Chimeric amino acid analogues

• US 5,120,859 A
• Filed: 09/22/1989
• Issued: 06/09/1992
• Est. Priority Date: 09/22/1989
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Webb, Thomas R.
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): CHANG, CELIA C
• Application Number:
  US07/411,088
• Time in Patent Office: 991 Days
• Field of Search: 548/557, 548/558, 548/566
• US Class Current: 548/557
• 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07K 5/1024 with the first amino acid being heterocyclic
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

A chimeric amino acid analogue is provided suitable for incorporating into peptides which compound is represented by Formula 1: ##STR1## where P₁ is preferably an amine protecting agent, and P₂ and P₃ are preferably amine or guanidine protecting agents. X can be OH, halide, or preferably an activating group suitable for conjugating the compound of Formula 1 to a peptide by conventional means, and m and n are 0-1 and 0-2 respectively.

Peptides containing the chimeric amino acid analog are provided and include a platelet-aggregation inhibitor represented by

Aaa.sub.1 -CPdl-Gly-Asp-Aaa.sub.2

where Aaa₁ is Gly or H, Cpdl is the compound of Formula 1 which has been deprotected and Aaa₂ is a hydrophobic amino acid preferably Val.

Claims

1. A compound of the formula:

##STR61## wherein m is equal to 0 or 1;

n is equal to 0, 1, or 2, provided that both m and n are not both 0;

X is selected from the group OH, Cl, N₃, NHR¹, ONHR², OCOR², OCH₂ CN, OCH₂ CO₂ R², OCH₂ COR², OCO₂ R³ and ZR⁴, Z being oxygen or sulfur

where

R¹ is H, substituted and unsubstituted CH₂ --C₆ -C₁₂ aryl the substituents being one or more of the group C₁ -C₆ alkoxy, and C₁ -C₄ alkyl,

R² is C₁ -C₁₀ alkyl, C₆ -C₁₈ aryl, C₂ -C₁₂ alkenyl, C₁ -C₆ alk C₆ -C₁₈ aryl,

R³ is C₁ -C₆ alkyl or benzyl,

R⁴ is selected from the group

i) substituted and unsubstituted C₆ -C₁₄ aryl, the substituents selected from NO₂, halo (F, Cl, Br, I), CN and SO₃ --C₁ -C₆ alkyl, or SO₃ H,

ii) substituted or unsubstituted C₁ -C₁₀ alk C₆ -C₁₄ aryl, the substituents selected from C₁ -C₁₀ alkyl, C₁ -C₆ alkoxy, and halo (F, Cl, Br, I),

iii) C₁ -C₁₅ alkyl and

iv) NR⁵ R⁶ where R⁵ and R⁶ are the same or different and are selected from C₁ -C₁₀ alkyl and C₁ -C₉ alkyl--(C═

O)--provided that at least one of R⁵ and R⁶ is C₁ -C₉ alkyl--(C═

O)--;

P₁ is CO₂ R⁷

where

R⁷ is selected from the group

i) Substituted and unsubstituted CH₂ --C₆ -C₁₂ aryl, the substituents being C₁ -C₆ alkoxy, and halo (F, Cl, Br, I),

ii) tertiary-C₄ -C₁₄ alkyl,

iii) C₁ -C₆ alk-C₆ -C₁₂ aryl, and

iv) C₃ -C₈ allyl;

P₂ is CO₂ R⁷ when m=0, and is R⁸ when m=1

where

R⁸ is selected from the group

i) NO₂, and

ii) SO₂ R⁹ where R⁹ is substituted or unsubstituted C₆ -C₁₄ aryl, the substituents selected from C₁ -C₈ alkoxy, C₁ -C₈ alkyl; and

P₃ is H when P₂ is R⁸, and CO₂ R⁷ when P₂ is CO₂ R⁷.

2. The compound of claim 1 wherein X is selected from the group consisting of OH, NH₂, N₃, Cl, O-dibenzyl phosphate, o- and p-nitrophenyl, 2-chloro-4-nitro-phenyl, cyanomethyl, trichlorophenyl, tetrafluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, o-nitro-osulfophenyl, N,N-diethyl-amino, tetrafluorothiophenyl, 2,3,5,6-tetrafluorophenyl and.

3. The compound of claim 1 wherein P₁, P₂ and P₃ are selected according to the following scheme:

When m=0, P₁ is BOC and P₂ is selected from the group allyloxy carbonyl, trifluoroacetyl, 4-chlorobenzyloxycarbonyl and 4-bromobenzyloxycarbonyl;

When m=0, P₁ is FMOC and P₂ is selected from the group allyloxycarbonyl, BOC and CBZ;

When m=1 and P₁ is BOC and P₃ is H then P₂ is selected from the group H, nitro, p-toluenesulfonyl, and benzenesulfonyl;

When m=1 and P₁ is BOC then P₂ and P₃ are both equal to CBZ; and

When m=1 and P₁ is FMOC and P₃ is H then P₂ is selected from the group 2,2,5,7,8-pentamethylchroman-6-sulfonyl, and 2,3,6-trimethyl-4-methoxyphenylsulfonyl

4. The compound of claim 1 wherein the chirality of substituents at positions 2 and 4 of the pyrrolidine ring are independently selected from R and S substantially free from contamination with the other enantiomer.