Cell adhesion ihibiting compounds

• US 6,235,711 B1
• Filed: 12/21/1998
• Issued: 05/22/2001
• Est. Priority Date: 06/21/1996
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Dutta, Anand Swaroop
• Primary Examiner(s): Carlson, Karen Cochrane
• Assistant Examiner(s): Gupta, Anish
• Application Number:
  US09/202,831
• Time in Patent Office: 883 Days
• Field of Search: 514/11, 514/16, 514/17, 514/863, 530/317, 530/328, 530/329, 530/333
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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: C07K 14/78 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]

Abstract

Cyclic peptide of formula (1) where Xaa₁ is selected from L-amino acids selected from Phe, Lys and Arg, D-amino acids selected from Phe and Met, the L- and D-amino acid optionally substituted on its α-carbon or its α-amino group with a C_1-4 alkyl group; and Melle; Xaa₂, Xaa₃ et Xaa₄ are respectively Leu, Asp and Val, optionally substituted on their α-carbon or α-amino group with a C_1-4 alkyl group; X¹ is selected from D-amino acids selected from Ala, Phe, Arg, Lys, Trp, hArg(Et)₂, Orn(CHMe₂), Orn(Me₂), Lys(CHMe₂) and Arg(Pmc), optionally substituted on their α-carbon or α-amino group with a C_1-4 alkyl group; Formula (II); NH(CH₂)₅CO; and NH(CH₂)₂S(CH₂)_yCO, where y is 1 or 2; X² is selected from D-amino acids selected from Ala, Arg, Lys, His, hArg(Et)₂, Orm(CHMe₂), and Om(Me₂), optionally substituted on their α-carbon or α-amino group with a C_1-4 alkyl group; NH(CH₂)SCH₂CO; and NH(CH₂)_xCO, where x is 2 or 3; Xaa₅ and Xaa₆ are each independently a D-amino acid selected from Ala and Arg, optionally substituted on its α-carbon or α-mino group with a C_1-4 alkyl group; p is 0 or 1; and q is 0 or when p is 1, q is 0 or 1; or a salt thereof. The cyclic peptides inhibit the interaction of vascular cell adhesion molecule−1 and fibronectin with integrin very late antigen 4 (α4β61) and of mucosal addressin cell adhesion molecule−1 (MAdCAM−1) with integrin α4β7. They have therapeutic applications such as in rheumatoid arthrids, multiple sclerosis, astlna, psoriasis, inflammatory bowel disease and insulin-dependent diabetes.

Claims

1. A cyclic peptide of the formula

where

Xaa₁ is selected from an L-amino acid or a D-amino acid, wherein the L-amino acid is selected from Phe, Lys and Arg, the D-amino acid is selected from Phe and Met, and the L- or D-amino acid optionally is substituted on its ax-carbon or ax-amino group with a C_1-4 alkyl group,

or

Xaa₁ is MeIle;

Xaa₂ is Leu, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

Xaa₃ is Asp, optionally substituted on its α

-carbon or cc-amino group with a C_1-4 alkyl group;

Xaa₄ is Val, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

X¹ is a D-amino acid selected from Ala, Phe, Arg, Lys, Trp, hArg(Et)₂, Orn(CHMe₂), Orn(Me₂), Lys(CHMe₂) and Arg(Pmc), optionally substituted on its α

-carbon or its α

-amino group with a C_1-4 alkyl group;

or

X¹ is

NH(CH₂)₅CO, or NH(CH₂)₂S(CH₂)_yCO where y is 1 or 2;

X² is a D-amino acid selected from Ala, Arg, Lys, His, hArg(Et)₂, Orn(CHMe₂), and Orn(Me₂), optionally substituted on its α

-carbon or its α

-amino group with a C_1-4 alkyl group,

or

x² is NH(CH₂)₂SCH₂CO, or NH(CH₂)_xCO where x is 2 or 3;

