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

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

2003-01-24

2003-11-04

Aulakh, Charanjit S. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S230000, C546S231000, C546S235000

Reexamination Certificate

active

06642386

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field
The invention is concerned with novel water soluble N-(4-carbamimidoyl-phenyl)-glycine derivatives.
2. Description
Inhibitors of factor VIIa have been suggested for the inhibition of the formation of thrombi and for the treatment of related diseases (WO 00/35858). Unfortunately, the compounds disclosed in WO 00/35858 have lower than desirable solubility in water and are not particularly suitable for subcutaneous applications.
Accordingly, there is a long felt need in the art for factor VIIa inhibitors that have increased water solubility and enhanced inhibitory activity.
SUMMARY OF THE INVENTION
The subject invention provides compounds of the formula:
wherein
R
1
is lower-alkoxy;
R
2
is halogen;
R
3
is piperidinyl or piperidinyl substituted with lower-alkyl, hydroxy-lower-alkyl, carboxy-lower-alkyl or lower-alkoxy-carbonyl-lower-alkyl;
R
4
is hydrogen or lower-alkyl;
A is —(CH
2
)
n
— or —(CH
2
)
n
— which is substituted with lower-alkyl; and
n is 0 to 3. Pharmaceutically acceptable salts of these compounds are also an aspect of this invention.
Certain preferred compounds are where R
1
is ethoxy, R
2
is fluorine, and R
3
is piperidinyl or piperidinyl substituted with methyl or hydroxy-ethyl, such as 1-methyl-piperidin-3-yl; 1-(2-hydroxy-ethyl)-piperidin-4-yl; 1-(2-hydroxy-ethyl)-piperidin-3-yl; piperidin-4-yl; or 1-methyl-piperidin-4-yl. R
4
is favorably hydrogen or ethyl, and especially hydrogen. It is preferred where n is 0 to 2, and favorably n is 0.
A preferred group of compounds are of the formula
wherein R
1
, R
2
, R
3
, R
4
, A, and n have the significances given above. As above, pharmaceutically acceptable salts of these compounds are also an aspect of this invention.
Other useful compounds are of the formula:
wherein R
1
, R
2
, R
3
, R
4
, A, and n have the significances given above. Pharmaceutically acceptable salt of these compounds are also an aspect of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting the invention in any way.
The invention is concerned with water soluble N-(4-carbamimidoyl-phenyl)-glycine derivatives of the formula (I)
wherein
R
1
is lower-alkoxy,
R
2
is halogen,
R
3
is piperidinyl optionally substituted with lower-alkyl, hydroxy-lower-alkyl, carboxy-lower-alkyl or lower-alkoxy-carbonyl-lower-alkyl,
R
4
is hydrogen or lower-alkyl,
n is 0 to 3, and the —(CH
2
)
n
— group can optionally be substituted with lower-alkyl, and pharmaceutically acceptable salts thereof.
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.
The compounds of formula (I) are active compounds and inhibit the formation of coagulation factors Xa, Ixa and thrombin induced by factor VIIa and tissue factor or are derivatives which are converted under physiological conditions to such active compounds. These compounds consequently influence both platelet aggregation which is induced by these factors and plasmatic blood coagulation. They therefore inhibit the formation of thrombi and can be used for the treatment and/or prevention of diseases, such as arterial and venous thrombosis, deep vein thrombosis, pulmonary embolism, unstable angina pectoris, cardiac infarction, stroke due to atrial fibrillation, inflammation and arteriosclerosis. Furthermore, these compounds have an effect on tumor cells and prevent metastases. They can therefore also be used as antitumor agents.
Inhibitors of factor VIIa had previously been suggested for the inhibition of the formation of thrombi and for the treatment of related diseases (WO 00/35858). However, there is still a need for factor VIIa inhibitors which exhibit a much higher solubility in water in order to be suitable for subcutaneous applications and which at the same time exhibit a higher inhibitory activity.
The present invention provides compounds of formula (I) which are factor VIIa inhibitors and unexpectedly exhibit the desired increased water solubility and increased inhibitory activity compared to the compounds known from WO 00/35858. These inventive compounds further exhibit improved pharmacological properties compared to the known compounds.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term “lower” is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term “halogen” refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
The term “alkyl”, alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. Lower-alkyl groups as described below also are preferred alkyl groups.
The term “lower-alkyl”, alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
The term “alkoxy” refers to the group R′—O—, wherein R′ is an alkyl. The term “lower-alkoxy” refers to the group R′—O—, wherein R′ is a lower-alkyl.
Compounds of formula (I) can form pharmaceutically acceptable acid addition salts. Examples of such pharmaceutically acceptable salts are salts of compounds of formula (I) with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term “pharmaceutically acceptable salts” refers to such salts. Compounds of formula (I) can further form salts with bases. Examples of such salts are alkaline, earth-alkaline and ammonium salts such as e.g. Na-, K-, Ca- and Trimethylammonium salt. The term “pharmaceutically acceptable salts” also refers to such salts.
In detail, the present invention relates to compounds of formula (I)
wherein
R
1
is lower-alkoxy,
R
2
is halogen,
R
3
is piperidinyl optionally substituted with lower-alkyl, hydroxy-lower-alkyl, carboxy-lower-alkyl or lower-alkoxy-carbonyl-lower-alkyl,
R
4
is hydrogen or lower-alkyl,
n is 0 to 3, and the —(CH
2
)
n
— group can optionally be substituted with lower-alkyl, and pharmaceutically acceptable salts thereof.
The compounds of formula (I) have at least,one asymmetric C atom and can therefore exist as an enantiomeric mixture, diastereomeric mixture or as optically pure compounds. Compounds of formula (I) can exist in tautomeric forms and the invention encompasses all such tautomeric forms.
Compounds of formula (I) are individually preferred and physiologically acceptable salts thereof are individually preferred, with the compounds of formula (I) being particularly preferred.
Preferred compounds of formula (I) are those, wherein R
1
is ethoxy. Another preferred embodiment of the present invention relates to compounds as described above, wherein R
2
is fluorine.
In a further preferred embodiment the invention relates to compounds as described above in which R
3
is piperidinyl optionally substituted with methyl or hydroxy-ethyl. Compounds in which R
3
is 1-methyl-piperidin-3-yl, 1-(2-hydroxy-ethyl)-piperidin-4-yl, 1-(2-hydroxy-ethyl)-piperidin-3-yl, piperidin-4-yl or 1-methyl-piperidin-4-yl are more preferred.
The invention embraces especially compounds in accordance with the above de

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