# US 4,396,543 A · Derivatives of A-21978C cyclic peptides

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- Number: US 4,396,543 A
- Document ID: US4396543A
- Status: Granted
- Kind: A
- Application number: 06/380,499
- Filed: 1982-05-21
- Granted: 1983-08-02
- Earliest claimed: 1982-05-21
- Assignees: Eli Lilly and Company
- Inventors: Manuel Debono
- Web page: https://patentgrep.com/patent/US4396543A

## CPC

- C12N 1/205: Bacterial isolates
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- 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)
- C12R 2001/045: Actinoplanes
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- Y10S 930/19: Antibiotic
- Y10S 930/27: Cyclic peptide or cyclic protein
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12R: INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

A-21978C cyclic peptide derivatives of the formula ##STR1## wherein R is hydrogen, a specified aminoacyl or N-alkanoylaminoacyl group, 8-methyldecanoyl, 10-methyldodecanoyl, 10-methylundecanoyl, the specific C.sub.10 -alkanoyl group of A-21978C.sub.0 or the specific C.sub.12 -alkanoyl groups of A-21978C factors C.sub.4 and C.sub.5 or an amino-protecting group; and R.sup.1 is hydrogen, an amino-protecting group, or a specified aminoacyl or N-alkanoylaminoacyl group; provided that, when R is other than aminoacyl or N-alkanoylaminoacyl, R.sup.1 must be aminoacyl or N-alkanoylaminoacyl; and, when R.sup.1 is an amino-protecting group, R must be aminoacyl or N-alkanoylaminoacyl; and the salts thereof, are useful as antibacterial agents or as intermediates to antibacterial agents.

## Claims

### Claim 1

An A-21978C cyclic peptide derivative of the formula: ##STR74## wherein R is hydrogen, 8-methyldecanoyl, 10-methyldodecanoyl, 10-methylundecanoyl, the specific C.sub.10 -alkanoyl group of A-21978C.sub.0 or the specific C.sub.12 -alkanoyl groups of A-21978C factors C.sub.4 and C.sub.5, an amino-protecting group, an aminoacyl group of the formula ##STR75## wherein Q is C.sub.1 -C.sub.16 alkylene, or an N-alkanoylamino acyl group of the formula ##STR76## wherein: W is a divalent aminoacyl radical of the formula: ##STR77## wherein A is C.sub.1 -C.sub.10 alkylene or C.sub.5 -C.sub.6 cycloalkylene; ##STR78## wherein R.sup.3 is hydroxymethyl, hydroxyethyl, mercaptomethyl, mercaptoethyl, methylthioethyl, 2-thienyl, 3-indole-methyl, phenyl, benzyl, or substituted phenyl or substituted benzyl in which the benzene ring thereof is substituted with chloro, bromo, iodo, nitro, C.sub.1 -C.sub.3 alkyl, hydroxy, C.sub.1 -C.sub.3 -alkoxy, C.sub.1 -C.sub.3 alkylthio, carbamyl, or C.sub.1 -C.sub.3 alkylcarbamyl; ##STR79## wherein X is hydrogen chloro, bromo, iodo, amino, nitro, C.sub.1 -C.sub.3 alkyl, hydroxy, C.sub.1 -C.sub.3 alkoxy, mercapto, C.sub.1 -C.sub.3 alkylthio, carbamyl, or C.sub.1 -C.sub.3 alkylcarbamyl; ##STR80## wherein X.sup.1 is chloro, bromo, iodo, amino, hydroxy, C.sub.1 -C.sub.3 alkyl or C.sub.1 -C.sub.3 alkoxy; ##STR81## wherein B is a divalent radical of the formula: --(CH.sub.2).sub.n -- and n is an integer from 1 to 3; --CH.dbd.CH--; --CH.dbd.CH--CH.sub.2 --; or ##STR82## R.sup.2 is C.sub.1 -C.sub.17 alkyl or C.sub.2 -C.sub.17 alkenyl; and R.sup.1 is hydrogen, an amino-protecting group, an aminoacyl group of the formula ##STR83## as herein defined, or an N-alkanoylaminoacyl group of the formula ##STR84## as herein defined; provided that, when R is other than aminoacyl or N-alkanoylaminoacyl, R.sup.1 must be aminoacyl or N-alkanoylaminoacyl; and, when R.sup.1 is an amino-protecting group, R must be aminoacyl or N-alkanoylaminoacyl; and the salts thereof.

### Claim 2 (depends on 1)

A compound of claim 1 wherein R is ##STR85## A is C.sub.1 -C.sub.10 alkylene and R.sup.2 is straight chain C.sub.1 -C.sub.17 alkyl.

