WO1989002739A1 - 4-aminopyridine derivatives - Google Patents

4-aminopyridine derivatives Download PDF

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Publication number
WO1989002739A1
WO1989002739A1 PCT/US1987/002546 US8702546W WO8902739A1 WO 1989002739 A1 WO1989002739 A1 WO 1989002739A1 US 8702546 W US8702546 W US 8702546W WO 8902739 A1 WO8902739 A1 WO 8902739A1
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WO
WIPO (PCT)
Prior art keywords
ppm
amino
group
compound according
formula
Prior art date
Application number
PCT/US1987/002546
Other languages
French (fr)
Inventor
Manoj Chandrasinhji Desai
Original Assignee
Pfizer Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to MX1327088A priority Critical patent/MX13270A/en
Priority to PCT/US1987/002546 priority patent/WO1989002739A1/en
Priority to US07/474,717 priority patent/US5202440A/en
Priority to PCT/US1988/001070 priority patent/WO1989002740A1/en
Priority to IL87861A priority patent/IL87861A0/en
Priority to AT88309040T priority patent/ATE123024T1/en
Priority to EP88309040A priority patent/EP0311303B1/en
Priority to ES88309040T priority patent/ES2072263T3/en
Priority to DE3853863T priority patent/DE3853863T2/en
Priority to PL1988275056A priority patent/PL159258B1/en
Priority to MYPI88001105A priority patent/MY104335A/en
Priority to ZA887399A priority patent/ZA887399B/en
Priority to PT88656A priority patent/PT88656B/en
Priority to HU885131A priority patent/HU203082B/en
Priority to AU23370/88A priority patent/AU619213B2/en
Priority to IE300388A priority patent/IE60718B1/en
Priority to CN88109023A priority patent/CN1032440A/en
Priority to NZ226445A priority patent/NZ226445A/en
Priority to FI884553A priority patent/FI93117C/en
Priority to NO884400A priority patent/NO176713C/en
Priority to KR1019880012933A priority patent/KR900007243B1/en
Priority to DD88320447A priority patent/DD273633A5/en
Priority to YU184988A priority patent/YU48197B/en
Priority to SU884356604A priority patent/RU1816283C/en
Priority to DK553988A priority patent/DK553988A/en
Priority to EG51088A priority patent/EG19973A/en
Priority to JP63251742A priority patent/JPH0692372B2/en
Publication of WO1989002739A1 publication Critical patent/WO1989002739A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/61—Carboxylic acid nitriles containing cyano groups and nitrogen atoms being part of imino groups bound to the same carbon skeleton
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
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    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9
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    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
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    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to 4-aminopyridine derivatives.
  • the compounds of the present invention inhibit brain acetylcholinesterase and are useful in the treatment of Alzheimer's disease.
  • Tetrahydroaminoacridine which has anticholine- sterase activity, has been reported to produce improved performance in psychological tests in patients afflicted with Alzheimer's disease (W. K. Summers et al., The New England Journal of Medicine, 315, 1241-1245 (1986)).
  • the anticholinesterase physostigmine has also been reportedly used in the experimental treatment of Alzheimer's disease (S. D. Brinkman et al., Neurobiol. Aging, 4_, 139-145 (1983)).
  • United States Patent 4,652,567 refers to benzo(C)-1,5-naphthyridines for treating Alzheimer's disease.
  • United States Patent 4,631,286 refers to 9-amino-l,2,3,4-tetrahydroacridine-l-ol and related compounds for treating Alzheimer's disease.
  • United States Patent 4,550,113 refers to 9-amino- 2,3,5,6,7,8-hexahydro-lH-cyclopenta(b)quinoline mono- hydrate hydrochloride for treating neuritis, injuries of the peripheral nervous system, hereditary neuromus- cular diseases, and disseminated sclerosis.
  • United States Patent 4,578,394 refers to dihydropyridines for treating Alzheimer's disease.
  • United States Patent 4,540,564 refers to dihydropyridines for delivering drugs to the brain.
  • British Patent Specifications 1,186,061, 1,186,062, and 1,186,063 refer to benzonaphthyridine derivatives.
  • the present invention relates to compounds of the formula
  • A is selec cted fmrom the group consisting of
  • R is hydrogen or C,-C fi alkyl
  • R is independently selected from the group consisting of hydrogen, C--C fi alkyl, C..-C fi alkoxy, C,-C, alkanoyl, di(C 1 -C, alkylaminoJ-C.-Cg alkyl, C..-C alkyl, halogen (e.g., fluoro, chloro, bromo or iodo) , hydroxy, nitro, phenyl, substituted phenyl, phenyl-C.-C, alkyl, substituted phenyl-C,-C fi alkyl, diphenyl-C ⁇ -C 8 alkyl wherein one or both of the phenyl groups may be replaced with a substituted phenyl group, furyl-C,-C 8 alkyl, thienyl-C, -C - alkyl, phenyloxy, substituted f ⁇ 7 phenyloxy, NHCOR and NR R , wherein the phenyl moi
  • R , R and R are independently selected from C- ⁇ -C alkyl and C--C 8 alkanoyl;
  • R is independently selected from the group consisting of 1,4-dihydropyridyl- C-,-Cg alkanoyl, C ⁇ -Cg alky1-1,4-dihydropyridyl-C ⁇ -Cg- alkanoyl, and the possible definitions set forth above for R 3 t except that R2 cannot be hydroxy, halogen,
  • R is independently selected from the possible definitions set forth above for R 3, except that R4 cannot be
  • R8 is C--C, alkyl or C_.-C ⁇ alkanoyl
  • Z 2 is O or S
  • Z5 is
  • A is a group of " the formula 1 ⁇ wherein there is no nitrogen at position a, b, c or d or A is a group of the formula 3_ or 4_, only one of Y 1 and Y2 can be CH 2 ; and pharmaceutically acceptable salts thereof.
  • the present invention also relates to a pharmaceu ⁇ tical composition for the treatment of Alzheimer's disease comprising a compound of the formula I and to the use of compounds of the formula I in treating Alzheimer's disease.
  • the present invention also relates to methods of preparing compounds of the formula I.
  • a preferred embodiment of the present invention relates to compounds of the formula I wherein A, B, Z ,
  • Z , Z , Z , Z and Z are as defined with respect to formula I; R 1, R2 and R4 are hydrogen; and R3 is hydrogen or halogen; and pharmaceutically acceptable
  • R is halogen
  • the halogen is preferably fluorine
  • A is a group of the formula 1_, wherein one of the CH moieties at positions a and b of formula .1 may be replaced by a nitrogen atom, or A is a group of the formula 3_;
  • R , R , R , Z , Z , Z and q are as defined with respect to formula I; n is 1 or 2; Z is S; and p is 1 or 2; with the proviso that
  • one of Y and Y can be CH 2 ;
  • R 1 , R2 and R4 are hydrogen and R 3 is hydrogen or halogen.
  • R3 is halogen, the halogen is preferably fluorine.
  • Another preferred embodiment of the present invention relates to compounds of the formula I, wherein B is a group of the formula 1_ or 8_ and A, ⁇ ⁇ . ⁇ , R 2, R3, Z1, Z2, q, Y1 and Y2 are as defined with respect to formula I, and pharmaceutically acceptable salts thereof.
  • R and R 2 are hydrogen and R3 is hydrogen or halogen.
  • the halogen is preferably fluorine.
  • a particularly preferred embodiment of the present invention relates to compounds of the formula I, wherein A is a group of the formula 1_, wherein one of the CH moieties at positions a and b of formula _1 may be replaced by a nitrogen atom, or A is a group of the formula 3_; B is a group of the formula ] ⁇ _ or Q_; R 1, R2, R 3, q, Y1 and Y2 are as defined for formula I; and n is
  • R 1, R2 and R4 are hydrogen and R 3 is hydrogen or halogen.
  • R3 is halogen, the halogen is preferably fluorine.
  • compositions of the present invention contain the foregoing preferred compounds. More preferred compositions of the present invention contain the foregoing more preferred compounds and specific preferred compounds. Detailed Description of the Invention Compounds of the present invention may be prepared as described below.
  • an aminonitrile of the formula II, wherein A is as defined above, is reacted with a ketone of the formula III wherein B is as defined above to prepare a ketimine of the formula IV.
  • the reaction is conducted in an inert solvent, preferably an aromatic solvent (e.g., benzene or toluene) , in the presence of an acid, preferably a strong acid (e.g. p-toluenesulfonic acid) .
  • the temperature should be at least about 100°C, but is otherwise not critical.
  • the reaction is conducted at the reflux temperature of the reaction mixture, e.g.
  • reaction pressure is not critical. Generally, the reaction will be conducted at a pressure of about 0.5 to about 2 atmospheres, preferably at ambient pressure (generally, about 1 atmosphere) .
  • the crude ketimine IV obtained after the removal of solvent is then reacted with a base (e.g., lithium diisopropylamide) in an inert solvent, preferably an anhydrous ether (e.g., tetrahydrofuran) , at a - temperature of about 0°C to about 25°C.
  • a base e.g., lithium diisopropylamide
  • an inert solvent preferably an anhydrous ether (e.g., tetrahydrofuran)
  • the reaction will be conducted at a pressure of about 0.5 to about 2 atmospheres, preferably at ambient pressure (generally, about 1 atmosphere) .
  • ambient pressure generally, about 1 atmosphere
  • the first method works especially well when an all carbon ketone is employed in the reaction.
  • Azeotropic removal (80°C, PTSA, 15 hours) of water from a benzene solution of nor ⁇ amphor (or an all carbon ketone) and anthranilonitrile afforded the corresponding ketimine 5 which on treatment with lithium diisopropylamide (0°C, 4 hours) in tetrahydrofuran afforded the compound of Example 1 in 25% yield.
  • the use of this procedure is also exemplified by the preparation of the compounds of Examples 2, 3, 4, 30 and 36.
  • the limitation in the general applicability of the first method is the difficulty of formation of ketimines from carbonyl compounds containing a nitrogen or oxygen atom. Titanium (IV) chloride, because of its high affinity for oxygen, has been used in the preparation of ketimines. (See H. Weingarten et al., J. Org. Che . , 32, 3246(1967)). This observation was adapted for the synthesis of 9-amino-l,2,3,4-tetrahydr- oacridine derivatives in a single step by the conden ⁇ sation of appropriate o-aminonitriles with diverse carbonyl components.
  • a compound of the formula II wherein A is defined as above is reacted with a carbonyl-containing compound of the formula III wherein B is as defined above.
  • the carbonyl-containing compound may be a ketone, a lactone, or the like.
  • the reaction is conducted in an inert solvent in the presence of a Lewis acid (e.g., titanium (IV) chloride) and, if necessary, in the presence of a base, preferably an amine base (e.g. triethylamine) .
  • Suitable solvents include aromatic solvents (e.g., benzene or toluene) and chlorinated solvents (e.g., methylene chloride or 1,2-dichloroethane) .
  • the reaction temperature should be at least about 0°C and is preferably about 25 to about 120°C.
  • the reaction pressure is not critical. Generally, the reaction will be conducted at a pressure of about 0.5 to about 2 atmospheres, preferably at ambient pressure (generally, about 1 atmosphere) .
  • condensation of delta- valerolactone with anthranilonitrile in methylene chloride by titanium (IV) chloride at 25°C in the presence of triethylamine (2 equivalents) afforded the compound of Example 7 (28%) .
  • the compounds of Formula I are capable of forming acid addition salts with pharmaceutically acceptable acids.
  • the acid addition salts may be prepared by reacting the base form of the appropriate compound of formula I with one or more equivalents, preferably with an excess, of the appropriate acid in an organic solvent, for example, diethyl ether or an ethanol diethyl ether mixture.
