Nova Patents
EP0407032A2

Aromatic and heteroaromatic amines for treating depressions, cerebral insufficiency disorders or dementia.

Abstract

The invention concerns compounds having formula: or a salt thereof, wherein E represents hydrogen, lower alkyl or a group Ar¹-A¹-; Ar and Ar¹ are the same or different aryl groups (including heteroaryl) which are optionally substituted, eg by one or more substituents commonly used in pharmaceutical chemistry; A and A¹ are the same or different alkylene groups having one or two carbon atoms linking Ar or Ar¹ to N and optionally substituted by lower alkyl and/or optionally substituted aryl, B is an alkylene group of 3 or 4 carbon atoms, which may be substituted by lower alkyl; D¹ represents halogen, CH₃, CR¹R²NH₂, SO₃H or SO₂NR⁶R⁷ where R¹ and R² are independently hydrogen or lower alkyl and R⁶ and R⁷ are each hydrogen, lower alkyl or aralkyl of 7 to 12 carbon atoms or R⁶ and R⁷ togehter with the nitrogen atom to which they are attached represent a 5 or 6 membered ring, which compounds are useful, for treating depression or cerebral insufficiency or dementias in animals.

EP0407032A2, drawing sheet 1
Sheet 1 of 30

Term

Term ended

Projected expiry passed 1 June 2010, 16.3 years ago.

