Tri- and tetracyclic compounds

• US 5,811,389 A
• Filed: 06/24/1996
• Issued: 09/22/1998
• Est. Priority Date: 08/31/1992
• Status: Expired due to Fees

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Bannwarth, Wilhelm, Knierzinger, Andreas, Grieder, Alfred, Gerber, Fernand, Obrecht, Daniel, Muller, Klaus, Trzeciak, Arnold
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): Gupta, Anish
• Application Number:
  US08/668,871
• Time in Patent Office: 820 Days
• Field of Search: 514/2, 514/9, 514/13, 514/14, 514/15, 514/16, 514/17, 514/18, 514/19, 514/185, 514/222.5, 514/224.8, 514/229.8, 530/317, 530/326, 530/327, 530/329, 530/330, 530/331, 530/328, 544/35, 544/101, 544/102, 549/388, 549/16
• US Class Current: 514/1.9
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 265/38 [b, e]-condensed with two six-membered rings
• CPC Class Codes: C07D 279/22 with carbon atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 311/82 Xanthenes
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 513/06 Peri-condensed systems
• CPC Class Codes: C07K 14/75 Fibrinogen
• CPC Class Codes: C07K 5/04 containing only normal peptide links
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/0606 the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
• CPC Class Codes: C07K 5/06069 Ser-amino acid
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06086 with the first amino acid being basic
• CPC Class Codes: C07K 5/06104 with the first amino acid being acidic
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/1008 : the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/101 : the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/1019 : with the first amino acid being basic
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids
• CPC Class Codes: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

There are described compounds of the formula ##STR1## Wherein the variables have been defined herein. The compounds are useful as research tools in the determination of biologically active peptides sequences and also potentially suitable as medicaments, some of them being useful in the prevention or control of the formation of blood platelet thrombi, and some compounds are useful as intermediates.

Claims

1. A compound of the formula ##STR21## wherein X signifies a group of the formula ##STR22##

2. The compound according to claim 1, wherein X signifies a group of formula (a) and R⁴ signifies methyl, ethyl, hexyl, benzyl, hydrogen, 4-methoxycarbonylbutyryl or 4-carboxybutyryl.

3. The compound according to claim 2, wherein R⁴ signifies 4-carboxybutyryl and R³ does not signify carboxyl.

4. The compound according to claim 1, wherein X signifies a group of formula (b) and R⁵ and R⁶ both signify methyl.

5. The compound according to claim 1, wherein the two symbols R¹ both signify methoxy or both signify ethoxy.

6. The compound according to claim 1, wherein R² signifies a residue of formula (c), R³ signifies a residue of formula (d) and R⁷ and R⁸ together signify a residue of an amino acid or a chain of up to 20 amino acid residues.

7. The compound according to claim 6, wherein R⁷ and R⁸ together signify a residue of an amino acid or a chain of up to 14 amino acid residues.

8. The compound according to claim 7, wherein the amino acid residue or the chain of amino acid residues does not contain protecting group(s).

9. The compound according to claim 8 containing

-Arg-

-Ala-

-Ala-Ala-

-Arg-Gln-

-Arg-Ser-

-Gln-Arg-

-Glu-Arg-

-Lys-Glu-

-Ser-Arg-

-Thr-Gly-

-Tyr-Phe-

-Leu-D-Tyr-D-Asp-

-Gly-Arg-Gly-

-Ile-Tyr-Ala-

-Leu-Tyr-Asp-

-Ala-Thr-Val-Gly-,-SEQ ID NO:

1-,

-Arg-Gly-Asp-Val-,-SEQ ID NO;

2-,

-Gly-Asp-Gly-Gly-,-SEQ ID NO;

3-,

-Gly-Gly-Ala-Gly-,-SEQ ID NO;

4-,

-Val-Arg-Lys-Lys-,-SEQ ID NO;

5-,

-Ala-Arg-Gly-Asp-Phe-Pro-,-SEQ ID NO;

6-,

-Glu-Arg-Gly-Asp-Val-Tyr-,-SEQ ID NO;

7-,

-Ile-Ala-Arg-Gly-Asp-Phe-Pro-Asp-,-SEQ ID NO;

8-,

-Val-Ala-Ala-Phe-Leu-Ala-Leu-Ala-,-SEQ ID NO;

9-,

-Arg-Ile-Ala-Arg-Gly-Asp-Phe-Pro-Asp-Asp-,-SEQ ID NO;

10-,

-Ala-Arg-Ile-Ala-Arg-Gly-Asp-Phe-Pro-Asp-Asp-Arg-, -SEQ ID NO;

11-,

-Arg-Gyl-Asp-Phe-,-SEQ ID NO;

12-,

-Val-Arg-Lys-Ile-, -SEQ ID NO;

14-,

-Ile-Val-Arg-Lys-Lys-Pro-, -SEQ ID NO;

15-,

-Gly-D-Arg-Lys-D-Ile, -SEQ ID NO;

16-,

-Arg-Lys-Ile-Gln-Ile-Val-Arg-Lys-Lys-Pro-Ile-Phe-Lys- Lys-, -SEQ ID NO;

17-,

as the amino acid residue or as the chain of amino acid residues.

10. The compound of claim 1, 4,5-cyclo- acetyl-L-alanyl-L-arginyl-L-isoleucyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-aspartyl-L-arginyl-aminomethyl!3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo-(acetyl-SEQ ID NO:

11-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene.

11. The compound of claim 1, 4,5-cyclo- acetyl-L-arginyl-L-isoleucyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-aspartyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO:

10-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene).

