Derivatives pyrrolidine possessing inhibitory activity against phospholipase a2

 

(57) Abstract:

The invention relates to the derivatives of pyrrolidine formula I

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where R1- H, C1-C6alkyl; phenyl, possibly substituted; biphenyl, possibly substituted; 1H, 5H - pyrido [3,2,1-ij] chinolin; phenyl WITH1-C6alkyl, optionally substituted; biphenyl WITH1-C6alkyl, optionally substituted; biphenylcarboxylic; terphenyl; naphthyl, optionally substituted; Z denotes-S-, -O-, -och2-, -N(R16), where R16- H, C1-C6alkyl, C3-C8cycloalkyl1-C6alkyl, panels1-C6alkyl, a chemical bond; X1means-CO-, -(CH2)r-CO-N(R17), where R17means H, C1-C6alkyl (where r = 0 or 1), -CH2NHSO2-, -(CH2)s-N (R18)-CO- (where R18- N, s=1-3), - CH2NHC2O-, -CH2N (R19Of PINES = CH- (where R19- H, -CH2OCH2-, -CH2-N (R20)-CH2- (where R20- H, C1-C6alkyl, C1-C6alkylsulphonyl, phenylcarbinol)1-C5alkylen,2-C4albaniles, a chemical bond; X2- phenylene, optionally substituted hydroxy, theoffender, purandar, piperidinyl, , chemical; and E each independently denotes-O - or-S-; D-N; V1-CO-; Y2Deputy formula:

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R2and R3each - H; and R4- phenyl, possibly substituted with halogen; R5- phenyl, possibly substituted; a cycle of G is phenyl,3-C7cycloalkyl, pyridyl, thienyl; loop J is phenyl; L is phenyl; p=0-2;----- means the presence or absence of the chemical bond; displays CIS - or TRANS-configuration D relative to E; provided that X1means-CH2NHC-, X2means 1,4-phenylene and X3means a chemical bond or a C1-C5alkylen, when the carbon atom bound CD and adjacent carbon atom in the cycle are connected by a simple relation and V1does not mean a chemical bond, when X1means-CH2O-; and pharmaceutically acceptable salt or hydrate compounds. The compounds I inhibit phospholipase a2and can be used in pharmaceutical compositions as the active agent. 2 C. and 14 C.p. f-crystals, 38 PL.

Description text in facsimile form. T

1. Derivatives pyrrolidine formula (I)

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where R1means a hydrogen atom, straight or branched C1-C6alkyl, phenyl, optionally substituted by one or nickoll, WITH3-C7cycloalkyl, halogen, C1-C6alkoxy, naphthyl, benzo-1,3-DIOXOLANYL, 2-pyridyl, panels1-C6alkyl, phenyloxy, mono - or disubstituted amino and N-methylpyrazine, biphenyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, trihalo1-C6alkyl and hydroxy, terphenyl, naphthyl, optionally substituted by one or more substituents selected from the group consisting of phenyl and halogen, phenyl condensed with C3-C7cycloalkyl, 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij] chinolin, panels1-C6alkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halogen, phenyl, naphthyl, thienyl, benzofuranyl, panels1-C6alkyl, phenyloxy, mono - or disubstituted amino and phenyl substituted by one or more substituents selected from the group consisting of C1-C6alkyl and halogen, biphenyls1-C6alkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, galoisian, and biphenylcarboxylic;

Z means-S-, -O-, -och2-, -N(R16)- (where R16means a hydrogen atom, a C1-C6alkyl, C3-C8cycloalkyl1-C6alkyl or panels1-C6alkyl), or a chemical bond;

X1means-CO-, -(CH2)r-CO-N(R17)- (where R17means a hydrogen atom or a C1-C6alkyl, and r is an integer from 0 to 1), -CH2NHSO2-, -(CH2)s-N(R18)-CO- (where R18means a hydrogen atom, a s denotes an integer from 1 to 3), -CH2NHCOCH2O-, -CH2N(R19)COCH=CH- (where R19means a hydrogen atom), -CH2OCH2-, -CH2-N(R20)-CH2- (where R20means a hydrogen atom, a C1-C6alkyl, C1-C6alkylsulphonyl or phenylcarbamoyl)1-C5alkylen,2-C4albaniles or a chemical bond;

X2means phenylene, optionally substituted hydroxy, theoffender, purandar, piperidinyl, or a chemical bond;

X3means1-C5alkylen,2-C4albaniles or a chemical bond;

A represents an oxygen atom;

B and E each independently from each other, means an oxygen atom or a sulfur atom;

D about the
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where R2and R3each means a hydrogen atom;

R4means phenyl which may be substituted with halogen;

