Imidazole compounds

Details Imidazole compounds Imidazole compounds

2001-03-09

2002-03-19

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S337100, C514S400000

Reexamination Certificate

active

06359145

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel imidazole compounds having pharmacological activity, to a process for their production and to a pharmaceutical composition containing the same.
BACKGROUND ART
Adenosine (Ado) is an endogenous purine nucleoside released by cells as part of the normal metabolic machinery. Ado has wide variety of biological activities, namely potent antiinflammatory and immunosuppressive properties, protective effects in cardiovascular and cerebrovascular ischemia, anticonvulsant effects and modulation effects of platelet aggregation, lipolysis, glycogenesis, blood flow and neurotransmission. Ado shows the biological activities by binding to its receptors anchored in the cell membrane. Therefore, it is the beneficial treatment for many diseases to perform the pharmacological elevation of extracellular Ado concentrations.
Adenosine deaminase (ADA) catalyzes an essentially irreversible deamination of adenosine or deoxyadenosine to inosine or deoxyinosine, respectively. In the last 10 years, ADA, which was considered to be cytosolic, has been found on the cell surface of many cells. Thus, blocking ADA activity with specific inhibitor is the potent way to elevate Ado concentrations in biological systems and the beneficial treatment for many diseases.
Some compounds have known to have inhibitory activity of ADA (J. Med. Chem. 27, 274-278, 1984; ibid. 31, 390-393, 1988; ibid. 34, 1187-1192, 1991; ibid. 35, 4180-4184, 1992; ibid. 37, 305-308, 1994; ibid. 37, 3844-3849, 1994; and WO98/02166).
Known imidazole compounds with pharmaceutical activity other than ADA inhibitory activity are described in U.S. Pat. No. 4,451,478 and WO97/26883.
Furthermore, some imidazole derivatives having ADA inhibitory activity have been reported, for example, as described in Drug Developement Research 28, 253-258, 1993.
DISCLOSURE OF THE INVENTION
This invention relates to novel imidazole compounds, which have pharmaceutical activity such as ADA inhibiting activity, to a process for their production, to a pharmaceutical composition containing the same and to a use thereof.
One object of this invention is to provide the novel imidazole compounds, which have an ADA inhibiting activity.
Another object of this invention is to provide a process for production of the imidazole compounds.
A further object of this invention is to provide a pharmaceutical composition containing the imidazole compound as an active ingredient.
Still further object of this invention is to provide a use of the imidazole compound for manufacturing a medicament for treating or preventing various diseases, or a method of treating or preventing various diseases by administering the imidazole compound in an effective amount to elevate adenosine concentration.
The imidazole compounds of this invention can be represented by the following formula (I):
wherein R
1
is hydrogen, hydroxy, protected hydroxy, or aryl optionally substituted with suitable substituent(s);
R
2
is hydrogen or lower alkyl;
R
3
is hydroxy or protected hydroxy;
R
4
is cyano, (hydroxy)iminoamino(lower)alkyl, carboxy, protected carboxy, heterocyclic group optionally substituted with amino, or carbamoyl optionally substituted with suitable substituent(s); and
—A— is —Q— or —O—Q—, wherein Q is single bond or lower alkylene, provided that when R
2
is lower alkyl, then R
1
is hydroxy, protected hydroxy, or aryl optionally substituted with suitable substituent(s), its prodrug, or their salt.
The compound (I), its prodrug, or their salt can be prepared by the following processes. In the following formulae, compounds may be prodrugs or their salts.
wherein R
1
, R
2
, R
3
, R
4
, and A re each as defined above, and X is hydroxy or a leaving group, provided that R
3
is not hydroxy.
In this process the compound (I) can be produced by reacting the compound (IV), where X is hydroxy, with alkanesulfonyl chloride (i.e., methanesulfonyl chloride, etc.) or arylsulfonyl chloride (i.e., toluenesulfonyl chloride, etc.) in the presence of a base such as triethylamine or pyridine in a solvent such as dichloromethane, chloroform, tetrahydrofuran, or diethyl ether from 0° C. to room temperature for about 1 hour and reacting the resulting sulfonate with the compound (III) in the presence of a base such as sodium hydride, potassium tert-butoxide, or potassium carbonate in a solvent such as dimethylformamide (DMF) from room temperature to 100° C. for 5 to 100 hours. Alternatively, the compound (III) can be reacted with the compound (IV) in the presence of a base such as sodium methoxide, potassium tert-butoxide, or sodium hydride to give the compound (I).
The compound (I) wherein R
3
is hydroxy can be obtained by the following process:
In the reaction formula R
1
and R
4
are as defined above and R′ is a hydroxy protective group.
In process 2, the compound (I-1) can be produced by reducing the compound (II) using a reducing agent such as sodium borohydride in a solvent such as methanol, ethanol, tetrahydrofuran, or water at 0° C. to reflux temperature for 30 minutes to 72 hours.
When the compound (I) contains a protected hydroxy group, the protected hydroxy group can be converted to a hydroxy group by a known method, for example, by reacting the compound with a deprotecting agent such as palladium hydroxide on carbon/cyclohexane, iodotrimethylsilane or tetrabutylammonium fluoride in a solvent such as ethanol, chloroform or tetrahydrofuran.
The compound (I) where R
4
is (hydroxy)iminoamino(lower)alkyl, heterocyclic group or substituted carbamoyl can be prepared from the compound (I) where R
4
is cyano or protected carboxy by reacting the latter with the compound corresponding to R
4
of the former with or without a condensing agent such as sodium methoxide at room temperature to 120° C. for 2 to 72 hours.
The starting compound (II) can be prepared by the following reaction.
In the reaction formula R
1
, R
4
, R′, and A are as defined above.
This reaction can be performed in the same manner as in Process 1.
In the following, suitable examples of the definitions to be included within the scope of the invention are explained in detail.
The term “lower” means a group having 1 to 6 carbon atom(s), unless otherwise provided.
Suitable “lower alkyl” and lower alkyl moiety of “lower alkoxy” include a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or the like, with methyl being preferred.
Suitable “lower alkylene” may be straight or branched one having 1 to 8. carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentametylene, hexamethylene, or the like.
Suitable “protected hydroxy” includes lower alkoxy optionally substituted with aryl; acyloxy; or tri(lower)alkylsilyloxy (i.e., trimethylsilyloxy, tert-butyldimethylsilyloxy, etc.); or the like.
Suitable hydroxy protective groups in the protected hydroxy group include lower alkyl optionally substituted with aryl; acyloxy; tri(lower)alkylsilyloxy (i.e., trimethylsilyloxy, tert-butyldimethylsilyloxy, etc.); or the like.
Suitable “halogen” includes fluorine, chlorine, bromine, or iodine.
Suitable “aryl” and aryl moeity of “aroyl” include phenyl, naphthyl, tolyl, xylyl, or the like, with phenyl and naphthyl being preferred.
Suitable “protected carboxy” includes lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), aryloxy-carbonyl (e.g., phenoxycarbonyl, 4-nitrophenoxycarbonyl, etc.), ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.), or the like.
Suitable carboxy protective groups in the protected carboxy group include lower alkyl (e.g., methyl, ethyl, or tert-butyl), halo(lower)alkyl (e.g., 2-iodomethyl or 2,2,2-trichloroethyl), ar(lower)alkyl (e.g., benzyl, trityl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl or 4-hydroxy-3,5-di-tert-butylbenzyl), aryl (e.g., phenyl, naphthyl, tolyl, or xylyl), and the like. More suitable examples are lower alkyl such as methyl, ethyl, or

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