  • Suitable acids to form these salts include the common mineral acids, e.g. hydrohalic, sulfuric or phosphoric acid; the organic acids, e.g. ascorbic, citric, lactic, aspartic or tartaric acid or their aqueous solutions whose pH has been adjusted to 5.5 or less; and acids which are sparingly soluble in body fluids and which impart slow-release properties to their respective salts, e.g. pa oic or tannic acid or carboxymethyl cellulose.
  • the preferred salt is the hydrochloride salt.
  • the compounds of formula I and the pharmaceuti ⁇ cally acceptable salts thereof are useful in the treatment of various memory dysfunctions associated with decreased cholinergic function such as Alzheimer's Disease. Additionally, the compounds lead to stimula- tion of neuromuscular transmission, enhancement of excitation in excitable tissues (nerve, and smooth and striated muscle) as well as restoration of conductance in nerves and neuromuscular synapses in the case of injury thereof.
  • the compounds of this invention also exhibit antidepressant activities which is particularly helpful for patients suffering from Alzheimer's Disease.
  • the compounds of this invention are, in general, less toxic and have a broader therapeutic window than known compounds such as tacrine and physotigmine, making them therapeutically preferred.
  • the dosage of the compounds of the present invention will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject as well as the age, weight and condition of the subject under treatment as well as with the nature and extent of the symptoms. Generally, however, a dose in the range of about 1 to about 300 mg/day, taken in single or divided doses, will be administered. The preferred dose is in the range of from about 1 to about 150 mg/day in single or divided doses. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circum ⁇ stances is reached.
  • the compounds of the present invention are used alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard medical practice. For example, they are administered orally in the form of capsules, tablets, suspensions or solutions or they may be injected parenterally. Capsules and tablets are the preferred mode of administration. For parenteral administration, they can be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
  • Capsule and tablet compositions may contain the active ingredient in admixture with one or more pharmaceutical excipients suitable for the manufacture of capsules and tablets.
  • suitable pharmaceutical excipients are, for example, starch, milk sugar, and certain types of clay.
  • the tablets can be uncoated or they can be coated by known techniques so as to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • Aqueous suspensions of the compounds of formula I contain the active ingredient in admixture with one or more pharmaceutical excipients suitable for the manufacture of aqueous suspensions. Suitable excipients are, for example, methylcellulose, sodium alginate, gum acacia, lecithin and so forth. Aqueous suspensions can also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Non-aqueous suspensions can be formulated by suspending the active ingredient in a vegetable oil for example, arachis oil, olive oil, sesame oil, or coconut oil, or in mineral oil, for example liquid paraffin, and the suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. These compositions can also contain a sweetening agent, flavoring agent and antioxidant.
  • a vegetable oil for example, arachis oil, olive oil, sesame oil, or coconut oil, or in mineral oil, for example liquid paraffin
  • a thickening agent for example beeswax, hard paraffin or cetyl alcohol.
  • sweetening agent for example beeswax, hard paraffin or cetyl alcohol.
  • Example 1 9-Amino-l,2,3,4-tetrahydro-l,4-methanoacridine
  • Anthranilonitrile 3.6 g, 30.0 mmole
  • norcamphor 3.3 g, 30.0 mmole
  • para-toluenesulfonic acid 50 mg
  • the reaction mixture was then cooled (25°C) and the separated water (about 1.5 ml) was withdrawn.
  • the excess benzene was then removed under vacuum (1 mm Hg, 15 minutes) .
  • Example 2 9-Amino-8-fluoro-1,2,3,4-tetrahydro-l,4-methanoacridine Following the procedure of Example 1, but substi ⁇ tuting 2-amino-6-fluorobenzonitrile for anthranilo ⁇ nitrile, afforded the title compound (23%, m.p. 173°C) .
  • ⁇ s-NM (CDC1 3 , 300 MHz, f ) : 2H, m, 1.28-1.5 ppm; 1H, bd, 1.68 ppm; 1H, bd, 1.89 ppm; 2H, , 1.98-2.18 ppm;
  • Example 3 9-Amino-7-chloro-l,2,3, -tetrahydro-l,4-methanoacridine Following the procedure of Example 1, but substituting 2-amino-5-chlorobenzonitrile for anthranilonitrile, afforded the title compound (14%, m.p. 183-184°C) .
  • Example 5 9-Amino-2-oxa-l,2,3,4-tetrahydroacridine Anthranilonitrile (25 mmole, 2.95 g) , zinc chloride (3.1 g, 25 mmole) and tetrahydro-4H-pyran-4- one were dissolved in toluene (40 ml) and heated to reflux for 2.5 days. At the end of this period, the reaction mixture was cooled (25°C) , was quenched with aqueous sodium hydroxide (70 ml) and was extracted with methylene chloride (4 x 60 ml) . The combined organic phases were washed with water (2 x 100 ml) and dried (anhydrous MgSO.) .
  • the resulting orange solid (5.2 g) was placed in a beaker containing a saturated solution of EDTA (ethylene diamine tetracetic acid) in water (125 ml) 5 and the pH was adjusted to 13 with the help of 12% NaOH.
  • the aqueous phase was then extracted with methylene chloride (4 x 50 ml) which was washed with water (2 x 70 ml) and dried (MgSO.) . Removal of methylene chloride under vacuum afforded a yellow paste B (2.0 g) which was triturated with ether and filtered to afford a light yellow solid (1.36 g, 29%, m.p. 205°C dec) .
  • reaction mixture immediately became dark in color and was allowed to warm to room temperature (about 25°C) and stirred further for 15 hours.
  • the reaction mixture was treated with 25% aqueous NaOH (40 ml) and methylene chloride (100 ml) and was filtered through a 2 inch diatomaceous earth pad (Celite (trademark) ) which was washed with methylene chloride (50 ml) and water (100 ml) .
  • the organic layer was separated, washed once with water (30 ml) and dried (anhydrous MgSO.) .
  • the methylene chloride was removed under vacuum to afford an oil which was triturated with ether to give the title compound as a white solid (565 mg, 28%) .
  • Example 8 9-Amino-8-fluoro-4-oxa-l,2,3,4-tetrahydroacridine Following the procedure of Example 7, but substituting 2-amino-6-fluorobenzonitrile for anthranilonitrile afforded the title compound (8%, m.p. 195-196°C) .
  • Example 9 9-&mino-7-chloro-4-oxa-l,2,3,4-tetrahydroacridine Following the procedure of Example 7, but substituting 2-amino-5-chlorobenzonitrile for anthranilonitrile afforded the title compound (2%, m.p. 278-279°C) .
  • Example 11 9-Amino-2,3 ,7,8-tetrahydro-lH-cyclopenta[e] 6H-pyrano- [2'3 r -b] pyridine Following the method of Example 7 , but substituting 2-amino-l-cyano-l-cyclopentene for anthranilonitrile, afforded the title compound (22%, m.p. 164°C) .
  • Tetrahydrothiophen-3-one (1 ml) and titanium(IV) chloride (1.0 ml) was then added to the reaction mixture and the mixture was stirred at 25°C for 16 hours. Thereafter, the reaction mixture was quenched with 12% aqueous NaOH (100 ml) and the reaction mixture was then stirred vigorously with additional methylene chloride (300 ml) . The reaction mixture was then filtered through diatomaceous earth (Celite (trademark)) and the organic phase was separated. The organic solvents were removed under vacuum to afford a residue which was loaded on a flash chromatography column.
  • Example 13 9-Amino-l,2,3,4,5,6,7,8-octahydro-l,4-methanoacridine
  • norcamphor 0.9 g, 8.2 mmole
  • methylene chloride 8.0 ml
  • 2-amino-l-cyano-l-cyclohexene 1.0 g, 8.2 mmole
  • reaction mixture was then quenched with 12% aqueous NaOH (60 ml) and was stirred vigorously with methylene chloride (60 ml) .
  • the reaction mixture was then filtered through a 2" pad of diatomaceous earth (Celite (trademark) ) .
  • the organic phase was separated, washed with water (2 x 50 ml) and then dried (anhydrous MgSO.) .
  • Methylene chloride was then removed under reduced pressure to afford an oil which was triturated with pentane to give the title compound as a off-white solid (225 mg, 13%, m.p. 131-133°C) .
  • Example 14 9-Amino-6-aza-l,2,3,4-tetrahydroacridine Titanium(IV) chloride (1.5 ml) was added to a stirred solution of 3-amino-4-cyano-pyridine (500 mg, 4.2 mmole) and cyclohexanone (0.5 ml) in 1,2-dichloro- ethane (15 ml) . The reaction mixture was then main ⁇ tained at 90°C for 12 hours. At the end of this period, cyclohexanone (2.0 ml) and 1,2-dichloroethane (5.0 ml) were added to the reaction mixture and the heating was continued for another 12 hours.
  • Example 15 9-Amino-5-aza-l,2,3,4-tetrahydroacridine Following the method of Example 14, but substituting 2-amino-3-cyano-pyridine for 3-amino-4- cyano-pyridine, afforded the title compound (38%, m.p. 225-228°C dec) .
  • Example 17 9-Amino-4,6-oxaza-l,2,3,4-tetrahydroacridine Following the method of Example 16, but substi ⁇ tuting 3-amino-4-cyano-pyridine for 2-amino-3-cyano- pyridine, afforded the title compound (16%, m.p.
  • Example 18 9-Amino-5-aza-l,2,3,4-tetrahydro-l,4-methanoacridine Following the method of Example 16, but substituting norcamphor for delta- alerolactone afforded the title compound (29%, m.p. 243-244°C) .
  • Example 26 9-Amino-4-thia-l,2,3,4-tetrahydroacridine Following the method of Example 7, but substitut ⁇ ing delta-thiovalerolactone for delta-valerolactone afforded the title compound (4%,m.p.190°C) .
  • Example 29 9-Amino-8-fluoro-2-thia-l,2,3,4-tetrahydroacridine Following the method of Example 7, but substituting tetrahydrothiopyran-4-one for delta-valerolactone and 2-amino-6-fluorobenzonitrile for anthranilonitrile, afforded the title compound (19%, m.p. 175-176°C) .
  • Example 30 9-Amino-l,2,3,4-tetrahydro-l , 4-ethanoacridine Following the method of Example 1, but substituting bicyclo [2.2.2]octan-2-one for norcamphor afforded the title compound (20%, m.p. 1S7-199°C) .
  • Example 37 The ability of the title compounds of Examples 1-16, 18, 26-29, 35 and 36 to inhibit brain acetyl- cholinesterase was determined by the spectrophotometric method of G. L. Ellman et al. (Biochemical Pharmacology, 1_, 88 (1961)). All of the compounds had IC 5Q (molar) values between 5 uM and 0.1 ⁇ M.

Abstract

Compounds of formula (I) wherein R1, R2, A and B are defined hereinbelow. The compounds of the present invention inhibit brain acetylcholinesterase and are useful in the treatment of Alzheimer's disease.

Description

4-AMINOPYRIDINE DERIVATIVES
Background of the Invention
The present invention relates to 4-aminopyridine derivatives. The compounds of the present invention inhibit brain acetylcholinesterase and are useful in the treatment of Alzheimer's disease.
Tetrahydroaminoacridine, which has anticholine- sterase activity, has been reported to produce improved performance in psychological tests in patients afflicted with Alzheimer's disease (W. K. Summers et al., The New England Journal of Medicine, 315, 1241-1245 (1986)). The anticholinesterase physostigmine has also been reportedly used in the experimental treatment of Alzheimer's disease (S. D. Brinkman et al., Neurobiol. Aging, 4_, 139-145 (1983)).
The compounds described in the following four documents are alleged to have anticholinesterase activity:
United States Patent 4,652,567 refers to benzo(C)-1,5-naphthyridines for treating Alzheimer's disease.