R5means phenyl, optionally substituted by one or more substituents selected from the group consisting of1-C6alkyl, halogen, amino and mono - or disubstituted amino, C3-C7cycloalkyl, thienyl and furyl;

cycle G means phenyl,3-C7cycloalkyl, pyridyl or thienyl;

cycle J means phenyl;

the loop L is phenyl;

p means an integer from 0 to 2;

the dotted line (---- means the presence or absence of chemical bonding;

the wavy line (~ ) displays a CIS - or TRANS-configuration D relative to E;

provided that X1means-CH2NHCO-, X2means 1,4-phenylene and X3means a chemical bond or a C1-C5alkylen, when the carbon atom that is associated with D, and the adjacent carbon atom in the cycle are connected by a simple relationship, and Y1does not mean a chemical bond, when X1means-CH2O-;

pharmaceutically acceptable salt or hydrate specified connection.

2. Connection on p. 1, represented by formula (II)

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where R1, Z, X1X21does not mean a chemical bond, when X1means-CH2O-,

pharmaceutically acceptable salt or hydrate specified connection.

3. Connection on p. 1, represented by formula (III)

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where R1, Z, X1X2X3, Y2, And the wavy line have the meanings indicated above,

pharmaceutically acceptable salt or hydrate specified connection.

4. Connection on p. 1, represented by formula (IV)

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where R1, Z, X1X2X3, Y2, And the wavy line have the meanings indicated above,

pharmaceutically acceptable salt or hydrate specified connection.

5. Connection on p. 1, represented by formula (V)

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where R1, Z, R18X3, Y2, And the wavy line have the meanings indicated above,

pharmaceutically acceptable salt or hydrate specified connection.

6. Connection on p. 1, represented by formula (VI)

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where R1, Z, R18X3, Y2, And the wavy line have the meanings indicated above,

pharmaceutically acceptable salt or hydrate specified connection.

7. Connection on p. 1, represented by formula (VII)
>pharmaceutically acceptable salt or hydrate specified connection.

8. Connection on p. 1, represented by formula (VIII)

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where R1, Z, Y2, And the wavy line have the meanings indicated above,

pharmaceutically acceptable salt or hydrate specified connection.

9. Connection on p. 1, represented by formula (IX)

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where R1, Z, Y2, And the wavy line have the meanings indicated above,

pharmaceutically acceptable salt or hydrate specified connection.

10. Connection on p. 1, represented by formula (X)

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where R1, Z, Y2, And the wavy line have the meanings indicated above,

pharmaceutically acceptable salt or hydrate specified connection.

11. Connection on p. 1, represented by formula (XI)

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where R1, Z, Y2, And the wavy line have the meanings indicated above,

pharmaceutically acceptable salt or hydrate specified connection.

12. The compound according to any one of paragraphs.1-3, where Z denotes-N(R16)-, pharmaceutically acceptable salt or hydrate specified connection.

13. The compound according to any one of paragraphs.5-7, where R18means a hydrogen atom, and X3means chemical with the C PP.1-13, where R1means phenyl, optionally substituted by one or more substituents selected from the group consisting of finals2-C4alkenyl,1-C6alkyl, C3-C7cycloalkyl, halogen, C1-C6alkoxy, naphthyl, benzo-1,3-DIOXOLANYL, 2-pyridyl, panels1-C6alkyl, phenyloxy, mono - or disubstituted amino and N-methylpyrazine, biphenyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, trihalo1-C6alkyl and hydroxy, terphenyl, naphthyl, optionally substituted by one or more substituents selected from the group consisting of phenyl and halogen, phenyl condensed with C2-C7cycloalkyl, 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]chinolin, panels1-C6alkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halogen, phenyl, naphthyl, thienyl, benzofuranyl, panels1-C6alkyl, phenyloxy, mono - or disubstituted amino, phenyl, substituted by one or more substituents selected from the group consisting of C1-C6alkyl and halogen, and Tami from the group contains1-C6alkyl, C1-C6alkoxy, halogen, trihalo1-C6alkyl, nitro, amino, naftilos1-C6alkyl, optionally substituted by phenyl; and pharmaceutically acceptable salt or hydrate specified connection.

15. The compound according to any one of paragraphs.1-14, where Y2means the Deputy formula

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where R5means phenyl, optionally substituted by one or more substituents selected from the group consisting of1-C6alkyl, halogen, amino and mono - or disubstituted amino;

pharmaceutically acceptable salt or hydrate specified connection.

16. Pharmaceutical composition for the inhibition of phospholipase A2the production of arachidonic acid, the production of prostaglandin E2or production of leukotriene C4, which contains a compound according to any one of paragraphs.1-15 as an active ingredient.

 

Same patents:

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