperature (20-25°) or preferably at 50-100°.
  • CHART T illustrates two important alternative approaches to the compounds claimed in this patent.
  • This compound is then converted into the hydroxy amide (S-3) as described in CHART S.
  • This hydroxy amide is converted into an alkylating agent (T-2, typical X is a mesylate or a bromide) by standard chemical transformations and is used to alkylate an appropriate 4-arylpiperazine or 4-arylpiperidine to provide the final compounds (LX).
  • T-2 typical X is a mesylate or a bromide
  • the hydroxy bromide (S-1) is converted into an alkylating agent (T-l, typical X is a mesylate or a bromide) by standard chemical transformations and is used to alkylate an appropriate 4-arylpiperazine or 4- arylpiperidine to provide the bromides (VI). These bromides are then converted into final compounds (LX) as previously illustrated.
  • CHART U discloses the conversion of chiral bromo acid (U-l) which is (XI) in CHART C to the amide alcohol (U-5) which is (S-3) in CHART T.
  • the bromo acid (U-l) is alkylated to the bromo ester (U-2) using methods known to those skilled in the art.
  • An example is treatment of the bromo acid (U-l) with 1,1'- carbonyldiimidazole in a solvent such as THF to form an activated ester, followed by an alcohol to form the bromo ester (U-2).
  • the bromo ester (U-2) is then treated under the conditions discussed for CHART V for the conversion of (V-l) to (V-2), to give the amide ester (U-3).
  • the acid amide (U-4) is then treated with reducing agents such as borane or borane-methyl sulfide in THF as solvent to give the amide alcohol (U-5).
  • CHART V discloses a method for the conversion of ester (V-l) to diamide (V- 4).
  • Ester (V-l) is prepared from bromo isochroman (T-l) and piperazine (Q-3), CHART Q, by methods discussed for CHART T.
  • Ester (V-l) is converted to the amide ester (V-2) using palladium (II) acetate, a co-catalyst such as bis(diphenylphosphino)propane, diisopropylethylamine, carbon monoxide and methyl amine as discussed with regard to CHART B.
  • Solvents for the conversion may be chosen from DMF, dimethylacetamide, N-methylformamide and acetonitrile with dimethylacetamide and N-methylformamide preferred when methyl amine gas is used. Preferred temperatures are 50 to 120°.
  • the amide ester (V-2) is further converted to the corresponding amide acid (V-3) using aqueous base followed by acid neutralization to give (V-3) or a salt thereof.
  • the ester is the tert-butyl ester
  • trifluoroacetic acid or hydrochloric acid in solvents such as ether or ethyl acetate are used to convert the amide ester (V-2) to the corresponding amide acid (V-3).
  • amide acid (V-3) then is treated with a condensing agent and an amine to provide the corresponding diamide (V-4) using methods known to those skilled in the art such as discussed with regrd to CHART W.
  • CHART W discloses a synthesis of hydroxamic acid derivatives (W-7) and (W-
  • the carboxylic acid (W-3) is then treated with a condensing agent such as carbonyldiimidazole, diethylcyanophosphonate, dicyclohexylcarbodiimide, or other suitable condensing agents (see, for example, Major Methods of Peptide Bond Formation, Volume One of The Peptides: Analysis, Synthesis, Biology, E. Gross and J. Meienhofer, eds., Academic Press) in solvents such as dichloromethane or DMF and a base such as triethylamine in the presence of an amine such as an O-alkyl, N-alkylhydroxylamine (itself prepared by the method of Sulsky et al., Tet. Lett.
  • a condensing agent such as carbonyldiimidazole, diethylcyanophosphonate, dicyclohexylcarbodiimide, or other suitable condensing agents (see, for example, Major Methods of Peptide Bond Formation
  • hydroxamate ether (W-4).
  • the hydroxamate ether (W-4) is then deprotected using methods such as those found in Protective Groups in Organic Synthesis by Theodora W. Greene and published by John Wiley and Sons to give the hydroxamate alcohol (W-5).
  • the hydroxyl group of hydroxamate alcohol (W-5) is then converted to a leaving group by one of the many methods known to those skilled in the art, such as forming a mesylate, tosylate, or chloride, bromide, or iodide, to give the hydroxamate (W-6); the hydroxamate (W-6) is then coupled to an amine such as piperazine (Q-3) of CHART Q or piperazine (R-3) of CHART R or commercially available amines to give hydroxamate amine (W-7).
  • amine such as piperazine (Q-3) of CHART Q or piperazine (R-3) of CHART R or commercially available amines
  • hydroxamate amine (W-7) can be further converted to hydroxamic acid amine (W-8) when alkyl- 1 is a protecting group such as benzyl by palladium on carbon or other such methods known to those skilled in the art.
  • CHART X discloses the synthesis of the carbamate (X-6). The phenol/aniline
  • (X-l) is reacted with alkyl diethoxyproprionate in a similar manner as the transformation of the 3-bromophenethanol (II) to the corresponding isochroman ester (III) of CHART A, to give the phenol/aniline ester (X-2).
  • the phenol/aniline ester (X- 2) is hydrolyzed to the phenol/aniline acid (X-3) by aqueous base followed by aqueous acid.
  • the phenol/aniline acid (X-3) is then condensed with piperazines (Q-3) of CHART Q or (R-3) of CHART R or commercially available amines to give the phenol/aniline amide (X-4) using methods such as those discussed in CHART W.
  • the phenol aniline amide (X-4) is then reduced to the phenol/aniline amine (X-5) with reducing agents such as borane or borane-methyl sulfide in solvents such as THF.
  • reducing agents such as borane or borane-methyl sulfide in solvents such as THF.
  • the phenol/aniline amine (X-5) is then reacted with 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium hydride or other such bases and an isocyanate in dichloromethane or THF as the solvent to give the carbamate/urea (X- 6).
  • CHART Y discloses the synthesis of racemic (Y-5) starting with the phenol (Y-l).
  • the phenol (Y-l) is reacted with chloropropionaldehyde diethyl acetal in the presence of a Lewis acid such as boron trifluoride etherate or titanium tetrachloride, in solvents such as dichloromethane or nitromethane, to give the chloro phenol (Y-2).
  • a Lewis acid such as boron trifluoride etherate or titanium tetrachloride
  • the phenol of chloro phenol (Y-2) is then converted to a leaving group using trifuoromethanesulfonic anhydride or N-phenyltrifluoromethanesulfonimide in the presence of a base such as triethylamine and optionally adding a catalyst such as 4- dimethylaminopyridine and in a solvent such as dichloromethane, to give the triflate (Y-3).
  • the triflate (Y-3) is then be converted to the amide chloride (Y-4) using palladium (II) acetate, a co-catalyst, diisopropylethylamine, carbon monoxide and methyl amine as discussed with regard to CHART W.
  • Solvents for the conversion include DMF, dimethylacetamide, N-methylformamide, and acetonitrile, with dimethylacetamide and N-methylformamide preferred when methyl amine gas is used. Preferred temperatures are about 50 to about 120°.
  • the amide chloride (Y-4) is then stirred at 60 to 110° in the presence of the piperazine (Q-3) or (R-3) or commercial amines, a base such as triethylamine or diisopropylethylamine, and a solvent such as ethylene glycol, THF, DMF or acetonitrile to give the amide amine (Y-5).
  • CHART Z describes the preparation of a number of aniline-based derivatives (Z-2), (Z-3), (Z-4), (Z-5), (Z-6) and (Z-7).
  • aniline (Z-l) itself prepared from the bromide (VI) via metal- halogen exchange (typically using either n-butyllithium or ⁇ -butyllithium) followed addition of diphenylphosphoryl azide (usually in THF at -78°) and subsequent reduction with bis(2-methoxyethoxy)aluminum hydride.
  • metal- halogen exchange typically using either n-butyllithium or ⁇ -butyllithium
  • diphenylphosphoryl azide usually in THF at -78°
  • This conversion of (VI) to (Z-l) closely follows known chemistry, see Tetrahedron Letters, 25, 429-432 (1984) and J. Am. Chem.
  • CHART AA illustrates the preparation of one-carbon homologated isochroman-6-carboxamides (AA-5).
  • the sequence involves metal-halogen exchange of the bromide (VI) using alkyllithium reagents (typically £-butyl lithium) followed by quenching of the resulting anion with DMF to give the aldehyde (AA-1).
  • This aldehyde is reduced using standard reagents (such as sodium borohydride in THF), and the resulting alcohol (AA-2) is converted to the nitrile (AA-3) by activation with methanesulfonyl chloride and displacement of the resulting mesylate with cyanide anion.
  • CHART BB illustrates a generalized procedure for the preparation of tethered amines such as (BB-2) by reduction of the corresponding amides (BB-1) utilizing standard amide reduction conditions as previously described (typically either employing borane or lithium aluminum hydride in THF).
  • CHART CC illustrates that functional groups on the arylpiperazine portion of these molecules (ie, Rl and R2) can be transformed into other functional groups.
  • CC-1 an aryl-ether
  • CC-2 a standard hydrogenolytic debenzylation of the an aryl-ether
  • CC-3 a standard hydrogenolytic debenzylation of the an aryl-ether
  • CC-3 Conversion of the phenol (CC-2) into the corresponding trifluoromethanesulfonate (CC-3) by standard methods is illustrative of typical derivations of phenols such as (CC-2).
  • Conversion of the triflate (CC-3) into numerous derivatives can be accomplished by palladium-mediated couplings. For example, coupling (CC-3) with enol-ethers provides ketone-substituted aryl derivatives.
  • CHART DD illustrates an alternative preparation of isochroman-6-triazoles (DD-4) and isochroman-6-oxadiazoles (DD-6).
  • P -CH -phenyl
  • This material is be reacted with amide acetals as described in CHART O and the resulting intermediate (DD-2) is treated with hydrazine, substituted hydrazine, hydroxyl amine, or N-substituted hydroxyl amines as described in CHART O to generate the triazoles (DD-3) or oxadiazoles (DD-5).
