Bis(trifluoromethyl)hydantoins as intermediates for...

Details Bis(trifluoromethyl)hydantoins as intermediates for... Bis(trifluoromethyl)hydantoins as intermediates for...

2002-03-08

2004-09-21

Chang, Ceila (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S319100, C548S320100

Reexamination Certificate

active

06794517

ABSTRACT:

This application claims priority to German Patent Application 10111876.7, filed Mar. 10, 2001, which is hereby incorporated by reference, in their entirety. All references cited below, including patents, patent applications and scientific journals and books also are herein incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
The present invention relates to hydantoins of formula I,
wherein R is a residue of an amino carboxylic acid or of an amino carboxylic acid derivative, which is obtained formally by removing an NH
2
group from an amino carboxylic acid or an amino carboxylic acid derivative. The present invention also relates to the preparation of such hydantoins and the use thereof as intermediates, particularly for preparing pharmaceutically active ingredients.
DESCRIPTION OF PRIOR ART
Various patent documents, for example U.S. Pat. No. 6,331,552 B, U.S. Pat. No. 6,034,238, EP-A-903353, EP-A-905139, EP-A-918059 and WO-A-99/60015, describe pharmaceutically active substituted hydantoins, which are inhibitors of the adhesion and migration of leukocytes and/or antagonists of the adhesion receptor VLA-4, which belongs to the integrin group, and are suitable, for example, for treating disorders such as rheumatoid arthritis, asthma, allergies, multiple sclerosis or atherosclerosis. In addition, these documents disclose various methods of synthesizing hydantoins using different starting compounds and proceeding via different intermediates. In these methods, it is possible, for example, to first assemble a hydantoin intermediate in which the ring nitrogen atoms do not carry substituents, i.e., they carry hydrogen atoms, and then introduce onto the nitrogen atoms of the hydantoin ring substituents, which can subsequently be modified. It is also possible to utilize starting compounds that contain substituents already bonded to nitrogen atoms in assembling hydantoin intermediates, which substituents then appear in the hydantoin intermediate. Certain hydantoins as intermediates for preparing pharmaceutically active ingredients are described in WO-A-96/33976.
In particular, it has now proved advantageous to utilize the hydantoins of formula I, which have not previously been described, as intermediates for preparing a group of certain pharmaceutically active hydantoins (=2,5-dioxoimidazolidines) that carry two trifluoromethyl groups as substituents on the carbon atom in the 4-position and are distinguished by a particularly favorable profile of properties.
SUMMARY
The present invention encompasses hydantoins of formula I:
wherein R is a residue of an amino carboxylic acid or of an amino carboxylic acid derivative, which is obtained formally by removing an NH
2
group from an amino carboxylic acid or an amino carboxylic acid derivative, or salts thereof, or stereoisomers thereof, or tautomers thereof.
The present invention also encompasses a process for preparing the hydantoin of formula I
which comprises reacting the compound of formula II with a compound of formula III
wherein R′ in formula III is defined as R in formula I, but wherein free carboxylic acid groups are present in the compounds of formula III in esterified form.
The invention further encompasses a process for preparing a pharmaceutically active ingredient derived from a hydantoin of formula I
preferably comprising a 2,5-dioxo-4,4-bis(trifluoromethyl)imidazolidine ring, which comprises reacting the compound of formula I at a functional group in the residue R with another synthetic building block.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention encompasses hydantoins of formula I:
wherein R is a residue of an amino carboxylic acid or of an amino carboxylic acid derivative, which is obtained formally by removing an NH
2
group from an amino carboxylic acid or an amino carboxylic acid derivative, or the salts thereof, or stereoisomers thereof, or tautomers thereof. Accordingly, the compounds of formula I contain at least one carboxylic acid group COOH or a derivative thereof in the residue R.
Amino carboxylic acid derivatives include compounds that are obtained formally from the relevant amino carboxylic acid by converting one or more carboxylic acid groups into other groups directly related to the carboxylic acid group. Amino carboxylic acid derivatives can be, for example, ester groups, amide groups, nitrile groups, aldehyde groups and hydroxymethyl groups. Preferably, the amino carboxylic acid derivatives are ester groups, such as, for example, (C
1
-C
6
)-alkyl esters or phenyl-(C
1
-C
4
)-alkyl esters. Preferred ester groups include, for example, methyl esters, ethyl esters, propyl esters (e.g., n-propyl esters and isopropyl esters), butyl esters (e.g, n-butyl esters, isobutyl esters, sec-butyl esters and tert-butyl esters), pentyl esters, hexyl esters, and benzyl esters. Preferred amide groups include, for example, unsubstituted amides (CONH
2
), N—(C
1
-C
4
)-alkylamides and N,N-di-((C
1
-C
4
)-alkyl)amides, such as N-methylamides and N,N-dimethylamides, N-methoxy-N-methylamides and N-benzylamides.
The amino carboxylic acid or derivative of the formula H
2
N—R, from which the residue R in formula I is derived, may be a natural or unnatural amino carboxylic acid or a derivative of a natural or unnatural amino carboxylic acid. In addition to the one or more carboxylic acid groups or derivatives of carboxylic acid groups that include ester groups, amide groups, nitrile groups, aldehyde groups or hydroxymethyl groups, the residue R or the amino carboxylic acid or the amino carboxylic acid derivative, from which the residue R is derived, may contain one or more other functional groups. All functional groups and carboxylic acid groups and derivatives of carboxylic acid groups may be present in protected form. Suitable protective groups include, but are not limited to, urethane protective groups, carboxylic acid protective groups and side-chain protective groups, which are described in Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23, and in Bullesbach, Kontakte (Merck) 1980, No. 1, pages 23 to 35. As examples, the following are suitable protective groups: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO
2
), Z(Hal
n
), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt and acetal groups and ketal groups, which latter two groups are protective groups for aldehyde and keto groups. Particular acetal and ketal groups include, for example geminal methoxy groups or ethoxy groups or ethylene-1,2-dioxy groups. Functional groups, which may be present in the residue R in addition to carboxylic acid groups and derivatives of carboxylic acid groups can be, for example, hydroxyl, (C
1
-C
4
)-alkoxy, ((C
1
-C
4
)-alkyl)carbonyloxy, benzyloxy, oxo, amino, ((C
1
-C
4
)-alkyl)carbonylamino such as acetylamino or isobutyrylamino, ((C
1
-C
4
)-alkoxy)carbonylamino, such as tert-butoxycarbonylamino, benzyloxycarbonylamino, 9-fluorenylmethyloxycarbonylamino, mercapto, (C
1
-C
4
)-alkylmercapto, amidino, guanidino, etc., and protected forms of these groups.
Compounds of formula I that contain one or more basic groups may be present in the form of acid addition salts. Such basic groups include, for example, amino groups, guanidino groups or basic nitrogen heterocycles. Acid addition salts may be prepared from inorganic acids and organic acids. Suitable inorganic acids in preparing acid addition salts, include hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid. Suitable organic acids include, for example, organic carboxylic acids or sulfonic acids, such as, for example, acetic acid, trifluoroacetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
Compounds of formula I that contain one or more acidic groups may be present in the form of metal salts or ammonium salts. Such acidic groups include, for example, carboxylic acid groups. Preferred metal salts include, for example, alkali metal salts or alkaline earth metal salts. More preferred metal

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