Cyclic cell adhesion modulation compounds

• US 5,192,746 A
• Filed: 07/09/1990
• Issued: 03/09/1993
• Est. Priority Date: 07/09/1990
• Status: Expired due to Fees

• Current Assignee: Tanabe Seiyaku Co Ltd (Mitsubishi Chemical Group Corp.)
• Original Assignee: Tanabe Seiyaku Co Ltd (Mitsubishi Chemical Group Corp.)
• Inventors: Cardarelli, Pina M., Lobl, Thomas J., Chiang, Shiu-Lan
• Primary Examiner(s): Lee, Lester L.
• Assistant Examiner(s): DAVENPORT, AVIS MICHELLE
• Application Number:
  US07/550,330
• Time in Patent Office: 974 Days
• Field of Search: 514/11, 514/13, 514/14, 514/15, 514/16, 514/17, 514/18, 514/9, 530/330, 530/329, 530/328, 530/327, 530/326, 530/325, 530/317
• US Class Current: 514/9.3
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/75 Fibrinogen
• CPC Class Codes: C07K 14/78 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
• CPC Class Codes: C07K 5/021 containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
• CPC Class Codes: C07K 5/1021 with the first amino acid being acidic
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/56 the cyclisation not occurring through 2,4-diamino-butanoic acid

Abstract

Cyclized integrin receptor antagonist compounds useful in modulating cell adhesion to integrin receptors, including adhesion related to fibronectin and/or fibronectin receptors, are disclosed. Methods for synthesizing, testing, formulating, and using the compounds as therapeutic agents are also disclosed.

Claims

1. A compound of the formula ##STR54## and pharmaceutically acceptable salts thereof, wherein L¹ and L² are each, or are together, a residue of an amino acid, an amino acid analog or an amino acid mimetic having a functional group suitable for the formation of a cyclizing bridge between L¹ and L² ;

Z is a cyclizing moiety or bond between L¹ and L² ;

1is optional and, where present, is selected from the group consisting of Leu, Sar, D-Nal, Tyr, Phe, Ile, Pro, Gly, Ala, Val, norLeu, norVal, β

-Ala, Trp, and (Ada -Ala;

2 is selected from the group consisting of Arg, homoArg and norArg.

4 is selected from Asp and, where 2 is norArg, Glu.

5 is optional and, where present, is selected from the group consisting of Ser, Thr, Tyr, Trp, Ala, Val, Phe ##STR55## wherein m is 2, 3 or 4;

6is optional and, where present, is selected from the group consisting Pro, 3-thioPro, 1,1-ACC, Dhp, Hyp, homoPro and Phe;

X¹ and Y¹ are each optional and, where present, are independently selected from sequences of 1 to 4 D- or L-amino acids or amino acid analogs;

X² is an optional N.sup.α

-substituent selected from R'"'"'-(including hydrogen) and R'"'"'CO--; and

Y² is an optional carboxyl terminal substituent selected from the group consisting of --OR'"'"' (including hydroxy), --NR'"'"'₂ (including --NH₂ and --NHR'"'"'), --NHNH₂ and --SR'"'"';

and wherein each R'"'"' is individually a pharmaceutically suitable substituent group, preferably one selected from the group consisting of hydrogen, linear and branched, unsubstituted and substituted C₁ -C₈ lower alkyls, C₂ -C₈ alkenyls, C₂ -C₈ alkenyls, C₂ -C₈ alkynyls, C₆ -C₁₄ aryls, C₇ -C₁₄ alkaryls, C₇ -C₁₄ alkaryls and C₃ -C₁₄ cycloalkyls, and, in the case of --NR'"'"'₂, from cyclized groups forming (in an attachment with the nitrogen atom) a 5-8 membered heterocyclic ring optionally containing oxygen, nitrogen or sulfur as a further ring heteroatom.

2. A compound of claim 1 wherein L¹ and L² each provide a sulfur-containing functional group, and cyclization is achieved through a disulfide bond.

3. A compound of claim 1 wherein L¹ is Cys.

4. A compound of claim 1 wherein L¹ and L² each provide sulfur-containing functional groups, and Z is a hydrocarbon bridge between said sulfur groups.

5. A compound of claim 1 wherein the linkage between L¹ and L² is a monosulfide linkage.

6. A compound of claim 1 wherein Z is a diketo, a diamino or a keto-amino moiety.

7. A compound of claim 6 wherein Z is a diketo moiety of the form ##STR56## wherein n, is from 1 to 8.

8. A compound of claim 1 wherein Z is a diamino moiety of the form

9. A compound of claim 1 wherein L¹ is directly bonded to L² via an amide bond.

10. A compound of claim 1 wherein the sequence 1-2-L¹ -4-5-6-L² is selected from the group consisting of

Leu-Arg-Cys-Asp-Ser-Pro-Cys,

Arg-Cys-Asp-Ser-Pro-Cys, and

Arg-Cys-Asp-Pro-Cys.

11. A compound of claim 1 selected from the group consisting of ##STR57##

12. A compound of claim 1 useful in modulating adhesion of a cell expressing a fibronectin receptor.

13. A pharmaceutical composition comprising a compound of claim 1.

14. A compound of claim 1 having an IC₅₀ in a U937 fibronectin adhesion assay of less than about 500 μ

M.

15. A compound of claim 1 having an IC₅₀ in a U937 fibronectin adhesion assay of less than about 100 μ

M.