  • the protecting group "P” is removed using standard conditions (typically hydrogenolysis using a transition metal catalyst such as palladium or platinum) and the resulting alcohol can be activated (usually as a sulfonate ester or halide) and reacted with the appropriate aryl piperazine as described previously in CHART T.
  • a transition metal catalyst such as palladium or platinum
  • n is 0 or 1; it is more preferred that n j is 0.
  • R j is -O-R j . , -CF 3 , -CO-N(R j . ) 2 , -CO-R . j and it is preferred that R . is C -C 3 alkyl.
  • R 2 is -H.
  • Q is selected from the group consisting of -CO-NQ j _ j Q j _ 2 , -S0 2 - NQJ. Q ._2 and -NQJ.JQJ_ 2 ; it is more preferred that Q j is -CO-NQJ.JQJ. 2 .
  • W j is nitrogen (-N-) and it is preferred that one of R j or R 2 is -H. It is preferred that Q j is (A) -CO-NQ j . j Q j .2 and that QJ.J is -H and that Q j _ 2 is -CH 3 (C j alkyl).
  • the 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) contain an asymmetric center and therefore produce two enantiomers one "S" which is (-) and the other "R” which is (+).
  • both enantiomers (+) and (-) are useful in the same way as the optically impure (racemic, ⁇ ) mixture. Hence, they may be utilized in the racemic form without separating them.
  • the optically impure mixture or intermediate can be resolved by means known to those skilled in the art. It is preferable to resolve the racemic intermediate (II) using the lipase method described in CHART C, alternatively chemical methods known to those skilled in the art can be used, see for example, Optical Resolution Procedures for Chemical Compounds, Vol 1, Amines and Related Compounds, Paul Newman, Optical Resolution Informa ⁇ tion Center, Manhattan College, Riverdale, NY, 10471, 1978.
  • optically impure mixture can also be separated using chromatographic techniques on chiral stationary phases, see Chromatographic Enantioseparation, 2nd edition, John Wiley & Sons, NY, 1992. These optically pure compounds are then used in the same way as the racemic mixture.
  • 1,6- disubstituted isochroman (I) aromatic bicyclic amines (ABA) refers to and includes both enantiomers as well as optically impure forms thereof, the most common of which is a racemic mixture ( ⁇ , dl).
  • 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) contain two asymmetric centers and therefore four stereoisomers (SS, RR, SR, RS) exist producing two diastereomeric pairs of enantiomers, one SS,RR and the other SR,RS.
  • the diastereomeric pairs of enantiomers can be readily separated by means known to those skilled in the art.
  • 1,6-disubstituted isochroman(I) and aromatic bicyclic amines (ABA) includes all four enantiomers as well as optically impure forms thereof, the most common of which is a racemic mixture ( ⁇ ).
  • the 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) are amines, and as such form acid addition salts when reacted with acids of sufficient strength.
  • Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The pharmaceutically acceptable salts are sometimes but not always preferred over the corresponding free amines since they produce compounds which are more water soluble and more crystalline.
  • the preferred pharmaceutically accep ⁇ table salts include salts of the following acids methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH 3 -(CH 2 ) n -COOH where n is 0 thru 4, HOOC-(CH 2 )n-COOH where n is as defined above.
  • the 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) of this invention posses selective pharmacological properties and are useful in treating humans with vascular headaches, particularly migraine and cluster headaches.
  • the 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) are also useful as analgesic agents.
  • 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) of the present invention will normally be administered orally, nasally, rectally, vaginally or by injection in the form of pharmaceutical compositions containing the active ingredient either as a free base or as a pharmaceutically acceptable acid addition salt in association with one or more pharmaceutically acceptable carriers. It is preferred that the 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) be administered either orally or nasally.
  • the suitable daily doses of the 1,6- disubstituted isochroman (I) are aromatic bicyclic amines (ABA) are from about 0.005 to about 50 mg/kg for oral or nasal application, preferably from about 0.1 to about 30 mg/kg, and from about 0.05 to about 10 mg/kg for parenteral application, preferably from about 0.03 to about 3 mg kg.
  • ABA aromatic bicyclic amines
  • the exact dosage and frequency of administration depends on the particular 1,6-disubstituted isochroman (I) or aromatic bicyclic amine (ABA) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the 1,6- disubstituted isochroman (I) and/or aromatic bicyclic amine (ABA) in the patient's blood and/or the patient's response to the particular condition being treated.
  • I 1,6-disubstituted isochroman
  • ABA aromatic bicyclic amine
  • variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, "Z j " or "R j " where "i" is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds.
  • Groups R j and R- would represent monoval- ent variable substituents if attached to the formula CH 3 -CH 2 -C(R j )(R j )-H.
  • variable sub ⁇ stituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis.
  • each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
  • both R j and R* are bonded to the preceding carbon atom.
  • Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion.
  • the cyclic molecular fragment, 4- (ethyl)- 1-piperazinyl can be represented by -N -(CH 2 ) 2 -N(C 2 H 5 )-CH 2 -C H 2 .
  • a rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound.
  • the two sub- stituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial.
  • the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other.
  • a substituent (X j ) which is "below” another substituent (X ⁇ will be identified as being in the alpha ( ⁇ ) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol " — " or "!.
  • the corresponding substituent attached “above” (X 2 ) the other (X ) is identified as being in the beta ( ⁇ ) configuration and is indicated by an unbroken line attachment to the carbon atom.
  • the valences may be taken together or separately or both in the definition of the variable.
  • R j is defined to consist of two monovalent variable substituents
  • the convention used to define the bivalent variable is of the form " ⁇ -R j . j i ⁇ -R j . j .” or some variant thereof.
  • both ⁇ -R j and ⁇ -R j .fc are attached to the carbon atom to give -C( ⁇ -R i . j )( ⁇ -R i . k )- .
  • the two monovalent variable substituents are ⁇ - R 6 . j : ⁇ -R 6 . 2 , .... ⁇ -Rg. 9 : ⁇ -R 6 . 10 , etc, giving -C( ⁇ -R 6 . j )( ⁇ -R 6 . 2 )- -C( ⁇ -R 6 .
  • bivalent variable may be defined as two separate monovalent variable substituents
  • two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable.
  • R j and R* may be defined to be taken together to form (1) a second bond between C j and C 2 or (2) a bivalent group such as oxa (-0-) and the formula thereby describes an epoxide.
  • the carbon atom content of variable substituents is indicated in one of two ways.
  • the first method uses a prefix to the entire name of the variable such as "C - C 4 ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable.
  • the prefix is separated from the variable by a space.
  • C -C 4 alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined.
  • C 2 -C 4 alkoxycarbonyl describes a group CH 3 -(CH 2 ) n -0-CO- where n is zero, one or two.
  • the carbon atom content of only each portion of the definition is indicated separately by enclosing the "C j -C-" designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined.
  • this optional convention (C j -C 3 )alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxy ⁇ carbonyl because the "C j -C 3 " refers only to the carbon atom content of the alkoxy group.
  • C 2 -Cg alkoxyalkyl and (C j -C 3 )alkoxy(C j -Cg)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms
  • the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
  • DMF refers to dimethylformamide.
  • DMSO refers to dimethylsulfoxide.
  • LDA refers to lithium diisopropylamide.
  • p-TSA refers to p-toluenesulfonic acid monohydrate.
  • TEA refers to triethylamine.
  • BOC refers to 1,1-dimethylethoxy carbonyl or tert-butoxycarbonyl -CO-O- C(CH 3 ) 3 .
  • DMAP refers to dimethylaminopyridine, (CH 3 ) 2 N-pyridin-l-yl.
  • TFA refers to trifluoracetic acid, CF 3 -COOH.
  • Saline refers to an aqueous saturated sodium chloride solution.
  • Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support; eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
  • IR refers to infrared spectroscopy.
  • CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm ( ⁇ ) downfield from TMS.
  • NMR nuclear (proton) magnetic resonance spectroscopy
  • chemical shifts are reported in ppm ( ⁇ ) downfield from tetramethylsilane.
  • - ⁇ refers to phenyl (CgHg).
  • [ ⁇ ]_ refers to the angle of rotation of plane polarized light (specific optical rotation) at 25° with the sodium D line (589A).
  • MS refers to mass spectrometry expressed as m/e or mass/charge unit.
  • [M + H] + refers to the positive ion of a parent plus a hydrogen atom.
  • El refers to electron impact.
  • Cl refers to chemical ionization.
  • FAB refers to fast atom bombardment.
  • HRMS refers to high resolution mass spectrometry.
  • Ether refers to diethyl ether.
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • compositions of solvents used are volume/volume (v/v).
  • Pharmaceutically acceptable anion salts include mesylate, chloride, sulfate, phosphate, nitrate, citrate, CH 3 -(CH 2 ) nj -COO "1 where n ⁇ is 0 thru 4, "1 OOC- (CHg j -COO "1 where n is as defined above, ⁇ -COO "1 ,
  • Ethyl 3,3-diethoxypropionate (90%, 19.1 mL) is added via syringe.
  • a titanium tetrachloride solution (1 M in methylene chloride, 236 mL) is added via a canula to an addition funnel and added semi-dropwise to the reaction mixture over one hr.
  • the reaction is then refluxed for 18 hr, after which time it is poured into a mixture of aqueous hydrochloric acid (IN) and saline (1/2) and extracted with methylene chloride. The organic phases are combined, dried over sodium sulfate, filtered, and concentrated.
  • Step 2 (R)-(+)-Ethyl (6-bromoisochroman-l-yl)acetate (XII) and (S)-(-)-(6- bromoisochroman-l-yl)acetic acid (XI).
  • the reaction is stirred vigorously and the hydrolysis is followed by HPLC as follows. A 100 ⁇ L aliquot is added to an opticlear vial containing hydrochloric acid (one drop). Ethyl acetate (1.5 mL) is then added to the vial and the contents are mixed well.
  • the filtrates are combined and extracted (two times) with ethyl acetate.
  • the combined organic extracts are washed with an equal volume of saturated aqueous sodium carbonate (3 x), dried over sodium sulfate, filtered and concentrated to give enantiomerically enriched (XII).
