Malonamide derivatives as γ-secretase inhibitors


FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

 

The text descriptions are given in facsimile form.

1. Compounds of General formula

where L represents a bond, -(CH2)1,2-, -CH(CH3)or;

is a cyclic the ring, selected from the group consisting of phenyl, pyridinyl, furanyl, benzo[b]thiophenyl, tetrahydronaphthyl, indanyl, 2,2-dimethyl-[1,3]DIOXOLANYL or tetrahydrofuranyl;

R1and R1are the same or different and represent hydrogen, lower alkyl, halogen, benzyl or lower alkenyl;

(R2)1,2,3independently of one another represent hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or trifluoromethyl;

R3represents a

phenyl or benzyl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen or cyano, or represents

lower alkyl,

two atoms of hydrogen

(CH2)1,2-S-lower alkyl,

(CH2)1,2-cycloalkyl,

(CH2)1,2-OH, or a group

or;

R4represents a mono-, di - or tricyclic group, unsubstituted or substituted R5-R10and

where groups can be linked using the-N(CH3)(CH2)0,1,2with-C(O) group in formula IB are selected from the group consisting of

,,, ,,,,,,,

,,,,,,,,or is a

where (R5)1,2independently from each other represents hydrogen, halogen, lower alkyl or -(CH2)1,2OH;

R6represents hydrogen, halogen or lower alkoxy;

R7represents hydrogen or-CH2Och3;

R8represents hydrogen or halogen;

R9represents hydrogen or amino;

(R10)1,2,3independently from each other represents hydrogen, lower alkyl, lower alkoxy, lower cycloalkyl, halogen, hydroxy, nitro, -CH2CN, -och2With6H5,

,,,or

or group

can represent the following rings:

,,,,or

where X represents-CH2, -S(O)2or-C(O)-;

R11represents hydrogen or lower alkyl;

R12represents hydrogen or halogen;

R13represents hydrogen, CN,or;

R14represents hydrogen, lower alkyl, -(CH2)2HE or -(CH2)2CN;

and their pharmaceutically acceptable acid additive salt.

2. Compounds according to claim 1 of General formula

where R1and R1'are the same or different and represent hydrogen, lower alkyl, halogen, benzyl or lower alkenyl;

(R2)1,2,3independently from each other represents hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl;

R3represents phenyl or benzyl, which are unsubstituted or substituted one and two alternates, selected from the group consisting of halogen or cyano, or represents

lower alkyl,

two atoms of hydrogen

(CH2)1,2-S-lower alkyl,

(CH2)1,2-cycloalkyl,

(CH2)1,2-OH, or a group

or;

R4is a is a mono-, di - or tricyclic group, unsubstituted or substituted R5-R10and

where groups can be linked using the-N(CH3)(CH2)0,1,2with-C(O)-group in formula IB are selected from the group consisting of

,,,,,,,,,,,,,,

,,,,or is a

where (R5)1,2 independently from each other represents hydrogen, halogen, lower alkyl or -(CH2)1,2OH;

R6represents hydrogen, halogen or lower alkoxy;

R7represents hydrogen or-CH2Och3;

R8represents hydrogen or halogen;

R9represents hydrogen or amino;

(R10)1,2,3independently from each other represents hydrogen, lower alkyl, lower alkoxy, lower cycloalkyl, halogen, hydroxy, nitro, -CH2CN, -och2With6H5,

,,,or;

or group

can represent the following rings:

,,,,or

where X represents-CH2, -S(O)2or-C(O)-;

R11represents hydrogen or lower alkyl;

R12represents hydrogen or halogen;

R13represents hydrogen, CN or;

and their pharmaceutically acceptable acid additive salt.

3. The compounds of formula IA according to claim 2.

4. The compounds of formula IA according to claim 3, whererepresentsandrepresents phenyl.

5. The compounds of formula IA according to claim 4, where connections are

N-(3,5-diferensial)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-(3,5-diferensial)-2-fluoro-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-(3,5-diferensial)-2-isopropyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-(3,5-diferensial)-2-ethyl-N'-(5-methyl-6-oxo-6,7-hydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-(3,5-diferensial)-2-fluoro-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-(3,5-diferensial)-2,2-dimethyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-(3,5-diferensial)-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-propyl-malonamic,

N-benzyl-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-(4-terbisil)-2-methyl-N'-(methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-(4-Chlorobenzyl)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azep the n-7-yl)-malonamide,

N-(3-terbisil)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-(2,5-diferensial)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N'-(2,3,5-triptorelin)-malonamide,

N-(2-terbisil)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-(2-Chlorobenzyl)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic or

N-(3-Chlorobenzyl)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic.

6. The compounds of formula IA according to claim 1, whererepresents (a) andrepresents a cyclic ring selected from the group consisting of furanyl, benzo[b]thiophenyl or indanyl.

7. The compounds of formula IA according to claim 6, where connections are

N-furan-2-ylmethyl-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide,

N-benzo[b]thiophene-3-ylmethyl-2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic or

N-(4,6-defterinden-1-yl)-2-methyl-N'-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic.

8. The compounds of formula IA according to claim 1 or 2, whererepresents.

9. The compounds of formula IA is about 8, where connections are

N-(3,5-diferensial)-2-methyl-N'-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-malonamide,

N-(3,5-diferensial)-2-fluoro-2-methyl-N'-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-malonamide,

N-(3,5-diferensial)-N'-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-2-propyl-malonamic,

N-(3,5-diferensial)-2-ethyl-N'-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-malonamic or

N-(4-Chlorobenzyl)-2-methyl-N'-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-malonamic.

10. The compounds of formula IA according to claim 1 or 2, whererepresents.

11. The compounds of formula IA of claim 10, where connections are

N-(5-benzyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d][1,4]diazepin-3-yl)-N'-(3,5-diferensial)-2-methyl-malonamide,

N-(5-benzazolyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-N'-(3,5-diferensial)-2-methyl-malonamic or

N-(5-benzoyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-N'-(3,5-diferensial)-2-methyl-malonamic.

12. The compounds of formula IA according to claim 1 or 2, whererepresents

13. The compounds of formula IA according to clause 12, where connections are

(2S-C is s)-N-(3,5-diferensial)-2-methyl-N'-{4-oxo-2-[(2-thiophene-2-yl-acetylamino)-(2R,S)-methyl]-1,2,4,5,6,7-hexahydroazepin[3,2,1-hi]indol-5-yl}-malonamic or

(2S-CIS)-N-(3,5-diferensial)-N'-(2-{[2-(4-forfinal)acetylamino]methyl}-4-oxo-1,2,4,5,6,7-hexahydroazepin[3,2,1-hi]indol-5-yl)-2,2-dimethyl-malonamide.

14. The compounds of formula IB according to claim 1 or 2.

15. Compounds of formula IA or IB according to claim 1 or 2, where at least one of R2)1,2,3represents fluorine.

16. Drug, possess inhibitory activity against γ-secretase containing one or more compounds according to any one of claims 1 to 15, and pharmaceutically acceptable excipients.

17. Drug in article 16, for the treatment of Alzheimer's disease.



 

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