Tachiquinine antagonist tricyclic compounds, preparation of same and pharmaceutical compositions containing such compounds

• US 5,731,285 A
• Filed: 10/17/1996
• Issued: 03/24/1998
• Est. Priority Date: 04/15/1992
• Status: Expired due to Fees

• Current Assignee: Laboratori Guidotti S.p.A. (A Menarini Industrie Farmaceutiche Riunite SRL), A Menatini Industrie Farmaceutiche, Malesci SPA Istituto Farmacobiologico
• Original Assignee: Laboratori Guidotti S.p.A. (A Menarini Industrie Farmaceutiche Riunite SRL), A Menatini Industrie Farmaceutiche, Malesci SPA Istituto Farmacobiologico
• Inventors: Quartara, Laura, Lombardi, Angelina, Pavone, Vincenzo, Maggi, Carlo Alberto, Pedone, Carlo
• Primary Examiner(s): Achutamurthy, Ponnathapura
• Assistant Examiner(s): Wessendorf, T. D.
• Application Number:
  US08/731,709
• Time in Patent Office: 523 Days
• Field of Search: 514/9, 514/10, 514/11, 514/2, 530/318, 530/317, 530/320
• US Class Current: 514/9.7
• 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: C07K 7/22 Tachykinins, e.g. Eledoisins , Substance P; Related peptides
• CPC Class Codes: C07K 7/56 the cyclisation not occurring through 2,4-diamino-butanoic acid

Abstract

Tachyikinin antagonist compounds of the general formula: ##STR1## are described where: X1, X2, X3, X4, X5, and X6 are identical or different and are --NR'"'"'--CO-- or --CO--NR"--, where R'"'"' is H or C_1-3 alkyl;

Y is --CONR--, --NRCO--, OCO, --COO--, --CH₂ --NR--, --NR--CH₂ --, --SS--, --CH₂ --CH₂ --, cis or trans --CH═CH-- where R is H or C_1-3 alkyl;

R1, R2, R3, and R4 are each a hydrophobic group;

n and m are identical or different and are each a whole number from 1 to 4. The preparation and pharmaceutical compositions of the compounds are also disclosed.

Claims

1. The compounds of formula (I) ##STR9## where:

the chiral carbons are in the D or L configuration and X1, X2, X3, X4, X5, and X6 are identical or different, and are each selected from the group consisting of --NR'"'"'--CO-- and --CO--NR'"'"'--, where R'"'"' is H;

Y is selected from the group consisting of --CONR--, --NRCO-- and --SS--;

where R is H;

wherein;

R1 is the same as R2 and is the hydrophobic group consisting of the side chains of amino acids selected from the group consisting of phenylalanine, tyrosine, glycine, alanine, valine, isoleucine, norleucine, norvaline and alloisoleucine;

R3 is the hydrophobic group consisting of the side chains of the amino acids selected from tryptophan and phenylalanine, and R4 are the hydrophobic groups consisting of the side chains of amino acids selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, norleucine, norvaline, alloisoleucine, cyclohexylglycine (Chg), alpha-amino-n-butyric acid (Aba), cyclohexylalanine (Cha), aminophenylbutyric acid (Pba) and the O-alkylated derivatives of serine, n and m are each independently a whole number from 1 to 4.

2. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR10## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--CONH--

Y=--CONH--

wherein chiral carbon atoms exhibit the L-configuration.

3. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR11## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--CONH--

Y=--NHCO-- wherein chiral carbon atoms exhibit the L-configuration.

4. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR12## R4=--CH₂ --C₆ H₁₁ X 1=X2=X3=X4=X5=X6=--CONH--

Y=--CONH-- wherein chiral carbon atoms exhibit the L-configuration.

5. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR13## R4=--CH₂ --C₆ H₁₁ X 1=X2=X3=X4=X5=X6=--CONH--

Y=--NHCO-- wherein chiral carbon atoms exhibit the L-configuration.

6. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR14## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--CONH--

Y=--SS--

wherein chiral carbon atoms exhibit the L-configuration.

7. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR15## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--CONH--

Y=--CONH--

m=2, n=4 wherein chiral carbon atoms exhibit the L-configuration.

8. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR16## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--CONH--

m=2, n=4 wherein chiral carbon atoms exhibit the L-configuration.

9. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR17## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--NHCO--

m=2, n=4 wherein chiral carbon atoms exhibit the L-configuration.

10. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR18## R4=--CH₂ --C₆ H₁₁ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--CONH--

m=2, n=4 wherein chiral carbon atoms exhibit the L-configuration.

11. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR19## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3 ⁼ X4=X5=X6=--NHCO--

Y=--CONH--

m=2, n=4 wherein chiral carbon atoms exhibit the L-configuration.

12. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR20## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--CONH--

m=1;

n=2 wherein chiral carbon atoms exhibit the L-configuration.

13. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR21## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--CONH--

m=1, n=3 wherein chiral carbon atoms exhibit the L-configuration.

14. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR22## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--CONH--

m=1, n=4 wherein chiral carbon atoms exhibit the L-configuration.

15. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR23## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--CONH--

m=2, n=1 wherein chiral carbon atoms exhibit the L-configuration.

16. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR24## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--CONH--

m=2, n=3 wherein chiral carbon atoms exhibit the L-configuration.

17. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR25## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--CONH--

m=2, n=2 wherein chiral carbon atoms exhibit the L-configuration.

18. The compounds of formula (I) according to claim 1 wherein:

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR26## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--CONH--

m=2, n=4 wherein chiral carbon atoms exhibit the L-configuration.

19. The compounds of formula (I) according to claim 1 wherein the carbon atoms in positions 5 and 6 exhibit D-configuration, and

R1=--CH₂ CH(CH₃)₂

R2=--CH₂ C₆ H₅ ##STR27## R4=--(CH₂)₂ --SCH₃ X 1=X2=X3=X4=X5=X6=--NHCO--

Y=--CONH--

wherein chiral carbon atoms exhibit the L-configuration.

20. A pharmaceutical composition containing a compound of formula (I) according to claim 1, mixed with suitable carriers.

21. A method for the treatment of hypertension, comprising administering 0.1 to 10 mg active ingredient consisting of the compounds of formula (I) according to claim 1.