  • the saturated aqueous sodium carbonate washes are acidified with concentrated hydrochloric acid and extracted three times with methylene chloride, dried over sodium sulfate, filtered and concentrated to give (XI).
  • the acid (XI) was assayed for enantiomeric purity as follows.
  • a mixture of the acid (XI, 15 mg) in THF (0.5 mL) is reduced with borane-THF complex (IM in THF, 0.12 mL) at -5° to 20-25° over 18 hrs.
  • the reaction is cooled to 0°, quenched with methanol (0.1 mL), then warmed to 20-25° and hydrochloric acid (IN, 0.4 mL) are added via pipette.
  • the reaction is then heated to reflux for 10 min., at which point the volatiles are removed under reduced pressure and the residue is partitioned between ethyl acetate and saturated aqueous sodium carbonate.
  • the organic phases are separated, dried over magnesium, filtered, and concentrated.
  • Step 3 (S)-(-)-l-[2-(6-Bromoisochroman-l-yl)acetyl]-4-(4-methoxyphenyl)- piperazine (S)-(V)
  • Step 4 (S)-(-)-l-[2-(6-Bromoisochroman-l-yl)ethyl]-4-(4-methoxyphenyl)- piperazine (S)-(VI)
  • the mixture is cooled to 20-25° and the solvents are removed under reduced pressure, and the aqueous residue is diluted with saline and basified to pH 14 with aqueous sodium hydroxide.
  • the mixture is extracted with dichloromethane and the combined organic phases are dried over sodium sulfate, filtered, and concentrated.
  • reaction After cooling to 20-25°, the reaction separated into two phases.
  • the reaction mixture is poured into aqueous hydrochloric acid (IN) and washed two times with ether.
  • the acidic solution is basified with aqueous sodium hydroxide and extracted three times with ethyl acetate. The ethyl acetate phases are combined and concentrated.
  • Step 2 (R)-(+)-l-[2-(6-Bromoisochroman-l-yl)acetyl]-4-(4-methoxyphenyl)- piperazine (R)-(V).
  • Step 2 (S)-(-)-l-[2-(6-Bromoisochroman-l-yl)ethyl]-4-(4- trifluoromethylphenyl)-piperazine (S)-(VI).
  • the reaction is treated with IM hydrochloric acid (6.0 mL), fitted with a reflux condenser, and heated to reflux for 1 hr.
  • the reaction is cooled to 20-25° with the volatiies removed under reduced pressure.
  • the resulting aqueous residue is diluted with water (30 mL), adjusted to pH > 10, and extracted twice with ethyl acetate (30 mL).
  • the combined organic extracts are washed once with saline (30 mL), dried over magnesium sulfate, filtered, and concentrated.
  • Step 2 (S)-(-)-6-Bromo-l-(bromoethyl)isochroman (S)-(-)-2-(6-Bromoisochroman-2-yl)ethyl alcohol (S-1) (Step 1, 14.0 g, 54 mmol) and 91 mL dichloromethane are combined. The resulting mixture is treated with 25 mL tetrahydrofuran. The suspension is treated with carbon tetrabromide (22.6 g, 68 mmol), cooled to 0°, and portion-wise treated with triphenyl phosphine (21.4 g, 82 mmol).
  • the filter cake is then dried under reduced pressure. After drying, the crude product is slurried in methanol/dichloromethane and silica gel is added to adsorb the mixture. After removal of the solvents, the silica gel slurry is poured onto the top of a silica gel column equilibrated with dichloromethane/methanol (95/5).
  • Step 4 (S)-(-)-l-[2-[4-[4-(Aminocarbonyl)phenyl]-l-piperazinyl]ethyl]-N- methylisochromanyl-6-carboxamide
  • the slurry is transferred to a 3-necked round bottom flask (using an additional 10 mL of DMF to rinse the flask) containing palladium acetate (0.084 g, 0.376 mmol) and l,3-bis(diphenylphosphino)propane (0.232 g, 0.564 mmol) and the flask is placed in an oil bath.
  • Diisopropylethylamine (2.6 mL, 15.3 mmol) is added and the mixture is again lightly degassed and released to argon. Carbon monoxide is blown onto the surface of the mixture as the temperature of the bath is raised to 60°.
  • Step 2 l-[2-(6-Bromoisochroman-l-yl)acetyl]-4-(4-methylphenyl)- piperazine (V)
  • Step 4 l-[2-[4-(4-Methylphenyl)-l-piperazinyl]ethyl-isochroman-6- carboxamide (LX)
  • Step 2 l-(4-Phenylmethyloxyphenyl)-4-[2-(6-bromoisochroman-l- yl)-ethyl]piperazine (VI)
  • Step 3 l-[2-[4-(4-Phenylmethyloxyphenyl)-l-piperazinyl]ethyl]- isochroman-6-carboxamide (VII) Following the general procedure of EXAMPLE 1, Step 5 and making non- critical variations but using l-(4-phenylmethyloxyphenyl)-4-[2-(6-bromoisochroman- l-yl)-ethyl]piperazine (VI), l-[2-[4-(4-phenylmethyloxyphenyl)- l-piperazinyl]ethyl]- isochroman-6-carboxamide (VII) is obtained, IR (mull) 3368, 3178, 1647, 1623, 1611, 1570, 1515, 1334, 124.6 and 1111 cm '1 ; NMR (300 MHz, CDClg) 7.58 (m,2H, aromatic H's), 7.43-7.30 (m, 5H, aromatic H's), 7.15
  • Step 3 l-[2-[4-(4-Diethylaminophenyl)-l-piperazinyl]ethyl]-isochroman-
  • EXAMPLE 12 l-[2-[4-(3-Trifluoromethylphenyl)-l- piperazinyl]ethyl]isochroman-6-carboxamide (VII)
  • Step 1 l-[2-(6-Bromoisochroman-l-yl)acetyl]-4-(3- trifluoromethylphenyl)-piperazine (V)
  • Step 3 l-[2-(6-bromoisochroman-l-yl)acetyl]-4-(3- trifluoromethylphenyDpiperazine
  • Step 2 l-[2-(6-Bromoisochroman-l-yl)-ethyl]-4-(3- trifluoromethylphenyD-piperazine (VI) Following the general procedure of EXAMPLE 1, Step 4 and making non- critical variations but using l-[2-(6-bromoisochroman-l-yl)acetyl]-4-(3- trifluoromethylphenyDpiperazine (V), the product is obtained.
  • Step 3 l-[2-[4* 3-Trffluoromethylphenyl)-l- piperazinyl]ethyl]isochroman-6-carboxamide (VII) Following the general procedure of EXAMPLE 1, Step 5 and making non- critical variations but using l-[2-(6-bromoisochroman-l-yl)-ethyl]-4-(3- trifluoromethylphenyDpiperazine (VI) the product is obtained.
  • This material is purified by LC (silica gel, 230-400, 120 g; acetone/hexane, 50/50) to give l-[2-[4-(3- trifluoromethylphenyl)-l-piperazinyl]ethyl]isochroman-6-carboxamide (VII).
  • EXAMPLE 13 l-[2-[4-(4-Methylsulfonylphenyl)-l-piperazinyl]ethyl]- isochroman-6-carboxamide (VII)
  • Step 1 l-[2-(6-Bromoisochroman-l-yl)acetyl]-4-(4- methylsulfonylphenyl)-piperazine (V)
  • Step 3 Following the general procedure of EXAMPLE 1, Step 3 and making non- critical variations but using racemic 6-bromoisochroman-l-yl-acetic acid (TV) and 4- methylsulfonylphenylpiperazine the product is obtained.
  • TV racemic 6-bromoisochroman-l-yl-acetic acid
  • 4- methylsulfonylphenylpiperazine the product is obtained.
  • Step 3 l-[2-[4-(4-Methylsulfonylphenyl)-l- piperazinyl]ethyl]isochroman-6-carboxamide (VII) Following the general procedure of EXAMPLE 1, Step 5 and making non-critical variations but using l-[2-(6-bromoisochroman-l-yl)-l-ethyl]-4-(4- methylsulfonylphenyDpiperazine (VI) the product is obtained.
  • EXAMPLE 14 (SH-)-l-[2-[4-(4-Trifluoromethylphenyl)-l-piperazinyl]ethyl]- isochroman-6-carboxamide (S)-(VII) Following the general procedure of EXAMPLE 1, Step 5 and making non-critical variations but using (S)-(-)-l-[2-(6-bromoisochroman-l-yl)-l-ethyl]-4-(4- trifluoromethylphenyDpiperazine (VI, EXAMPLE 5, Step 2, 13.15 g, 28.0 mmol) the product is obtained.
  • Step 2 l-[2-(6-Bromoisochroman-l-yl)-ethyl]-4-(4-ethoxyphenyl)- piperazine (VI)
  • V l-[2-(6-bromoisochroman-l-yl)acetyl]-4-(4-ethoxyphenyl)- piperazine (V)
  • Step 3 l-[2-[4-(4-Propoxyphenyl)-l-piperazinyl]ethyl]-N-methyl- isochroman-6-carboxamide (LX) Following the general procedure of EXAMPLE 5, Step 3 and making non- critical variations but using l-[2-(6-bromoisochroman-l-yl)-ethyl]-4-(4- propoxyphenyl)-piperazine (VI) the product is obtained.
  • Step 2 (S)-(-)-l-[2-(6-Bromoisochroman-l-yl)-ethyl]-4-(4- trifluoromethoxyphenyD-piperazine (S)-(VI)
  • (S)-(-)-l-[2-(6-Bromoisochroman-l-yl)-ethyl]-4-(4- trifluoromethoxyphenyD-piperazine (S)-(VI) Following the general procedure of EXAMPLE 1, Step 4 and making non- critical variations but using (S)-(-)-l-[2-(6-bromoisochroman-l-yl)acetyl]-4-(4- trifluoromethoxyphenyDpiperazine (S)-(V), (S)-(-)-l-[2-(6-bromoisochroman-l-yl)- ethyl]-4-(4-trifluoromethoxyphenyl)piperazine (S)-(VI
  • Step 3 (SM-)- l-[2-[4-(4-Trifluoromethoxyphenyl)- l-piperazinyl]ethyl]-N- methylisochroman-6-carboxamide (S)-(LX)
  • Step 3 (S)-(-)-l-[2-[4-(4-Ethylphenyl)-l-piperazinyl]ethyl]-N-methyl- isochroman-6-carboxamide (S)-(LX) Following the general procedure of EXAMPLE 5, Step 3 and making non- critical variations but using (S)-(-)-l-[2-(6-bromoisochroman-l-yl)-ethyl]-4-(4- ethylphenyl)-piperazine (S)-(VI) the desired product is obtained.