United States Patent 4,631,286 refers to 9-amino-l,2,3,4-tetrahydroacridine-l-ol and related compounds for treating Alzheimer's disease.
United States Patent 4,550,113 refers to 9-amino- 2,3,5,6,7,8-hexahydro-lH-cyclopenta(b)quinoline mono- hydrate hydrochloride for treating neuritis, injuries of the peripheral nervous system, hereditary neuromus- cular diseases, and disseminated sclerosis.
United States Patent 4,578,394 refers to dihydropyridines for treating Alzheimer's disease. United States Patent 4,540,564 refers to dihydropyridines for delivering drugs to the brain.
G. K. Patnaik et al., J. Med. Chem. , 9_, 483-488 (1966), refer to 4-substituted 2,3-polymethylene- quinolines having analgetic, local anesthetic, analeptic, and respiratory stimulant activities.
British Patent Specifications 1,186,061, 1,186,062, and 1,186,063 refer to benzonaphthyridine derivatives.
Summary of the Invention
The present invention relates to compounds of the formula
R1 R2
\ /
N
wherein A is selec cted fmrom the group consisting of
d
Figure imgf000004_0001
a 1
Figure imgf000004_0002
wherein one of the CH moieties at positions a, b, c and d of formula 1_ may be replaced by a nitrogen atom or each of the CH moieties at positions a and d, a and c or b and d may be replaced by a nitrogen atom; B is selected from the group consisting of
Figure imgf000005_0001
Figure imgf000005_0002
10
wherein the broken line represents an optional double
1 bond; R is hydrogen or C,-Cfi alkyl;
R is independently selected from the group consisting of hydrogen, C--Cfi alkyl, C..-Cfi alkoxy, C,-C, alkanoyl, di(C1-C, alkylaminoJ-C.-Cg alkyl, C..-C
Figure imgf000005_0003
alkyl, halogen (e.g., fluoro, chloro, bromo or iodo) , hydroxy, nitro, phenyl, substituted phenyl, phenyl-C.-C, alkyl, substituted phenyl-C,-Cfi alkyl, diphenyl-C^-C8 alkyl wherein one or both of the phenyl groups may be replaced with a substituted phenyl group, furyl-C,-C8 alkyl, thienyl-C, -C - alkyl, phenyloxy, substituted fι 7 phenyloxy, NHCOR and NR R , wherein the phenyl moieties on the substituted phenyl and substituted phenylalkyl groups are substituted with one or more substituents selected from the group consisting of halogen (e.g., fluoro, chloro, bro o or iodo) , c-t-cg alkyl, trifluoro- methyl, C_ 1.-CΛO _-alko -xy-C S,.-C -jO-. alkyl, hydroxy and nitro, and wherein R , R and R are independently selected from C-±-C alkyl and C--C8 alkanoyl; R is independently selected from the group consisting of 1,4-dihydropyridyl- C-,-Cg alkanoyl, C^-Cg alky1-1,4-dihydropyridyl-C^-Cg- alkanoyl, and the possible definitions set forth above for R 3 t except that R2 cannot be hydroxy, halogen,
4
C^-C8 alkoxy, phenyloxy or substituted phenyloxy; R is independently selected from the possible definitions set forth above for R 3, except that R4 cannot be
5 6 7 1 halogen, nitro, NHCOR or NR R ; n is 1, 2 or 3; Z is
NH, 0, S or N 8 wherein R8 is C--C, alkyl or C_.-C^ alkanoyl; Z 2 is O or S; Z3 and Z14 a6re independe1ntl -y selected from (CH-) , 0, S, S=0 and S0_, with the proviso that at lea Pst one of Z3 and Z4 is CH„; Z5 is
6 CH2, 0, S, S=0 or S02; Z is 0, S, S=0 or S02 p is
1, 2 or 3; q is 1 or 2;
Y is CH9, CH0H, 0, C=0, S, S=0 or S0 ; and Y 2 is CH2, O, S, S=0 or S02, with the proviso that when
A is a group of"the formula 1^ wherein there is no nitrogen at position a, b, c or d or A is a group of the formula 3_ or 4_, only one of Y 1 and Y2 can be CH2; and pharmaceutically acceptable salts thereof. The present invention also relates to a pharmaceu¬ tical composition for the treatment of Alzheimer's disease comprising a compound of the formula I and to the use of compounds of the formula I in treating Alzheimer's disease. The present invention also relates to methods of preparing compounds of the formula I.
A preferred embodiment of the present invention relates to compounds of the formula I wherein A, B, Z ,
Z , Z , Z , Z and Z are as defined with respect to formula I; R 1, R2 and R4 are hydrogen; and R3 is hydrogen or halogen; and pharmaceutically acceptable
3 salts thereof. When R is halogen, the halogen is preferably fluorine.
Another preferred embodiment of the present invention relates to compounds of the formula I wherein
A is a group of the formula 1_, wherein one of the CH moieties at positions a and b of formula .1 may be replaced by a nitrogen atom, or A is a group of the formula 3_;
1 2 3 4 3 4 5 B, R , R , R , R , Z , Z , Z and q are as defined with respect to formula I; n is 1 or 2; Z is S; and p is 1 or 2; with the proviso that
(a) when A is a group of the formula 1_ wherein there is no nitrogen at either position a or position b, Z 3 is 0, S or CH9; R4 is hydrogen or C,-C, alkyl; Z 4 is (CH ) , wherein p is 1
1 ^ P 2 or 2, or S; Y is CH2, C=0, O, or S, and Y is CH,,, 0 or S, with the proviso that only
1 2 one of Y and Y can be CH2;
(b) when A is a group of the formula JL wherein there is a nitrogen at either position a or position b, Y 1 is O, S or CH2 and Y2 is CH2; and (c) when A is a group of the formula ~ , Y is 0,
S or CH2; and Y2 is CH2; and the pharmaceutically acceptable salts thereof. In a more preferred embodiment, R 1 , R2 and R4 are hydrogen and R 3 is hydrogen or halogen. When R3 is halogen, the halogen is preferably fluorine.
Another preferred embodiment of the present invention relates to compounds of the formula I, wherein B is a group of the formula 1_ or 8_ and A, ~\.~ , R 2, R3, Z1, Z2, q, Y1 and Y2 are as defined with respect to formula I, and pharmaceutically acceptable salts thereof. In a more preferred embodiment, R and R 2 are hydrogen and R3 is hydrogen or halogen. When R3 is halogen, the halogen is preferably fluorine.
A particularly preferred embodiment of the present invention relates to compounds of the formula I, wherein A is a group of the formula 1_, wherein one of the CH moieties at positions a and b of formula _1 may be replaced by a nitrogen atom, or A is a group of the formula 3_; B is a group of the formula ] ~_ or Q_; R 1, R2, R 3, q, Y1 and Y2 are as defined for formula I; and n is
1 or 2; with the proviso that
(a) when A is a group of the formula 1^ wherein there is no nitrogen at either position a or position b, Y 1 is CH~, C=0, 0 or S, and Y2 is CH_, 0 or S, with the proviso that only one of Y1 and Y2 can be CH2
(b) when A is a group of the formula 1_ wherein there is a nitrogen at either position a or position b, Y 1 is O, S or CH2 and Y2 is CH2; and
(c) when A is a group of the formula 3^, Y is 0,
2 S or CH2; and Y is CH2; and the pharmaceutically acceptable salts thereof. In a more preferred embodiment, R 1, R2 and R4 are hydrogen and R 3 is hydrogen or halogen. When R3 is halogen, the halogen is preferably fluorine.
Specific preferred compounds of the present invention are the following:
9-amino-l,2,3,4-tetrahydro-l,4-methanoacridine; 9-amino-8-fluoro-1,2,3,4-tetrahydro-l,4-methano- acridine;
9-amino-2-oxa-l,2,3,4,-tetrahydroacridine;
9-amino-2-thia-l,2,3,4-tetrahydroacridine;
9-amino-4-oxa-l,2,3,4-tetrahydroacridine; 9-amino-8-fluoro-4-oxa-l,2,3,4-tetrahydroacridine; 9-amino-4-oxa-l,2,3,4,5,6,7,8-octahydroacridine;
2,3-dihydrothieno [3,2-b]quinoline-9-amine;
9-amino-5-aza-l,2,3,4-tetrahydroacridine;
2,3-dihydro-8-fluoro-thieno [3,2-b]quinolin-9-amine; 1,3-dihydro-8-fluoro-thieno [3,4-b]quinolin-9-amine;
9-amino-l,2-dihydroacridine-4 (3H) -one;
9-amino-4-thia-l,2,3,4-tetrahydroacridine; and
9-amino-8-fluoro-2-thia-l,2,3,4-tetrahydroacridine.
Other compounds of the present invention are the following:
9-amino-4,5-thiaza-l,2,3, 4-tetrahydroacridine;
9-amino-4-thia-l,2,3,4,5,6,7,8-octahydroacridine;
9-amino-2-thia-l,2,3,4,5,6,7,8-octahydroacridine;
9-amino-2-oxa-l,2,3,4,5,6,7,8-octahydroacridine; 9-amino-5,7-diaza-l,2,3,4-tetrahydroacridine;
9-amino-3-methyl-7-phenyl-4-oxa-l,2,3,4-tetrahydro- acridine;
9-amino-7-trifluoromethyl-1,4-methano-l,2,3,4-tetra- hydroacridine; 9-amino-5, 8-diaza-l,4-methano-l,2,3,4-tetrahydro- acridine;
9-amino-l-thia-l,2,3,4-tetrahydroacridine;
9-amino-3-thia-l,2,3,4-tetrahydroacridine;
4-amino-5,6,7,8-tetrahydro-lH-imidazo [4,5-b]- quinoline;
4-amino-5,6,7,8-tetrahydro-oxazolo [4,5-b]quinoline;
4-amino-5,6,7,8-tetrahydro-thiazolo [4,5-b]quinoline; and
9-amino-l,2,3,4-tetrahydroacridine-4-ol. Preferred compositions of the present invention contain the foregoing preferred compounds. More preferred compositions of the present invention contain the foregoing more preferred compounds and specific preferred compounds. Detailed Description of the Invention Compounds of the present invention may be prepared as described below.
Scheme I
Figure imgf000010_0001
V
As shown in Scheme I, an aminonitrile of the formula II, wherein A is as defined above, is reacted with a ketone of the formula III wherein B is as defined above to prepare a ketimine of the formula IV. The reaction is conducted in an inert solvent, preferably an aromatic solvent (e.g., benzene or toluene) , in the presence of an acid, preferably a strong acid (e.g. p-toluenesulfonic acid) . The temperature should be at least about 100°C, but is otherwise not critical. Generally, the reaction is conducted at the reflux temperature of the reaction mixture, e.g. , by refluxing the reaction mixture in a Dean Stark apparatus, preferably for about 6 to about 16 hours, and removing the water periodically. The reaction pressure is not critical. Generally, the reaction will be conducted at a pressure of about 0.5 to about 2 atmospheres, preferably at ambient pressure (generally, about 1 atmosphere) . The crude ketimine IV obtained after the removal of solvent is then reacted with a base (e.g., lithium diisopropylamide) in an inert solvent, preferably an anhydrous ether (e.g., tetrahydrofuran) , at a - temperature of about 0°C to about 25°C. The reaction pressure is not critical. Generally, the reaction will be conducted at a pressure of about 0.5 to about 2 atmospheres, preferably at ambient pressure (generally, about 1 atmosphere) . ° The first method works especially well when an all carbon ketone is employed in the reaction. Azeotropic removal (80°C, PTSA, 15 hours) of water from a benzene solution of norσamphor (or an all carbon ketone) and anthranilonitrile afforded the corresponding ketimine 5 which on treatment with lithium diisopropylamide (0°C, 4 hours) in tetrahydrofuran afforded the compound of Example 1 in 25% yield. The use of this procedure is also exemplified by the preparation of the compounds of Examples 2, 3, 4, 30 and 36. The limitation in the general applicability of the first method is the difficulty of formation of ketimines from carbonyl compounds containing a nitrogen or oxygen atom. Titanium (IV) chloride, because of its high affinity for oxygen, has been used in the preparation of ketimines. (See H. Weingarten et al., J. Org. Che . , 32, 3246(1967)). This observation was adapted for the synthesis of 9-amino-l,2,3,4-tetrahydr- oacridine derivatives in a single step by the conden¬ sation of appropriate o-aminonitriles with diverse carbonyl components.