Xaa₅ and Xaa₆ are each, independently, a D-amino acid selected from Ala and Arg, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

p is 0 or 1; and

q is 0 or when p is 1, q is 0 or 1;

or a salt thereof;

with the proviso that when Xaa₁ is MeIle, Xaa₂ is Leu, Xaa₃ is Asp, Xaa₄ is Val and p and q are both 0, then

i) X² is not D-Ala, D-Arg, or D-Lys when X¹ is D-Ala;

ii) X² is not D-Arg when X¹ is

iii) X² is not D-Ala, D-Arg or D-His when X¹ is D-Arg;

iv) X² is not D-Ala when X¹ is D-Orn(CHMe₂) or D-Arg(Pmc);

v) x² is not D-Ala or D-Lys when X¹ is D-Lys; and

vi) X² is not D-Lys or D-Arg when X¹ is D-Phe or D-Trp.

2. A cyclic peptide according to claim 1

where

Xaa₁ is an L-amino acid selected from Meae, MePhe, Lys and Arg, or a D-amino acid selected from Phe and Met;

Xaa₂, Xaa₃ and Xaa₄ are, respectively, Leu, Asp, and Val;

X¹ is a D-amino acid selected from Ala, Phe, Arg, Lys, Trp, hArg(Et)₂, Orn(CHMe₂), Orn(Me₂), Lys(CHMe₂) and Arg(Pmc),

or

X¹ is

NH(CH₂)₅CO, or NH(CH₂)₂S(CH₂)_yCO where y is 1 or 2;

X² is a D-amino acid selected from Ala, Arg, Lys, His, hArg(Et)₂, Orn(CHMe₂), and Orn(Me₂),

or

X² is NH(CH₂)₂SCH₂CO, or NH(CH₂)_xCO where x is 2 or 3;

Xaa₅ and Xaa₆ are each, independently, a D-amino acid selected from Ala and Arg;

or a salt thereof.

5. A cyclic peptide according to claim 1 where any two of X¹, X², (Xaa₅)_p and (Xaa₆)_q are D-Arg or a salt thereof.

9. A cyclic peptide according to claim 1 where the cyclic peptide is selected from

c(MeIle-Leu-Asp-Val-D-Orn(CHMe₂)-D-Orn(CHMe₂))

c(MeIle-Leu-Asp-Val-D-Lys(CIHMe₂)-D-Ala)

c(MeIle-Leu-Asp-Val-D-Orn(Me₂)-D-Orn(Me₂))

c(MeIle-Leu-Asp-Val-D-Ala-D-hArg(Et)₂)

c(MeIle-Leu-Asp-Val-D-Phe-D-hArg(Et)₂)

c(MeIle-Leu-Asp-Val-D-hArg(Et)₂-D-hArg(Et)₂)

c(MeIle-Leu-Asp-Val-D-Lys-D-His)

c(Melle-Leu-Asp-Val-D-Arg(Pmc)-D-Lys)

c(MeIle-Leu-Asp-Val-D-Lys-D-Arg)

c(MePhe-Leu-Asp-Val-D-Ala-D-Lys)

c(MeIle-Leu-Asp-Val-D-Arg-D-Lys)

c(Lys-Leu-Asp-Val-D-Ala-D-Ala)

c(Arg-Leu-AspVal-D-Ala-D-Ala)

c(D-Phe-Leu-Asp-Val-D-Ala-D-Lys)

c(MePhe-Leu-Asp-Val-D-Ala-D-Ala)

c(D-Phe-Leu-Asp-Val-D-Ala-D-Lys)

c(D-Met-Leu-Asp-Val-D-Ala-D-Lys)

c(MePhe-Leu-Asp-Val-D-Arg-D-Arg)

c(MePhe-Leu-Asp-Val-D-Arg-D-His)

c(MePhe-Leu-Asp-Val-D-Trp-D-Arg)

c(MePhe-Leu-Asp-Val-D-Arg-D-Ala-D-Arg)

c(MeIle-Leu-Asp-Val-D-Ala-D-Ala-D-Arg)

c(MeIle-Leu-Asp-Val-D-Arg-D-Ala-D-Arg)

c(MeIle-Leu-Asp-Val-D-Ala-D-Arg-D-Arg)

c(MePhe-Leu-Asp-Val-D-Ala-D-Arg-D-Arg)