  • Step 2 (S)-(-)-l-t2-(6-Bromoisochroman-l-yl)-ethyl]-4-(4-ethoxyphenyl)- piperazine (S)-(VI)
  • Step 3 (S)-(-)-l-[2-[4-(4-Ethoxyphenyl)-l-piperazinyl]ethyl]-N-methyl- isochroman-6-carboxamide (S)-(LX)
  • Step 3 Following the general procedure of EXAMPLE 5, Step 3 and making non- critical variations but using (S)-(-)-l-[2-(6-bromoisochroman-l-yl)-ethyl]-4-(4- ethoxyphenyl)piperazine (S)-(VI) gives (S)-(-)-l-[2-[4-(4-ethoxyphenyl)-l- piperazinyl]ethyl]-N-methyl-isochroman-6-carboxamide (S)-(LX).
  • Step 2 (S)-(-)-l-[2-(6-Bromoisochroman-l-yl)-ethyl]-4-(4- phenylmethyloxyphenyDpiperazine (S)-(VI)
  • (S)-(-)-l-[2-(6-Bromoisochroman-l-yl)-ethyl]-4-(4- phenylmethyloxyphenyDpiperazine (S)-(VI) Following the general procedure of EXAMPLE 1, Step 4 and making non- critical variations but using (S)-(-)-l-[2-(6-bromoisochroman-l-yl)acetyl]-4-(4- phenylmethyloxyphenyl)piperazine (V, 5.96 g, 11.4 mmol) gives (S)-(-)-l-[2-(6- bromoisochroman-l-yl)-ethyl]-4-(4-phenylmethyloxyphenyl)-piperazine
  • Step 3 (S)-(-)-l-[2-[4-(4-Phenylmethyloxyphenyl)-l-piperazinyl]ethyl]-N- methyl-isochroman-6-carboxamide (S)-(LX) Following the general procedure of EXAMPLE 5, Step 3 and making non- critical variations but using (S)-(-)-l-[2-(6-bromoisochroman-l-yl)-ethyl]-4-(4- phenylmethyloxyphenyDpiperazine (S)-(VI, 5.08 g, 11.4 mmol) gives the product.
  • Step 2 (R)-(+)-l-[2-(6-Bromoisochroman-l-yl)-ethyl]-4-(4-ethoxyphenyl)- piperazine (R-VI)
  • Step 3 (R)-(+)-l-[2-[4-(4-Ethoxyphenyl)-l-piperazinyl]ethyl]-N-methyl- isochroman-6-carboxamide (R-LX)
  • EXAMPLE 22 l-[2-[4-(3-Trifluoromethylphenyl)-l-piperazinyl]ethyl]-N- methylisochroman-6-carboxamide (LX) Step 1: l-[2-[4-(3-Trifluoromethylphenyl)-l-piperazinyl]ethyl]-N,N-di-t- butyloxycarbonylisochroman-6-carboxamide (VIII) Following the general procedure of EXAMPLE 3, Step 1 and making non-critical variations but using l-[2-[4-(3-trifluoromethylphenyl)-l- piperazinyl]ethyl]-isochroman-6-carboxamide gives crude product.
  • Step 2 l-[2-[4-(3-Trifluoromethylphenyl)-l-piperazinyl]ethyl]-N-methyl- isochroman-6-carboxamide (LX) Following the general procedure of EXAMPLE 3, Step 2 and making non-critical variations but using l-[2-[4-(3-trifluoromethylphenyl)-l- piperazinyl]ethyl]-N,N-di-t-butyloxycarbonylisochroman-6-carboxamide (VIII, 1.13 g, 1.8 mmol) gives crude product.
  • Step 1 l-[2-[4-(4-Methylsulfonylphenyl)- l-piperazinyl]ethyl]-N,N-di-t- butyloxycarbonyUsochroman-6-carboxamide (VIII) Following the general procedure of EXAMPLE 3, Step 1 and making non-critical variations but using l-[2-[4-(4-methylsulfonylphenyl)-l- piperazinyl]ethyl]-isochroman-6-carboxamide (825 mg, 1.9 mmol) gives crude product.
  • Step 2 l-[2-[4-(4-Methylsulfonylphenyl)-l-piperazinyl]ethyl]-N-methyl- isochroman-6-carboxamide (LX) Following the general procedure of EXAMPLE 3, Step 2 and making non-critical variations but using l-[2-[4-(4-methylsulfonylphenyl)-l- piperazinyl]ethyl]-N,N-di-t-butyloxycarbonylisochroman-6-carboxamide (VIII, 650 mg, 1.0 mmol) gives crude product.
  • Step 2 l-[2-(6-Bromoisochroman-l-yl)ethyl]* -(4-methoxyphenyl)- piperazine (VI)
  • Step 3 l-[2-[4-(4-Methoxyphenyl)-l-piperazinyl]ethyl]-isochroman-6- carboxamide (VII)
  • THF 18 mL
  • t-Butyllithium in hexanes 1.7M, 5.4 mL, 9.2 mmol
  • a mixture l-[2-(6- bromoisochroman-l-yl)ethyl]-4-(4-methoxyphenyl)piperazine (VI) in THF (20 mL) is added via canula.
  • EXAMPLE 25 l-[2-[4-(4-Methoxyphenyl)-l-piperazinyl]ethyl]-N-propyl- isochroman-6-carboxamide (EX) Step 1: l-[2-[4-(4-Methoxvphenyl)-l-piperazinyl]ethyl]-N,N-di-t- butyloxycarbonylisochroman-6-carboxamide (VIII) Following the general procedure of EXAMPLE 3, Step 1 and making non- critical variations but starting with l-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]- isochroman-6-carboxamide (VII, EXAMPLE 24), l-[2-[4-(4-methoxyphenyl)-l- piperazinyl]ethyl]-N,N-di-t-butyloxycarbonylisochroman-6-carbox
  • Step 2 l-[2-[4-(4-Methoxyphenyl)-l-piperazinyl]ethyl]-N-propyl- isochroman-6-carboxamide (LX)
  • EXAMPLE 27 l-[2-[4-(4-Methoxyphenyl)-l-piperazinyl]ethyl]-N-ethyl- isochroman-6-carboxamide (LX) Following the general procedure of EXAMPLE 25, Step 2 and making non- critical variations but using ethylamine (approx 2 mL, condensed at 0°) gives crude product. This material is purified by LC (slicia gel, 230-400 mesth, 30 g; methanol/ethyl acetate, 5/95) to give product.
  • EXAMPLE 28 l-[2-[4-(4-Methoxyphenyl)-l-piperazinyl]ethyl]-N-propargyl- isochroman-6-carboxamide (LX) Following the general procedure of EXAMPLE 25, Step 2 and making non- critical variations but using propargylamine (1.6 mL, 23.0 mmol) gives crude product.
  • EXAMPLE 29 l-[2-[4-(4-Methoxyphenyl)-l-piperazinyl]ethyl]-N-(4- methoxyphenylmethyl)-isochroman-6-carboxamide (LX) Following the general procedure of EXAMPLE 25, Step 2 and making non- critical variations but using 4-methoxyphenylmethylamine (1.2 mL, 9.2 mmol) gives crude product.
  • EXAMPLE 30 l-[2-t4-(4-Methoxyphenyl)-l-piperazinyl]ethyl]-N-phenylmethyl- isochroman-6-carboxamide (LX)
  • Carbon monoxide atmosphere is established in the vial.
  • To the reaction vessel is introduced via syringe DMF (3.75 mL), phenylmethyl amine (1.15 mL, 10.5 mmol) and diisopropylethylamine (0.52 mL, 3 mmol).
  • the mixture is heated to 100° over 10 hours. After cooling to 20-25°, it separated into two phases.
  • the reaction mixture is poured into ethyl acetate. The mixture is washed one time with aqueous sodium hydroxide (IN).
  • EXAMPLE 32 l-[2-[4-(4-Methoxyphenyl)-l-piperazinyl]ethyl]-N-[(R)- ⁇ - methylphenylmethyl]-isochroman-6-carboxamide (LX) Following the general procedure of EXAMPLE 30 and making non-critical variations but using (R)-(+)- ⁇ -methylphenylmethylamine (98%, 0.90 mL, 7 mmol) gives crude product which is purified by flash chromatography on 100 g silica gel using a gradient of 0-4% methanol in ethyl acetate.
  • EXAMPLE 33 l-[2-[4-(4-Methoxvphenyl)-l-piperazinyl]ethyl]-N-[(S)- ⁇ - methylphenylmethyl]isochroman-6-carboxamide (LX) Following the general procedure of EXAMPLE 30 and making non-critical variations but using (S)-(-)- ⁇ -methylphenylmethylamine (98%, 0.90 mL, 7 mmol) gives crude product which is purified by flash chromatography on 100 g silica gel using a gradient of 0-7% methanol in ethyl acetate.
  • N-methyl-isochroman-6-carboxamide (LX) Following the general procedure of EXAMPLE 30 and making non-critical variations but using phenylmethylmethylamine (1.4 mL, 10.5 mmol) gives crude product which is purified by LC on 77 g (230-400) silica gel eluting with acetone/hexane (40/60) and gradually increasing to acetone/hexane (60/40) to give product. This material is disolved in ether and treated with gaseous hydrochloric acid resulting in the formation of a solid.
