Patent EA-002201-B1 (EA)
Title: Novel arylglycinamide derivatives, method of producing said derivatives and phatmaceutical compositions containing these compounds
Inventor: ESSER FRANZ
IPC: C07D213/74
Filed: 1997-03-03
Abstract: 1. Arylglycinamide derivatives of general formula I   or the pharinaceutically acceptable salts thereof, wherein Ar denotes unsubstituted or 1-5 substituted phenyl, or unsubstituted or 1-2 substituted naphthyl, wherein the substituents of the phenyl and naphthyl independently of one another denote halogen (F, Cl, Br, I), alkyl with 1-4 carbon atoms, O-(C1-C4)alkyl, trifluoromethyl, trifluoromethoxy or NR<12>R<13>, wherein R<12> and R<13> independently of one another denote H, methyl or acetyl, or Ar is phenyl substituted by -O-CH2-O- or O-(CH2)2-O; R<1> and R<2> together with the N to which they are bound denote a ring of the formula       or   wherein r, s and t are 2 or 3; R<6> denotes H, alkyl with 1-5 carbon atoms, alkenyl with 3-5 carbon atoms, propynyl, hydroxy-(C2-C4)alkyl, methoxy-(C2-C4)alkyl, di-(C1-C3)-alkylamino-(C2-C4)-alkyl, aminoalkyl with 2-4 carbon atoms, amino, di-(C1-C3)-alkylamino, monofluoro-perfluoroalkyl with 1-2 carbon atoms, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or the group -CH2-C(O)NR<14>R<15>, wherein R<14> is H or alkyl with 1-4 carbon atoms and R<15> is H, alkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms, hydroxy-(C2-C3)-alkyl, phenyl-(C1-C4)-alkyl, or R<14> and R<15> together with the N to which they are bound form a ring (1-pyrrolidinyl, piperidino, morpholino or l-methylpiperazin-4-yl); R<7> has one of the definitions (a) to (d), (a) hydroxy, (b) 4-piperidinopiperidyl, (c)  wherein R<16> and R<17> independently of one another denote H, alkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms, hydroxy-(C2-C4) alkyl, (C1-C3)-alkoxy-(C2-C4)-alkyl, phenyl-(C1-C4)-alkyl or di-(C1-C3)-alkylamino-(C2-C4)-alkyl, or if R<16> is H or alkyl with 1-4 carbon atoms, R<17> may also be -CH2C(O)NR<18>R<19>, wherein R<18> and R<19> are defined as R<14> and R<15> hereinbefore; (d)   wherein R<20> denotes H, alkyl with 1-4 carbon atoms, cycloalkyl with 4-6 carbon atoms or CH2C(O)NR<21>R<22>, wherein R<21> and R<22> are defined as R<14> and R<15> hereinbefore; R<8> is H R<8> and R<10> independently of each other denote alkyl with 1-4 carbon atoms; R<11> denotes H, alkyl with 1-5 carbon atoms, alkenyl with 3-5 carbon atoms, propynyl, hydroxy-(C2-C4)-alkyl, methoxy-(C2-C3)alkyl, di-(C1-C3)-alkylamino-(C2-C3)-alkyl, amino-(C2-C3)-alkyl, amino, di-(C1-C3)-alkylamino, monofluoro-perfluoro-(C1-C2)-alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or the group -CH2C(O)NR<23>R<24>, wherein R<23> and R<24> are defined as R<14> and R<15> hereinbefore; R<3> denotes H, alkyl with 1-4 carbon atoms, unsubstituted or mono- to trisubstituted phenyl, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C1-C4) alkyl with 1-4 carbon atoms, O-(C1-C4)alkyl, trifluoromethyl, trifluoromethoxy, or NR<25>R<26> (wherein R<25> and R<26> independently of one another denote H, methyl or acetyl); R<4> denotes phenyl-(C1-C4)-alkyl or naphthyl-(C1-C4)-alkyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), alkyl with 1-4 carbon atoms, O-(C1-C4)-alkyl, trifluoromethyl, trifluoromethoxy, or NR<27>R<28> (wherein R<27> and R<28> independently of one another denote H, methyl or acetyl); and R<5> denotes H, alkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms, CH2C(O)NH2 , or phenyl-(C1-C4)-alkyl. 