### Claim 3 (depends on 2)

A compound of claim 2 wherein R.sup.1 is hydrogen.

### Claim 4 (depends on 3)

The compound of claim 3 wherein R is 5-[N-(n-dodecanoyl)amino]-n-pentanoyl.

### Claim 5 (depends on 3)

The compound of claim 3 wherein R is 11-[N-(n-dodecanoyl)amino]-n-undecanoyl.

### Claim 6 (depends on 3)

The compound of claim 3 wherein R is 11-[N-(n-heptanoyl)amino]-n-undecanoyl.

### Claim 7 (depends on 1)

A compound of claim 1 wherein R is ##STR86## X is hydrogen and R.sub.2 is straight chain C.sub.1 -C.sub.17 alkyl.

### Claim 8 (depends on 7)

A compound of claim 7 wherein R.sup.1 is hydrogen.

### Claim 9 (depends on 8)

The compound of claim 8 wherein R is p-[N-(n-dodecanoyl)amino]benzoyl.

### Claim 10 (depends on 8)

The compound of claim 8 wherein R is m-[N-(n-dodecanoyl)amino]benzoyl.

### Claim 11 (depends on 8)

The compound of claim 8 wherein R is p-[N-(n-tetradecanoyl)amino]benzoyl.

### Claim 12 (depends on 1)

A compound of claim 1 wherein R is ##STR87## X.sup.1 is chloro, bromo, iodo, amino, C.sub.1 -C.sub.3 alkyl, hydroxy, or C.sub.1 -C.sub.3 alkoxy, and R.sup.2 is straight chain C.sub.1 -C.sub.17 alkyl.

### Claim 13 (depends on 12)

A compound of claim 12 wherein R.sup.1 is hydrogen.

### Claim 14 (depends on 13)

The compound of claim 13 wherein R is 5-amino-4-[N-(n-dodecanoyl)amino]-2-hydroxybenzoyl.

### Claim 15 (depends on 13)

The compound as defined in claim 13 wherein R is 3-[N-(n-dodecanoyl)amino]-2,5-dichlorobenzoyl.

### Claim 16 (depends on 1)

The compound of claim 1 wherein R is p-[N-(n-dodecanoyl)amino]phenylacetyl and R.sup.1 is hydrogen.

### Claim 17 (depends on 1)

The compound of claim 1 wherein R is p-[N-(n-dodecanoyl)amino]cinnamoyl and R.sup.1 is hydrogen.

### Claim 18 (depends on 1)

The compound of claim 1 wherein R is p-[N-(n-dodecanoyl)amino]hippuryl and R.sup.1 is hydrogen.

### Claim 19

The compound of claim wherein R is 2-[N-(n-dodecanoyl)amino]nicotinoyl and R.sup.1 is hydrogen.

### Claim 20 (depends on 1)

A compound of claim 1 wherein R is ##STR88## R.sup.2 is C.sub.1 -C.sub.17 alkyl and R.sup.3 is phenyl, benzyl or 3-indole-methyl.

### Claim 21 (depends on 20)

A compound of claim 20 wherein R.sup.1 is hydrogen.

### Claim 22 (depends on 21)

The compound of claim 21 wherein R is N-(n-dodecanoyl)phenylalanyl.

### Claim 23 (depends on 21)

The compound of claim 21 wherein R is N-(n-octanoyl)phenylalanyl.

### Claim 24 (depends on 21)

The compound of claim 21 wherein R is N-(n-nonanoyl)phenylalanyl.

### Claim 25 (depends on 21)

The compound of claim 21 wherein R is N-(n-decanoyl)phenylalanyl.

### Claim 26 (depends on 21)

The compound of claim 21 wherein R is N-(n-undecanoyl)phenylalanyl.

### Claim 27 (depends on 21)

The compound of claim 21 wherein R is N-(n-tridecanoyl)phenylalanyl.

### Claim 28 (depends on 21)

The compound of claim 21 wherein R is N-(n-tetradecanoyl)phenylalanyl.

### Claim 29 (depends on 21)

The compound of claim 21 wherein R is N-(n-hexanoyl)tryptophanyl.

### Claim 30 (depends on 21)

The compound of claim 21 wherein R is N-(n-dodecanoyl)tryptophanyl.

### Claim 31 (depends on 20)

A compound of claim 20 wherein R is N-(n-hexanoyl)tryptophanyl.

### Claim 32 (depends on 31)

The compound of claim 31 wherein R.sup.1 is 8-methyldecanoyl.

### Claim 33 (depends on 31)

The compound of claim 31 wherein R.sup.1 is 10-methyldodecanoyl.

### Claim 34 (depends on 31)

The compound of claim 31 wherein R.sup.1 is 10-methylundecanoyl.