  • EXAMPLE 39 l-[2-[4-(4-Chlorophenyl)-l-piperazinyl]ethyl]-N,N-dimethyl- isochroman-6-carboxamide (LX) Following the general procedure of EXAMPLE 36 and making non-critical variations but using l-[2-(6-bromoisochroman-l-yl)-ethyl]-4-(4-chlorophenyl)- piperazine (VI, EXAMPLE 8, Step 2, 188 mg, 0.43 mmol) and dimethylamine gave 50 mg (27%) of l-[2-[4-(4-chlorophenyl)-l-piperazinyl]ethyl]-N,N- dimethyhsochroman-6-carboxamide (LX) as product.
  • Step 3 l-[2-[4-Phenylpiperazinyl]ethyl]-isochroman-6-carboxamide
  • the aryl lithium is stirred 10 min and is added via cannula to a flame-dried 25 mL flask equipped with spinbar containing freshly distilled trimethylsilylisocyanate (0.22 mL, 1.6 mmol) and 2 mL tetrahydrofuran also cooled to -78°.
  • the combined organic extracts are washed once with saline (25 mL), dried over magnesium sulfate, filtered, and concentrated.
  • Step 2 l-[2-(6-Bromoisochroman-l-yl)-ethyl]-4-(3,4-dichlorophenyl)- piperazine (VI)
  • V l-[2-(6-bromoisochroman-l-yl)acetyl]*4-(3,4- dichlorophenyD-piperazine
  • Step 3 l-[2-[4-(3,4-Dichlorophenyl)-l-piperazinyl]ethyl]isochroman-6- carboxamide (VII)
  • VI isochroman-6-carboxamide
  • Rf 0.13 (ethyl acetate)
  • NMR 300 MHz, CDClg) 7.59 (m, 2H, aromatic H's), 7.24 (2 m, 3H, aromatic H's), 6.94 and 5.74 (two d, IH, aromatic H) 5.90 (broad d, 2H, PhC(0)N-H 2 ), 4.
  • EXAMPLE 42 l-[2-[4-(4-Fluorophenyl)-l-piperazinyl]ethyl]isochroman-6- carboxamide (VII) Step 1: l-[2-(6-Bromoisochroman-l-yl)acetyl] ⁇ 4-(4- fluorophenyl)piperazine (V) Following the general procedure of EXAMPLE 1, Step 3 and making non- critical variations but using racemic 6-bromoisochroman-l-yl-acetic acid (IV, EXAMPLE 7, Step 1) and 4-fluorophenylpiperazine gives l-[2-(6-bromoisochroman- l-yl)acetyl]-4-(4-fluorophenyl)piperazine (V), IR (neat) 1641, 1510, 1482, 1464, 1444, 1278, 1232, 1107, 827, 817 cm '1 ; NMR (300 MHz, CDCl
  • Step 2 l-[2-(6-Bromoisochroman-l-yl)ethyl]-4-(4- fluorophenyl)piperazine (VI)
  • V l-[2-(6-bromoisochroman-l-yl)acetyl]-4-(4-fluorophenyl)- piperazine
  • V gives l-[2-(6-bromoisochroman-l-yl)ethyl]-4-(4-fluorophenyl)piperazine
  • Step 2 (S)-(-)-l-[2-(6-Bromoisochroman-l-yl)ethyl]-4-(4-methoxyphenyl)- piperidine (S)-(VI)
  • (S)-(-)-l-[2-(6-Bromoisochroman-l-yl)ethyl]-4-(4-methoxyphenyl)- piperidine (S)-(VI) Following the general procedure of EXAMPLE 1, Step 4 and making non- critical variations but using (S)-(-)-l-[2-(6-bromoisochroman-l-yl)acetyl]-4-(4- methoxyphenyDpiperidine (S)-(V) gives predict which is purified by LC on 47 g (230- 400) silica gel eluting with 75% ethyl acetate/hexane to give (S)-(-)-l-[2-(6- bromoisochroman-l
  • EXAMPLE 46 l-(4-Methoxyphenyl)-4-[2-[6-(5-methyloxazole-2-yl)isochroman-l- yl)ethyl]piperazine (P-2) An oven-dried 25 mL flask equipped with spinbar and reflux condenser is charged with l-[2-[4-(4-methoxyphenyl)- l-piperazinyl]ethyl-N-propargylisochroman- 6-carboxamide (LX, EXAMPLE 28, 433 mg, 1.0 mmol) and mercuric acetate (19 mg, 0.06 mmol). The mixture is diluted with 12 mL acetic acid and heated to reflux.
  • EXAMPLE 47 l-[2-(6-Aminoisochroman-l-yl)-ethyl]-4-(4-methoxyphenyl)- piperazine (Z-l)
  • a 10 mL oven dried two neck round bottom under argon atmosphere is charged with a solution of l-[2-(6-bromoisochroman-l-yl)-ethyl]-4-(4- methoxyphenyDpiperazine (VI, 406 mg, 0.94 mmol) in THF (2 mL).
  • the mixture is cooled to -78° and t butyl lithium (1.7 M in pentane, 1.081 mL, 1.83 mmol) is added dropwise.
  • the aryl lithium is added dropwise via a canula to a solution of diphenylphosphorylazid (98%, 0.188 mL, 0.85 mmol) in THF (9 mL) at -78°.
  • the reaction mixture is maintained at -78° for two hours then warmed to -20° over 40 min, and then recooled to -78°.
  • Sodium bis(2- methoxyethoxy)aluminum hydride (3.4 M in toluene, 1.11 mL, 3.77 mmol) is added slowly via syringe. As the reaction is warmed to 0°, effervescence of nitrogen is observed.
  • the reaction mixture is stirred at 0° for two hours and then at 20-25° for 30 min. After cooling to 0°, the reaction is quenched very slowly with water. After effervescence subsided, the crude is warmed to 20-25°, and filtered on a glass frit, alternatively washing with water and ethyl acetate until no more product is observed by TLC in the filtrate. The combined filtrates were transferred to a separatory funnel, salted out with sopdium chloride, shaken and the layers were separated. The organic layer is washed one time with 1% aqueous sodium hydroxide and one time with saline, dried with sodium sulfate, filtered and concentrated.
  • the mixture is cooled to 0° and borane methyl sulfide complex (10M, 1.73 mL, 17.3 mmol) is added slowly via syringe. The ice bath is removed when effervescence subsided. The mixture is then heated to gentle reflux for 3 hours, then at 20-25° for three days. The reaction is cooled to 0° and methanol (30 mL) is added dropwise (effervescence) then stirred for 1 hour at 20-25°, followed by reflux for 2 hours. After cooling to 20-25°, the volatiies are removed under reduced pressure and the aqueous residue is basified with aqueous sodium hydroxide and extracted 80 mL ethyl acetate (three times).
  • PhCH-H 2, 2.92 (s, 6H, two of NC-Hg), 2.62 (m's, 7H, PhCH-H, NC-H 2 and four pip- H), 2.10 (m, IH, PhCHCH-H), 2.00 (m, IH, PhCHCH-H) ⁇ ; CMR (75 MHz, CDClg) 153.8, 149.2, 145.8, 134.6, 126.3, 125.4, 118.1, 114.4, 112.5, 112.1, 111.4, 74.6, 63.4, 55.6, 55.0, 53.5, 50.6, 46.8, 40.7, 33.4, 29.7 ⁇ .
  • EXAMPLE 65 l-(4-Methoxyphenyl)-4-[2-(6-methylaminomethylisochroman-l- yl)ethyl]piperazine (BB-2) Following the general procedure of EXAMPLE 1, Step 4 and making non- critical variations but using l-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]-N- methyl-isochroman-6-carboxamide (LX, EXAMPLE 37) gives crude product.
  • the resulting mixture is purged six times with carbon monoxide/under reduced pressure followed by heating to 100°. After 18 hours, the mixture is cooled to 20-25°, concentrated under high vacuum, diluted with 20 mL IM sodium hydroxide, and extracted twice with ethyl acetate (20 mL). The combined organics are washed once with saline (20 mL), dried over magnesium sulfate, filtered, and concentrated to give product.
  • EXAMPLE 68 6-Acetyl-l-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]- isochroman, hydrochloride salt (XXTV) An oven-dried 10 mL flask equipped with spinbar and reflux condenser is charged with l-[2-(6-bromoisochroman-l-yl)ethyl]-4-(4-methoxyphenyl)-piperazine (VI, EXAMPLE 24, Step 2, 431 mg, 1.0 mmol), palladium II acetate (11 mg, 0.05 mmol), l,3-bis(diphenylphosphino)propane (25 mg, 0.06 mmol), thallium II acetate (290 mg, 1.1 mmol), 3.0 mL dimethylformamide, triethylamine (0.28 mL, 2.0 mmol), and vinyl butylether (0.65 mL, 5.0 m
  • EXAMPLE 69 6-Formyl-l-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl]- isochroman (AA-1) l-[2-(6-Bromoisochroman-l-yl)ethyl]-4-(4-methoxyphenyl)piperazine (VI, EXAMPLE 24, Step 2, 2.80 g, 6.5 mmol) and freshly distilled tetrahydrofuran (16 mL) are mixed followed by cooling to -78°. The mixture is treated with a 1.7 M solution of tert-butyllithium (7.7 mL, 13.0 mmol).
  • the aryl lithiium is treated with dimethylformamide (1.0 mL, 13 mmol).
  • the reaction is warmed to 20- 25° over 1.5 hours then is diluted with 75 mL water and extracted twice with ethyl acetate (75 mL).
  • the combined organics are washed once with saline (50 mL), dried over magnesium sulfate, filtered, and concentrated to give crude product.
  • EXAMPLE 70 2-[Isochroman-l-[2-[4-(4-methoxyphenyl)piperazin-l-yl]ethyl]-6- yljacetamide (AA-4) Step 1: l-[2-(6-Hydroxymethylisochroman-l-yl)-ethyl]-4-(4- methoxyphenyl)piperazine (AA-2) 6-Formyl-l-[2-[4-(4-methoxyphenyl)-l-piperazinyl]ethylisochroman (AA-1,
  • EXAMPLE 71 2.51 g, 6.6 mmol
  • 25 mL methanol 25 mL methanol are mixed followed by cooling to 0°.