Thus, in a second method for preparing compounds of the present invention, a compound of the formula II wherein A is defined as above is reacted with a carbonyl-containing compound of the formula III wherein B is as defined above. The carbonyl-containing compound may be a ketone, a lactone, or the like. The reaction is conducted in an inert solvent in the presence of a Lewis acid (e.g., titanium (IV) chloride) and, if necessary, in the presence of a base, preferably an amine base (e.g. triethylamine) .
Suitable solvents include aromatic solvents (e.g., benzene or toluene) and chlorinated solvents (e.g., methylene chloride or 1,2-dichloroethane) . The reaction temperature should be at least about 0°C and is preferably about 25 to about 120°C. The reaction pressure is not critical. Generally, the reaction will be conducted at a pressure of about 0.5 to about 2 atmospheres, preferably at ambient pressure (generally, about 1 atmosphere) . Thus, for example, condensation of delta- valerolactone with anthranilonitrile in methylene chloride by titanium (IV) chloride at 25°C in the presence of triethylamine (2 equivalents) afforded the compound of Example 7 (28%) . This method was adopted for the synthesis of the compounds of Examples 7-19, 26-29, 31-33 and 35. The compounds of Examples 5 and 6 were prepared by condensing anthranilonitrile with the appropriate ketones in the presence of anhydrous zinc chloride at elevated temperature ( 140°C) . Monoalkylation of the amine group in compounds of the present invention may be achieved by heating them with appropriate alkyl halides in the presence of sodium hydride in dimethylformamide. This is exemplified by the synthesis of the compounds of Examples 20-25 and 34.
The compounds of Formula I are capable of forming acid addition salts with pharmaceutically acceptable acids. The acid addition salts may be prepared by reacting the base form of the appropriate compound of formula I with one or more equivalents, preferably with an excess, of the appropriate acid in an organic solvent, for example, diethyl ether or an ethanol diethyl ether mixture. Suitable acids to form these salts include the common mineral acids, e.g. hydrohalic, sulfuric or phosphoric acid; the organic acids, e.g. ascorbic, citric, lactic, aspartic or tartaric acid or their aqueous solutions whose pH has been adjusted to 5.5 or less; and acids which are sparingly soluble in body fluids and which impart slow-release properties to their respective salts, e.g. pa oic or tannic acid or carboxymethyl cellulose. The preferred salt is the hydrochloride salt.
The compounds of formula I and the pharmaceuti¬ cally acceptable salts thereof are useful in the treatment of various memory dysfunctions associated with decreased cholinergic function such as Alzheimer's Disease. Additionally, the compounds lead to stimula- tion of neuromuscular transmission, enhancement of excitation in excitable tissues (nerve, and smooth and striated muscle) as well as restoration of conductance in nerves and neuromuscular synapses in the case of injury thereof. The compounds of this invention also exhibit antidepressant activities which is particularly helpful for patients suffering from Alzheimer's Disease. The compounds of this invention are, in general, less toxic and have a broader therapeutic window than known compounds such as tacrine and physotigmine, making them therapeutically preferred.
In treating Alzheimer's disease, the dosage of the compounds of the present invention will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject as well as the age, weight and condition of the subject under treatment as well as with the nature and extent of the symptoms. Generally, however, a dose in the range of about 1 to about 300 mg/day, taken in single or divided doses, will be administered. The preferred dose is in the range of from about 1 to about 150 mg/day in single or divided doses. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circum¬ stances is reached. The compounds of the present invention are used alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard medical practice. For example, they are administered orally in the form of capsules, tablets, suspensions or solutions or they may be injected parenterally. Capsules and tablets are the preferred mode of administration. For parenteral administration, they can be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
Capsule and tablet compositions may contain the active ingredient in admixture with one or more pharmaceutical excipients suitable for the manufacture of capsules and tablets. Suitable pharmaceutical excipients are, for example, starch, milk sugar, and certain types of clay. The tablets can be uncoated or they can be coated by known techniques so as to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Aqueous suspensions of the compounds of formula I contain the active ingredient in admixture with one or more pharmaceutical excipients suitable for the manufacture of aqueous suspensions. Suitable excipients are, for example, methylcellulose, sodium alginate, gum acacia, lecithin and so forth. Aqueous suspensions can also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
Non-aqueous suspensions can be formulated by suspending the active ingredient in a vegetable oil for example, arachis oil, olive oil, sesame oil, or coconut oil, or in mineral oil, for example liquid paraffin, and the suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. These compositions can also contain a sweetening agent, flavoring agent and antioxidant. The following examples illustrate the preparation and properties of the compounds of the present invention. All melting points are uncorrected. Thin layer chromatography (TLC) was conducted on silica gel.
Example 1 9-Amino-l,2,3,4-tetrahydro-l,4-methanoacridine A solution of anthranilonitrile (3.6 g, 30.0 mmole) , norcamphor (3.3 g, 30.0 mmole) and para-toluenesulfonic acid (50 mg) in benzene (50 ml) was heated to reflux using a Dean Stark apparatus. After heating for 18 hours, the reaction mixture was then cooled (25°C) and the separated water (about 1.5 ml) was withdrawn. The excess benzene was then removed under vacuum (1 mm Hg, 15 minutes) . The oily residue thus obtained was dissolved in tetrahydrofuran (THF, 10 ml) and was cooled to 0°C and a solution of lithium diisopropylamide in THF (1M, 36 ml, 36 mmole) was then added. This reaction mixture was then stirred at 0°C for 3 hours. At the end of this period, the reaction mixture was quenched with 40 ml of water and was extracted with methylene chloride (200 ml) . The resulting organic phase was washed with water (2 x 50 ml) and dried (anhydrous MgSO .) . The methylene chloride was removed under vaccum to afford a residue which was loaded on a silica gel flash chromatography column. Elution with 5% methanol in methylene chloride containing 1% triethylamine afforded the title compound 1.6 g, 25%) as an oil which solidified on standing (m.p. 185-186°C) . "''H-NMR (CDC1-, 300 MHz,f ) : 2H, m, 1.22-1.42 ppm; 1H, d, 1.64 ppm (J = 7.0 Hz) ; 1H, d, 1.86 ppm (J = 6.0 Hz) ; 2H, m, 1.9-2.04 ppm; 2H, bd, 3.46 ppm; 2H, bs, 4.49 ppm; 1H, t, 7.38 ppm (J = 6.0 Hz) ; 1H, t, 7.55 ppm (J = 6.0 Hz) ; 1H, d, 7.67 ppm (J = 6.0 Hz) ; 1H, d, 7.92 ppm (J = 6.0 Hz) .
Example 2 9-Amino-8-fluoro-1,2,3,4-tetrahydro-l,4-methanoacridine Following the procedure of Example 1, but substi¬ tuting 2-amino-6-fluorobenzonitrile for anthranilo¬ nitrile, afforded the title compound (23%, m.p. 173°C) . ■ s-NM (CDC13, 300 MHz, f ) : 2H, m, 1.28-1.5 ppm; 1H, bd, 1.68 ppm; 1H, bd, 1.89 ppm; 2H, , 1.98-2.18 ppm;
2H, bs, 3.5 ppm; 2H, bs, 5.18 ppm; 1H, dd, 7.0 ppm (J = 12.5, 8.0 Hz) ; 1H, m, 7.44 ppm (J = 12.5, 8.0 HZ) ; 1H, d, 7.75 ppm (J = 8.0 Hz) . HRMS: Calculated - 228.1062; Found - 228.1049. TLC: (90:1 :1-methylene chloride:methanol:28% aqueous ammonia) R - = 0.7.
Example 3 9-Amino-7-chloro-l,2,3, -tetrahydro-l,4-methanoacridine Following the procedure of Example 1, but substituting 2-amino-5-chlorobenzonitrile for anthranilonitrile, afforded the title compound (14%, m.p. 183-184°C) . 1H-NMR (CDC13 , 300 MHz, ) : 2H, m, 1.3-1.56 ppm; 1H, bd, 1.65 ppm; 1H, bd, 1.92 ppm; 2H, m, 1.98-2.18 ppm; 1H, bs, 3.5 ppm; 1H, bs, 3.54 ppm; 2H, bs, 4.45 ppm; 1H, dd, 7.5 ppm (J = 2, 9.0 Hz) ; Ih, d, 7.65 ppm (J = 2 Hz) ; IH, d, 7.84 ppm (J = 9.0 Hz) . HRMS: Calculated - 244.0767; Found - 244.0750. TLC: (90:10:1-methylene chloride:methanol:28% aqueous ammonia) R- = 0.7. Example 4
9-Amino-l,4-dihydro-l,4-methanoacridine Following the procedure of Example 1, but substituting 5-norbornen-2-one for norcamphor, afforded the title compound (26%, m.p. 123°C) . H-NMR (CDC13, 300 MHz, f) : IH, d, 2.4 ppm (J = 8.0 Hz) , IH, dt, 2.5 ppm (J = 1.7, 8.0 Hz) ; IH, bs, 3.88 ppm; IH, bs, 4.07 ppm; IH, bs, 4.46 ppm, 2H, s, 6.86 ppm; IH, t, 7.44 ppm (J = 8.0 Hz) ; IH, t, 7.6 ppm (J = 8.0 Hz) ; IH, d, 7.68 ppm (J = 8.0 Hz) ; IH, d, 7.94 ppm (J = 8.0 Hz) . HRMS: Calculated - 208.2622; Found - 208.0974.
TLC: (90:10 : 1-methylene chloride:methanol:28% aqueous ammonia) Rf = 0.57.