c(Melhe-Leu-Asp-Val-D-Arg-D-Arg-D-Ala)

c(MePhe-Leu-Asp-Val-D-Arg-D-Arg-D-Ala)

c(Melhe-Leu-Asp-Val-D-Ala-D-Ala-D-Arg-D-Arg)

c(MePhe-Leu-Asp-Val-D-Ala-D-Ala-D-Arg-D-Arg)

c(MeIle-Leu-Asp-Val-D-Arg-D-Arg-D-Ala-D-Ala)

c(D-Arg-MeIle-Leu-Asp-Val-NH(CH₂)₅CO)

c(D-Arg-MeIle-Leu-Asp-Val-NH(CH₂)₂—

S—

(CH₂)₂—

CO)

c(D-Arg-MeIle-Leu-Asp-Val-NH(CH₂)₂—

S—

CH₂—

CO)

c(MeIle-Leu-Asp-Val-D-Arg-NH(CH₂)₂—

S—

CH₂—

CO)

c(MeIle-Leu-Asp-Val-NH-CH₂—

CH₂—

S—

CH₂—

CO-D-Arg-D-Arg), and

c(MePhe-Leu-Asp-Val-NH-CH₂—

CH₂—

S—

CH₂—

CO-D-Arg-D-Arg).

10. A cyclic peptide according to claim 9 selected from

c(MeIle-Leu-Asp-Val-D-hArg(Et)₂-D-hArg(Et)₂)

c(MePhe-Leu-Asp-Val-D-Arg-D-Arg)

c(MePhe-Leu-Asp-Val-D-Arg-D-His)

c(MePhe-Leu-Asp-Val-D-Trp-D-Arg)

c(MePhe-Leu-Asp-Val-D-Arg-D-Ala-D-Arg)

c(MeIle-Leu-Asp-Val-D-Arg-D-Ala-D-Arg)

c(MeIle-Leu-Asp-Val-D-Ala-D-Arg-D-Arg)

c(MePhe-Leu-Asp-Val-D-Ala-D-Arg--D-Arg)

c(MeIle-Leu-Asp-Val-D-Arg-D-Arg-D-Ala)

c(MePhe-Leu-Asp-Val-D-Arg-D-Arg-D-Ala)

c(MeIle-Leu-Asp-Val-D-Ala-D-Ala-D-Arg-D-Arg)

c(MePhe-Leu-Asp-Val-D-Ala-D-Ala-D-Arg-D-Arg)

c(MeIle-Leu-Asp-Val-D-Arg-D-Arg-D-Ala-D-Ala)

c(MeIle-Leu-Asp-Val-NH-CH₂—

CH₂—

S—

CH₂—

CO-D-Arg-D-Arg), and

c(MePhe-Leu-Asp-Val-NH-CH₂—

CH₂—

S—

CH₂—

CO-D-Arg-D-Arg).

11. A cyclic peptide according to claim 10 of formula c(MePhe-Leu-Asp-Val-D-Arg-D-His).

12. A cyclic peptide according to claim 10 of formula c(MePhe-Leu-Asp-Val-D-Arg-D-Arg).

13. A cyclic peptide according to claim 10 of formula c(MePhe-Leu-Asp-Val-D-Ala-D-Arg-D-Arg).

14. A cyclic peptide according to claim 10 of formula c(MePhe-Leu-Asp-Val-D-Ala-D-Ala-D-Arg-D-Arg).

15. A pharmaceutical composition comprising a cyclic peptide according to any one of claims 1, 2, 5, 3, 6, 4 and 7 to 14, or and 7 to 14, or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable diluent or carrier.

16. A method for inhibiting the interaction between VCAM-1 and/or fibronectin and the integrin receptor VLA-4 in mammals in need of such treatment which comprises administering to said mammal an effective amount of a cyclic peptide according to any one of claims 1, 2, 5, 3, 6, 4 and 7 to 14, or a pharmaceutically acceptable salt thereof.