  • the mixture is treated with a single portion of sodium borohydride (500 mg, 13.2 mmol).
  • the reaction is gradually warmed to 20-25° over 2 hours and is diluted with 75 mL water and extracted twice with ethyl acetate (75 mL).
  • the combined organics are washed once with saline (50 mL), dried over magnesium sulfate, filtered and concentrated.
  • Step 2 l-[2-(6-Cyanomethylisochroman-l-yl)ethyl]-4-(4- methoxyphenyl)-piperazine (AA-3) l-[2-(6-Hydroxymethylisochroman-l-yl)-ethyl]-4-(4-methoxyphenyl)piperazine (AA-2, 2.33 g, 6.1 mmol), 61 mL dichloromethane and triethylamine (1.3 mL, 9.1 mmol) are mixed followed by cooling to 0°. The mixture is treated with methanesulfonylchloride (0.52 mmol, 6.7 mmol).
  • the reaction is warmed to 20-25° over 1.5 hours and concentrated under reduced pressure.
  • the crude mesylate is diluted with 31 mL dimethylsulfoxide and treated with sodium cyanide (896 mg, 18.3 mmol). This mixture is heated to 60°. After 2 hours, the volatiies are removed under high vacuum with the resulting residue diluted with 100 mL water and extracted twice with ethyl acetate (75 mL). The combined organics are washed once with saline (75 mL), dried over magnesium sulfate, filtered and concentrated.
  • Step 3 2-[Isochroman- l-[2-[4-(4-methoxyphenyl)piperazin- l-yl]ethyl]-6- yl]acetamide (AA-4) l-[2-(6-Cyanomethylisochroman-l-yl)ethyl]-4-(4-methoxyphenyl)piperazine
  • EXAMPLE 71 2-tIsochroman-l-t2-t4-(4-methoxyphenyl)piperazin-l-yl]ethyl]-6- yl]-N-methylacetamide (AA-5) Following the general procedure of EXAMPLE 3, Step 1 and making non-critical variations but using 2-[isochroman-l-[2-[4-(4-methoxyphenyl)piperazin-l- yl]ethyl]-6-yl]acetamide (AA-4, 446 mg, 1.09 mmol) crude product is obtained.
  • EXAMPLE 72 l-[2-[4-(4-Hydroxyphenyl)-l-piperazinyl]ethyl]-isochroman-6- carboxamide (CC-2) l-[2-[4-(4-Phenylmethyloxyphenyl)-l-piperazinyl]ethyl]isochroman-6- carboxamide (CC-1, EXAMPLE 9, 0.42 mmol, 200 mg), palladium on carbon (10%, 20 mg), ethanol (5 mL) and methylene chloride (2 mL) are combined. After four days the starting material is consumed.
  • the resulting mixture is heated to 50°. After 16 hours, the reaction is cooled to 20-25°, treated with 8 mL IM hydrochloric acid, and is stirred for 1 hour. This acidic mixture is concentrated under reduced pressure, diluted with 15 mL IM sodium hydroxide, and extracted twice with dichloromethane (25 mL). The combined organics are washed once with saline (15 mL), dried over magnesium sulfate, filtered, and concentrated.
  • Step 2 (S)-(-)-l-(4-Methoxyphenyl)-4-[2-[6-(l,2,4-triazol-3- yl)isochroman-l-yl]ethyl]piperazine (S)-(0-2)
  • the mixture is stirred at 20-25° for a total of 70 minutes.
  • the reaction is diluted with water and the pH is raised to 8 with saturated aqueous sodium bicarbonate.
  • the aqueous mixture is extracted twice with methylene chloride.
  • the organics are combined, dried with sodium sulfate, filtered and concentrated.
  • Argon atmosphere is established and the reaction is heated to 90° for two hours.
  • the reaction is diluted with water and the pH is raised to 8 with saturated aqueous sodium bicarbonate.
  • the resulting mixture is diluted with IM sodium hydroxide (150 mL) and extracted three times with ethyl acetate (100 mL). The combined organics are washed once with saline (100 mL), dried over magnesium sulfate, filtered and concentrated.
  • Step 2 (S)-(-)-l-(2-Hydroxyethyl)isochroman-6-carboxylic acid, methyl ester (S)-(S-2) (S)-(-)-6-Bromo-l-(2-hydroxyethyl)isochroman (S)-(S-l, 5.14 g, 20.0 mmol), palladium II acetate (225 mg, 1.0 mmol), l,3-bis(diphenylphosphino)propane (495 mg, 1.2 mmol), 40.0 mL dimethylformamide, diisopropylethylamine (10.5 mL, 60.0 mmol), and methanol (16 mL, 0.40 mol mmol) are combined.
  • the resulting mixture is purged six times with carbon monoxide/reduced pressure followed by heating to 75° quickly.
  • the reaction mixture is stirred for 19 hours.
  • the mixture is cooled to 20-25°, diluted with 200 mL water, and extracted twice with dichloromethane (200 mL).
  • the combined organics are washed once with water (100 mL), once with saline (100 mL), dried over magnesium sulfate, filtered and concentrated.
  • Step 4 (S)-(-)-l-(2-Methanesulfonyloxyethyl)-N-methylisochroman-6- carboxamide (S)-(T-2) (S)-(-)-l-(2-Hydroxyethyl)-N-methylisochroman-6-carboxamide (S)-(S-3, 383 mg, 1.6 mmol), 16 mL dichloromethane and triethylamine (0.34 mL, 2.4 mmol) are combined followed by cooling to 0°. The mixture is treated with methanesulfonyl chloride (0.15 mL, 1*95 mmol).
  • Step 5 (SM-)-N-Methyl- l-[2-[4-(4-propionylphenyl)- l-piperazinyl]ethyl ]- isochroman-6-carboxamide (S)-(LX)
  • S)-(LX) A mixture of (S)-(-)-l-(2-methanesulfonyloxyethyl)-N-methyl-isochroman-6- carboxamide (S)-(T-2, 509 mg, 1.5 mmol), 4'-piperazinopropiophenone (393 mg, 1.8 mmol), and potassium carbonate (622 mg, 4.5 mmol) in acetonitrile (7.5 mL) is heated to 50° overnight, then refluxed for an additional 5 hours.
  • reaction mixture is then cooled to 20-25° and concentrated to a residue, which is partitioned between water and dichloromethane.
  • the aqueous layer is extracted twice more with dichloromethane and the combined organic layers are washed once with water, once with saline, dried over magnesium sulfate, filtered and concentrated.
  • This material is purified by LC on 36 g (230-400) silica gel eluting with 60% acetone/hexane.
  • EXAMPLE 83 l-[l-[2-[4-(4-Methoxyphenyl)-l-piperazinyl]ethyl]-isochroman-6- yl]carbonyl]pyrrolidine (LX) Following the general procedure of EXAMPLE 30 and making non-critical variations but using pyrrolidine (1.26 mL, 15.0 mmol) gives crude product. The crude is purified by flash chromatography on 100 g silica gel using a gradient of 5- 10% methanol in ethyl acetate as the eluent to give purified product.
  • (+/-)-2-(6-bromoisochroman-l-yl)acetic acid (IV, Step 1; 0.82 g, 3.0 mmol) in dry THF (20 mL) is added borane-methyl sulfide (0.86 g, 9.1 mmol). After stirring for 2.5 hr, methanol is added and the mixture is concentrated under reduced pressure. Methanol is again added and the mixture concentrated twice more.
  • (+/-)-2-(6-bromoisochroman-l-yl)ethyl alcohol (S-1), NMR (CDClg) 2.0, 2.2, 2.64, 2.69, 3.02, 3.70-3.79, 3.82-3.86, 4.15, 4.92, 7.28 ⁇ .
  • Step 3 (+/-)- l-[2-(6-Bromoisochroman-l-yl)ethyl]-4-phenylpiperidine
  • Methanesulfonyl chloride (0.22 mL, 2.84 mmol) is added to an ice water- cooled mixture of (+/-)-2-(6-bromoisochroman-l-yl)ethyl alcohol (S-1, step 2; 0.599 g, 2.33 mmol), 4-dimethyla ⁇ nopyridine (0.016 g, 0.131 mmol), diisopropylethylamine (0.49 mL, 2.81 mmol) and dry THF (7.5 mL). The ice water bath is removed and the mixture is allowed to warm to 20-25°.
  • (+/-)- l-[2-(4-Phenyl-l-piperidinyl)ethyl]isochroman-6-carboxamide A mixture of (+/-)- l[2-(6-bromoisochroman-l-yl)ethyl]4-phenylpiperidine (VI, step 1; 0.422 g, 1.05 mmol), DMF (2.7 mL), 1,1,1,3,3,3-hexamethyldisilazane (Aldrich; 1.6 mL, 7.58 mmol), diisopropylethylamine (0.38 mL, 2.18 mmol), palladium (II) acetate (0.012 g, 0.053 mmol) and l,3-bis(diphenylphosphino)propane (0.026 g, 0.064 mmol) is degassed six times under reduced pressure and released to carbon monoxide each time.
  • the mixture is heated at 90° overnight and then the cooled mixture is poured into hydrochloric acid (IN, 11 mL) and extracted with ether.
  • the pH of the aqueous layer is adjusted to 12 using aqueous sodium hydroxide.
  • the aqueous layer then is extracted three times with ethyl acetate and the combined organic layers are washed with saline, dried over magnesium sulfate and concentrated under reduced pressure.
  • (+/-)-N-Bis(tert-butyloxycarbonyl)-l-[2-(4-phenyl-l- piperidinyl)ethyl]isochroman-6-carboxamide Following the general procedure of EXAMPLE 3, step 1, and making non- critical variations, (+/-)- l-[2-(4-phenylpiperdin- l-yl)ethyl]isochroman-6-carboxamide (VII, EXAMPLE 84, 0.231 g, 0.634 mmol), 4-dimethylaminopyridine (0.0098 g, 0.0802 mmol) and di-tert-butyldicarbonate (0.312 g, 1.43 mmol) give (+/-)-N-bis(tert- butyloxycarbonyl)- l-[2-(4-phenyl- l-piperdinyl)ethyl]isochroman-6-carboxamide (VIII) after chromatography (silica gel
  • Step 2 N-Methyl-l-[2-(4-phenyl-l-piperidinyl)ethyl]isochroman-6- carboxamide, maleic acid salt Methyl amine gas is condensed into a glass high pressure reaction vessel cooled at -78° (under an argon atomosphere) and containing a mixture of (+/-)-N- bis(tert-butyloxycarbonyl)-l-[2-(4-phenyl-l-piperdinyl)ethyl]isochroman-6- carboxamide (VIII, step 1, 0.2818 g, 0.499 mmol) and dichloromethane (4 mL).