Example 5 9-Amino-2-oxa-l,2,3,4-tetrahydroacridine Anthranilonitrile (25 mmole, 2.95 g) , zinc chloride (3.1 g, 25 mmole) and tetrahydro-4H-pyran-4- one were dissolved in toluene (40 ml) and heated to reflux for 2.5 days. At the end of this period, the reaction mixture was cooled (25°C) , was quenched with aqueous sodium hydroxide (70 ml) and was extracted with methylene chloride (4 x 60 ml) . The combined organic phases were washed with water (2 x 100 ml) and dried (anhydrous MgSO.) . The organic solvents were removed under vacuum to yield a yellow residue which was loaded on a silica gel flash chromatography column. Elution with 5% methanol in methylene chloride afforded the title compound as yellow crystals (155 mg, 31%, m.p. 195-196°C) . 1H-NMR (CDC13 , 300 MHz, ) : 2H, t, 3.08 ppm (J = 6.0 Hz) ; 2H, t, 4.06 ppm (J = 6.0 Hz) ; 2Hr bs, 4.47 ppm; 2H, s, 4.74 ppm; IH, t, 7.34 (J = 8.0 Hz) ; 1H, t, 7.54 (J = 8.0 Hz) ; IH, d, 7.64 (J = 8.0 Hz) ; IH, d, 7.84 (J - 8.0 Hz) . TLC: (TLC plate pretreated with 2% triethylamine in hexane; eluant: 5% methanol in methylene chloride) R_ = 0.25. 5 Example 6
9-Amino-2-thia-l,2,3,4-tetrahydroacridine Anthranilonitrile (2.6 g, 21.5 mmole) , tetrahydro- thiopyran-4-one (5.0 g, 43 mmole) and zinc chloride (2.54 g, 21.5 mmole) were combined and heated to 120°C 0 for 20 minutes. The reaction mixture was cooled and the solid residue was filtered using ethyl ether (100 ml) . The resulting orange solid (5.2 g) was placed in a beaker containing a saturated solution of EDTA (ethylene diamine tetracetic acid) in water (125 ml) 5 and the pH was adjusted to 13 with the help of 12% NaOH. The aqueous phase was then extracted with methylene chloride (4 x 50 ml) which was washed with water (2 x 70 ml) and dried (MgSO.) . Removal of methylene chloride under vacuum afforded a yellow paste B (2.0 g) which was triturated with ether and filtered to afford a light yellow solid (1.36 g, 29%, m.p. 205°C dec) . H-NMR (CDC13, 300 MHz, f) : 2H, 5, 3.0 ppm (J = 6.0 Hz) ; 2H, t, 3.35 ppm (J = 6.0 Hz) ; 2H, s, 3.72 ppm; 2H, bs, 4.69 ppm; IH, t, 7.4 (J = 8.0 Hz) ; IH, t, 5 7.6 (J = 8.0 Hz) ; IH, d, 7.69 (J = 8.0 Hz) ; IH, d, 7.88 (J = 8.0 Hz) . HRMS: Calculated - 216.0719; Found - 216.0688. TLC: (TLC plate pretreated with 2% triethylamine in hexane; eluant:5% methanol in methylenechloride) - = 0.23. 0 Example 7
9-Amino-4-oxa-l,2,3,4-tetrahydroacridine To a stirred solution of delta-valerolactone (1.0 g, 10.0 mmole) in methylene chloride (10 ml) at -20°C, a 1M solution of titanium(IV) chloride in methylene 5 chloride (20 ml) was added. The reaction mixture became dark yellow in color and to it a mixture of triethylamine (2.0 g, 20 mmole) and anthranilonitrile (1.2 g, 10.0 mmlole) in methylene chloride (30 ml) were added. The reaction mixture immediately became dark in color and was allowed to warm to room temperature (about 25°C) and stirred further for 15 hours. At the end of this period, the reaction mixture was treated with 25% aqueous NaOH (40 ml) and methylene chloride (100 ml) and was filtered through a 2 inch diatomaceous earth pad (Celite (trademark) ) which was washed with methylene chloride (50 ml) and water (100 ml) . The organic layer was separated, washed once with water (30 ml) and dried (anhydrous MgSO.) . The methylene chloride was removed under vacuum to afford an oil which was triturated with ether to give the title compound as a white solid (565 mg, 28%) . H-NMR (CDC13, 300 MHz, J") : 2H, m, 2.02-2.18 ppm; 2H, t, 2.63 ppm (J = 6.0 Hz); 2H, t, 4.36 ppm (J = 6.0 Hz); 2H, s, 4.64 ppm; IH, t, 7.25 (J = 8.0 Hz); IH, t, 7.5 (J = 8.0 Hz); IH, d, 7.72 (J = 8.0 Hz).
HRMS: Calculated - 200.2396; Found - 200.0945. Analysis: Calculated for C12H12 20: 71.98%C; 6.04%H; 13.99%N. Found: 70.91%C; 6.01%H; 14.19%N. TLC: (90:10:1-methylene chloride:methanol:28% aqueous ammonia) Rf = 0.45.
Example 8 9-Amino-8-fluoro-4-oxa-l,2,3,4-tetrahydroacridine Following the procedure of Example 7, but substituting 2-amino-6-fluorobenzonitrile for anthranilonitrile afforded the title compound (8%, m.p. 195-196°C) . 1H-NMR (CDC13, 300 MHz, f ) : 2H, , 2.06-2.2 ppm; 2H, t, 2.6 ppm (J = 6.0 Hz); 2H, t, 4.37 ppm (J = 6.0 Hz); 2H, bs, 5.4 ppm; IH, dd, 6.88 (J = 14.0,7.5 Hz); IH, , 7.3-7.44; IH, d, 7.56 (J = 8.6 Hz). HRMS: Calculated - 218.0801; Found - 218.0284 TLC: (90:10:1-methylene chloride:methanol:28% aqueous ammonia) R,- = 0.7.
Example 9 9-&mino-7-chloro-4-oxa-l,2,3,4-tetrahydroacridine Following the procedure of Example 7, but substituting 2-amino-5-chlorobenzonitrile for anthranilonitrile afforded the title compound (2%, m.p. 278-279°C) .1H-NMR(CDC13, 300 MHz, f) : 2H, m, 2.06-2.2 ppm; 2H, 5, 2.66 ppm (J = 6.0 Hz) ; 2H, t, 4.37 ppm (J = 6.0 Hz); 2H, bs, 4.61 ppm; IH, dd, 7.45 (J = 9.0,
1.0 Hz) ; IH, bs, 7.58 ppm (J =~-l Hz) ; IH, d, 7.66 (J = 9.0 Hz) . HRMS: Calculated - 234.056; Found - 234.0566. TLC: (90:10:1-methylene chloride:methanol:28% aqueous ammonia) R^ = 0.6. Example 10
9-Amino-4-oxa-l,2,3,4,5,6,7,8-octahydroacridine Following the method of Example 7, but substituting 2-amino-l-cyano-l-cyclohexene for anthranilonitrile, afforded the title compound (8%, m.p. 145°) . - a- MR (CDC13 300 MHz, if) : 4H, m,
1.65-1.9 ppm; 2H, q, 2.07 ppm (J = 6.0 Hz) ; 2H, t, 2.4 ppm (J = 6.0 Hz); 2H, t, 2.5 ppm (J = 6.0 Hz) ; 2H, t, 2.76 ppm (J = 6.0 Hz) ; 4H, bt, 4.26 ppm. HRMS: Calculated - 204.2712; Found - 204.1227. TLC: (90:10:1-methylene chloride:methanol:28% aqueous ammonia) Rf = 0.46.
Example 11 9-Amino-2,3 ,7,8-tetrahydro-lH-cyclopenta[e] 6H-pyrano- [2'3r-b] pyridine Following the method of Example 7 , but substituting 2-amino-l-cyano-l-cyclopentene for anthranilonitrile, afforded the title compound (22%, m.p. 164°C) . " s-NMR (CDC13, 300 MHz, ) : 4H, m, 2.0-2.2 ppm; 2H, t, 2.48 ppm (J = 6.0 Hz) ; 2H, t, 2.68 ppm (J = 6.0 Hz) ; 2H, t, 2.87 ppm (J = 6.0 Hz) ; 2H, bs, 4.06 ppm (J = 6.0 Hz); 2H, t, 4.24 ppm. HRMS: Calculated - 190.1107; Found - 190.1107. TLC: (90:10:1-methylene chloride methanol:28% aqueous ammonia) R- = 0.86. Example 12
2,3-Dihydrothieno[3,2-b]quinolin-9-amine To a stirred solution of tetrahydrothiophen-3-one (1.1 g, 11 mmole) in methylene chloride (10 ml) at -78°C, a 1M solution of titanium(IV) chloride in methylene chloride (11 ml) was added. A mixture of triethylamine (2.2 g, 22 mmole) and anthranilonitrile (1.2 gms, 10.0 mmole) in methylene chloride (30 ml) was then added to the reaction mixture over a period of 5 minutes. The reaction mixture was then slowly warmed to room temperature and stirred for 2 hours.
Tetrahydrothiophen-3-one (1 ml) and titanium(IV) chloride (1.0 ml) was then added to the reaction mixture and the mixture was stirred at 25°C for 16 hours. Thereafter, the reaction mixture was quenched with 12% aqueous NaOH (100 ml) and the reaction mixture was then stirred vigorously with additional methylene chloride (300 ml) . The reaction mixture was then filtered through diatomaceous earth (Celite (trademark)) and the organic phase was separated. The organic solvents were removed under vacuum to afford a residue which was loaded on a flash chromatography column. Elution with 5% methanol in methylene chloride containing 1% triethylamine, afforded the title compound (1.3 gms, 64%) which was crystallized from chloroform (560 mg, 32%, m.p. 208-210°C) . 1H-NMR
(CDC1 , 300 MHz, f ): 4H, m, 3.4-3.56 ppm; 2H, bs, 4.51 ppm; IH, dt, 7.37 ppm (J = 7.0, 1.0 Hz); IH, dt, 7.52 ppm (J = 7.0, 1.10 ppm); IH, dd, 7.61 ppm (J = 7.0, 1.0 ppm); IH, dd, 7.61 ppm (J = 7.0, 1.0 ppm), IH, dd, 7.86 ppm (J = 7.0, 1.0 ppm). HRMS: Calculated - 202.0575; Found - 202.0545. Analysis: Calculated for cιιH ιn N2S: 65.32%C; 4.98%H; 13.85%N; 15.85%S. Found: 65.06%C; 5.00%H; 13.79%N; 15.63%S.
Example 13 9-Amino-l,2,3,4,5,6,7,8-octahydro-l,4-methanoacridine To a stirred solution of norcamphor (0.9 g, 8.2 mmole) in methylene chloride (8.0 ml) at -20°C, a mixture of triethylamine (1.7 g, 16.4 mmole) and 2-amino-l-cyano-l-cyclohexene (1.0 g, 8.2 mmole) in methylene chloride (24 ml) was added and the resulting mixture was stirred at 25°C for 15 hours. The reaction mixture was then quenched with 12% aqueous NaOH (60 ml) and was stirred vigorously with methylene chloride (60 ml) . The reaction mixture was then filtered through a 2" pad of diatomaceous earth (Celite (trademark) ) . The organic phase was separated, washed with water (2 x 50 ml) and then dried (anhydrous MgSO.) . Methylene chloride was then removed under reduced pressure to afford an oil which was triturated with pentane to give the title compound as a off-white solid (225 mg, 13%, m.p. 131-133°C) . XH-NMR (CDC13, 300 MHz, f) : 2H, m, 1.15-2.38 ppm; IH, , 1.5 ppm; 7H, m, 165-2.0 ppm; 2H, bs, 2.4 ppm; 2H, bd, 2.8 ppm; 2H, bd 3.3 ppm; 2H, s, 3.95 ppm. HRMS: Calculated - 214.3096; Found - 214.1466. TLC: ( 0:10:1-methylene chloride: methanol:28% aqueous ammonia) R_ = 0.25
Example 14 9-Amino-6-aza-l,2,3,4-tetrahydroacridine Titanium(IV) chloride (1.5 ml) was added to a stirred solution of 3-amino-4-cyano-pyridine (500 mg, 4.2 mmole) and cyclohexanone (0.5 ml) in 1,2-dichloro- ethane (15 ml) . The reaction mixture was then main¬ tained at 90°C for 12 hours. At the end of this period, cyclohexanone (2.0 ml) and 1,2-dichloroethane (5.0 ml) were added to the reaction mixture and the heating was continued for another 12 hours. Additional cyclohexanone (2.0 ml) and titanium tetrachloride (1.2 ml) were then added and the reaction mixture was maintained at 90°C for 6 hours. The reaction mixture was then cooled and was quenched with 5% aqueous NaOH (250 ml) and was stirred vigorously with methylene chloride (200 ml, 25 minutes) . The reaction mixture was then treated as in Example 8 to afford the title compound (170 mg, 95% pure, 20%) after flash chromatography on silica gel (eluant:95 :5: 1; methylene chloride: methanol:ammonium hydroxide. This material was further purified by chromatography to afford the title compound (75 mg, m.p. 180-181°C) . 1H-NMR (CDC13 + CD3OD, 300 Hz, f ) : 4H, m, 1.9 ppm; 2H, bt, 2.54 ppm; 2H, s, 2.9 ppm; 2H, bt, 2.94 ppm; IH, d, 7.52 ppm (J = 6.0 HZ) ; IH, d, 8.24 ppm (J = 6.0 Hz) ; IH, s, 9.06 ppm. HRMS: Calculated - 199.1109; Found - 199.1079.