17. The method according to claim 16 for treating multiple sclerosis, rheumatoid arthritis, asthma or psoriasis.

18. A method for inhibiting the interaction between MAdCAM-1 and the integrin α

4β

7 in mammals in need of such treatment which comprises administering to said mammal an effective amount of a cyclic peptide according to any one of claims 1, 2, 5, 3, 6, 4 and 7 to 14, or a pharmaceutically acceptable salt thereof.

19. A process for the manufacture of a cyclic peptide or a salt thereof as claimed in any of claims 1, 2, 5, 3, 4, and 7 to 14, selected from process routes (a), (b) and (c):

(a) assembling the required linear peptide in a stepwise manner (adding one amino acid at a time) followed by selective removal of any N- and C-terminal protecting groups, cyclisation and finally deprotonation to give said cyclic peptide, and optionally converting said cyclic peptide into a salt thereof;

(b) forming an amide bond by coupling two peptide units, one containing a carboxylic acid group, or a reactive derivative thereof, and the other containing an amino group, such that said cyclic peptide in protected or unprotected form is produced, and removing any protecting group using process route (c) below, and optionally converting the product thus obtained into a salt thereof; and

(c) removing one or more conventional peptide protecting groups from a protected cyclic peptide of formula

where Pr¹ is a protecting group on the acid group in the side of chain of Xaa₃ to give said cyclic peptide in protected or unprotected form, simultaneously or subsequently removing any additional conventional peptide protecting group present, and optionally converting the product thus obtained into a salt thereof.

3. A cyclic peptide of the formula

where

Xaa₁ is an L-amino acid selected from Phe, Lys and Arg, a D-amino acid selected from Phe and Met, and the L- or D-amino acid optionally is substituted on its α

-carbon or its α

-amino group with a C_1-4 alkyl group,

or

Xaa₁ is MeIle;

Xaa₂ is Leu, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

Xaa₃ is Asp, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

Xaa₄ is Val, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

X¹ is a D-amino acid selected from Ala, Phe, Arg, Lys, Trp, hArg(Et)₂, Orn(CHMe₂), Orn(Me₂), Lys(CHMe₂) and Arg(Pmc), optionally substituted on its α

-carbon or its α

-amino group with a C_1-4 alkyl group,

or

X¹ is

NH(CH₂)₅CO, or NH(CH₂)₂S(CH₂)_yCO where y is 1 or 2;

X² is a D-amino acid selected from Ala, Arg, Lys, His, hArg(Et)₂, Orn(CHMe₂), and Orn(Me₂), optionally substituted on its oα

-carbon or its α

-amino group with a C_1-4 alkyl group,

or

X² is NH(CH₂)₂SCH₂CO, or NH(CH₂)_xCO where x is 2 or 3;

Xaa₅ and Xaa₆ are each, independently, a D-amino acid selected from Ala and Arg, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

is 0 or 1; and

q is 0 or when p is 1, q is 0 or 1;

or a salt thereof,

with the proviso that when p and q are both 0, Xaa₁ is not MeIle.

6. A cyclic peptide according to claim 3 where Xaa₁ is MePhe.

4. A cyclic peptide of the formula

where

Xaa₁ is a L-amino acid selected from MePhe and MeIle;

Xaa₂ is Leu, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

Xaa₃ is Asp, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

Xaa₄ is Val, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

X¹ is a D-amino acid selected from Ala and Arg, optionally substituted on its α

-carbon or its α

-amino group with a C_1-4 alkyl group;

or

X¹ is

or NH(CH₂)₂S(CH₂)_yCO where y is 1 or 2;

X² is a D-amino acid selected from Ala and Arg, optionally substituted on its α

-carbon or its α

-amino group with a C_1-4 alkyl group,

or

X² NH(CH₂)_xCO where x is 2 or 3;

Xaa₅ and Xaa₆ are each, independently, a D-amino acid selected from Ala and Arg, optionally substituted on its α

-carbon or α

-amino group with a C_1-4 alkyl group;

p is 1; and

q is 0 or 1;

or a salt thereof.

7. A cyclic peptide according to claim 4 where p is 1 and q is 1;

or a salt thereof.

8. A cyclic peptide according to claim 4 where p is 1 and q is 0;

or a salt thereof.