2. Arylglycinamide derivatives of general formula I according to Claim 1 wherein Ar denotes unsubstituted or mono- or disubstituted phenyl, or unsubstituted naphthyl, or Ar is phenyl substituted by O-CH2-O or O-(CH2)2-O-; R<1> and R<2> together with the N to which they are bound denote a ring of the formula   or   wherein r is 2 or 3 and s and t are 2; R<6>, R<7>, R<8>, R<9>, R<10> and R<11> are defined above, R<3> is H or alkyl with 1-4 carbon atoms, R<4> denotes phenyl-(C1-C4)-alkyl or naphthyl-(C1-C4)-alkyl, wherein phenyl may be substituted by 1 or 2 substituents, wherein the substituents independently of one another are halogen (F, Cl, Br, I), alkyl with 1-4 carbon atoms, O-(C1-C4)-alkyl, trifluoromethyl, trifluoromethoxy; and R<5> denotes H, alkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms, hydroxy or phenyl-(C1-C4)-alkyl. 3. Arylglycinamide derivatives of according to Claim 1 or 2, wherein Ar is unsubstituted or mono- or disubstituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently on one another denote halogen (P, Cl, Br, I), methyl, methoxy, trifluoromethyl, trifluoromethoxy or Ar is phenyl substituted by -O-CH2-O- or O-(CH2)2-O. 4. Arylglycinamide derivatives according to Claim 3, wherein Ar is phenyl, naphthyl, phenyl substituted by methoxy or halogen in position 3 and/or 4 or phenyl wherein positions 2 and 3 or 3 and 4 are linked by O-CH2-O-. 5. Arylglycinamide derivatives according to Claim 4, wherein Ar is phenyl, phenyl substituted by methoxy in positions 3 and 4 or phenyl in which positions 3 and 4 or 2 and 3 are linked by -O-CH2-O-. 6. Arylglycinamide derivatives according to one of Claims 1 to 5, wherein in the ring   r is 2 or 3 and R<6> denotes H, alkyl with 1-4 carbon atoms, alkenyl with 3-5 carbon atoms, propynyl, hydroxy-(C2-C4)-alkyl, methoxy-(C2-C4)-alkyl, di-(C1-C3)-alkylamino-(C2-C4)-alkyl, amino-(C2-C4)-alkyl, amino, di-(C1-C3)-alkylamino, monofluoro-perfluoro-(C1-C2)-alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, or   7. Arylglycinamide derivatives according to Claim 6, wherein r is 3 and R<6> is methyl. 8. Arylglycinamide derivatives according to Claim 6, wherein r is 2 and R<6> is H, alkyl with 1-4 carbon atoms, propenyl, propynyl, hydroxy-(C2-C3)-alkyl, methoxyethyl, di-(C1-C2)-alkylamino-(C2-C3)-alkyl, aminoethyl, amino, dimethylamino, CH2CF3, N-methylpiperidinyl, pyridyl, pyrimidinyl or   9. Arylglycinamide derivatives according to Claim 8 wherein r is 2 and R<6> is H, alkyl with 1-3 carbon atoms, allyl, 2-propynyl, hydroxy-(C2-C3)-alkyl, -CH2CH2OCH3, -CH2CH2N(CH3)2, N-methylpiperidinyl, 2-pyrimidinyl or   10. Arylglycinamide derivatives according to Claim 9, wherein r is 2 and R<6> is H, methyl, propyl, isopropyl, CH2CH2OH, CH2CH2OCH3 or CH2CH2N(CH3)2. 11. Arylglycinamide derivatives according to one of Claims l to 5, wherein R<1> and R<2> together with the N to which they are bound form the ring   wherein R<8> is H and R<7> is hydroxy     wherein R<16> and R<17> independently of one another denote H, alkyl with 1-3 carbon atoms, cyclopentyl, (CH2)nOH, wherein n = 2, 3 or 4 or (CH2)2OCH3, (CH2)n`Ph, wherein n` = 2 or 4, (CH2)2N(CH3)2,  ,   or  . 