12. The compound of claim 1, 4,5-cyclo- acetyl-L-isoleucyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-L-aspartyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO:

8-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene).

13. The compound of claim 1, 4,5-cyclo-(acetyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO:

6-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene).

14. The compound of claim 1, 4,5-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO:

12-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene).

15. The compound of claim 1, 4,5-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO:

2-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene).

16. The compound of claim 1, 10-methyl-4,6-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!-phenothiazine (10-methyl-4,6-cyclo- acetyl-SEQ ID NO:

2-aminomethyl!phenothiazine).

17. The compound of claim 1, 4,6-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl-!-3,7-diethoxy-10-ethyl-10H-dibenz b,e! 1,4!-oxazine (4,6-cyclo- acetyl-SEQ ID NO:

2-aminomethyl!-3,7-diethoxy-10-ethyl-10H-dibenz b,e! 1,4!oxazine).

18. The compound of claim 1, 10-hexyl-3,7-dimethoxy-4,6-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!phenothiazine (10-hexyl-3,7-dimethoxy-4,6-cyclo- acetyl-SEQ ID NO:

2-aminomethyl!phenothiazine).

19. The compound of claim 1, 3,7-dimethoxy-10-methyl-4,6-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!phenothiazine (3,7-dimethoxy-10-methyl-4,6-cyclo- acetyl-SEQ ID NO:

2-aminomethyl!phenothiazine).

20. A composition of a compound having the formula ##STR23## wherein X signifies a group of the formula ##STR24## Y signifies oxygen or sulphur;

R¹ signifies hydrogen or lower alkyl;

R² signifies a residue of the formula --NH--R⁷ (c);

R³ signifies a residue of the formula --CO--R⁸ (d);

R⁴ signifies lower alkyl, aryl, aryl-lower alkyl, hydrogen or acyl;

R⁵ and R⁶ each signify lower alkyl, aryl or aryl-lower alkyl; and

R⁷ and R⁸ together signify a residue selected from an amino acid or a chain of up to 20 amino acid residues, the amino acid residue or the amino acid residues optionally protected;

or of a pharmaceutically useable salt thereof and a pharmaceutically useable adjuvant.

21. A method for treating disease states by effecting inhibition of platelet aggregation, which comprises administering to a mammal in need such treatment a compound selected from the group consisting of

4,5 -cyclo- acetyl-L-alanyl-L-arginyl-L-isoleucyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-aspartyl-L-arginyl-aminomethyl!3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO:

11 -aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

26. The method of claim 21 wherein said disease states are selected from thrombosis, stroke, cardiac infarct, inflammation, and arteriosclerosis.

22. 5-cyclo- acetyl-L-arginyl-L-isoleucyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-aspartyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO:

10-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

4,5-cyclo- acetyl-L-isoleucyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-L-aspartyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO;

8-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

4,5-cyclo- acetyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO;

6-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

4,5-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO;

12-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

4,5-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO;

2-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

10-methyl-4,6-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!-phenothiazine (10-methyl-4,6-cyclo- acetyl-SEQ ID NO;

2-aminomethyl!phenothiazine);

4,6-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!-3,7-diethoxy-10-ethyl-10H-dibenz b,e! 1,4!oxazine (4,6-cyclo- acetyl-SEQ ID NO;

2-aminomethyl!-3,7-diethoxy-10-ethyl-10H-dibenz b,3! 1,4!oxazine);

and

10-hexyl-3,7-dimethoxy-4,6-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!phenothiazine (10-hexyl-3,7-dimethoxy-4,6-cyclo- acetyl-SEQ ID NO;

2-aminomethyl!phenothiazine);

or a pharmaceutically useable salt thereof in an amount which is effective in treating the disease states by inhibiting platelet aggregation.

27. The method of claim 22 wherein said disease states are selected from thrombosis, stroke, cardiac infarct, inflammation, and arteriosclerosis.

23. A method of prophylaxis in disease states against inhibiting platelet aggregation in mammals susceptible thereto, which comprises administering to said mammal a compound selected from the group consisting of

24. 5-cyclo- acetyl-L-alanyl-L-arginyl-L-isoleucyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-aspartyl-L-arginyl-aminomethyl!3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO:

11 -aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

4,5-cyclo- acetyl-L-arginyl-L-isoleucyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-aspartyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO;

10-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

4,5-cyclo- acetyl-L-isoleucyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-L-aspartyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO;

8-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

4,5-cyclo- acetyl-L-alanyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-L-prolyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO;

6-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

4,5-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-phenylalanyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO;

12-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

25. 5-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene (4,5-cyclo- acetyl-SEQ ID NO:

2-aminomethyl!-3,6-dimethoxy-9,9-dimethylxanthene);

10-methyl-4,6-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!-phenothiazine (10-methyl-4,6-cyclo- acetyl-SEQ ID NO;

2-aminomethyl!phenothiazine);

4,6-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!-3,7-diethoxy-10-ethyl-10H-dibenz b,e! 1,4!oxazine (4,6-cyclo- acetyl-SEQ ID NO;

2-aminomethyl!-3,7-diethoxy-10-ethyl-10H-dibenz b,3! 1,4!oxazine);

and

10-hexyl-3,7-dimethoxy-4,6-cyclo- acetyl-L-arginyl-glycyl-L-aspartyl-L-valyl-aminomethyl!phenothiazine (10-hexyl-3,7-dimethoxy-4,6-cyclo- acetyl-SEQ ID NO;

2-aminomethyl!phenothiazine);

or a pharmaceutically useable salt thereof in an amount which is effective as a prophylaxis for treating disease states by inhibiting platelet aggregation.