  • N-Methyl- l-[2-(4-phenyl- l-piperidinyl)ethyl]isochroman-6-carboxamide is treated with maleic acid (0.0360 g, 0.310 mmol) in dichloromethane/methanol to give N-methyl-l-[2-(4-phenyl-l-piperidinyl)ethyl]isochroman-6-carboxamide, maleic acid salt (B-LX), NMR (CDC1 3 ) 1.84, 2.05-2.20, 2.52-2.66, 2.72-2.78, 3.01, 3.41, 3.49, 3.78, 4.13, 4.85, 6.12, 7.16-7.32 and 7.53 ⁇ .
  • (+/-)- l-[2-(6-Bromoisochroman-l-yl)ethyl]-4-(2,4- dichlorophenyDpiperazine Following the general procedure of EXAMPLE 84, step 3 and making non- critical variations, (+/-)-2-(6-bromoisochroman-l-yl)ethyl alcohol (S-1) (EXAMPLE 84, step 2; 0.60 g, 2.31 mmol), 4-dimethylaminopyridine (0.018 g, 0.147 mmol), diisopropylethylamine (0.49 mL, 2.81 mmol), methanesulfonyl chloride (0.22 mL, 2.84 mmol) and dry THF (7.5 mL) are converted to the mesylate (T-l).
  • the mesylate is treated with diisopropylethylamine (1.0 mL, 5.7 mmol), l-(2,4- dichlorophenyl)piperazine (Q-3, step 1; 0.65 g, 2.82 mmol) and ethylene glycol to give, after chromatography (silica gel; methanol/dichloromethane, 2/98) (+/-)- 1-[2-(6- bromoisochroman-l-yl)ethyl]-4-(2,4-dichlorophenyl)piperazine (VI), NMR (CDC1 3 ) 2.01, 2.10, 2.55-2.71, 2.95, 3.05, 3.74, 4.11, 4.78, 6.96, 7.18 and 7.26-7.36 ⁇ .
  • (+/-)-l-[2-[4-(2,4-Dichlorophenyl)-l- piperazinyl]ethyl]isochroman-6-carboxamide Following the general procedure of EXAMPLE 84, step 4, and making non- critical variations, (+/-)- l-[2-(6-bromoisochroman-l-yl)ethyl]-4-(2,4- dichlorophenyDpiperazine (VI, step 1; 0.373 g, 0.794 mmol), gives 0.095 g of (+/-)- 1- [2-[4-(2,4-dichlorophenyl)-l-piperazinyl]ethyl]isochroman-6-carboxamide (VII) after chromatography (silica gel; methanol/dichloromethane, 2/98), NMR (CDC1 3 ) 2.05, 2.15, 2.50-2.80, 3.05, 3.78, 4.15, 4.87, 5.62, 6.04, 6.96, 7.
  • (+/-)-N-Methyl-l-[2-[4-(2,4-dichlorophenyl)-l- piperazinyl]ethyl]isochroman-6-carboxamide Following the general procedure of EXAMPLE 85, step 2, and making non- critical variations, (+/-)-N-bis(tert-butyloxycarbonyl)-l-[2-[4-(2,4-dichlorophenyl)-l- piperazinyl]ethyl]isochroman-6-carboxamide (VIII, step 1; 0.104 g, 0.164 mmol) gives after chromatography (silica gel; methanol/dichloromethane, 1.5/98.5 to 3/97 to 5/95) a solid.
  • Step 1 l-(3-Chloro-4-methoxyphenyl)piperazine
  • 3-chloro-p-anisidine R-2, 0.633 g, 4.00 mmol
  • bis(2- chloroethyl)amine hydrochloride 0.860 4.80 mmol
  • potassium carbonate 1.11 g, 8.00 mmol
  • dimethylacetamide 6 mL
  • (+/-)-2-(6- bromoisochroman-l-yl)ethyl alcohol (S-1, EXAMPLE 84, step 3, 0.450 g, 1.75 mmol), 4-dimethylaminopyridine (0.012g, 0.0990 mmol), diisopropylethylamine (0.32 mL, 1.84 mmol), methanesulfonyl chloride (0.14 mL, 1.81 mmol) and dry THF (5.6 mL) are converted to the mesylate.
  • diisoproplyethylamine (0.18 mL, 1.03 mmol) and methanesulfonyl chloride (0.08 mL, 1.03 mmol) are added to complete the formation of the mesylate.
  • mesylate To the mesylate then is added diisopropylethylamine (0.65 mL, 4.26 mmol), l-(3-chloro-4-methoxyphenyl)piperazine (step 1; 0.398 g, 1.75 mmol) and ethylene glycol (1.8 mL). The mixture is stirred at 80° for 3 hr and then overnight at 20-25°, after which the mixture again is heated for 4 hr at 80°.
  • (+/-)- l-[2-[4-(3-chloro-4-methoxyphenyl)-l- piperazinyl]ethyl]isochroman-6-carboxamide (VII, EXAMPLE 88, step 3; 0.153 g, 0.355 mmol), 4-dimethylaminopyridine (0.0086 g, 0.0704 mmol) and di-tert- butyldicarbonate (0.186 g, 0.853 mmol) give, after chromatography (silica gel; methanol/dichloromethane, 2/98), (+/-)-N-bis(tert-butyloxycarbony
  • (+/-)-N-Methyl-l-[2-[4-(3-chloro-4-methoxyphenyl)-l- piperzinyl]ethyl]isochroman-6-carboxamide Following the general procedure of EXAMPLE 85, step 2, and making non- critical variations, (+/-)-N-bis(tert-butyloxycarbonyl)-l-[2-[4-(3-chloro-4- methoxyphenyl)-l-piperazinyl]ethyl]isochroman-6-carboxamide (VIII, step 1; 0.183 g, 0.290 mmol) gives 0.118 g of product after chromatography (silica gel; methanol/dichloromethane, 2/98).
  • step 1 (+/-)- 1-[2-[4-(4- methoxyphenyl)-l-piperazinyl]ethyl]isochroman-6-carboxamide (VII, step 3; 1.97 g, 4.97 mmol), 4-dimethylaminopyridine (0.0816 g, 0.668 mmol) and di-tert-butyl- dicarbonate (2.56 g, 0.0117 mol) gives (+/-)-N-bis(tert-butyloxycarbonyl)-l-[2-[4-
  • the mixture is heated for 1 hour at 40°, at which time i-butanol (26 mL, 0.272 mol) and DBU (20.5 mL, 0.137 mol) are added. After stirring overnight at 40°, the cooled mixture is poured into ethyl ether (1300 mL) and washed with hydrochloric acid (10%, 250 mL), followed by water (250 mL) and then potassium carbonate (10%, 250 mL). The ether layer is dried over sodium sulfate and concentrated under reduced pressure.
  • Step 3 (S)-(-)-4-[4-[2-(6-bromoisochroman-l-yl)ethyl]-l- piperazinyl]benzoic acid, tert-butyl ester (V-l) Following the general procedure of EXAMPLE 84, step 3, and making non- critical variations, (S)-(-)-2-(6-bromoisochroman-l-yl)ethyl alcohol (S-1) (EXAMPLE 6, step 1; 4.95 g, 0.0193 mol) and 4-(piperazin-l-yl)benzoic acid, tert-butyl ester (Q-3) (step 2; 5.42 g, 0.0206 mol) gives the title compound, MS (m/z) 500; NMR (CDClg) 1.57, 2.02, 2.12, 2.50-2.70, 2.95, 3.32, 3.73, 4.10, 4.79, 6.85, 6.97, 7.29 and 7.86 ⁇ .
  • the mixture is degassed a second time, releasing to argon.
  • the mixture is heated at 60-65° while carbon monoxide is bubbled into the mixture. After several minutes methylamine is also bubbled into the mixture. After heating for 6.5 hours at 60-65°, the mixture is stored overnight in the refrigerator.
  • the mixture then is filtered through diatomaceous earth and additional portions of palladium (II) acetate (0.065 g, 0.290 mmol), l,3-bis(diphenylphosphino)propane (0.162 g, 0.392 mmol) and diisopropylethylamine (1.8 mL, 0.0103 mol) are added to the filtrate, which is heated at 60° for 4 hr with the addition of carbon monoxide and methylamine gases, after which the mixture is cooled and concentrated under reduced pressure. The residue is partitioned between dichloromethane and water. The combined organic layers are washed with water and saline and dried over sodium sulfate and concentrated under reduced pressure.
  • palladium (II) acetate 0.065 g, 0.290 mmol
  • l,3-bis(diphenylphosphino)propane 0.162 g, 0.392 mmol
  • diisopropylethylamine 1.8
  • Step 2 (+/-)-2-(6-Hydroxyisochroman-l-yl)acetic acid
  • ethyl ester (X-2) step 1; 2.38 g, 10.1 mmol
  • sodium hydroxide (2N, 10 mL) is added to ethanol (10-15 mL)
  • the mixture is stirred overnight and ethanol is then removed under reduced pressure.
  • the resulting aqueous mixture is then diluted with several mLs of saline and acidified with hydrochloric acid (3N), and the mixture is extracted with ethyl ether and concentrated. To remove remaining starting material, the residue is partitioned between aqueous sodium bicarbonate and dichloromethane.
