N-(4-carbamimidoyl-phenyl)-glycine derivatives

Details N-(4-carbamimidoyl-phenyl)-glycine derivatives N-(4-carbamimidoyl-phenyl)-glycine derivatives

2001-05-16

2003-04-15

Killos, Paul J. (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C562S440000, C558S394000

Reexamination Certificate

active

06548694

ABSTRACT:

BACKGROUND OF THE INVENTION
The subject invention relates to novel N-(4-carbamimidoyl-phenyl)-glycine derivatives.
SUMMARY OF THE INVENTION
The subject invention provides compounds of the formula:
wherein
R
1
is alkyl;
R
2
is hydrogen, hydroxyalkoxy, alkoxycarbonyloxyalkoxy, or halogenalkoxycarbonyloxyalkoxy;
R
3
is hydrogen, alkoxy, or heterocycloalkyloxy;
R
4
is hydrogen or the residue of an ester group which is cleavable under physiological conditions;
R
5
is hydrogen, hydroxy, alkoxycarbonyl, halogenalkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, arylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or arylaminocarbonyl; and
X is F, Cl, or Br;
or a hydrate or solvates thereof, or a physiologically acceptable salt thereof or a physiologically acceptable ester thereof,
with the provisio that the compound of formula I is not selected from the group consisting of:
(RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid,
(RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid, and
(RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid ethyl ester.
Certain preferred compounds are where R
1
is ethyl or where only one of R
2
and R
3
is hydrogen. Other compounds are where R
2
is hydrogen, or hydroxyalkoxy, or 2-hydroxy-ethoxy, or alkoxycarbonyloxyalkoxy, or halogenalkoxycarbonyloxyalkoxy, or alkoxycarbonyloxyalkoxy, or halogenalkoxycarbonyloxyalkoxy, for exampe 2-(2,2,2-trichloro-ethoxycarbonyloxy)-ethoxy.
R
3
can be hydrogen, or alkoxy, for example ethoxy, or heterocycloalkyloxy, for example tetrahydrofuran-3-yloxy. It is also preferred where R
4
is hydrogen, alkyl, or aryl-alkyl. Where R
4
is alkyl, preferred groups include ethyl, iso-propyl, butyl, or iso-butyl. A preferred aryl-alkyl is benzyl.
For R
5
, hydrogen, hydroxy, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, methoxycarbonyl, 4-fluoro-phenyloxycarbonyl, benzyloxycarbonyl, 2-methoxy-ethoxycarbonyl, 2-isopropyl-5-methyl-cyclohexyloxycarbonyl, prop-2-ynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, benzoyloxy, ethylaminocarbonyloxy, phenylaminocarbonyloxy, benzoyl, 3-fluoro-benzoyl, 4-fluoro-benzoyl, 2,4-difluoro-benzoyl, 3,4-dimethoxy-benzoyl, 3,5-dimethoxy-benzoyl, 4-methyl-benzoyl, 4-trifluoromethyl-benzoyl, phenylaminocarbonyl, or isobutoxycarbonyl are preferred. While each of these substituents is useful, another grouping is where R
5
is alkoxycarbonyl, halogenalkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, arylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or arylaminocarbonyl. A further subset is where R
5
is alkoxycarbonyl, halogenalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, alkylaminocarbonyloxy, or alkylcarbonyl. R
5
may also be 2,2,2-trichloro-ethoxycarbonyl, or alkylaminocarbonyloxy, or a substituent selected from the group consisting of aryloxycarbonyl, arylalkoxycarbonyl, arylaminocarbonyloxy, arylcarbonyl, and arylaminocarbonyl. Specific favored R
5
substituents include benzoyl, or alkylaminocarbonyloxy, or arylcarbonyloxy or arylaminocarbonyloxy, or 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, or heteroarylcarbonyl.
While the halogens recited above are all effective as X, flourine is currently preferred.
The subject invention further provides compounds according to claim
1
, wherein the compound is of the formula:
wherein R
1
, R
2
, R
3
, R
4
, R
5
, and X are as defined above.
Other convenient groupings are where R
3
is hydrogen or heterocycloalkyloxy, R
4
is aryl-alkyl, and R
5
is hydroxy, alkoxycarbonyl, halogenalkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, arylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or arylaminocarbonyl. X is conveniently Cl, or Br.
The subject invention also provides compounds of the formula:
wherein
R
1
is alkyl;
R
2
is hydrogen, hydroxyalkoxy, alkoxycarbonyloxyalkoxy, or halogenalkoxycarbonyloxyalkoxy;
R
3
is hydrogen, alkoxy, or heterocycloalkyloxy;
R
4
is hydrogen or the residue of an ester group which is cleavable under physiological conditions; and
X is F, Cl, or Br.
Although various combinations of R
1
, R
2
, R
3
, R
4
, R
5
and X have been set out above, all combinations of these substituents are possible and are intended to be covered by this description as if specifically written out.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set foth to aid in understanding the invention but are not to be construed as limiting.
The invention is concerned with novel N-(4-carbamimidoyl-phenyl)-glycine derivatives of the formula I
wherein
R
1
represents alkyl,
R
2
represents hydrogen, hydroxyalkoxy, alkoxycarbonyloxyalkoxy, or halogenalkoxycarbonyloxyalkoxy,
R
3
represents hydrogen, alkoxy, or heterocycloalkyloxy,
R
4
represents hydrogen or the residue of an ester group which is cleavable under physiological conditions;
R
5
represents hydrogen, hydroxy, alkoxycarbonyl, halogenalkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, alkoxyalkoxycarbonyl, cycloalkyloxycarbonyl, alkynyloxycarbonyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, arylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or arylaminocarbonyl,
X represents F, Cl, or Br,
as well as hydrates or solvates and/or physiologically acceptable salts thereof and/or physiologically acceptable esters thereof,
with the provisio that said compound of formula I is not selected from the group consisting of:
(RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester,
(RS)-(4-carbamimidoyl-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid,
(RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid, and
(RS)-(4-carbamimidoyl-phenylamino)-(2-fluoro-3,5-dimethoxy-phenyl)-acetic acid ethyl ester.
Further, the invention is concerned with a process for the manufacture of the above compounds, pharmaceutical preparations which contain such compounds as well as the use of these compounds for the production of pharmaceutical preparations.
Examples of physiologically usable salts of these compounds of formula I are salts with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term “physiologically acceptable salts” refers to such compounds.
Examples of physiologically acceptable esters are esters of the compounds of formula I, in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms. The term “physiologically acceptable esters” refers to such compounds.
The compounds of formula I can be solvated, especially hydrated. The terms “solvates” and “hydrates” refer to compounds of formula 1 which additionally comprise solvent molecules or, in the case of hydrates, water molecules respectively. The hydration can take place in the course of the manufactu

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