Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-12-10
2003-11-04
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S112000
Reexamination Certificate
active
06642381
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to pyrimido[5,4-e][1,2,4]triazine-5,7-diamine compounds which are useful for inhibiting protein tyrosine phosphatases, particularly PTP1B.
BACKGROUND OF THE INVENTION
Protein tyrosine phosphatases (PTPases) are key enzymes in the processes that regulate cell growth and differentiation. The inhibition of these enzymes can play a role in the modulation of multiple signaling pathways in which tyrosine phosphorylation dephosphorylation plays a role. PTP1B is a particular protein tyrosine phosphatase that is often used as a prototypical member of that class of enzymes.
PTPase inhibitors are recognized as potential therapeutic agents for the treatment of diabetes. See, e.g. Moeller et al., 3(5):527-40, Current Opinion in Drug Discovery and Development, 2000; or Zhang, Zhong-Yin, 5:416-23, Current Opinion in Chemical Biology, 2001.
SUMMARY OF THE INVENTION
It has been discovered that compounds of the formula:
and the pharmaceutically acceptable salts thereof, wherein R
1
and R
2
are as defined below, inhibit protein tyrosine phosphatases, particularly PTP1B and so would be useful for lowering blood glucose concentrations in mammals.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
As used in the specification, the term “lower alkyl”, alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like. Lower alkyl groups may be unsubstituted or substituted by one or more groups selected independently from cycloalkyl, nitro, aryloxy, aryl, hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl and substituted amino. Examples of substituted lower alkyl groups include 2-hydroxyethyl, 3-oxobutyl, cyanomethyl and 2-nitropropyl.
The term “cycloalkyl” means an unsubstituted or substituted 3- to 7-membered carbocyclic ring. Substituents useful in accordance with the present invention are hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkyl, aroyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl, heteroaryl and substituted amino.
The term “lower alkoxy” means a straight-chain or branched-chain alkoxy group containing a maximum of six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.
The term “lower alkylthio” means a lower alkyl group bonded through a divalent sulfur atom, for example, a methyl mercapto or a isopropyl mercapto group.
The term “aryl” means a mono- or bicyclic aromatic group, such as phenyl or naphthyl, which is unsubstituted or substituted by conventional substitutent groups. Preferred substituents are lower alkyl, lower alkoxy, hydroxy lower alkyl, hydroxy, hydroxyalkoxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, nitro, perfluoroalkyl, alkanyoyl, aroyl, aryl alkynyl, lower alkynyl and lower alkanoylamino. The especially preferred substituents are lower alkyl, lower alkoxy, hydroxy, halogen, cyano and perfluoro lower alkyl. Examples of aryl groups that may be used in accordance with this invention are phenyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, m-hydroxy phenyl, m-methylthiophenyl, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, 1-naphthyl and the like.
The term “lower alkyl-aryl” means a lower alkyl group as hereinbefore defined in which one or more hydrogen atoms is/are replaced by an aryl group as hereinbefore defined. Any conventional lower alkyl-aryl may be used in accordance with this invention, such as benzyl and the like.
The term “lower alkoxy-aryl” means a lower alkoxy group as hereinbefore defined in which one or more hydrogen atoms is/are replaced by an aryl group as hereinberfore defined. Any conventional lower alkoxy-aryl may be used in accordance with this invention, such as benzyloxy.
The term “lower alkoxycarbonyl” means a lower alkoxy group bonded via a carbonyl group. Examples of alkoxycarbonyl groups are ethoxycarbonyl and the like.
The term “pharmaceutically acceptable salts” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. The chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp: 196 and 1456-1457.
The present invention comprises compounds of the formula I:
and the pharmaceutically acceptable salts thereof. In accordance with the invention,
R
1
and R
2
are individually selected from the group consisting of hydrogen, or
R
1
and R
2
together form a bond, —CH
2
—, —O—, —NH— or —N—R
3
,
R
3
is lower alkyl or —CH
2
—Ar, and
Ar is selected from the group consisting of unsubstituted phenyl; unsubstituted naphthyl; phenyl mono- or bi-substituted with lower alkyl, lower alkoxy, aryl, cycloalkyl, lower alkyl-aryl, lower alkoxy-aryl, lower alkyl-cycloalkyl, lower alkoxy-cycloalkyl, halo, cyano or trifluoromethyl; and naphthyl mono- or bi-substituted with lower alkyl, lower alkoxy, aryl, cycloalkyl, lower alkyl-aryl, lower alkoxy-aryl, lower alkyl-cycloalkyl, lower alkoxy-cylcoalkyl or halo.
Among the compounds of formula 1, preferred compounds are those of formula II:
where Ar is selected from the group consisting of unsubstituted phenyl; unsubstituted naphthyl; phenyl mono- or bi-substituted with lower alkyl, lower alkoxy, aryl, cycloalkyl, lower alkyl-aryl, lower alkoxy-aryl, lower alkyl-cycloalkyl, lower alkoxy-cycloalkyl, halo, cyano or trifluoromethyl; and naphthyl mono- or bi-substituted with lower alkyl, lower alkoxy, aryl, cycloalkyl, lower alkyl-aryl, lower alkoxy-aryl, lower alkyl-cycloalkyl, lower alkoxy-cylcoalkyl or halo.
In one preferred embodiment of the compounds of formula II, Ar is unsubstituted phenyl or unsubstituted naphthyl.
In another preferred embodiment of the compounds of formula II, Ar is phenyl mono-substituted with lower alkyl, lower alkoxy, aryl, cycloalkyl, lower alkyl-aryl, lower alkoxy-aryl, halo, cyano or trifluoromethyl.
In yet another preferred embodiment of the compounds.of formula II, Ar is phenyl mono-substituted with lower alkyl, lower alkoxy, halo, cyano or trifluoromethyl.
In still another preferred embodiment of the compounds of formula II, Ar is phenyl bi-substituted with lower alkyl, lower alkoxy, halo or cyano.
In a further preferred embodiment of the compounds of formula II, Ar is naphthyl mono-substituted with lower alkyl, lower alkoxy, lower alkyl-aryl, lower alkoxy-aryl or halo.
In yet a further preferred embodiment of the compounds of formula II, Ar is naphthyl mono-substituted with lower alkyl, lower alkoxy or halo.
In still a further preferred embodiment of the compounds of formula II, Ar is naphthyl bi-substituted with lower alkyl, lower alkoxy or halo.
The compounds of the invention can exist as stereoisomers and diastereomers, all of which are encompassed within the scope of the present invention.
The compounds of the invention inhibit PTP1B in vitro and have been shown to lower blood glucose levels in vivo. Thus, the compounds of the present invention would be use
Guertin Kevin Richard
Setti Lina Quattrocchio
Ebel Eileen M.
Ford John M.
Hoffman-La Roche Inc.
Johnston George W.
Tramaloni Dennis P.
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