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Aryl sulphonamides and analogues

Imported: 23 Feb '17 | Published: 22 Oct '02

Joachim Mittendorf, Jürgen Dressel, Michael Matzke, Jörg Keldenich, Frank Mauler, Jean-Marie-Victor de Vry, Jürgen Franz, Peter Spreyer, Verena Vöhringer, Joachim Schumacher, Michael-Harold Rock, Ervin Horvàth, Arno Friedl, Klaus-Helmut Mohrs, Siegfried Raddatz, et al.

USPTO - Utility Patents

Abstract

The present invention relates to novel arylsulphonamides and analogues, to processes for their preparation and to their use for the prophylaxis and treatment of neurodegenerative disorders, in particular for the treatment of cerebral apoplexy, craniocerebral trauma, pain and spasticity.

Claims

1. Compounds of the general formula (I)

R

1—A—D—E—G—L—R

2  (I)

in which

and a radical of the formula

in which

—(CH

2)

i—NR

27R

28,

and pharmaceutically acceptable salts thereof.

2. Compounds of the general formula (I) according to claim 1,

and where the ring systems listed above are optionally substituted, optionally geminally, by one or more identical or different substituents selected from the group consisting of:

—NR

15 R

16 or —NR

17—OC—,

and pharmaceutically acceptable salts thereof.

3. Compounds of the general formula (I), according to claim 1

in which

and pharmaceutically acceptable salts thereof.

4. Compounds of the general formula (I), according to claim 1, in which

and pharmaceutically acceptable salts thereof.

5. The compound according to claim 1

6. A process for preparing an arylsulphonamide according to claim 1, wherein

R

1—A—D—E—G—M—H  (II)

are reacted with compounds of the general formula (III)

R

43—U—R

2  (III)

in which

to give compounds of the general formula (Ia)

R

1—A—D—E—G—M—U—R

2  (Ia)

in which

in inert solvents,

are initially reacted with trialkylsilyl chlorosulphonates, admixed with an acid and then reacted with a chlorinating agent, to give a compound of the general formula (IV)

R

1—A—D—E—G—M—SO

2—Cl  (IV)

in which

followed by reaction with compounds of the general formula (V)

H—V—R

2  (V)

in which

to give compounds of the general formula (Ib)

R

1—A—D—E—G—M—SO

2—V—R

2  (Ib)

in inert solvents in the presence of Bzl-NEt

3

+Cl

and a base,

or

R

1—A—D—H  (VI)

are reacted with compounds of the general formula (VII)

R

44—E—G—SO

2—NH—R

2  (VII)

in which

to give compounds of the general formula (Ic)

R

1—A—D—E—G—SO

2—NH—R

2  (Ic)

in which

R

45—A—D—E—G—L—R

2  (Id)

are reacted with chloroformate, and then with alcohols, to give compounds of the general formula (Ie)

R

47—A—D—E—G—L—R

2  (Ie)

in which

are reacted with (C

1-C

6)-ketones or (C

1-C

6)-aldehydes in the presence of a reducing agent, to give compounds of the general formula (If)

R

48—A—D—E—L—R

2  (If)

in which

R

49—Q  (VIII)

in inert solvents, to give compounds of the general formula (Ig)

R

50—A—D—E—G—L—R

2  (Ig)

in which

are converted by free-radical bromination, in an inert solvent into compounds of the general formula (Ii)

in which

and one of the substituents W or X represents bromine and the other represents hydrogen,

and subsequently reacted with compounds of the general formula (IX)

CH

2(CO

2R

51)

2  (IX)

in which

R

52—A—D—E—G—L—R

2  (Ij)

to give compounds of the general formula (X)

in which

and finally reduced to the methylhydroxy function,

or

compounds of the general formula (XI)

R

1—(CR

9R

10)

c—OH  (XI)

are reacted with compounds of the general formula (XII)

in which

in inert solvents,

and the amino protective group is cleaved off,

and, in the last step, a reduction with BH

3xS(CH

3)

2 in tetrahydrofuran is carried out,

and, in the case of the pure enantiomers, an HPLC separation is carried out, and, in the case that D=—SO— or —SO

2—, an oxidation is carried out on the corresponding amines.

7. A pharmaceutical composition which comprises, as an active component, at least one compound according to claim 1 in combination with at least one pharmaceutically acceptable non-toxic vehicle or excipient.

8. A method for the treatment of neurodegenerative disorders comprising administering to a mammal an effective amount of a compound according to claim 1.

9. A method for the treatment of cerebral ischaemias and craniocerebral trauma comprising administering to a mammal an effective amount of a compound according to claim 1.

10. A method for the treatment of pain, emesis, nausea, glaucoma, asthma, anorexia, convulsions, rheumatism, sedation, and mobility disorders comprising administering to a mammal an effective amount of a compound according to claim 1.

11. A method for the treatment of bacterial or viral infections, autoimmune diseases, inflammatory or autoimmunologically related diseases of the joints of the bone and muscle apparatus, of the internal organs, of the central nervous system, of the sense organs and of the haematogenic system comprising administering to a mammal an effective amount of a compound according to claim 1.

12. A method for the treatment of migraine and spasticity comprising administering to a mammal an effective amount of a compound according to claim 1.

13. The process of claim 6, wherein said trialkysilyl chlorosulphonate is trimethylsilyl chlorosulphonate and said chlorinating agent is phosphorus pentachloride.

14. The process of claim 6, wherein R

44 is selected from the group consisting of fluorine, chlorine, and bromine.

15. The process of claim 6, wherein said chloroformate is selected from the group consisting of 1-(1-chloro)ethyl chloroformate and methyl chloroformate.

16. The process of claim 6, wherein said reducing agent is sodium cyanoborohydrate.

17. The process of claim 6, wherein R

49 is a halogen.

18. The process of claim 6, wherein said free-radical bromination is performed using N-bromosuccinimide.

19. The process of claim 6, wherein R

12′ is tert-butyloxycarbonyl.

20. The process of claim 6, wherein, after removal of the amino protective group, the amino group is reductively alkylated or dialkylated with an aldehyde, ketone, or halide.