WO1989002739A1 - Derives de 4-aminopyridine - Google Patents

Derives de 4-aminopyridine 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
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English (en)
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 PCT/US1987/002546 priority Critical patent/WO1989002739A1/fr
Priority to MX1327088A priority patent/MX13270A/es
Priority to PCT/US1988/001070 priority patent/WO1989002740A1/fr
Priority to US07/474,717 priority patent/US5202440A/en
Priority to IL87861A priority patent/IL87861A0/xx
Priority to ES88309040T priority patent/ES2072263T3/es
Priority to DE3853863T priority patent/DE3853863T2/de
Priority to AT88309040T priority patent/ATE123024T1/de
Priority to EP88309040A priority patent/EP0311303B1/fr
Priority to ZA887399A priority patent/ZA887399B/xx
Priority to MYPI88001105A priority patent/MY104335A/en
Priority to PL1988275056A priority patent/PL159258B1/pl
Priority to PT88656A priority patent/PT88656B/pt
Priority to AU23370/88A priority patent/AU619213B2/en
Priority to DD88320447A priority patent/DD273633A5/de
Priority to DK553988A priority patent/DK553988A/da
Priority to NO884400A priority patent/NO176713C/no
Priority to SU884356604A priority patent/RU1816283C/ru
Priority to YU184988A priority patent/YU48197B/sh
Priority to KR1019880012933A priority patent/KR900007243B1/ko
Priority to CN88109023A priority patent/CN1032440A/zh
Priority to IE300388A priority patent/IE60718B1/en
Priority to NZ226445A priority patent/NZ226445A/xx
Priority to FI884553A priority patent/FI93117C/fi
Priority to HU885131A priority patent/HU203082B/hu
Priority to EG51088A priority patent/EG19973A/xx
Priority to JP63251742A priority patent/JPH0692372B2/ja
Publication of WO1989002739A1 publication Critical patent/WO1989002739A1/fr

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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
    • 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
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    • 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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    • C07D221/22—Bridged 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
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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
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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
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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
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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.

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Abstract

La présente invention se rapporte à des composés représentés par la formule (I), où R1, R2, A et B sont définis ci-dessous. Ces composés inhibent l'acétylcholinestérase du cerveau et servent dans le traitement de la maladie d'Alzheimer.
PCT/US1987/002546 1987-10-05 1987-10-05 Derives de 4-aminopyridine WO1989002739A1 (fr)

