# US 5,710,247 A · Process and intermediates for the synthesis of LHRH antagonists

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 5,710,247 A
- Document ID: US5710247A
- Status: Granted
- Kind: A
- Application number: 08/618,674
- Filed: 1996-03-19
- Granted: 1998-01-20
- Earliest claimed: 1996-03-19
- Assignees: Abbott Laboratories
- Inventors: Kenneth W. Funk; Edwin O. Lundell; Robert B. Miller; Jane L. Chang; Vimal Kishore; James J. Napier; Michael A. Staeger
- Web page: https://patentgrep.com/patent/US5710247A

## CPC

- C07K 7/23: Luteinising hormone-releasing hormone [LHRH]; Related peptides
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/08: for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/08: of the prostate
- A61P 35/00: Antineoplastic agents
- C07D 307/14: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)

## Abstract

A method is provided for preparing decapeptide and undecapeptide derivatives of LHRH by solution phase peptide chemistry as well as intermediate peptides useful in the same method.

## Claims

### Claim 1

A process for preparing an LHRH antagonist having the structure Q-D2Nal.sup.1 -D4ClPHe.sup.2 -D3Pal.sup.3 -Ser.sup.4 -NMeTyr.sup.5 -DLys(Nic).sup.6 -Leu.sup.7 -Lys(iPr).sup.8 -Pro.sup.9 DAla.sup.10 NH.sub.2 wherein Q is selected from the group consisting of N-acetyl and THF-Gly, comprising the steps of:
(a) fully deprotecting a first protected oligopeptide compound having the formula
P.sup.1 Ser(P.sup.2)-NMeTyr(P.sup.3)-D-Lys(Nic)-Leu-Lys(iPr)-pro-D-AlaNH.sub.2(IV)
wherein P.sup.1 is an amino protecting group, and P.sup.2 and P.sup.3 are independently selected --OH protecting groups; and
(b) coupling the unprotecting compound from step (a) with a second oligopeptide compound having the formula
Q-D-2Nal-D-4ClPhe-D-3Pal-OH (III)
to produce said LHRH antagonist.

### Claim 2 (depends on 1)

The process of claim 1 wherein said --OH protecting group is selected from the group consisting of allyl, cyclohexyl, methyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, 1-ethoxyethyl, t-butyl, benzyl, p-nitrobenzyl, 2,6-dichlorobenzyl, triphenylmethyl, trimethylsilyl, 9-fluorenylmethyl, isopropyldimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, acetate, trichloroacetate, phenacyl, phenoxyacetate, pivaloate, adamantoate, benzoate, mesitoate, allyl carbonate, methyl carbonate, 2,2,2-trichloroethyl carbonate, benzyl carbonate, p-nitrobenzyl carbonate, and 2-bromobenzyl carbonate.

### Claim 3 (depends on 1)

The process of claim 1 wherein Q is THF-Gly.

### Claim 4 (depends on 1)

The process of claim 1 wherein Q is N-acetyl.

### Claim 5 (depends on 1)

The process of claim 1 wherein P.sup.2 and P.sup.3 are independently selected from benzyl and dichlorobenzyl.

### Claim 6 (depends on 1)

The process of claim 1 further comprising the step of preparing compound IV by coupling a compound I having the formula
P.sup.1 -aa.sub.1 -Lys(iPr)-Pro-D-AlaNH.sub.2
wherein aa.sub.1 is absent or is Leu with a compound 1I having the formula
P.sup.1 Ser(P.sup.2)-NMeTyr(P.sup.3)-D-Lys(Nic)-aa.sub.1 -0H
with the proviso that aa.sub.1 is not simultaneously present in both compounds I and II.

### Claim 7 (depends on 6)

The process of claim 6 further comprising the step of preparing compound I from P.sup.1 -Lys(P.sup.5)-Pro-D-AlaNH.sub.2 wherein P.sup.5 is an amino protecting group orthogonal to P.sup.1.

### Claim 8 (depends on 7)

The process of claim 7 wherein P.sup.5 is Fmoc, Boc or Cbz.

### Claim 9 (depends on 6)

The process of claim 6 further comprising the step of preparing compound II from a compound B.sub.3 having the formula P.sup.1 -Ser(P.sup.2)-NMeTyr(P.sup.3)-D-Lys(Nic)-aa.sub.1 -O-P.sup.4 wherein P.sup.4 is a carboxyl protecting group.

### Claim 10 (depends on 9)

The process of claim 9 wherein P.sup.4 is selected from the group consisting of 9-fluorenylmethyl, methoxymethyl, benzyl, p-nitrobenzyl, 2,2,2,-trichloroethyl, methylthiomethyl, benzyloxymethyl, t-butyl, methyl, ethyl, cyclohexyl, allyl and trimethylsilyl.

### Claim 11 (depends on 10)

The process of claim 10 wherein P.sup.4 is allyl or benzyl.

### Claim 12 (depends on 1)

The process of claim 1 further comprising the step of preparing compound III from a compound C.sub.3 having the formula Q-D-2Nal-D-4ClPHe-D-3Pal-O-P.sup.4 wherein P.sup.4 is a carboxyl protecting group as defined above.

### Claim 13 (depends on 12)

The process of claim 12 wherein Q is THF-Gly.

### Claim 14 (depends on 13)

The process of claim 13 further comprising the step of preparing compound C.sub.3 by first reacting THF-Gly-OH with P.sup.1 -D-2Nal-D-4ClPhe-D-3Pal-O-P.sup.4.

### Claim 15 (depends on 14)

The process of claim 14 further comprising the step of preparing THF-Gly-OH from THF-Gly-O-P.sup.4.

### Claim 16 (depends on 15)

The process of claim 15 further comprising the step of preparing THF-Gly-O-P.sup.4 by reacting the dicyclohexylamine salt of tetrahydrofuroic acid with the p-toluenesulfonic acid salt of Gly-O-P.sup.4 and then hydrogenating the resulting product.

### Claim 17 (depends on 12)

The process of claim 12 wherein Q is N-acetyl.

### Claim 18 (depends on 1)

The process of claim 1 wherein P.sup.1 is selected from the group consisting of tert-butyloxycarbonyl, benzyloxycarbonyl, biphenylisopropyloxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, (alpha,alpha)-dimethyl-3,5-dimethoxybenzyl-oxycarbonyl, o-nitrophenylsulfenyl, 2-cyano-t-butyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl.