Classifications

• • 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
• Chromans and aryl piperazines linked together with an alkyl chain are also known.
• 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 -alkyl-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 of vascular (migraine and cluster) headaches and CNS and cardiovascular disorders.
• benzothiepines with hydroxy, alkoxy, or o-methylenedioxy functionality attached to their aromatic rings, and linked to aryl piperazines(piperidines) by alkyl chains are known, useful as antipsychotics and hypotensives.
• the compounds of 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 1-[(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.
• 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.
• 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.
• 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 1-(4-methoxyphenyl)-4-[2-(6-aminocarbonylisochroman-1-yl)-ethylpiperazine (EXAMPLE 138) and 1-(4-methoxyphenyl)-4-[2-(6-methylaminocarbonylisochroman-1-yl)-ethylpiperazine (EXAMPLE 139).
• W 1 is a nitrogen (-N-) or carbon (-CH-) atom
• R 1-1A is -H, C 1 -C 6 alkyl, -CF 3 or
• R 1-1A and R 1-1B are the same or different and where R 1-1B is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 - ⁇ , and where R 1- 1A is as defined above,
• n 2 is as defined above and - ⁇ is optionally substituted with one or two: (a) -F, -Cl, -Br, -I,
• R 1-3A is -H, C 1 -C 6 alkyl, -CF 3 or
• R 1-3A and R 1-3B are the same or different and where R 1-3B is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 - ⁇ , and whereR 1-3A is as defined above,
• R 2 is defined the same as R 1 , R 2 can be the same or different than R 1 ;
• n 2 is as defined above and - ⁇ is optionally substituted with one or two:
• n 9 and n 10 are the same or different and are 0 thru 4, where Q 1-2B is -O- or -NQ 1-2D -, where Q 1-2D is:
• n 7 is as defined above and - ⁇ is optionally substituted with one or two:
• Q 1-1 is as defined above, with the proviso that when X 1 is -(CH 2 ) n1 -, where n 1 is 0 and Q 1 is:
• Q1-1 and Q1-2 cannot both be selected from:
• aromatic bicyclic amines of the formula (ABA) are also disclosed.
• W 1 is a nitrogen (-N-) or carbon (-CH-) atom
• R 2 is defined the same as R 1 , R 2 can be the same or different than R 1 ; 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
• 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
• II Standard hydrolysis using lithium hydroxide in THF-water provides the acid (IV), which can be coupled to a variety of substituted arylpiperazines or 4-arylpiperidines to give the amides (V).
• the arylpiperazine moiety carries the R 1 and R 2 substituents.
• R 1 and R 2 substituents be on the aryl group prior to the production of the amide (V).
• the starting R 1 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 (IX) directly.
• the 6-bromoisochroman (VI) can be reacted with carbon monoxide in the presence of palladium (II) acetate, 1,3-bisdiphenylphosphinopropane, diisopropylamine, and hexamethyldisilazane in solvents such as DMF to give the amide (VII).
• Other palladium catalysts such as in situ prepared palladium(0) with organophosphines, or pre-prepared palladium(0) phosphine catalysts can be utilized.
• the amide (VII) can be converted into either substituted amides (IX) or esters (X) via the bis-BOC derivative (VIII) using the procedure described in J. Org. Chem., 56, 5482 (1991).
• the 6-bromoisochroman (VI) can be converted to N-methyl substituted amides (IX) directly by using either methylamine or N-methylformamide in place of
• 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-1-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.
• 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 t-butoxide or ethoxide.
• a proton donor Virtually any proton donor is operable, for example even water will quench the reaction. However, operationally water is not preferred.
• the proton donor is an acid. Most common proton donors (hydrochloric acid, ammonium chloride) used to quench enolate anions can be used for this quenching, however, for ease of workup and purification, acetic acid or trifluoroacetic acid is preferred.
• 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 (IV) 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 (XXIV) following standard acidic hydrolysis of the enol-ether intermediate.
• CHART H describes the preparation of the sulfonamides (XXVII) and the sulfones (XXIX).
• 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). This sulfide is then oxidized using standard procedures and oxidants such as m-chloroperbenzoic acid to give the sulfone (XXIX).
• CHART I describes the preparation of the sulfones (XXXIV) in which the sulfone moiety is linked to the isochroman nucleus with a methylene tether of 1, 2, or 3 carbon atoms.
• XXXIV the sulfone moiety is linked to the isochroman nucleus with a methylene tether of 1, 2, or 3 carbon atoms.
• 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 (XXXIV) 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 ( ⁇ Q 1-1 Q 1-2 ) 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 (XXXIX) 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 (XLIV) 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 (O-2) is nitrogen
• the product is a triazole.
• X in (O-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-1).
• CHART Q discloses the synthesis of piperazine (Q-3) in which R 1 is an electron withdrawing substituent ortho or para to the aniline nitrogen of the piperazine.
• Amine (Q-1) 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-1) or diisopropylethylamine, potassium carbonate or the like) at elevated temperature (60-200°) to give piperazine (Q-3).
• a polar solvent such as water, DMF, dimethylacetamide, or other such solvents
• a base either excess (Q-1) or diisopropylethylamine, potassium carbonate or the like
• CHART R discloses the synthesis of piperazines (R-3).
• Nitro aryl (R-1) is reduced to aniline (R-2) using hydrogen and a catalyst such as palladium on carbon, Raney nickel, stannous chloride or the like.
• (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 (IX).
• the hydroxy bromide (S-1) is converted into an alkylating agent (T-1, 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 (IX) as previously illustrated.
• CHART U discloses the conversion of chiral bromo acid (U-1) which is (XI) in CHART C to the amide alcohol (U-5) which is (S-3) in CHART T.
• the bromo acid (U-1) 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-1) 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-1) to (V-2), to give the amide ester (U-3).
• CHART V discloses a method for the conversion of ester (V-1) to diamide (V-4).
• Ester (V-1) is prepared from bromo isochroman (T-1) and piperazine (Q-3), CHART Q, by methods discussed for CHART T.
• Ester (V-1) is converted to the amide ester (V-2) using palladium (II) acetate, a co-catalyst such as
• 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.
• 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).
• the 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- 8). These compounds are also prepared by the processes of CHARTS A and B.
• the alcohol group of the ester alcohol (S-2) , Chart S, is protected with a suitable protecting group such as a dihydropyranyl group, which is stable to basic conditions, to give tetrahydropyranyl ether (W-2).
• the ester group of the ether (W-2) is then hydrolyzed with aqueous base and then acidified carefully (so as not to remove the protecting group) to give carboxylic acid (W-3).
• the carboxylic acid (W-3) is then treated with a condensing agent such as carbonyldiimidazole,
• 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).
• the 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
• CHART X discloses the synthesis of the carbamate (X-6).
• (X-1) 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-1).
• the phenol (Y-1) 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
• solvents such as dichloromethane or nitromethane
• 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). These compounds arise from standard derivations of the aniline (Z-1), itself prepared from the bromide (VI) via metal-halogen exchange (typically using either n-butyllithium or t-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 t-butyllithium
• diphenylphosphoryl azide usually in THF at -78°
• 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 t-butyl lithium) followed by quenching of the resulting anion with DMF to give the aldehyde (AA-1).
• 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, R1 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
• 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.
• coupling (CC-3) with enol-ethers provides ketone-substituted aryl derivatives.
• These reactions are typically carried out in DMF or acetonitrile using palladium(II) acetate, 1,3-bis(diphenylphosphin
• CHART DD illustrates an alternative preparation of isochroman-6-triazoles (DD-4) and isochroman-6-oxadiazoles (DD-6).
• P -CH 2 -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
• n 1 is 0 or 1; it is more preferred that n 1 is 0. It is preferred that R 1 is -O-R 1-1 , -CF 3 , -CO-N(R 1-1 ) 2 , -CO-R 1-1 and it is preferred that R 1-1 is C 1 -C 3 alkyl. It is preferred that R 2 is -H. It is preferred that Q 1 is selected from the group consisting of -CO-NQ 1-1 Q 1-2 , -SO 2 - NQ 1-1 Q 1-2 and -NQ 1-1 Q 1-2 ; it is more preferred that Q 1 is -CO-NQ 1-1 Q 1-2 .
• W 1 is nitrogen (-N-) and it is preferred that one of R 1 or R 2 is -H. It is preferred that Q 1 is (A) -CO-NQ 1-1 Q 1-2 and that Q 1-1 is -H and that Q 1-2 is -CH 3 (C 1 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. However, if it is desired to utilize one of the enantiomers, the optically impure mixture or
• racemic 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 Information Center, Manhattan College, Riverdale, NY, 10471, 1978.
• the 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 refers to and includes both enantiomers as well as optically impure forms thereof, the most common of which is a racemic mixture ( ⁇ , d1).
• 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 acceptable 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
• R i and R j would represent monovalent variable substituents if attached to the formula CH 3 -CH 2 -C(R i )(R j )-H.
• variable substituents 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 i and R j 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 substituents 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 1 ) which is "below” another substituent (X 2 ) 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 1 ) is identified as being in the beta ( ⁇ ) configuration and is indicated by an unbroken line attachment to the carbon atom.
• variable substituent when a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable.
• R i when a bivalent variable, R i , is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form " ⁇ -R i-j : ⁇ -R i-k " or some variant thereof.
• both ⁇ -R i-j and ⁇ -R i-k are attached to the carbon atom to give -C( ⁇ -R i-j )( ⁇ -R i-k )-
• the two monovalent variable substituents are ⁇ -R 6-1 : ⁇ -R 6-2 , .... ⁇ -R 6-9 : ⁇ -R 6-10 , etc, giving -C( ⁇ -R 6-1 )( ⁇ -R 6-2 )-,... -C( ⁇ -R 6-9 )( ⁇ -R 6-10 )-, etc.
• 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 i and R j may be defined to be taken together to form (1) a second bond between C 1 and C 2 or (2) a bivalent group such as oxa (-O-) 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 1 -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 1 -C 4 alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary 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 -O-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 i -C j " designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined.
• C 1 -C 3 )alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl because the "C 1 -C 3 " refers only to the carbon atom content of the alkoxy group.
• C 2 -C 6 alkoxyalkyl and (C 1 -C 3 )alkoxy(C 1 -C 3 )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.
• one name for the compound of example 6 is (S)-(-)-1-[2-[4-[4-(aminocarbonyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide or (S)-(-)-1-(benzamide-4-yl)-4-[2-(6-methylaminocarbonylisochroman-1-yl)ethylpiperazine.
• TLC refers to thin-layer chromatography
• HPLC refers to high pressure liquid chromatography.
• THF refers to tetrahydrofuran
• DMF refers to dimethylformamide
• DMSO 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-1-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
• 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
• - ⁇ refers to phenyl (C 6 H 5 ).
• [ ⁇ ] D 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.
• the ratios of solvents used are volume/volume (v/v).
• Step 2 (R)-(+)-Ethyl (6-bromoisochroman-1-yl)acetate (XII) and (S)-(-)-(6-bromoisochroman-1-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.
• ester (XII) could be analyzed in a similar way following hydrolysis (vide infra). If needed, the enantiomerically enriched ester could be re-subjected to another cycle of the enzymatic hydrolysis if indicated by the HPLC analysis.
• Step 3 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)acetyl]-4-(4-methoxyphenyl)-piperazine (S)-(V)
• Step 4 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)ethyl]-4-(4-methoxyphenyl)-piperazine (S)-(VI)
• reaction After cooling to 20-25°, the reaction separated into two phases.
• the reaction mixture is poured into aqueous hydrochloric acid (1N) 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)-(+)-1-[2-(6-Bromoisochroman-1-yl)acetyl]-4-(4-methoxyphenyl)-piperazine (R)-(V).
• Step 1 (S)-(-)-N,N-Di-t-butyloxycarbonyl-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-isochroman-6-carboxamide (S)-(VIII)
• Step 1 (R)-(+)-N,N-Di-t-butyloxycarbonyl-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-isochroman-6-carboxamide (R)-(VIII)
• Step 1 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)acetyl]-4-(4-trifluoromethylphenyl)-piperazine (S)-(V)
• Step 2 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)ethyl]-4-(4-trifluoromethylphenyl)-piperazine (S)-(VI).
• reaction is treated with 1M 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 volatiles 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.
• dimethylformamide, diisopropylethylamine (0.52 mL, 3.0 mmol), and N-methylformamide (1.8 mL, 30 mmol) are combined and purged six times with carbon monoxide/house vacuum followed by heating to 120°. After 16 hours, the mixture is cooled to 20-25°, treated with 25 mL 1M hydrochloric acid, and stirred for 10 min. This acidic solution is adjusted to pH 12 and extracted three times with ethyl acetate (20 mL). The combined organic extracts are washed once with saline (30 mL), dried over magnesium sulfate, filtered, and concentrated.
• triphenyl phosphine oxide is removed by recrystallization from ethyl acetate/hexane with the mother liquor giving a solid.
• 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). Elution is begun using dichloromethane/methanol (95/5) and then changed to
• Step 4 (S)-(-)-1-[2-[4-[4-(Aminocarbonyl)phenyl]-1-piperazinyl]ethyl]-N-methylisochromanyl-6-carboxamide
• 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°. As the temperature increased, the mixture became homogeneous and the tip of the needle is then placed slightly below the surface of the solution. After bubbling carbon monoxide into the solution for several minutes, methyl amine gas also is bubbled into the solution. Carbon monoxide and methyl amine addition were continued for 6 hr or until the starting material is consumed, after which the mixture is cooled and DMF removed under reduced pressure. The residue is applied to a silica gel column andl eluted with
• Step 2 1-(4-Phenylmethyloxyphenyl)-4-[2-(6-bromoisochroman-1- yl)-ethyl]piperazine (VI)
• Step 1 1-[2-(6-Bromoisochroman-1-yl)acetyl]-4-(4-diethylaminophenyl)- piperazine (V)
• Step 1 1-[2-(6-Bromoisochroman-1-yl)acetyl]-4-(4- methylsulfonylphenyl)-piperazine (V)
• Step 3 1-[2-[4-(4-Methylsulfonylphenyl)-1- piperazinyl]ethyl]isochroman-6-carboxamide (VII) Following the general procedure of EXAMPLE 1, Step 5 and making non-critical variations but using 1-[2-(6-bromoisochroman-1-yl)-1-ethyl]-4-(4-methylsulfonylphenyl)piperazine (VI) the product is obtained.
• Step 1 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)acetyl]-4-(4- trifluoromethoxyphenyl)piperazine (S)-(V)
• Step 2 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)-ethyl]-4-(4- trifluoromethoxyphenyl)-piperazine (S)-(VI)
• Step 1 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)acetyl]-4-(4-ethylphenyl)- piperazine (S)-(V)
• Step 2 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)-ethyl]-4-(4-ethylphenyl)- piperazine (S)-(VI)
• Step 1 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)acetyl]-4-(4-ethoxyphenyl)- piperazine (S)-(V)
• Step 2 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)-ethyl]-4-(4-ethoxyphenyl)- piperazine (S)-(VI)
• Step 1 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)acetyl]-4-(4- phenylmethyloxyphenyl)piperazine (S)-(V)
• Step 1 1-[2-[4-(3-Trifluoromethylphenyl)-1-piperazinyl]ethyl]-N,N-di-t- butyloxycarbonylisochroman-6-carboxamide (VIII)
• Step 1 1-[2-[4-(4-Methylsulfonylphenyl)-1-piperazinyl]ethyl]-N,N-di-t- butyloxycarbonylisochroman-6-carboxamide (VIII)
• Step 2 1-[2-[4-(4-Methylsulfonylphenyl)-1-piperazinyl]ethyl]-N-methylisochroman-6-carboxamide (IX) Following the general procedure of EXAMPLE 3, Step 2 and making non-critical variations but using 1-[2-[4-(4-methylsulfonylphenyl)-1-piperazinyl]ethyl]-N,N-di-t-butyloxycarbonylisochroman-6-carboxamide (VIII, 650 mg, 1.0 mmol) gives crude product.
• Step 1 1-[2-[4-(4-Methoxvphenyl)-1-piperazinyl]ethyl]-N,N-di-t- butyloxycarbonylisochroman-6-carboxamide (VIII)
• 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 1 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)acetyl]-4-(4- methoxyphenyl)-piperidine (S)-(V)
• Step 2 (S)-(-)-1-[2-(6-Bromoisochroman-1-yl)ethyl]-4-(4-methoxyphenyl)- piperidine (S)-(VI)
• 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.
• Acetic anhydride (0.32 mL, 3.43 mmol) is cooled to 0°.
• Acetic formic anhydride is generated by the dropwise addition of 98% formic acid (0.20 mL, 5.2 mmol) to the acetic anhydride.
• the mixture is heated to 55° for 2 hours and then cooled to 0°.
• THF (1 mL) is added via syringe, followed by a solution of (S)-(-)-1-[2-(6-aminoisochroman-1-yl)-ethyl]-4-(4-methoxyphenyl)piperazine (S)-(Z-1, 600 mg, 1.63 mmol) in THF (2 mL).
• reaction is stirred at 20-25° for 1.5 hours.
• the reaction is then partitioned between 0.5 M aqueous sodium hydroxide and methylene chloride. The layers were separated and the aqueous portion is extracted one more time with methylene chloride. The organics were combined, dried with sodium sulfate, filtered and concentrated.
• Acetic anhydride (0.32 mL, 3.43 mmol) is cooled to 0°.
• Acetic formic anhydride is generated by the dropwise addition of 98% formic acid (0.20 mL, 5.2 mmol) to the acetic anhydride.
• the mixture is heated to 55° for 2 hours and then cooled to -15° with an ethylene glycol/carbon dioxide bath.
• 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 volatiles 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-H 3 ), 2.62 (m's, 7H, PhCH-H, NC-H 2 and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2.00 (m, 1H, PhCHCH-H) ⁇ ; CMR (75 MHz, CDCl 3 ) 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 ⁇ .
• 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 1M 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.
• Step 1 1-[2-(6-Hydroxymethylisochroman-1-yl)-ethyl]-4-(4- methoxyphenyl)piperazine (AA-2)
• 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 1-[2-(6-Cyanomethylisochroman-1-yl)ethyl]-4-(4- methoxyphenyl)-piperazine (AA-3)
• Step 3 2-[Isochroman-1-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-6- yl]acetamide (AA-4)
• reaction is cooled to 20-25°, treated with 8 mL 1M hydrochloric acid, and is stirred for 1 hour.
• This acidic mixture is concentrated under reduced pressure, diluted with 15 mL 1M 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.
• the mixture is heated to 100° over 18 hours. After cooling to 20-25°, the reaction is diluted with aqueous sodium hydroxide and extracted three times with ethyl acetate. The organics are combined and concentrated. Residual DMF is removed under high vacuum.
• Step 1 (S)-(-)-1-[2-[4-(4-Methoxyphenyl)-1-piperazinyl]ethyl]-N- dimethylaminomethyleneisochroman-6-carboxamide (S)-(O-1) (S)-(-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide (S)-(VII, 395.5 mg, 1 mmol) and N,N-dimethylformamidedimethylacetal (94%, 0.34 mL, 2.4 mmol) and toluene (1 mL) are combined. The reaction mixture is heated to 90° for 1.5 hours.
• Step 2 (S)-(-)-1-(4-Methoxyphenyl)-4-[2-[6-(1,2,4-triazol-3- yl)isochroman-1-yl]ethyl]piperazine (S)-(O-2)
• the aqueous mixture is extracted twice with methylene chloride. The organics are combined, dried with sodium sulfate, filtered and concentrated.
• Step 1 (S)-(-)-6-Bromo-1-(2-hydroxyethyl)isochroman (S)-(S-1)
• the resulting mixture is diluted with 1M 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)-(-)-1-(2-Hydroxyethyl)isochroman-6-carboxylic acid, methyl ester (S)-(S-2)
• Step 4 (S)-(-)-1-(2-Methanesulfonyloxyethyl)-N-methylisochroman-6- carboxamide (S)-(T-2)
• Step 5 (S)-(-)-N-Methyl-1-[2-[4-(4-propionylphenyl)-1-piperazinyl]ethyl]- isochroman-6-carboxamide (S)-(IX)
• (+/-)-2-(6-bromoisochroman-1-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. The residue is then partitioned between dichloromethane and aqueous sodium
• (+/-)-2-(6-bromoisochroman-1-yl)ethyl alcohol (S-1), NMR (CDCl 3 ) 2.0, 2.2, 2.64, 2.69, 3.02, 3.70-3.79, 3.82-3.86, 4.15, 4.92, 7.28 ⁇ .
• Methanesulfonyl chloride (0.22 mL, 2.84 mmol) is added to an ice water- cooled mixture of (+/-)-2-(6-bromoisochroman-1-yl)ethyl alcohol (S-1, step 2; 0.599 g, 2.33 mmol), 4-dimethylaminopyridine (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°.
• (+/-)-1-[2-(4-Phenyl-1-piperidinyl)ethyl]isochroman-6-carboxamide A mixture of (+/-)-1[2-(6-bromoisochroman-1-yl)ethyl]4-phenylpiperidine (VI, step 1; 0.422 g, 1.05 mmol), DMF (2.7 mL), 1,1,1,3,3,3-hexamethyldisilazane
• (+/-)-1-[2-(4-phenylpiperdin-1-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)-1-[2-(4-phenyl-1-piperdinyl)ethyl]isochroman-6-carboxamide (VIII) after chromatography (silica gel; methanol/dichloromethane, 2/98), NMR (CDCl 3 ) 1.39, 1.84, 2.00-2.20, 2.44-2.63, 2.71-2.81, 2.94-3.15, 3.78, 4.14, 4.89, 7.
• Step 2 N-Methyl-1-[2-(4-phenyl-1-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)-1-[2-(4-phenyl-1-piperdinyl)ethyl]isochroman-6-carboxamide (VIII, step 1, 0.2818 g, 0.499 mmol) and dichloromethane (4 mL).
• N-Methyl-1-[2-(4-phenyl-1-piperidinyl)ethyl]isochroman-6-carboxamide is treated with maleic acid (0.0360 g, 0.310 mmol) in dichloromethane/methanol to give N-methyl-1-[2-(4-phenyl-1-piperidinyl)ethyl]isochroman-6-carboxamide, maleic acid salt (B-IX), NMR (CDCl 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 ⁇ .
• (+/-)-2-(6-bromoisochroman-1-yl)ethyl alcohol (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-1).
• the mesylate is treated with diisopropylethylamine (1.0 mL, 5.7 mmol), 1-(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-1-yl)ethyl]-4-(2,4-dichlorophenyl)piperazine (VI), NMR (CDCl 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 ⁇ .
• (+/-)-1-[2-[4-(2,4-Dichlorophenyl)-1- piperazinyl]ethyl]isochroman-6-carboxamide Following the general procedure of EXAMPLE 84, step 4, and making non-critical variations, (+/-)-1--2-(6-bromoisochroman-1-yl)ethyl]-4-(2,4-dichlorophenyl)piperazine (VI, step 1; 0.373 g, 0.794 mmol), gives 0.095 g of (+/-)-1-[2-[4-(2,4-dichlorophenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide (VII) after chromatography (silica gel; methanol/dichloromethane, 2/98), NMR (CDCl 3 ) 2.05, 2.15, 2.50-2.80, 3.05, 3.78, 4.15, 4.87, 5.62, 6.04, 6.96, 7.19, 7.35
• (+/-)-N-Methyl-1-[2-[4-(2,4-dichlorophenyl)-1- piperazinyl]ethyl]isochroman-6-carboxamide Following the general procedure of EXAMPLE 85, step 2, and making non- critical variations, (+/-)-N-bis(tert-butyloxycarbonyl)-1-[2-[4-(2,4-dichlorophenyl)-1-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 1-(3-Chloro-4-methoxyphenyl)piperazine
• R-2 3-chloro-p-anisidine
• bis(2-chloroethyl)amine hydrochloride 0.860 4.80 mmol
• potassium carbonate 1.11 g, 8.00 mmol
• dimethylacetamide 6 mL
• the mixture is partitioned between dichloromethane, water and aqueous sodium bicarbonate and the organic layers are dried with sodium sulfate and concentrated. The residue is chromatrographed (silica gel;
• (+/-)-2-(6-bromoisochroman-1-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.
• (+/-)-1-[2-(6-bromoisochroman-1-yl)ethyl]-4-(3-chloro-4-methoxyphenyl)piperazine (VI, Step 2; 0.420 g, 0.902 mmol), DMF (2.3 mL), 1,1,1,3,3,3-hexamethyldisilazane (1.4 mL, 6.64 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol), palladium (II) acetate (0.0110 g, 0.049 mmol) and 1,3-bis(diphenylphosphino)propane (0.024 g, 0.0575 mmol) give (+/-)-1-[2-[4-(3-chloro-4- methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide (VII).
• (+/-)-1-[2-[4-(3-chloro-4-methoxyphenyl)-1-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;
• (+/-)-N-bis(tert-butyloxycarbonyl)-1-[2-[4-(3-chloro-4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide (VIII, step 1; 0.183 g, 0.290 mmol) gives 0.118 g of product after chromatography (silica gel;
• (+/-)-2-(6-bromoisochroman-1-yl)acetic acid (IV, EXAMPLE 84, step 1; 4.66 g, 0.0172 mol), dichloromethane (18 mL), DMF (18 mL), diethyl cyanophosphonate (3.4 mL, 0.022 mol), 1-(4-methoxyphenyl)piperazine hydrochloride (R-3) (Aldrich; 4.78 g, 0.021 mol) and triethylamine (6.5 mL, 0.047 mol) is stirred at 20-25° for 2.5 hours.
• (+/-)-1-[2-(6-bromoisochroman-1-yl)ethyl]-4-(methoxyphenyl)piperazine (VI, step 2; 4.29 g, 9.95 mmol) gives (+/-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]isochroman-6-carboxamide (VII), NMR (CDCl 3 ) 2.06, 2.16, 2.54-2.79, 2.99, 3.11, 3.77, 4.15, 4.87, 5.64, 6.06, 6.87, 7.19 and 7.59 ⁇ .
• (+/-)-N-Bis(tert-butyloxycarbonyl)-1-[2-[4-(methoxyphenyl)-1- piperazinyl]ethyl]isochroman-6-carboxamide Following the general procedure of EXAMPLE 3, step 1, (+/-)-1-[2-[4-(4-methoxyphenyl)-1-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-butyldicarbonate (2.56 g, 0.0117 mol) gives (+/-)-N-bis(tert-butyloxycarbonyl)-1-[2-[4-
• a mixture of 4-fluorobenzoic acid, tert-butyl ester (Q-2) (step 1; 20.5 g, 0.105 mol), piperazine (52.8 g, 0.613 mol) and dimethylacetamide (121 mL) is heated at 150-155° for 160 minutes. After cooling, the solid is removed by filtration and washed with hexane. The combined filtrates are concentrated under high vacuum and the residue is partitioned between dichloromethane and water. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The slightly solvent-wet solids are slurried in hexane and the solid is collected and washed with hexane.

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