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PCT/US1987/002546 WO1989002739A1 (fr) 1987-10-05 1987-10-05 Derives de 4-aminopyridine
MX1327088A MX13270A (es) 1987-10-05 1987-10-05 Procedimiento para la preparacion de derivados de 4-aminopiridina
PCT/US1988/001070 WO1989002740A1 (fr) 1987-10-05 1988-03-30 Derives de 4-aminopyridine
US07/474,717 US5202440A (en) 1987-10-05 1988-03-30 Certain 9-amino-2-(or 4)-oxa 1,2,3,4-tetrahydro- or 1,2,3,4,5,6,7,8-octahydro-acridines
IL87861A IL87861A0 (en) 1987-10-05 1988-09-28 4-aminopyridine derivatives
ES88309040T ES2072263T3 (es) 1987-10-05 1988-09-29 Derivados de 4-aminopiridina.
DE3853863T DE3853863T2 (de) 1987-10-05 1988-09-29 4-Aminopyridinderivate.
AT88309040T ATE123024T1 (de) 1987-10-05 1988-09-29 4-aminopyridinderivate.
EP88309040A EP0311303B1 (fr) 1987-10-05 1988-09-29 Dérivés de la 4-aminopyridine
ZA887399A ZA887399B (en) 1987-10-05 1988-10-03 4-aminopyridine derivatives
MYPI88001105A MY104335A (en) 1987-10-05 1988-10-03 4-aminophridine deravatives
PL1988275056A PL159258B1 (pl) 1987-10-05 1988-10-03 Sposób wytwarzania nowych pochodnych 4-aminopirydyny PL PL PL
PT88656A PT88656B (pt) 1987-10-05 1988-10-03 Processo para a preparacao de derivados 4-aminopiridina
AU23370/88A AU619213B2 (en) 1987-10-05 1988-10-04 4-aminopyridine derivatives
DD88320447A DD273633A5 (de) 1987-10-05 1988-10-04 Verfahren zur herstellung von 4-aminopyridin-derivaten
DK553988A DK553988A (da) 1987-10-05 1988-10-04 4-aminopyridin-derivater og farmaceutiske praeparater indeholdende disse
NO884400A NO176713C (no) 1987-10-05 1988-10-04 Analogifremgangsmåte for fremstilling av terapeutisk aktive 4-aminopyridinderivater
SU884356604A RU1816283C (ru) 1987-10-05 1988-10-04 Способ получени производных 4-аминопиридина
YU184988A YU48197B (sh) 1987-10-05 1988-10-04 Derivati 4-aminopiridina i postupak za dobijanje njihovih smeša
KR1019880012933A KR900007243B1 (ko) 1987-10-05 1988-10-04 4-아미노피리딘 유도체
CN88109023A CN1032440A (zh) 1987-10-05 1988-10-04 4-氨基吡啶衍生物类
IE300388A IE60718B1 (en) 1987-10-05 1988-10-04 4-aminopyridine derivatives
NZ226445A NZ226445A (en) 1987-10-05 1988-10-04 Aminopyridine derivatives and pharmaceutical compositions containing such
FI884553A FI93117C (fi) 1987-10-05 1988-10-04 Analogiamenetelmä terapeuttisesti käyttökelpoisten 9-aminotetrahydroakridiinijohdannaisten valmistamiseksi
HU885131A HU203082B (en) 1987-10-05 1988-10-04 Process for producing condensed 4-aminopyridine derivatives
EG51088A EG19973A (en) 1987-10-05 1988-10-05 Process for preparing of 4-aminopyridine derivatives
JP63251742A JPH0692372B2 (ja) 1987-10-05 1988-10-05 ４−アミノピリジン誘導体

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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
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
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 (fr) * 1995-12-11 1997-06-19 Mayo Foundation For Medical Education And Research Analogues de tha utiles en tant qu'inhibiteurs de cholinesterase
EP0867192A2 (fr) * 1997-02-26 1998-09-30 Hoechst Aktiengesellschaft Compositions combinées pour le traitement de la démence contenant au moins un produit à effet inhibiteur de acetylcholinestérase ou muscarinique et un produit qui accroit le niveau d'adénosine endogène extracellular
US5929093A (en) * 1996-06-13 1999-07-27 Mayo Foundation For Medical Education And Research Bifunctional acetylcholinesterase reactivators
WO2002072583A1 (fr) * 2001-03-09 2002-09-19 Merck Patent Gmbh Derives de quinoxaline tricyclique utilises comme filtre uv
US7354927B2 (en) 2004-09-07 2008-04-08 Wyeth 6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents
CN114853672A (zh) * 2022-05-12 2022-08-05 中国人民解放军北部战区总医院 作为CDKs抑制剂的他克林衍生物及其应用

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US4897400A (en) * 1987-02-13 1990-01-30 Hoeschst-Roussel Pharmaceuticals, Inc. 9-amino-1,4-ethano-1,2,3,4-tetrahydroacridine and related compounds useful for incresing the cholinergic function in a mammal
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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PT88656A (pt) 1988-11-01
ZA887399B (en) 1990-05-30
WO1989002740A1 (fr) 1989-04-06
RU1816283C (ru) 1993-05-15
KR900007243B1 (ko) 1990-10-06
PT88656B (pt) 1992-12-31
FI93117B (fi) 1994-11-15
FI884553A0 (fi) 1988-10-04
PL275056A1 (en) 1989-05-30
ATE123024T1 (de) 1995-06-15
KR890006590A (ko) 1989-06-14
EG19973A (en) 1996-10-31
MX13270A (es) 1993-06-01
DD273633A5 (de) 1989-11-22
MY104335A (en) 1994-03-31
FI884553A (fi) 1989-04-06
FI93117C (fi) 1995-02-27
PL159258B1 (pl) 1992-12-31

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