  • (+/-)- l-2-(6-Hydroxyisochroman-l-yl)acetyl-4-(4- methoxyphenyl)piperazine To a mixture of (+/-)-2-(6-hydroxyisochroman-l-yl)acetic acid (X-3) (step 2; 0.361 g, 1.73 mmol), l-(4-methoxyphenyl)piperazine dihydrochloride (0.458 g, 1.73 mmol), dichloromethane (5 mL), and DMF (0.5 mL) is added triethylamine (0.80 mL, 5.72 mmol) and then diethyl cyanophosphonate (0.29 mL, 1.91 mmol).
  • (+/-)- l-(2-Chloroethyl)isochroman-6-ol, trifluoromethanesulfonate ester To a mixture of (+/-)-l-(2-chloroethyl)isochroman-6-ol (Y-2, Step 1; 0.079 g, 0.371 mmol), triethylamine (0.0413 g, 0.408 mmol), 4-dimethylaminopyridine (0.0009 g, 0.0074 mmol) and dichloromethane (1 mL) cooled at -78° is added trifuoromethanesulfonic acid anhydride (0.069 g, 0.408 mmol).
  • (+/-)- l-(2-Chloroethyl)-N-methylisochroman-6-carboxamide A mixture of (+/-)- l-(2-chloroethyl)isochroman-6-ol, trifluoromethanesulfonate ester (Y-3, Step 2; 0.291 g, 0.844 mmol) in DMF (1.5 mL) is de-gassed under reduced pressure for five minutes, after which palladium (II) acetate (0.019 g, 0.084 mmol) and l,3-bis(diphenylphosphino)propane (0.52, 0.127 mmol) is added.
  • palladium (II) acetate 0.019 g, 0.084 mmol
  • l,3-bis(diphenylphosphino)propane 0.52, 0.127 mmol
  • Carbon monoxide gas is bubbled in and diisopropylethylamine (0.29 mL, 1.69 mmol) is added. Methylamine gas is then bubbled in and the bath temperature is raised to 50°. The addition of methylamine gas and carbon monoxide gas is continued for 1 hR, at which time an additional palladium acetate (0.010 g) and 1,3- bis(diphenylphosphino)propane (0.025 g) are added. After an additinal 4 hr the mixture is allowed to cool and then is partitioned between ether, aqueous ammonium chloride, saline-ammonium chloride, and saline. The organic phases are separated, dried over magnesium sulfate and concentrated.
  • (+/-)- l-[2-[4-[4-(Aminocarbonyl)phenyl]-l-piperazinyl]ethyl]-N- methylisochromanyl-6-carboxamide Y-4, step 3; 0.0937 g, 0.369 mmol
  • 4-(piperazin-l-yl)benzamide Q-3, PREPARATION 1, 0.114 g, 0.554 mmol
  • diisopropylethylamine (0.0716 g, 0.554 mmol
  • sodium iodide 0.007 g
  • ethylene glycol (2 mL) is heated at 100° for 6.5 hr, after which an additional 0.056 g of 4-(piperazin-l-yl)benzamide is added.
  • (+/-)- l-[2-[4-[4-(aminocarbonyl)phenyl ]- l-piperazinyl]ethyl]-N- methylisochromanyl-6-carboxamide (Y-5, EXAMPLE 96) into its plus and minus enantiomers is achieved by preparative chromatography on a chiral phase pre ⁇ packed column using as solvent ethyl alcohol/isopropyl alcohol/triethylamine in a ratio of 4/1/0.08 (V/V) and using detection at 295 nM.
  • Peak 1 (S)-(-)-l-[2-[4-[4- (aminocarbonyl)phenyl]-l-piperazinyl]ethyl]-N-methylisochromanyl-6-carboxamide (EXAMPLE 6), eluted first, followed by Peak 2, R)-(+)-l-[2-[4-[4- (aminocarbonyl)phenyl]-l-piperazinyl]ethyl]-N-methylisochromanyl-6-carboxamide (Y-5), MS (m z) 422.
  • Step 2 (S)-(-)-l-[2-t(Tetrahydropyran-2-yl)oxy]ethyl]isochroman-6- carboxylic acid
  • (S)-(-)-l-[2-[(tetrahydropyran-2-yl)oxy]ethyl]isochroman-6- carboxylic acid, methyl ester (W-2, step 1, 1.55 g, 4.85 mmol), ethanol (12 mL), sodium hydroxide (2N, 3.6 mL, 7.2 mmol) and water (1 mL) is stirred for 6.5 hours at 20-25°, at which time the mixture is stored in the refrigerator overnight. The mixture is then stirred an additional 2.5 hours at 20-25° and then is concentrated under reduced pressure.
  • Step 4 (S)-(-)-l-(2-Hydroxyethyl)-N-methyl-N- phenylmethoxyisochroman-6-carboxamide
  • S)-(-)-N-methyl-N-(phenylmethoxy)-l-[2-[(tetrahydropyran-2- yl)oxy]ethyl]isochroman-6-carboxamide (W-4, step 3; 0.131 g, 0.308 mmol) is stirred at 20-25° in a mixture of acetic acid/THF/water (4/2/1, 5 mL) for 2 hr and then at 60° for 4 hr, at which time it is stored in the refrigerator overnight.
  • (+/-)- l-[2-[4-[4-(Aminosulfonyl)phenyl]-l-piperazinyl]ethyl]-N- methylisochroman-6-carboxamide Following the general procedure of EXAMPLE 96 and making non-critical variations, (+/-)- l-(2-Chloroethyl)-N-methylisochroman-6-carboxamide (Y-4, EXAMPLE 96, step 3, 0.024 g, 0.095 mmol) and 4-(piperaziny-l- yl)benzenesulfonamide (Q-3, Step 1) gives (+/-)- l-[2-[4-[4-(aminosulfonyl)phenyl]-l- piperazinyl]ethyl]-N-methylisochroman-6-carboxamide (Y-5), NMR (CDClg) 2.05, 2.19, 2.5-2.8, 3.01, 3.34, 3.42, 3.79, 4.16
  • EXAMPLE 102 (S)-(-)-N-Methyl-l-[2-t4-[4-(methylaminocarbonyl)phenyl]-l- piperazinyl]ethyl]isochroman-6-carboxamide
  • EXAMPLE 103 (S)-(-)-N-Methyl-l-[2-[4-[4-(dimethylaminocarbonyl)phenyl]-l- piperazinyl]ethyl]isochroman-6-carboxamide
  • EXAMPLE 104 (S)-(-)-N-Methyl-l-[2-[4-[4-(n-propylam ocarbonyl)phenyl]-l- piperazinyl]ethyl]isochroman-6-carboxamide Following the general procedure of EXAMPLE 100 and making non-critical variations and using the reactants corresponding to the products, the compounds of EXAMPLES 105-108 are obtained: EX
  • EXAMPLE 108 (S)-(-)-N-Hydroxy-N-methyl-l-[2-[4-[4-(methylcarbonyl)phenyl]- l-piperazinyl]ethyl]isochroman-6-carboxamide Following the procedure of CHART DD and making non-critical variations known to those skilled in the art the compounds of EXAMPLES 109 thru 120 are obtained.

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Abstract

La présente invention se rapporte à des isochromans 1,6-disubstitués représentés par la formule (I) et à des amines bicyliques aromatiques (ABA) qui s'avèrent utiles s'agissant du traitement des céphalées, et particulièrement des migraines et des céphalées vasculaires de Horton et qui sont également utiles en tant qu'antipsychotiques et s'agissant du traitement d'autres CNS et/ou troubles cardio-vasculaires et en tant qu'analgésiques.
EP96921264A 1995-06-30 1996-06-07 Isochromans 1,6-disubstitues destines au traitement des cephalees de type migraine Withdrawn EP0836599A1 (fr)

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PCT/US1996/008681 WO1997002259A1 (fr) 1995-06-30 1996-06-07 Isochromans 1,6-disubstitues destines au traitement des cephalees de type migraine

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US7335660B2 (en) 2001-12-19 2008-02-26 Eli Lilly And Company Isochroman compounds for treatment of CNS disorders
GB0130339D0 (en) * 2001-12-19 2002-02-06 Lilly Co Eli Isochroman compounds
US7110576B2 (en) 2002-12-30 2006-09-19 Pitney Bowes Inc. System and method for authenticating a mailpiece sender
ES2338668T3 (es) 2004-05-05 2010-05-11 F. Hoffmann-La Roche Ag Arilsulfonil benzodioxanos utiles para la modulacion del receptor 5-ht6 y del receptor 5-ht2a o ambos.
DK1831159T3 (da) 2004-12-21 2010-03-22 Hoffmann La Roche Tetralin og indanderivater samt anvendelser deraf
RU2388748C2 (ru) 2004-12-21 2010-05-10 Ф. Хоффманн-Ля Рош Аг Производные тетралина и индана и их применения в качестве антагонистов 5-нт
WO2006066756A1 (fr) 2004-12-21 2006-06-29 F. Hoffmann-La Roche Ag Derives de chromane utiles dans le traitement des troubles du systeme nerveux central
AU2005318596B2 (en) 2004-12-21 2010-12-23 F. Hoffmann-La Roche Ag Chroman derivatives and their use as 5-HT receptor ligands
KR100899061B1 (ko) 2004-12-21 2009-05-25 에프. 호프만-라 로슈 아게 테트랄린 및 인단 유도체 및 이의 용도
CN101300246A (zh) 2005-11-03 2008-11-05 弗·哈夫曼-拉罗切有限公司 作为5－ht6抑制剂的芳基磺酰基色满类化合物作为蛋白激酶抑制剂的吲哚基马来酰亚胺衍生物
BRPI0713736A2 (pt) 2006-06-20 2014-11-18 Hoffmann La Roche Derivados de tetralina e indano e emprego destes
BRPI0713742A2 (pt) 2006-06-20 2013-02-13 Hoffmann La Roche derivados de arilsulfonila naftaleno e usos destes
KR101064001B1 (ko) 2006-06-20 2011-09-08 에프. 호프만-라 로슈 아게 아릴설폰아미딜 테트랄린 유도체 및 이의 용도
EP2404897A4 (fr) * 2009-03-05 2014-02-26 Sumitomo Chemical Co Procédé de production de benzène diméthanol à substitution halogène

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