# US 7,060,845 B2 · Stabilized activated derivatives of carbamic acid, their process of preparation and their use for the preparation of ureas

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- Number: US 7,060,845 B2
- Document ID: US7060845B2
- Status: Granted
- Kind: B2
- Application number: 09/904,459
- Filed: 2001-07-16
- Published: 2002-10-03
- Granted: 2006-06-13
- Earliest claimed: 1999-01-14
- Assignees: Neomps; Centre National De La Recherche Scientifique
- Applicants: Marie-Christine Galas-Rodriguez, legal representative; Pierre Rodriguez, legal representative; Elisa Rodriguez, legal representative; Romain Rodriguez, legal representative
- Inventors: Gilles Guichard; Vincent Semetey; Jean-Paul Briand
- Web page: https://patentgrep.com/patent/US7060845B2

## CPC

- C07D 207/404: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
- A61P 31/18: for HIV
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 275/14: being further substituted by nitrogen atoms not being part of nitro or nitroso groups
- C08G 71/02: Polyureas
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS

## Abstract

Process for the preparation of stable activated derivatives of carbamic acid, comprising at least one protected amino group and an activated carbamic acid function, from an amino acid derivative in which the amino group is protected. The process includes: a) a step of transformation of the —COOH group of the amino acid derivative into a —CON3 group to obtain an acyl azide; b) a step of transformation of the —CON3 group of the acyl azide into a —NCO group to obtain an isocyanate; c) a step of treating the isocyanate to obtain a stable derivative of carbamic acid.

## Claims

### Claim 1

A compound having the formula (I bis)
wherein
“n” is 1 or 2,
“i” is a whole number varying from 2 to n+1,
GP is selected from the group consisting of:
an oxycarbonyl group ROCO, R representing an alkyl group of 1 to 20 carbon atoms, unsubstituted or substituted with an aryl group whose cyclic structure contains 5 to 20 carbon atoms, said alkyl group being saturated or not,
an acyl group RCO, R being chosen from: an alkyl group of 1 to 20 carbon atoms or an aryl group whose cyclic structure contains 5 to 20 carbon atoms, said alkyl group being possibly substituted with an aryl group whose cyclic structure contains 5 to 20 carbon atoms, said alkyl group being saturated or not,
GP along with R1 and the N then are bonded to form a phthalimido group of formula:
a biotinyle group having the following formula
groups R1 and Ri can each represent independently from each other: a hydrogen, a halogen, the protected or unprotected side chain of an amino acid selected from natural and synthetic amino acids, a (C1–C20) alkyl group, unsubstituted or substituted, an aryl group whose cyclic structure contains 5 to 20 carbon atoms, a group ORa, —NH2, —OH, —COORa, —CONHRa, —CONH2, —CH2COORa, —CH2CONHRa, —CH2CONH2,
Ra representing an alkyl group, saturated or not, having 1 to 20 carbon atoms, an aralkyl group having 1 to 20 carbon atoms, or an aryl group whose cyclic structure contains 5 to 20 carbon atoms,
R1 and Ri groups can also form a cycle with N, said cycle being selected from the group consisting of
X group represents a group having one of the following formula:
wherein said compound is not one of the following compounds selected from the group consisting of:
n=2, GP=Boc, R1=isobutyl, R2=R3=H, X=4-nitrophenol;
n=2, GP=Boc, R1=benzyl, R2=R3=H, X=4-nitrophenol;
n=2, GP=Boc, R1=CH2-p-C6H4Ot-Bu, R2=R3=H, X=4-nitrophenol;
n=2, GP=Boc, R1=H, R2=R3=H, X=4-nitrophenol.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein GP represents an oxycarbonyl group chosen from Boc, Fmoc, benzyloxycarbonyl or allyloxycarbonyl.

### Claim 3 (depends on 1)

The compound according to claim 1, in which X is a N-hydroxysuccinimide group and has the following formula:

### Claim 4 (depends on 1)

The compound according to claim 1, wherein the alkyl group corresponding to R1 or Ri is substituted with one or several substituents selected from the group consisting of —COORh, —CONHRh, —COOH, —OH, —ORh, —NHRh, —NH2, —NH(CO)Rh, an aryl group whose cyclic structure contains 5 to 20 carbon atoms, halogen, carbonyl, nitrile, and guanidino,
Rh representing an alkyl group, saturated or not, having 1 to 20 carbon atoms, an aralkyl group having 1 to 20 carbon atoms, or an aryl group whose cyclic structure contains 5 to 20 carbon atoms.