  1. Priority
  2. Filed
  3. Published
  4. Projected expiry
  5. Today

14 claims: 12 independent, 2 dependent

  1. 1
    Use of a compound having formula:or a salt thereof, wherein E represents hydrogen, lower alkyl or a group Ar¹ -A¹- ;Ar and Ar¹ are the same or different aryl groups (including heteroaryl) which are optionally substituted, eg by one or more substituents commonly used in pharmaceutical chemistry;A and A¹ are the same or different alkylene groups having one or two carbon atoms linking Ar or Ar¹ to N and optionally substituted by lower alkyl and/or optionally substituted aryl, B is an alkylene group of 3 or 4 carbon atoms, which may be substituted by lower alkyl;D¹ represents halogen, CH₃, CR¹R²NH₂, SO₃H or SO₂NR⁶R⁷ where R¹ and R² are independently hydrogen or lower alkyl and R⁶ and R⁷ are each hydrogen, lower alkyl or aralkyl of 7 to 12 carbon atoms or R⁶ and R⁷ together with the nitrogen atom to which they are attached represent a 5 or 6 membered ring eg pyrrolidine or piperidine in the manufacture of a medicament for the treatment of depression or cerebral insufficiency disorders or dementias. 1. Use of a compound having formula: or a salt thereof, wherein E represents hydrogen, lower alkyl or a group Ar¹-A¹-;Ar and Ar¹ are the same or different aryl groups (including heteroaryl) which are optionally substituted, eg by one or more substituents commonly used in pharmaceutical chemistry;A and A¹ are the same or different alkylene groups having one or two carbon atoms linking Ar or Ar¹ to N and optionally substituted by lower alkyl and/or optionally substituted aryl, B is an alkylene group of 3 or 4 carbon atoms, which may be substituted by lower alkyl;D¹ represents halogen, CH₃, CR¹R²NH₂, SO₃H or SO₂NR⁶R⁷ where R¹ and R² are independently hydrogen or lower alkyl and R⁶ and R⁷ are each hydrogen, lower alkyl or aralkyl of 7 to 12 carbon atoms or R⁶ and R⁷ together with the nitrogen atom to which they are attached represent a 5 or 6 membered ring eg pyrrolidine or piperidine in the manufacture of a medicament for the treatment of depression or cerebral insufficiency disorders or dementias.
  2. 2
    A compound of formula Ia or a salt thereof as shown and defined in Claim 1 for use as a pharmaceuticals with the provisos;(i) when D¹ is CH₂NH₂, then B is other than -(CH₂)₄- providing that when B is (CH₂)₃- then Ar-A- is other than unsubstituted benzyl(ii) when D¹ is chlorine, Ar-A- is other than benzyl and(iii) when Ar-A- represents 2-(3-indolyl)ethyl and D¹ is CH₃ then E is other than hydrogen or lower alkyl 2. A process for preparing a pharmaceutical compositionwhich comprises mixing a compound of formula Ia or a pharmaceutically acceptable salt thereof as shown and defined in Claim 1 and a pharmaceutically acceptable carrier with the provisos;(i) when D¹ is CH₂NH₂, then B is other than -(CH₂)₄- providing that when B is -(CH₂)₃- then Ar A- is other than unsubstituted benzyl(ii) when D¹ is chlorine, Ar-A- is other than benzyl and (iii) when Ar-A- represents 2-(3-indolyl)ethyl and D¹ is CH₃ then E is other than hydrogen or lower alkyl
  3. 3
    A pharmaceutical composition comprising a compound of formula Ia or a pharmaceutically acceptable salt thereof as shown and defined in Claim 1 and a pharmaceutically acceptable carrier with the provisos;(i) when D¹ is CH₂NH₂, then B is other than -(CH₂)₄- providing that when B is -(CH₂)₃ then Ar-A- is other than unsubstituted benzyl(ii) when D¹ is chlorine, Ar A- is other than benzyl and(iii) when Ar A- represents 2-(3-indolyl)ethyl and D¹ is CH₃ then E is other than hydrogen or lower alkyl 3. A use or composition as claimed in Claim 1 or Claim 2 wherein Ar and Ar¹ when present are each independently optionally substituted mono- or bi-cyclic aryl groups, said aryl groups being selected from carbocyclic groups of 6 to 10 carbon atoms and heteroaryl groups of 5 to 10 ring atoms in which the heteroatom(s) is (are) selected from oxygen, nitrogen and sulphur.
  4. 4
    A compound, use or composition as claimed in any one of Claims 1 to 3 wherein Ar and Ar¹ when present are each independently optionally substituted mono or bi-cyclic aryl groups, said aryl groups being selected from carbocyclic groups of 6 to 10 carbon atoms and heteroaryl groups of 5 to 10 ring atoms in which the heteroatom(s) is (are) selected from oxygen, nitrogen and sulphur. 4. A use or composition as claimed in Claim 3 in which Ar and Ar¹ when present are selected from optionally substituted phenyl, naphthyl, pyridyl, furyl, thienyl, thiazolyl, quinolyl and benzofuranyl.
  5. 7
    A compound, use or composition as claimed in anyone of Claims 1 to 6 wherein A and A¹ are independently -(CH₂)m- optionally substituted by lower alkyl and/or aryl where m is 1 or 2. 7. A use or composition as claimed in Claim 6 wherein A and A¹ independently represent -CHR³- where R³ is hydrogen, lower alkyl or optionally substituted aryl as defined for Ar.
  6. 8
    A compound, use or composition as claimed in Clain 7 wherein A and A¹ independently represent -CHR³- where R³ is hydrogen, lower alkyl or optionally substituted aryl as defined for Ar. 8. A use or composition as claimed in any one of claims 1 to 7 wherein B is -CH₂CH₂CH₂- or such a group substituted by methyl.
  7. 9
    A compound, method, use or composition as claimed in any one of Claims 1 to 8 where D¹ is CH₃ ,SO₃H or SO₂NH₂ . 9. A compound, use or composition as claimed in any one of claims 1 to 8 wherein B is -CH₂CH₂CH₂- or such a group substituted by methyl.
  8. 10
    A compound, use or composition as claimed in any one of Claims 1 to 9 where in D¹ is CH₃ ,SO₃H or SO₂NH₂ . 10. A use or composition as claimed in any one of Claims 1 to 2 in which the compound of formula Ia is N-butyl-4-chlorobenzenemethanamine, N-(1-methylbutyl)-4-chlorobenzenemethanamine;N-butyl-N-methyl-4-chlorobenzenemethanamine;N-butyl-N-methylbenzenemethanamine;N,N-bis(4-chlorobenzyl)butylamine;N-butyldibenzylamine;N,N-dibenzyl-1,4-diaminobutane;N-(3-chloropropyl)dibenzylamine or 3-[N,N-benzyl]aminopropanesulphonic acid or a salt thereof.
  9. 11
    A process for preparing a compound of formula Ia or a salt thereof as shown and defined in Claim 1 with the provisos that (i) when D¹ is CH₃ and E is hydrogen, lower alkyl of 1-4 carbon atoms, benzyl, methylbenzyl, chlorobenzyl or bromobenzyl then Ar-A is other than benzyl,bromobenzyl or chlorobenzyl; and (ii) when NR⁶R⁷ represents a 5- or 6 membered ring, Ar represents optionally substituted phenyl and A represents ethylene optionally substituted by lower alkyl, then E is other than lower alkyl; and (iii) when Ar-A- represents 2-(3-indolyl)ethyl and D¹ is CH₃ then E is other than hydrogen or lower alkyl, and (iv) when D¹ is chlorine, Ar-A- is other than benzyl, and (v) when D¹ is CH₂NH₂, then B is other than -(CH₂)₄- providing that when B is -(CH₂)₃- then Ar-A- is other than unsubstituted benzyl, which comprises a) alkylating a compound of formula II, IIa or IIb Ar-A-NH-E      II Ar-A-NH-B-D²      IIa E-NH-B-D²      IIb wherein Ar, E and A are as defined in Claim 21 and D² is CH₃ or SO₂NR⁶R⁷ with an appropriate compound of formula III; IIIa or IIIb:hal B-D²      (III) E¹-hal      (IIIa) Ar-A-hal      (IIIb) wherein B, Ar and A are as defined in Claim 21, hal represents chlorine or bromine, and E¹ is E excepting hydrogen, to give a compound of formula Ia wherein D¹ is CH₃ or SO₂NR⁶R⁷;or b) carrying out a reductive alkylation of a compound of formula II, IIa or IIb as defined above using an appropriate compound of formula IV, IVa or IVb OHC-B¹-D²      (IV) OHC-E²      (IVa) OHC-A²-Ar      (IVb) wherein D² is as defined above E² is alkyl of 1 to 5 carbon atoms or Ar¹-CH₂-, A² is CH₂ and B¹ is an alkylene chain of 2 or 3 carbon atoms optionally substituted by lower alkyl, in the presence of a reducing agent such as sodium cyanoborohydride to give a corresponding compound of formula Ia wherein D¹ is CH₃ or SO₂NR⁶R⁷;or (c) reducing a compound of formula (V) wherein D³ is CH₃, CR¹R²NH₂ or CONH₂, R⁴ is alkyl of 1 to 5 carbon atoms or Ar¹-A²- ;Ar, Ar¹, A and B are as defined above, and A² represents a direct bond or alkylene of 1 carbon atom optionally substituted by lower alkyl and/or aryl to give a corresponding compound of formula Ia as defined above wherein D¹ is CH₃ or CR¹R² NH₂ and E is R⁴CH₂ wherein R⁴ is as defined above;or (d) reducing a compound of formula (VI) Ar A--CO-B¹-D¹      (VI) wherein Ar, A and E are as defined above, D³ is as defined above and B¹ is as defined in connection with formula IV to give a corresponding compound of formula I wherein B is -CH₂B¹- and D¹ is CH₃ or CR¹R²NH₂ or (e) reacting a compound of formula Ar-A-OH      (VII) with an amine of formula: ENH B-D¹      (VIII) wherein Ar, A, E and B are as defined above and D¹ is CH₃ in the presence of an acid, to give a compound of formula I wherein D¹ is CH₃, or (f) performing a Mannich reaction with an aryl anion of formula Ar⊖, formaldehyde and an amine of formula VIII to give a compound of formula Ia wherein D¹ is CH₃ or (g) halogenating a compound of formula wherein Ar, A, B and E are as defined above, eg using thionyl chloride, phosphorus oxychloride, PBr₃ or an acid HX where X is halogen, to give a compound of formula Ia wherein D¹ is halogen or (h) reacting a compound formula X wherein D¹ is halogen with (i) an alkali metal azide followed by hydrogenation or (ii) performing a Gabriel synthesis, to give a corresponding compound of formula Ia wherein D¹ is NH₂ or (i) reducing a compound of formula wherein Ar, A, E and B are as defined above, to give a compound of formula Ia wherein D¹ is -CH₂NH₂;or (j) oxidising a compound of formula therein Ar, A, B and E are as defined above to give a corresponding compound of formula I wherein D¹ is SO₃H, or (k) reacting a reactive derivative of a compound of formula wherein Ar, A, E and B are as defined above with an amine of formula HNR⁶R⁷      (XIV) to give a corresponding compound of formula I wherein D¹ is SO₂NR⁶R⁷;of (1) acidifying a compound of formula Ia to give an acid addition salt thereof or neutralising an acid addition salt to give the free base form. or (m) reacting a compound of formula II with a sultone of formula to give a compound of formula I wherein D¹ is SO₃H or a salt thereof. 11: A compound, use or composition as claimed in any one of Claims 1 to 4 in which the compound of formula Ia is N-butyl-4-chlorobenzenemethanamine;N-(1-methylbutyl)-4-chlorobenzenemethanamine;N-butyl-N-methyl-4-chlorobenzenemethanamine;N-butyl-N-methylbenzenemethanamine;N,N-bis(4-chlorobenzyl)butylamine;N-butyldibenzylamine;N,N-dibenzyl-1,4-diaminobutane;N-(3-chloropropyl)dibenzylamine;3-[N,N-benzyl]aminopropanesulphonic acid or a salt thereof.