12. Arylglycinamide derivatives according to Claim 11, wherein R<16> and R<17> are both methyl or ethyl or R<16> is H or methyl and R<17> is alkyl, with 1-3 carbon atoms, cyclopentyl, (CH2)2OH, (CH2)4OH or  . 13. Arylglycinamide derivatives according to Claim 11 wherein R<7> denotes   N(CH3)2,     14. Arylglycinamide derivatives according to Claim 11, wherein R<1> and R<2> together with the N to which they are bound form the ring   wherein (a) R<8> is H and R<7> is   wherein R<16> and R<17> both represent methyl, ethyl or CH2CH2OH, or R<16> is H, methyl and R<17> is alkyl with 1-3 carbon atoms, cyclopentyl, (CH2)2OH or (CH2)4OH, or (b) R<8> is H and R<7> is   15. Arylglycinamide derivatives according to one of Claims l to 5, wherein R<1> and R<2> together with the N to which they are bound form the ring   16. Arylglycinamide derivatives according to one of Claims 1 to 5, wherein R<1> and R<2> together with the N to which they are bound form the ring   wherein R<11> is H or alkyl with 1-3 carbon atoms. 17. Arylglycinamide derivatives according to Claim 16, wherein R<11> is iso-propyl. 18. Arylglycinamide derivatives according to one of Claims 1 to 17, wherein R<3> is H. 19. Arylglycinamide derivatives according to one of Claims 1 to 18, wherein R<4> - phenyl-(C1-C4)-alkyl, wherein phenyl may be substituted by 1 or 2 substituents, in which the substituents independently of one another are halogen (F, Cl, Br, I), alkyl with 1-4 carbon atoms, O-(C1-C4)-alkyl, trifluoromethyl or trifluoromethoxy; R<5> denotes H, alkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms, hydroxy or phenyl-(C1-C4)-alkyl. 20. Arylglycinamide derivatives according to Claim 19, wherein R<4> denotes phenyl-(C2-C4)-alkyl, wherein the substituents are in positions 3 and/or 5 of the phenyl ring and R<5> is H, methyl, hydroxy or phenethyl. 21. Arylglycinamide derivatives according to Claim 20, wherein R<4> is   and R<5> is methyl. 22. Process for preparing arylglycinamide derivatives of general formula (I) according to one of Claims 1 to 21, characterized in that an acid   or a halide or alkyl ester thereof is reacted with an amine   thus obtained isolated free compound or as pharmaceutically acceptable salts thereof. 23. Process for preparing arylglycinamide derivatives of general formula (I) according to one of Claims 1 to 21, characterized in that α-haloarylacetamide   is reacted with an amine   thus obtained isolated free compound or as pharmaceutically acceptable salts thereof. 24. Process for preparing arylglycinamide derivatives of general formula (I) according to one of Claims 1 to 21, wherein R<5> has the above mentioned meanings with the exception of H, characterized in that a compound of general formula (I) wherein R<5> is H is N-alkylated with further isolating as a free compound or as a pharmaceutically acceptable salt thereof. 25. Pharmaceutical preparation containing arylglycinamide derivatives according to one of Claims 1 to 21 and pharmaceutically acceptable carriers and excipients. 26. Use of arylglycinamide derivatives according to one of Claims 1 to 21 for preparing a pharmaceutical preparation for the treatment and prevention of neurokinin-mediated diseases. 27. Use of arylglycinamide derivatives according to one of Claims 1 to 21 for the treatment and prevention of neurokinin-mediated diseases.