Protein tyrosine phosphatase inhibitors

Details Protein tyrosine phosphatase inhibitors Protein tyrosine phosphatase inhibitors

2001-08-23

2002-10-29

Lambkin, Deborah C. (Department: 1621)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S434000

Reexamination Certificate

active

06472545

ABSTRACT:

TECHNICAL FIELD
The instant invention is directed to compounds useful for inhibiting protein tyrosine phosphatase PTP1B, preparation of the compounds, compositions containing the compounds, and treatment of diseases using the compounds.
BACKGROUND OF THE INVENTION
PTP1B belongs to a family of protein tyrosine phosphatases involved in the regulation of the cellular signaling mechanisms which are involved in metabolism, growth, proliferation, and differentiation (
Science
253:401-6 (1991)). Overexpression or altered activity of tyrosine phosphatase PTP1B can contribute to the progression of various diseases (
Ann. Rev. Biochem.,
54:897-930 (1985)); and there is evidence which suggests inhibition of protein tyrosine phosphatase PTP1B is therapeutically beneficial for the treatment of diseases such as type I and II diabetes, obesity, autoimmune disease, acute and chronic inflammation, osteoporosis, and various forms of cancer (
J. Natl. Cancer Inst.
86:372-8 (1994);
Mol. Cell. Biol.
14: 6674-6682 (1994);
The EMBO J.
12:1937-46 (1993);
J. Biol. Chem.
269:30659-30667 (1994); and
Biochemical Pharmacology
54:703-711 (1997)).
Because of the important role played by unregulated protein tyrosine phosphatase PTP1B in these diseases, agents which inhibit the enzyme have been the subject of active current research for their clinical potential. Reference is made to WO 99/46236, WO 99/46237, WO 99/46267 and WO 99/46268; and although each teaches protein tyrosine phosphatase PTP1B inhibitors, there is still a need for protein tyrosine phosphatase PTP1B inhibitors with modified or improved profiles of activity.
SUMMARY OF THE INVENTION
In its principle embodiment, therefore, the instant invention provides compounds of formula (I)
or therapeutically acceptable salts thereof, wherein
R
1
is selected from the group consisting of benzodioxolyl, dibenzofuranyl, indolyl, phenyl, and thianthrenyl;
wherein the benzodioxolyl, the dibenzofuranyl, the indolyl, and the thianthrenyl can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, aryl, arylalkyl, carbonyloxy, carboxy, cyano, cycloalkyl, cycloalkylalkyl, halo, hydroxy, hydroxyalkyl, nitro, perfluoroalkoxy, perfluoroalkyl, and thioalkoxy; and
wherein the phenyl is substituted with one, two, three, or four substituents independently selected from the group consisting of perfluoroalkoxy and phenyl.
In still another embodiment the instant invention provides a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (I).
In still another embodiment the instant invention provides a method for treating diseases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (I).
In still another embodiment the instant invention provides a composition comprising a compound of formula (I) in combination with a therapeutically acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention provides a series of compounds which inhibit protein tyrosine phosphatase PTP1B. As used throughout the specification of the instant invention, the following terms, as used herein, have the meanings indicated:
The term “alkanoyl,” as used herein, represents an alkyl group attached to the parent molecular moiety through a carbonyl group.
The term “alkoxy,” as used herein, represents an alkyl group attached to the parent molecular moiety through an oxygen atom.
The term “alkoxycarbonyl,” as used herein, represents an alkoxy group attached to the parent molecular moiety through a carbonyl group.
The term “alkyl,” as used herein, represents a saturated, monovalent straight or branched chain hydrocarbon having from one to six carbons.
The term “amino,” as used herein, represents —NR
2
R
3
, wherein R
2
and R
3
are independently selected from the group consisting of hydrogen, alkanoyl, alkoxycarbonyl, alkyl, cycloalkyl, cycloalkylalkyl, a nitrogen protecting group, phenyl, and phenylalkyl; or R
2
and R
3
, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of morpholinyl, oxazinanyl, piperazinyl, piperidinyl, and pyrrolidinyl.
The term “aryl,” as used herein, represents dihydronaphthyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. Aryl groups having an unsaturated or partially saturated ring fused to an aromatic ring can be attached through the saturated or the unsaturated part of the group.
The term “arylalkyl,” as used herein, represents an aryl group attached to the parent molecular moiety through an alkyl group.
The term “carbonyl,” as used herein, represents —C(O)—.
The term “carbonyloxy,” as used herein, represents an alkanoyl group attached to the parent molecular group through an oxygen atom.
The term “carboxy,” as used herein, represents —CO
2
H.
The term “cyano,” as used herein, represents —CN.
The term “cycloalkyl,” as used herein, represents a monovalent saturated cyclic or bicyclic hydrocarbon group of three to twelve carbons.
The term “cycloalkylalkyl,” as used herein, represents a cycloalkyl group attached to the parent molecular moiety through an alkyl group.
The term “halo,” as used herein, represents F, Cl, Br, or I.
The term “hydroxy,” as used herein, represents —OH.
The term “hydroxyalkyl,” as used herein, represents a hydroxy group attached to the parent molecular group through an alkyl group.
The term “nitro,” as used herein, represents —NO
2
.
The term “nitrogen protecting group,” as used herein, represents selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures. Examples of amino protecting groups include methoxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl (Cbz), chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-butoxycarbonyl (Boc), para-methoxybenzyloxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), methylsulfonyl, phenylsulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triphenylsilyl, and the like.
The term “perfluoroalkoxy,” as used herein, represents a perfluoroalkyl group attached to the parent molecular moiety through an oxygen atom.
The term “perfluoralkyl,” as used herein, represents an alkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
The term “phenylalkyl,” as used herein, represents a phenyl group attached to the parent molecular group through an alkyl group.
The term “thioalkoxy,” as used herein, represents an alkyl group attached to the parent molecular moiety through a sulfur atom.
The instant compounds can exist as therapeutically acceptable salts. The term “therapeutically acceptable salt,” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible; suitable for treatment of diseases without undue toxicity, irritation, and allergic response; commensurate with a reasonable benefit/risk ratio; and effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the amino group of the compounds with a suitable acid. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetic, trifluoroacetic, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. The amino groups of the compounds can also be quaternized with alkyl chlorides, bromides, and iodides such as methyl,

Affiliated with

Also associated with

Rating

Protein tyrosine phosphatase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Protein tyrosine phosphatase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Protein tyrosine phosphatase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2923851