  10. 12
    A compound of formula Ia or a salt thereof as shown and defined in Claim 1 with the provisos that (i) when D¹ is CH₃ and E is hydrogen, lower alkyl of 1-4 carbon atoms, benzyl, methylbenzyl, chorobenyl or bromobenyl then Ar-A-is other than benzyl, bromobenzyl or chlorobenzyl;and (ii) when NR⁶R⁷ represents a 5- or 6- membered ring, Ar represents optionally substituted phenyl and A represents ethylene optionally substituted by lower alkyl, then E is other than lower alkyl;and (iii) when Ar-A- represents 2-(3-indolyl)ethyl and D¹ is CH₃ then E is other than hydrogen or lower alkyl, and (iv) when D¹ is chlorine, Ar-A- is other than benzyl, and (v) when D¹ is CH₂NH₂, then B is other than -(CH₂)₄- providing that when B is -(CH₂)₃- then -Ar-A- is other than unsubstituted benzyl.
  11. 13
    A compound of formula Ia is N-(1-methylbutyl)-4-chlorobenzenemethanamine;3-[N,N-ben­zyl]aminopropanesulphonic acid;3-(1,2-Diphenylethylamino)propanesulphonic acid, or 3-[(Dip henylmethyl)amino]-1-propanesulphonic acid, or a salt thereof.
  12. 14
    A process for preparing a compound claimed in Claim 12 which comprises one of the following a) alkylating a compound of formula II, IIa or IIb Ar-A NH E      II Ar-A-NH B-D²      IIa E-NH-B-D²      IIb wherein Ar, E and A are as defined in Claim 21 and D² is CH₃ or SO₂NR⁶R⁷ with an appropriate compound of formula III; IIIa or IIIb:hal-B-D²      (III) E¹-hal      (IIIa) Ar-A-hal      (IIIb) wherein B, Ar and A are as defined in Claim 21, hal represents chlorine or bromine, and E¹ is E excepting hydrogen, to give a compound of formula Ia wherein D¹ is CH₃ or SO₂NR⁶R⁷ ;or b) carrying out a reductive alkylation of a compound of formula II, IIa or IIb as defined above using an appropriate compound of formula IV, IVa or IVb OHC-B¹-D²      (IV) OHC-E²      (IVa) OHC-A²-Ar      (IVb) wherein D² is as defined above E² is alkyl of 1 to 5 carbon atoms or Ar¹-CH₂-, A² is CH₂ and B¹ is an alkylene chain of 2 or 3 carbon atoms optionally substituted by lower alkyl, in the presence of a reducing agent such as sodium cyanoborohydride to give a corresponding compound of formula Ia wherein D¹ is CH₃ or SO₂NR⁶R⁷;or (c) reducing a compound of formula (V) wherein D³ is CH₃, CR¹R²NH₂ or CONH₂, R⁴ is alkyl of 1 to 5 carbon atoms or Ar¹-A-;Ar, Ar¹, A and B are as defined above, and A² represents a direct bond or alkylene of 1 carbon atom optionally substituted by lower alkyl and/or aryl to give a corresponding compound of formula Ia as defined above wherein D¹ is CH₃ or CR¹R² NH₂ and E is R⁴CH₂ wherein R⁴ is as defined above;or (d) reducing a compound of formula (VI) Ar-A--CO-B¹-D¹      (VI) wherein Ar, A and E are as defined above, D³ is as defined above and B¹ is as defined in connection with formula IV to give a corresponding compound of formula I wherein B is -CH₂B¹- and D¹ is CH₃ or CR¹R²N₂ or (e) reacting a compound of formula Ar-A-OH      (VII) with an amine of formula: ENH-B-D¹      (VIII) wherein Ar, A, E and B are as defined above and D¹ is CH₃ in the presence of an acid, to give a compound of formula I wherein D¹ is CH₃, or (f) performing a Mannich reaction with an aryl anion of formula Ar formaldehyde and an amine of formula VIII to give a compound of formula Ia wherein D¹ is CH₃ or (g) halogenating a compound of formula wherein Ar, A, B and E are as defined above eg using thionyl chloride, phosphorus oxychloride, PBr₃ or an acid HX where X is halogen, to give a compound of formula Ia wherein D¹ is halogen or (h) reacting a compound formula X wherein D¹ is halogen with (i) an alkali metal azide followed by hydrogenation or (ii) performing a Gabriel synthesis, to give a corresponding compound of formula Ia wherein D¹ is NH₂ or (i) reducing a compound of formula wherein Ar, A, E and B are as defined above, to give a compound of formula Ia wherein D¹ is -CH₂NH₂;or (j) oxidising a compound of formula therein Ar, A, B and E are as defined above to give a corresponding compound of formula I wherein D¹ is SO₃H, or (k) reacting a reactive derivative of a compound of formula wherein Ar, A, E and B are as defined above with an amine of formula HNR⁶R⁷      (XIV) to give a corresponding compound of formula I wherein D¹ is SO₂NR⁶R⁷;of (1) acidifying a compound of formula Ia to give an acid addition salt thereof or neutralising an acid addition salt to give the free base form. or (m) reacting a compound of formula II with a sultone of formula to give a compound of formula I wherein D¹ is SO₃H or a salt thereof.
Independent claims12