Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents

• US 6,069,150 A
• Filed: 11/12/1998
• Issued: 05/30/2000
• Est. Priority Date: 04/04/1996
• Status: Expired due to Fees

• Current Assignee: F Hoffmann-La Roche AG (Roche Holding AG)
• Original Assignee: F Hoffmann-La Roche AG (Roche Holding AG)
• Inventors: Krell, Hans-Willi, Menta, Ernesto, Spinelli, Silvano
• Primary Examiner(s): Jones, Dwayne C.
• Application Number:
  US09/142,058
• Time in Patent Office: 565 Days
• Field of Search: 514/322, 546/87
• US Class Current: 514/312
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

The present invention concerns the use of beta-carboline derivatives of formula I bearing at least a free or esterified carboxylic group on the piperidine ring, for the preparation of pharmaceutical compositions having antimetastatic properties.

Claims

1. A method for inhibiting metallo-proteinase activity, comprising administering a compound selected from the group consisting of formula (I), enantiomers, racemates, diastereoisomers, salts, and pharmaceutically acceptable acids and bases thereof, to a patient in need of such inhibition ##STR2## wherein:

R is selected from the group consisting of hydrogen, linear or branched (C₁ -C₅) alkyl, phenyl which is unsubstituted or substituted with a (C₁ -C₅) alkoxy group, and --(CH₂)_n --COOH, wherein n is an integer from 1 to 3;

R₁ is hydrogen or a --COOR₄ group, wherein R₄ is hydrogen or (C₁ -C₅) alkyl;

R₂ is hydrogen or a --COOR₄ group, wherein R₄ is hydrogen or (C₁ -C₅) alkyl;

R₃ is selected from the group consisting of hydrogen, halogen, (C₁ -C₄) alkoxy and benzyloxy.

2. The method according to claim 1, wherein said halogen is selected from the group consisting of chlorine, bromine, fluorine and iodine.

3. The method according to claim 1, wherein said compound is selected from the group consisting of

6-methoxy-1,2,3,4-tetrahydronorharmane;

1,2,3,4-tetrahydronorharman-3-carboxylic acid;

6-methoxy-1,2,3,4-tetrahydronorharman-1-carboxylic acid;

1-(4-methoxyphenyl)-1,2,3,4-tetrahydronorharman-3-carboxylic acid;

1-metil-1,2,3,4-tetraidronorharman-3-carboxylic acid;

1-methyl-1,2,3,4-tetrahydronorharman-1,3-dicarboxylic acid;

1-(diethylmethyl)-1,2,3,4-tetrahydronorharman-3-carboxylic acid;

6-bromo-1,2,3,4-tetrahydranorharman-1-yl)-3-propionic acid;

1-isobutyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid;

1-phenyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid;

1-propyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid;

1-methyl-1-methoxycarbonyl-6-benzyloxy-1,2,3,4-tetrahydronorharmane;

1-methyl-1-methoxycarbonyl-6-methoxy-1,2,3,4-tetrahydronorharmane;

1-methyl-1-methoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydronorharmane;

1-methyl-1-methoxycarbonyl-6-chloro-1,2,3,4-tetrahydronorharmane;

1-methyl-1-methoxycarbonyl-6-bromo-1,2,3,4-tetrahydronorharmane; and

1-methyl-1-methoxycarbonyl-1,2,3,4-tetrahydronorharmane.

4. The method according to claim 3, wherein said compound is selected from the group consisting of

6-methoxy-1,2,3,4-tetrahydronorharmane;

6. The method according to claim 1, wherein said patient is suffering from a condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, septic arthritis, ulceration of the cornea, epidermic or gastric ulcerations, coronary thrombosis, proteinuria, and pathological consequences of traumas.

7. The method according to claim 1, wherein said inhibition of metallo-proteinase activity results in the prevention of ovulation or the prevention of the implantation of an ovule on a uterine wall.

9. The method according to claim 7, wherein said halogen is selected from the group consisting of chlorine, bromine, fluorine and iodine.

10. The method according to claim 7, wherein said compound is selected from the group consisting of

6-methoxy-1,2,3,4-tetrahydronorharmane;

1,2,3,4-tetrahydronorharman-3-carboxylic acid;

6-methoxy-1,2,3,4-tetrahydronorharman-1-carboxylic acid;

1-(4-methoxyphenyl)-1,2,3,4-tetrahydronorharman-3-carboxylic acid;

1-metil-1,2,3,4-tetraidronorharman-3-carboxylic acid;

1-methyl-1,2,3,4-tetrahydronorharman-1,3-dicarboxylic acid;

1-(diethylmethyl)-1,2,3,4-tetrahydronorharman-3-carboxylic acid;

(6-bromo-1,2,3,4-tetrahydronorharman-1-yl)-3-propionic acid;

1-isobutyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid;

1-phenyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid;

1-propyl-1,2,3,4-tetrahydronorharman-3-carboxylic acid;

1-methyl-1-methoxycarbonyl-6-benzyloxy-1,2,3,4-tetrahydronorharmane;

1-methyl-1-methoxycarbonyl-6-methoxy-1,2,3,4-tetrahydronorharmane;

1-methyl-1-methoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydronorharmane;

1-methyl-1-methoxycarbonyl-6-chloro-1,2,3,4-tetrahydronorharmane;

1-methyl-1-methoxycarbonyl-6-bromo-1,2,3,4-tetrahydronorharmane; and

1-methyl-1-methoxycarbonyl-1,2,3,4-tetrahydronorharmane.

11. The method according to claim 9, wherein said compound is selected from the group consisting of

6-methoxy-1,2,3,4-tetrahydronorharmane;

5. 2,3,4-tetrahydronorharman-3-carboxylic acid;

and

6-methoxy-1,2,3,4-tetrahydronorharman-1-carboxylic acid.

8. A method for inhibiting tumor invasion and metastases, comprising administering a compound selected from the group consisting of formula (I), enantiomers, racemates, diastereoisomers, salts, and pharmaceutically acceptable acids and bases thereof, to a patient in need of such inhibition ##STR3## wherein:

R is selected from the group consisting of hydrogen, linear or branched (C₁ -C₅) alkyl, phenyl which is unsubstituted or substituted with a (C₁ -C₅) alkoxy group, and --(CH₂)_n --COOH, wherein n is an integer from 1 to 3;

R₁ is hydrogen or a --COOR₄ group, wherein R₄ is hydrogen or (C₁ -C₅) alkyl;

R₂ is hydrogen or a --COOR₄ group, wherein R₄ is hydrogen or (C₁ -C₅) alkyl;

R₃ is selected from the group consisting of hydrogen, halogen, (C₁ -C₄) alkoxy and benzyloxy.

12. 2,3,4-tetrahydronorharinan-3-carboxylic acid;

and

6-methoxy-1,2,3,4-tetrahydronorharman-1-carboxylic acid.