### Claim 5 (depends on 1)

The compound according to claim 1, having the following formula
wherein R2 represents a (C1–C20) alkyl group, optionally substituted with a phenyl group, and wherein said phenyl group is optionally substituted with an alkoxy group.

### Claim 6 (depends on 1)

The compound according to claim 1, having the following formula:
wherein R2 represents a (C1–C20) alkyl group, optionally substituted with a pvhenyl group, and wherein said phenyl group is optionally substituted with an alkoxy group.

### Claim 7

A compound having the following formula:

### Claim 8 (depends on 1)

A process for preparing a compound according to claim 1, comprising:
providing a compound of formula (IX)
transforming said compound (IX) into a corresponding acyl azide (XII)
transforming said acyl azide (XII) by Curtius rearrangement into a corresponding isocyanate (II),
treating said isocyanate (II) under conditions that provide a carbamic acid compound of formula (I bis).

### Claim 9 (depends on 8)

The process according to claim 8, wherein transforming said compound (IX) into a corresponding acyl azide (XII) is carried out by treatment of a mixed anhydride, formed by the reaction of acid compound (IX) with ethyl or isobutyl chloroformiate in the presence of a tertiary amine, wherein said tertiary amine is NMM (N-methylmorpholine), DIEA (di-isopropylethylamine), or Et3N in THF (tetrahydrofurane) with a sodium azide solution,
wherein said step of transforming acyl azide (XII) into a corresponding isocyanate (II), is carried out by heating a solution of acyl azide in a solvent, and
wherein a compound selected from the group consisting of N-hydroxysuccinimide is the compound treating isocyanate (II) to obtain a carbamic acid derivative of formula (I bis).

### Claim 10

A compound having the formula (I bis)
wherein
“n” is 1 or 2,
“i” is a whole number varying from 2 to n+1,
GP is selected from the group consisting of:
an oxycarbonyl group ROCO, R representing an alkyl group of 1 to 20 carbon atoms, unsubstituted or substituted with an aryl group whose cyclic structure contains 5 to 20 carbon atoms, said alkyl group being saturated or not,
an acyl group RCO, R being chosen from: an alkyl group of 1 to 20 carbon atoms or an aryl group whose cyclic structure contains 5 to 20 carbon atoms, said alkyl group being possibly substituted with an aryl group whose cyclic structure contains 5 to 20 carbon atoms, said alkyl group being saturated or not,
GP along with R1 and the N then are bonded to form a phthalimido group of formula:
a biotinyle group having the following formula
groups R1 and Ri can each represent independently from each other: a hydrogen, a halogen, the protected or unprotected side chain of an amino acid selected from natural and synthetic amino acids, a (C1–C20) alkyl group, unsubstituted or substituted, an aryl group whose cyclic structure contains 5 to 20 carbon atoms, a group ORa, —NH2, —OH, —COORa, —CONHRa, —CONH2, —CH2COORa, —CH2CONHRa, —CH2CONH2,
Ra representing an alkyl group, saturated or not, having 1 to 20 carbon atoms, an aralkyl group having 1 to 20 carbon atoms, or an aryl group whose cyclic structure contains 5 to 20 carbon atoms,
wherein R1 Ri groups can also form a cycle with N, said cycle being selected from the group consisting of
X group represents O-succinimidyl, wherein said compound is not one of the following compounds selected from the group consisting of:
n=2, GP=Boc, R1=isobutyl, R2=R3=H, X=4-nitrophenol;
n=2, GP=Boc, R1=benzyl, R2=R3=H, X=4-nitrophenol;
n=2, GP=Boc, R1=CH2-p-C6H4Ot-Bu, R2=R3=H, X=4-nitrophenol;
n=2, GP=Boc, R1=H, R2=R3=H, X=4-nitrophenol.

### Claim 11 (depends on 10)

The compound according to claim 10, wherein GP represents an oxycarbonyl group chosen from Boc, Fmoc, benzyloxycarbonyl or allyloxycarbonyl.

### Claim 12 (depends on 10)

The compound according to claim 10, wherein X is a O-succinimidyl.

### Claim 13 (depends on 10)

The compound according to claim 10, wherein the alkyl group corresponding to R1 or Ri is substituted with one or several substituents selected from the group consisting of —COORh, —CONHRh, —COOH, —OH, —ORh, —NHRh, —NH2, —NH(CO)Rh, an aryl group whose cyclic structure contains 5 to 20 carbon atoms, halogen, carbonyl, nitrile, and guanidino,
Rh representing an alkyl group, saturated or not, having 1 to 20 carbon atoms, an aralkyl group having 1 to 20 carbon atoms, or an aryl group whose cyclic structure contains 5 to 20 carbon atoms.