Example 15 9-Amino-5-aza-l,2,3,4-tetrahydroacridine Following the method of Example 14, but substituting 2-amino-3-cyano-pyridine for 3-amino-4- cyano-pyridine, afforded the title compound (38%, m.p. 225-228°C dec) . 1H-NMR (CDC13+CD30D, 300 MHz , J") : 4H, bs, 1.86 ppm; 2H, bt, 2.5 ppm; 2H, bt, 2.97 ppm; 2H, vbs, 3.0-3.3 ppm; IH, dd, 7.2 ppm (J = 8.0, 4.0 Hz) ;
IH, dd, 8.18 ppm (J = 8.0, 1-2 Hz); IH, dd, 8.77 ppm (J = 4.0, 1-2 Hz) . HRMS: Calculated - 199.1109; Found - 199.1102.
Example 16 9-Amino-4 ,5-oxaza-l,2,3,4-tetrahydroacridine
To a stirred solution of 2-amino-3-cyano-pyridine (360 mg, 3.0 mmole) and delta-valerolactone (360 mg, 3.6 mmole) in 1 , 2-dichloroethane (7.0 ml) , titaniu (IV) chloride (0.9 ml) was added and then the reaction mixture was maintained at 90°C for 18 hours. The reaction mixture was then quenched with 15% aqueous NaOH (200 ml) and was stirred vigorously with methylene chloride (200 ml, 25 minutes) . The reaction mixture was then worked up as in example 15 to afford the title compound (8%, m.p. 269-270°C dec) . H-NMR (CDC13+CD30D, 300 MHz, ) : 2H, q, 2.04 ppm (J = 6.5 Hz) ; 2H, t, 2.57 ppm (J = 6.5 ppm) ; 2H, bs, 3.76 ppm; 2H, t, 4.28 ppm (J = 6.5 Hz) ; IH, dd, 7.11 ppm (J = 8.0, 4.0 Hz); IH, dd, 8.16 ppm (J = 8.0, 1-2 Hz) ; IH, dd, 8.64 ppm (J = 4.0, 1-2 Hz) .HRMS: Calculated - 201.0902; Found - 201.0864.
Example 17 9-Amino-4,6-oxaza-l,2,3,4-tetrahydroacridine Following the method of Example 16, but substi¬ tuting 3-amino-4-cyano-pyridine for 2-amino-3-cyano- pyridine, afforded the title compound (16%, m.p.
237-238°C) . 1H-NMR (CDC13+CD30D, 300 MHz, f ) : 2H, q, 2.06 ppm (J = 6.5 Hz) ; 2H, t, 2.59 ppm (J = 6.5 ppm); 2H, s, 3.56 ppm; 2H, t, 4.3 ppm (J = 6.5 Hz) ; IH, d, 7.56 ppm (J = 6.0 Hz) ; IH, d, 8.18 ppm (J = 6.0 Hz) ; IH, s, 8.84 ppm. HRMS: Calculated - 201.0902; Found - 201.0892.
Example 18 9-Amino-5-aza-l,2,3,4-tetrahydro-l,4-methanoacridine Following the method of Example 16, but substituting norcamphor for delta- alerolactone afforded the title compound (29%, m.p. 243-244°C) . 1H-NMR (CDC13+CD30D, 300 MHz, £ ) : 2H, m, 1.2-1.4 ppm; IH, bd, 1.6 ppm (J = 6.0 Hz) ; IH, bd, 1.81 ppm (J = 6.0 Hz); 2H, m, 1.88-2.04 ppm; 2H, bs, 3.26 ppm; IH, bs, 3.43 ppm; IH, bs, 3.48 ppm; IH, dd, 7.23 ppm (J = 8.03, 3.0 Hz) ; IH, d, 8.17 ppm (J = 8.0 Hz) ; IH, d, 8.76 ppm (J = 3.0' Hz) . HRMS: Calculated - 211.1109. Found - 211.1120. Example 19 9-Amino-6-aza-l,2,3,4-tetrahydro-l , 4-methanoacridine
Following the method of Example 16, but substituting norcamphor for delta-valerolactone and 3-amino-4-cyano-pyridine for 2-amino-3-cyano-pyridine, afforded the title compound (16%, m.p. 236-237°C) . 1H-NMR (CDC13+CD30D, 300 MHz, $ ) : 2H, bq, 1.3 ppm; IH, bd, 1.62 ppm; IH, bd, 1.83 ppm; 2H, m, 1.9-2.1 ppm; 2H, s, 3.4 ppm; IH, bs, 3.42 ppm; IH, bs, 3.5 ppm; IH, d, 7.6 ppm (J = 6.0 Hz) ; IH, d, 8.31 ppm (J = 6.0 Hz) ; IH, s, 9.07 ppm. HRMS: Calculated - 211.1109; Found - 211.1103.
Example 20 9-Cyclohexylmethylamino-8-fluoro-4-oxa-l,2,3, 4-tetra- hydroacridine
A mixture of sodium hydride (60% oil, 110 mg, 2.75 mmole) , the title compound of Example 6 (600 mg, 2.75 mmole, cyclohexylmethyl bromide (487 mg, 2.75 mmole) and dimethylformamide (3.0 ml) were heated with stirring at 25°C for 12 hours and then at 65°C for 12 hours. At the end of this period, the reaction mixture was quenched by pouring it into water (45 ml) and the resulting mixture was then extracted with ethyl acetate (3 x 35 ml) . The combined organic layer was washed with water (2 x 40 ml) and dried (anhydrous MgS04) .
The ethyl acetate was removed under vacuum to afford a residue which was loaded on a flash chromatography column packed with silica gel. Elution with ethyl acetate afforded an oil which solidified on standing. Trituration of this solid with pentane afforded the title compound (110 mg, 13%) as a tan. crystalline solid (m.p. 100°C) . 1H-NMR (CDC1, , 300 MHz £ ) : 2H, m, 0.9-1.04 ppm; 3H, , 1.04-1.32 ppm; 6H, , 1.6-1.86 ppm; 2H, m, 1.88-2.04 ppm; 2H, t, 2.79 ppm (J = 6.0 Hz) ; 2H, bs, 3.17 ppm; 2H, t, 4.38 ppm (J = 6.0 Hz) ; 1H, bd, 5.79 ppm (J = 20 Hz) ; IH, dd, 6.84 ppm (J = 140, 7.5 Hz) ; IH, dd, 7.32 ppm; IH, d, 7.48 ppm (J = 8.2 Hz) . HRMS: Calculated - 314.1759; Found - 314.1787. TLC: (ethylacetate) Rf = 0.35. Example 21
9-Cyclohexylethylamino-8-fluoro-4-oxa-l,2,3,4-tetrahydro- acridine
Following the method of Example 20, but substi¬ tuting cyclohexylethyl bromide for cyclohexylmethyl bromide, afforded the title compound (34%) . H-NMR (CDC13, 300 MHz, £) : 2H, m, 0.8-1.02 ppm; 4H, m, 1.02-1.4 ppm; 2H, m, 1.44-1.56 ppm; 5H, bd, 1.56-1.8 ppm; 2H, q, 1.92-2.04 ppm (J = 6.0 Hz); 2H, t, 2.8 ppm (J = 6 Hz); 2H, bt, 3.33 ppm; 2H, t, 4.36 ppm (J = 6 Hz) ; IH, bd, 5.6 ppm (J = 20 Hz) ; IH, dd, 6.38 ppm (J = 14.0, 7.5 Hz) ; IH, dd, 7.24-7.38 ppm; IH, d, 7.48 ppm (J = 8.2 Hz) . HRMS: Calculated - 328.1951; Found - 328.1909. Analysis: Calculated for C2QH25 2OF:73.14%C; 7.67%H; 8.53%N. Found: 73.23%C; 7.93%H; 8.52%N. TLC: (ethyl acetate) Rf = 0.45.
Example 22 9-Benzylamino-8-fluoro-4-oxa-l,2,3,4-tetrahydroacridine
Following the method of Example 20, but substituting benzyl bromide for cyclohexylmethyl bromide, afforded the title compound (38%, m.p.
134-135°C) . ^Η-NMR (CDC13, 300 MHz, J" ) : 2H, q, 1.98 ppm (J = 6 Hz) ; 2H, t, 2.87 ppm (J = 6.0 Hz) ; 2H, t, 4.37 ppm (J = 6 Hz) ; 2H, bs, 4.48 ppm; IE, bd, 5.87 ppm (J = 20 Hz) ; IH, dd, 6.84 ppm (J = 14, 7.5 Hz) ; 6H, m, 7.22-7.4 ppm; IH, d, 7.52 ppm (J = 8.2 Hz) . HRMS: Calculated - 308.1325; Found - 308.1316. Analysis: Calculated for C^^ N OF:74.01%C; 5.56%H; 9.08%N. Found: 73.68%C; 5.61%H; 9.01%N. TLC: (ethyl acetate) Rf = 0.37. Example 23
9-Phenethylamino-8-fluoro-4-oxa-l,2,3,4-tetrahydro- acridine
Following the method of Example 20 but substituting (2-bromoethyl)benzene for cyclohexylmethyl bromide afford the title compound (20%, m.p. 125-126°C) .
1H-NMR (CDC13, 300 MHz, f ) : 2H, q, 1.92 ppm (J = 6
Hz); 2H,- t, 2.69 ppm (J = 6.0 Hz); 2H, m, 2.9-3.0 ppm;
2H, bt, 3.38 ppm; 2H, m, 4.3-4.42 ppm; IH, bd, 5.96 ppm (J = 20 Hz); IH, dd, 6.78 ppm (J = 14, 7.5 Hz); IH, d,
7.14 ppm (J = 8.6 Hz); 6H, m, 7.22-7.4 ppm. HRMS:
Calculated - 322.3809; Found- 322.1486. TLC: (ethyl acetate) Rf = 0.53.
Example 24 9-Phenpropylamino-8-fluoro-4-oxa-l,2,3,4-tetrahydro- acridine
Following the method of Example 20, but substituting l-bromo-3-phenylpropane for cyclohexylmethyl bromide,
1 afforded the title compound (53% oil) . H-NMR (CDC13, 300 MHz, ) : 4H, m, 1.82-2.02 ppm; 4H, m, 2.62-2.78 ppm; 2H, bs, 2.34 ppm; 2H, t, 4.35 ppm (J = 6.0 Hz); IH, bd, 5.7 ppm (J = 20 Hz); IH, dd, 6.86 ppm (J = 14, 7.5 Hz); 6H, , 7.04-7.4 ppm; IH, d, 7.51 ppm (J = 8.2 Hz). HRMS: Calculated - 336.1638; Found - 336.1649. TLC: (ethyl acetate) Rf = 0.38.
Example 25 9-(3,3-Diphenylpropylamino) -8-fluoro-4-oxa-l,2,3,4- tetrahydroacridine
Following the method of Example 20, but substitu- ting l-bromo-3,3-diphenylpropane for cyclohexylmethyl bromide, afforded the title compound (32%, m.p. 134-135°C) . 1H-NMR (CDC13, 300 MHz, ) : 2H, q, 1.9 ppm (J = 6 Hz); 2H, q, 2.36 ppm (J = 6.0 Hz); 2H, t, 2.51 ppm (J = 6 Hz); 2H, bs, 3.32 ppm; IH, t, 4.0 (J = 6 Hz); 2H, t, 4.31 ppm (J = 6 Hz); IH, bs, 5.72 ppm (J = 20 Hz) ; IH, dd, 6.9 ppm (J = 14.0, 7.5 Hz) ; 10H, m, 7.1-7.3 ppm; IH, dd, 7.3-7.4 ppm; IH, d, 7.52 ppm (J = 8.2 Hz) . HRMS: Calculated - 412.1951; Found - 412.2004. Analysis: Calculated for C27H25 2O :78.62%c 6.11%H; 6.79%N. Found: 78.08%C; 5.95%H; 6.70%N. TLC: (ethyl acetate) R - = 0.48.
Example 26 9-Amino-4-thia-l,2,3,4-tetrahydroacridine Following the method of Example 7, but substitut¬ ing delta-thiovalerolactone for delta-valerolactone afforded the title compound (4%,m.p.190°C) . H-NMR (CDC13, 300 MHz,^) : 2H, m, 2.22-2.3 ppm; 2H, t, 2.73 ppm
Figure imgf000028_0001
Hz) ; 2H, m, 3.1-3.2 ppm; 2H, bs, 4.66 ppm; IH, t, 7.32 ppm (J=8 Hz) ; IH, t, 7.54 ppm (J=8 Hz) ; 1 H, d, 7.62 ppm (J=8 Hz) ; IH, d, 7.8 ppm (J=8 Hz) . HRMS: Calculated - 216.0723; Found - 216.0735. TLC: (90:10:1-methylene chloride : methanol : 28% aqueous ammonia) R--0.61. Example 27
9-Amino-3-methyl-4-oxa-l,2,3,4-tetrahydroacridine Following the method of Example 7, but substituting 6-methyl-tetrahydropyran-2-one for delta-valerolactone, afforded the title compound (23%,m.p.202-203°C) . 1H-NMR (CDC1.,, 300 MHz,«f) : 3H, d, 1.45 ppm (J=6.5 Hz) ; IH, m, 1.7-1.84 ppm; IH, m, 2.04-2.18 ppm; 2H, m, 2.58-2.64 ppm; IH, m, 4.22-4.36 ppm; 2H, bs, 4.69ppm; IH, t, 7.22 ppm (J=7.5 Hz) ; IH, t, 7.47 ppm (J=7.5 Hz) ; IH, d, 7.58 ppm (J=7.5 Hz) ; IH, d, 7.71 ppm (J=7.5 Hz) . HRMS: Calculated - 214.269; Found - 214.1138. Example 28 9-Amino-3-methyl-8-fluoro-4-oxa-l,2,3, 4-tetrahydroacri- dine
Following the method of Example 7, but substituting 6-methyl-tetrahydropyran-2-one for delta-valerolactone and 2-amino-6-fluorobenzonitrile for anthranilonitrile afforded the title compound (13%, m.p. 217-218°C) . ^Η-NMR (CDC13, 300 MHz,if) : 3H, d, 1.45 ppm (J= 6.5 Hz) ; IH, m, 2.65-2.84 ppm; IH, m, 2.06-2.19 ppm; 2H, m, 2.5-2.6 ppm: IH, m, 4.21-4.38 ppm; 2H, bs, 5.25 ppm; IH, dd, 6.8 ppm (J=7.5, 14 Hz) ; IH, dd, 7.32 ppm (J=8 Hz, 14.0 Hz) ; IH, d, 7.5 ppm (J=8 Hz) . HRMS: Calculated - 232.1026; Found - 232.1012 TLC: (90:10: 1-methylene chloride : methanol : 28% aqueous ammonia) R--0.76.
Example 29 9-Amino-8-fluoro-2-thia-l,2,3,4-tetrahydroacridine Following the method of Example 7, but substituting tetrahydrothiopyran-4-one for delta-valerolactone and 2-amino-6-fluorobenzonitrile for anthranilonitrile, afforded the title compound (19%, m.p. 175-176°C) . 1H-NMR (CDC13, 300 MHz,j") : 2H, t, 2.96 ppm (J=6.2 Hz) ; 2H, t, 3.3 ppm (J=6.2 Hz) ; 2H, s, 3.6 ppm; 2H, bs, 5.34 ppm; IH, dd, 6.94 ppm (J=6.2, 14 Hz) ; IH, dd, 7.42 ppm (J=8.6, 14 Hz) ; IH, d, 7.61 ppm (J=8.6 Hz) . HRMS: Calculated - 234.067; Found - 234.0605; TLC: (ethyl acetate) Rf - 0.23.
Example 30 9-Amino-l,2,3,4-tetrahydro-l , 4-ethanoacridine Following the method of Example 1, but substituting bicyclo [2.2.2]octan-2-one for norcamphor afforded the title compound (20%, m.p. 1S7-199°C) . 1H-NMR (CDC13, 300 MHz ) : 2H, m, 1.4-1.58 ppm; 2E, , 1.58-1.74 ppm; 4H, m, 1.8-2.0 ppm; 2H, bs, 3.2 ppm; 2H, bs, 4.65 ppm; IH, t, 7.4 ppm (J=8.5Hz) ; IH, t, 7.58 ppm (J=8.5 Hz) ; IH, d, 7.71 ppm (J=8.5 Hz) ; IH, 7.97 ppm (J=8.5 Hz) . TLC: (90:10:l-methylene chloride:methanol:28% aqueous ammonia) R--0.35.
Example 31 2,3-Dihydrofuro [2,3-b]quinolin-4-amine Following the method of Example 7, but substituting gamma-butyrolactone for delta- valerolactone afforded the title compound (m.p. 300°C dec) . " ϊ-NMR (CDC13 , 300 MHz,!") : 2H, t, 3.17 ppm (J=8
Hz) ; 2H, bs, 4.6 ppm; 2H, t, 4.69 ppm (J=8 Hz); IH, t, 7.28 ppm (J=8 Hz) ; IH, t, 7.53 ppm (J=8 Hz) ; IH, d, 7.62 ppm (J=8 Hz) ; IH, d, 7.77 ppm (J=8 Hz) . LRMS: Found - 186. Example 32
6H- [1]Benzopyrano [4,3-b]quinolin-7-amine Following the method of Example 7, but substituting 4-chromanone for delta-valerolactone afforded the title compound (3%, m.p. 275°C dec) . H-NMR (DMSO, 300 MHz,f) : 2H, s, 5.3 ppm; IH, d, 6.97 ppm (J=8.2 Hz) ; IH, t, 7.08 ppm (J=7.0 Hz) ; 2H, m, 7.15-7.4 ppm; IH, t, 7.57 ppm (J=7.0 Hz) ; IH, d, 7.78 ppm (J=7.0 Hz) ; IH, d, 8.16 ppm (J=8.0Hz) ; ~IH, dd, 8.24 ppm (J=7.0, 2.0 Hz) . HRMS: Calculated - 248.287; Found - 248.0908; TLC: (90:10 :l-methylene chloride:methanol:28% aqueous ammonia) R--0.65.
Example 33 6H- [l]Benzothiopyrano [4,3-b]quinolin-7-amine Following the method of Example 7, but substituting thiochroman-4-one for delta-valerolactone afforded the title compound (13%, m.p. 211-212°C) . ^- MR (CDC13, 300 MHz,f) : 2H, s, 3.94 ppm; 2H, bs 4.7 ppm; 4H, m, 7.23-7.44 ppm; IH, t, 7.61 ppm (J=7 Hz); IH, d, 7.7 ppm (J=7 Hz) ; IH, d, 8.02 ppm (J=7.0 Hz) ; IH, 8.5 ppm (J=7.0,2.0 Hz) . HRMS: Calculated - 264.0721; Found - 264.0715; TLC: (90 : 10:1-methylene chloride:methanol:28% aqueous ammonia) Rf-0.77.
Example 34
9-Methylamino-8-fluoro-4-oxa-l,2,3,4-tetrahydroacridine
Following the method Example 20, but substituting iodomethane for cyclohexylmethyl bromide afforded the
1 title compound (for HC1 salt:m.p. 240°C) . H-NMR
(DMSO, 300 MHz,ό) : 2H, m, 2.0 ppm; 2H, t, 2.95 ppm
(J=6.5Hz) ; 3H, bd, 3.3 ppm; 2H, t, 4.53 ppm (J=6.5 Hz) ;
IH, dd, 7.34 ppm (J=8 , 14 Hz) ; IH, dd, 7.44 ppm
(J=8.0Hz) ; IH, m, 7.7-7.8 ppm; IH, bm, 7.94-8.06 ppm.
Example 35
2,3-Dihydro-8-fluorothieno [3,2-b]quinolin-9-amine
(Compound A) and l,3-Dihydro-8-fluoro-thieno [3, 4-b]quinolin-9-amine
(Compound B)
Following the method of Example 12 but substituting 2-amino-6-fluorobenzonitrile for anthranilonitrile afforded a 1:1 mixture of the two title compounds. Compound A (m.p. 137°C) : H-NMR
(CDC13, 300 MHz, ) : 4H, m, 3.48 ppm; 2H, bs, 5.09 ppm; IH, dd, 6.98 ppm (J=7.3, 14.5 Hz) ; IH, dd, 7.38 ppm (J=7.3, 10.5 Hz) ; IH, d, 7.64 ppm (J=10.5Hz) ; TLC: (ethyl acetate) R--0.38. Compound B (m.p. 198°C dec.) 1H-NMR (CDC13, 300 MHz, f) : 2H, s, 4.09 ppm; 2H, s, 4.38 ppm; 2H, bs, 5.3 ppm; IH, dd, 7.0 ppm (J=7.3, 14.5 Hz); IH, dd, 7.47 ppm (J=7.3, 10.5 Hz) ; IH, d, 7.68 ppm (J=10.5Hz) , TLC: (ethyl acetate) Rf-0.49. Example 36
9-Amino-l,2-dihyroacridine-4 (3H) -one Following the method of Example 1, but substituting 1 ,2-cyclohexanedione for norcamphor, afforded the title compound (11%, m.p. 240°C dec) . H-NMR (CDC13, 300MHz, ) : 2H, quin, 2.31 ppm; 4H, mt, 2.8-2.95 ppm; 2H, bs, 4.95 ppm; IH, t, 7.29 ppm (J=8.5 Hz); IH, t, 7.64 ppm (J=8.5 Hz); IH, d, 7.74 ppm (J=8.5 Hz); IH, d, 8.2 ppm (J=8.51Hz); HRMS: Calculated - 212.0950; Found - 212.0941; TLC: (90:10:1-methylene chloride: methanol:28% aqueous ammonia) R--0.41.
Example 37 The ability of the title compounds of Examples 1-16, 18, 26-29, 35 and 36 to inhibit brain acetyl- cholinesterase was determined by the spectrophotometric method of G. L. Ellman et al. (Biochemical Pharmacology, 1_, 88 (1961)). All of the compounds had IC5Q (molar) values between 5 uM and 0.1 μM.

Claims

1. A compound of the formula
Figure imgf000033_0001
wherein A is selected from the group consisting of
d
Figure imgf000033_0002
2 3_
Figure imgf000033_0003
5
wherein one of the CH moieties at positions a, b, c and d of formula _1_ may be replaced by a nitrogen atom or each of the CH moieties at positions a and d, a and c or b and d may be replaced by a nitrogen atom; B is selected from the group consisting of
Figure imgf000034_0001
Figure imgf000034_0002
10
wherein the broken line represents an optional double bond; R is hydrogen or C-.-C, alkyl;
3 I D
R is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C.-C8 alkoxy, c ι _c 6 alkanoyl, di(C1~Cg alkylamino)-C--C8 alkyl, C.,-Cg alkoxy-C^-Cg alkyl, halogen, hydroxy, nitro, phenyl, substituted phenyl, phenyl-C.-C8 alkyl, substituted phenyl-C,-C8 alkyl, diph.enyl-C.-C8 alkyl wherein one or both of the phenyl groups may be replaced with a substituted phenyl group, furyl-C1-C, alkyl, thienyl-C.-C,. alkyl,
5 6 "~- phenyloxy, substituted phenyloxy, NHCOR and NR R' , wherein the phenyl moieties on the substituted phenyl and substituted phenylalkyl groups are substituted with one or more substituents selected from the group consisting of halogen, C,-C,- alkyl, trifluoromethyl,
C.-C8 alkoxy-C.-C8 alkyl, hydroxy and nitro, and wherein R , R and R. are independently selected from
2 C^-Cg alkyl and C.-C8 alkanoyl; R is independently selected from the group consisting of 1,4- dihydropyridyl-C1~Cg alkanoyl, C1-C8 alky1-1,4-dihydro- pyridyl-C--C8-alkanoyl, and the possible definitions set forth above for R 3, except that R2 cannot be hydroxy, halogen, C.-C-. alkoxy, phenyloxy or substituted phenyloxy; R 4 is independently selected
3 from the possible definitions set forth above for R , except that R 4 cannot be halogen, nitro, NHCOR5 or
6 7 1 8 8
NR R ; n is 1, 2 or 3; Z is NH, 0, S or NR wherein R is Cτ-Cg alkyl or 1-Cg alkanoyl; Z 2 is 0 or S; Z3 and
Z are independently selected from (CH ) , 0, S, S=0
P 3 and S0?, with the proviso that at least one of Z and
Z 4 i.s CH2; Z5 i.s CH2, 0, S, S=0 or S02; Z6 i.s 0, S, S=0 or S0_; p is 1, 2 or 3; q is 1 or 2;
Y1 is CH2, CHOH, 0, C=0, S, S=0 or S02 and
Y is CH2, 0, S, S=0 or S02, with the proviso that when
A is a group of the formula JL wherein there is no nitrogen at position a, b, c or d or A is a group of the formula 3_ or 4_, only one of Y 1 and Y2 can be CH„; and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein R ,
R 2 and R4 are hydrogen and R3 is hydrogen or halogen.
3
3. A compound according to claim 2, wherein R is hydrogen or fluorine.
4. A compound according to claim 1, said compound being selected from the group consisting of compounds of the formula I wherein A is a group of the formula JL, wherein one of the CH moieties at positions a and b of formula 1_ may be replaced by a nitrogen atom or A is a group of the formula 3_; B, R 1, R2, R3, R 4, Z3, Z4, Z5 and q are as defined in claim 1; c n is 1 or 2; Z is S; and p is 1 or 2; with the proviso that
(a) when A is a group of the formula 1_ wherein there is no nitrogen at either position a or
3 position b, Z is 0, S or CH2; R. is hydrogen or C..-C-. alkyl; Z is (CH_) , wherein p is 1
1 ^ P or 2, or S; Y is CH2, C=0, 0, or S, and Y is CH9, 0 or S, with the proviso that only one of Y 1 and Y2 can be CH2; (b) when A is a group of the formula 1_ wherein there is a nitrogen at either position a or position b, Y 1 is 0, S or CH- and Y2 is CH„; and
(c) when A is a group of the formula 3_, Y is 0, S or CH2 and Y is CH2; and pharmaceutically acceptable salts thereof.
5. A compound according to claim 4, wherein R ,
2 4 3
R and R are hydrogen and R is hydrogen or halogen.
3
6. A compound according to claim 5, wherein R is hydrogen or fluorine.
7. A compound according to claim 1, wherein B is a group of the formula 7 or .
1
8. A compound according to claim 7, wherein R ,
2 4 3
R and R are hydrogen and R is hydrogen or halogen.
3
9. A compound according to claim 8, wherein R is hydrogen or fluorine.
10. A compound according to claim 4, wherein B is a group of the formula 1_ or ..•
11. A compound according to claim 10, wherein R ,
2 4 3
R and R are hydrogen and R is hydrogen or halogen.
12. A compound according to claim 1, wherein R ,
2 4 3
R and R are hydrogen and R is hydrogen or halogen.
13. A compound according to claim 1, said compound being selected from the group consisting of:
9-amino-l,2,3,4-tetrahydro-l,4-methanoacridine; 9-amino-8-fluoro-1,2,3,4-tetrahydro-l,4-methano- acridine;
9-amino-2-oxa-l,2,3,4,-tetrahydroacridine; 9-amino-2-thia-l,2,3,4-tetrahydroacridine; 9-amino-4-oxa-l,2,3,4-tetrahydroacridine; 9-amino-8-fluoro-4-oxa-l,2,3,4-tetrahydroacridine; 9-amino-4-oxa-l,2,3,4,5,6,7,8-octahydroacridine; 2,3-dihydrothieno [3,2-b]quinoline-9-amine; 9-amino-5-aza-l,2,3,4-tetrahydroacridine; 2,3-dihydro-8-fluoro-thieno[3,2-b]quinolin-9-amine; 9-amino-l,2-dihydroacridine-4 (3H)-one; 1,3-dihydro-8-fluoro-thieno[3,4-b]-quinolin-9-amine; 9-amino-4-thia-l,2,3,4-tetrahydroacridine; and 9-amino-8-fluoro-2-thia-l,2,3,4-tetrahydroacridine; and the pharmaceutically acceptable salts thereof.
14. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a memory enhancing effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a memory enhancing effective amount of a compound according to claim 2 and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a memory enhancing effective amount of a compound according to claim 4 and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a memory enhancing effective amount of a compound according to claim 7 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a memory enhancing effective amount of a compound according to claim 10 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition for the treatment of Alzheimer's disease comprising a memory enhancing effective amount of a compound according to claim 11 and a pharmaceutically acceptable carrier.
20. A method of treating Alzheimer's disease comprising administering to a patient in need of such treatment a memory enhancing effective amount of a compound according to claim 1.
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US4927820A (en) * 1988-11-25 1990-05-22 Hoechst Roussel Pharmaceuticals Inc. Fused heterocyclic derivatives of 1,2,3,4-tetrahydroacridine
US4994452A (en) * 1989-11-28 1991-02-19 Hoechst-Roussel Pharmaceuticals Inc. Hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepines and related compounds
US5002955A (en) * 1987-04-23 1991-03-26 Hoechst-Roussel Pharmaceuticals Inc. Fused heteroalkylene quinolinamines and use as cholinergic agents
US5013741A (en) * 1987-09-08 1991-05-07 Hoechst-Roussel Pharmaceuticals Incorporated N-[substituted alkylidene]-1,2,3,4-tetrahydro-9-acridinamines useful for enhancing the cholinergic function in a mammal
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US5112829A (en) * 1989-11-28 1992-05-12 Hoechst-Roussel Pharmaceuticals Inc. Hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepines and related compounds
US5210087A (en) * 1991-02-13 1993-05-11 Hoechst-Roussel Pharmaceuticals Inc. 9-aminotetrahydroacridines and related compounds
US5234947A (en) * 1991-11-07 1993-08-10 New York University Potassium channel activating compounds and methods of use thereof
US5422350A (en) * 1992-09-10 1995-06-06 Warner-Lambert Company Nitrogen substituted acridine and cytochrome P450 inhibitors and methods of use
US5466696A (en) * 1992-09-10 1995-11-14 Warner Lambert Company Tacrine and cytochrome P450 oxidase inhibitors and methods of use
WO1997021681A1 (en) * 1995-12-11 1997-06-19 Mayo Foundation For Medical Education And Research Tha analogs useful as cholinesterase inhibitors
EP0867192A2 (en) * 1997-02-26 1998-09-30 Hoechst Aktiengesellschaft Combinatory compositions for the treatment of dementia containing at least a compound having acetylcholinesterase-inhibitory or muscarinic activity and a compound that enhances the endogenous extracellular adenosine levels
US5929093A (en) * 1996-06-13 1999-07-27 Mayo Foundation For Medical Education And Research Bifunctional acetylcholinesterase reactivators
WO2002072583A1 (en) * 2001-03-09 2002-09-19 Merck Patent Gmbh Tricyclic quinoxaline derivatives as a uv filter
US7354927B2 (en) 2004-09-07 2008-04-08 Wyeth 6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents
CN114853672A (en) * 2022-05-12 2022-08-05 中国人民解放军北部战区总医院 Tacrine derivatives as CDKs inhibitors and application thereof

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US5013741A (en) * 1987-09-08 1991-05-07 Hoechst-Roussel Pharmaceuticals Incorporated N-[substituted alkylidene]-1,2,3,4-tetrahydro-9-acridinamines useful for enhancing the cholinergic function in a mammal
US5037833A (en) * 1988-07-25 1991-08-06 Hoechst-Roussel Pharmaceuticals Inc. N-[substituted alkylidene]fused-bicycloalkylidene quinolinamines useful for enhancing the cholinergic function in a mammal
US4927820A (en) * 1988-11-25 1990-05-22 Hoechst Roussel Pharmaceuticals Inc. Fused heterocyclic derivatives of 1,2,3,4-tetrahydroacridine
US4994452A (en) * 1989-11-28 1991-02-19 Hoechst-Roussel Pharmaceuticals Inc. Hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepines and related compounds
US5112829A (en) * 1989-11-28 1992-05-12 Hoechst-Roussel Pharmaceuticals Inc. Hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepines and related compounds
US5210087A (en) * 1991-02-13 1993-05-11 Hoechst-Roussel Pharmaceuticals Inc. 9-aminotetrahydroacridines and related compounds
US5502203A (en) * 1991-02-13 1996-03-26 Hoechst-Roussel Pharmaceuticals Inc. Certain 6,7-dihydro-3(2-nitrophenyl)-1,2-benzisoxazol-4(5H)-ones as intermediates
US5234947A (en) * 1991-11-07 1993-08-10 New York University Potassium channel activating compounds and methods of use thereof
US5466696A (en) * 1992-09-10 1995-11-14 Warner Lambert Company Tacrine and cytochrome P450 oxidase inhibitors and methods of use
US5422350A (en) * 1992-09-10 1995-06-06 Warner-Lambert Company Nitrogen substituted acridine and cytochrome P450 inhibitors and methods of use
WO1997021681A1 (en) * 1995-12-11 1997-06-19 Mayo Foundation For Medical Education And Research Tha analogs useful as cholinesterase inhibitors
US5783584A (en) * 1995-12-11 1998-07-21 Mayo Foundation For Medical Education And Research THA analogs useful as cholinesterase inhibitors
US5886007A (en) * 1995-12-11 1999-03-23 Mayo Foundation For Medical Education And Research THA analogs useful as cholinesterase inhibitors
US5929093A (en) * 1996-06-13 1999-07-27 Mayo Foundation For Medical Education And Research Bifunctional acetylcholinesterase reactivators
EP0867192A2 (en) * 1997-02-26 1998-09-30 Hoechst Aktiengesellschaft Combinatory compositions for the treatment of dementia containing at least a compound having acetylcholinesterase-inhibitory or muscarinic activity and a compound that enhances the endogenous extracellular adenosine levels
EP0867192A3 (en) * 1997-02-26 2000-12-06 Hoechst Aktiengesellschaft Combinatory compositions for the treatment of dementia containing at least a compound having acetylcholinesterase-inhibitory or muscarinic activity and a compound that enhances the endogenous extracellular adenosine levels
WO2002072583A1 (en) * 2001-03-09 2002-09-19 Merck Patent Gmbh Tricyclic quinoxaline derivatives as a uv filter
US7354927B2 (en) 2004-09-07 2008-04-08 Wyeth 6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents
CN114853672A (en) * 2022-05-12 2022-08-05 中国人民解放军北部战区总医院 Tacrine derivatives as CDKs inhibitors and application thereof

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MX13270A (en) 1993-06-01
PT88656A (en) 1988-11-01
FI884553A0 (en) 1988-10-04
EG19973A (en) 1996-10-31
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RU1816283C (en) 1993-05-15
MY104335A (en) 1994-03-31

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