Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-12
2002-08-13
Shah, Mukund J. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S540000, C514S423000, C514S343000, C514S226200, C546S279100, C546S208000, C544S332000
Reexamination Certificate
active
06432969
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the area of dipeptidyl peptidase-IV inhibition and, more particularly, relates to certain N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing said compounds, and the use of said compounds in inhibiting dipeptidyl peptidase-IV.
1. Background of the Invention
Dipeptidyl peptidase-IV (DPP-IV) is a serine protease which cleaves N-terminal dipeptides from a peptide chain containing, preferably, a proline residue in the penultimate position. Although the biological role of DPP-IV in mammalian systems has not been completely established, it is believed to play an important role in neuropeptide metabolism, T-cell activation, attachment of cancer cells to the endothelium and the entry of HIV into lymphoid cells.
Likewise, it was discovered that DPP-IV is responsible for inactivating glucagon-like peptide-1 (GLP-1). Since GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal, DPP-IV inhibition appears to represent an attractive approach for treating non-insulin-dependent diabetes mellitus (NIDDM).
2. Description of the Prior Art
WO95/15309 discloses certain peptide derivatives which are inhibitors of DPP-IV and, therefore, are useful in treating a number of DPP-IV mediated processes.
Archives of Biochemistry and Biophysics, Vol. 323, No. 1, pgs. 148-154 (1995) discloses certain aminoacylpyrrolidine-2-nitriles which are useful as DPP-IV inhibitors.
Bioorganic and Medicinal Chemistry Letters, Vol. 6, No. 10, pgs. 1163-1166 (1996) discloses certain 2-cyanopyrrolidines which are inhibitors of DPP-IV.
European Journal of Medicinal Chemistry, Vol. 32, pgs. 301-309 (1997) discloses certain pyrrolidides which are useful as DPP-IV inhibitors.
WO98/19998 discloses certain N-substituted-2-cyanopyrrolidines which are useful as DPP-IV inhibitors.
Biochemistry, Vol. 38, pgs. 11597-11603 (1999) discloses (1-[[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) as a slow-binding inhibitor of DPP-IV.
SUMMARY OF THE INVENTION
The present invention provides new DPP-IV inhibitors which are effective in treating conditions mediated by DPP-IV inhibition. More particularly, the present invention relates to certain N-(substituted glycyl)-2-cyanopyrrolidines which inhibit DPP-IV. In addition, the present invention provides pharmaceutical compositions useful in inhibiting DPP-IV comprising a therapeutically effective amount of a certain N-(substituted glycyl)-2-cyanopyrrolidine. Moreover, the present invention provides a method of inhibiting DPP-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a certain N-(substituted glycyl)-2-cyanopyrrolidine.
DETAILED DESCRIPTION OF THE INVENTION
The essence of the instant invention is the discovery that certain N-(substituted glycyl)-2-cyanopyrrolidines are useful in inhibiting DPP-IV. In one embodiment, the present invention provides compounds of formula I:
where Y is:
a) a group of the formula
where R is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is mono- or independently di-substituted by halo, trifluoromethyl, cyano, nitro or C
1-6
alkyl; unsubstituted benzoyl; a benzoyl group which is mono- or di-substituted by halo or C
1-6
alkyl; C
1-6
alkylcarbonyl; di-C
1-6
alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is mono- or di-substituted on the phenyl ring by halo or C
1-6
alkyl;
b) a group of the formula
where R
1
is an unsubstituted pyridine, pyrimidine or phenyl ring; a pyridine, pyrimidine or phenyl ring which is mono- or independently di-substituted by halo, trifluoromethyl, cyano, nitro or C
1-6
alkyl; an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is mono- or di-substituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C
1-6
alkyl; unsubstituted benzoyl; a benzoyl group which is mono- or di-substituted by halo or C
1-6
alkyl; C
1-6
alkylcarbonyl; thienyl sulfonyl; unsubstituted benzothiazole; or a benzothiazole group which is substituted on the phenyl ring by halo or C
1-6
alkyl;
c) a group of the formula
where R
2
is an unsubstituted phenyl ring; or a phenyl ring which is mono- or di-substituted by halo or C
1-6
alkyl;
d) a group of the formula
where R
3
is an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is mono- or di-substituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C
1-6
alkyl; C
1-6
alkylcarbonyl; di-C
1-6
alkylaminocarbonyl; C
3-8
cycloalkylcarbonyl; unsubstituted benzoyl; a benzoyl group which is mono- or di-substituted by halo or C
1-6
alkyl; unsubstituted phenylaminocarbonyl; phenylaminocarbonyl which is mono- or di-substituted on the phenyl ring by halo or C
1-6
alkyl; a substituted thiazole ring; or a phenyl-substituted thiazole ring wherein the phenyl ring is mono- or di-substituted by halo or C
1-6
alkoxy;
e) a (4-pentylbicyclo[2.2.2]oct-1-yl) amine group; or
f) a group of the formula
where R
4
is an unsubstituted phenyl ring; or a phenyl ring which is mono- or di-substituted by halo, trifluoromethyl, cyano, nitro or C
1-6
alkyl; or an acid addition salt thereof.
Preferred compounds are those of formula Ia:
where Y′ is:
a) a group of the formula
where R′ is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is mono- or independently di-substituted by halo, trifluoromethyl or cyano; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C
1-6
alkyl; C
1-6
alkylcarbonyl; di-C
1-6
alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is monosubstituted on the phenyl ring by halo or C
1-6
alkyl;
b) a group of the formula
where R
1
′
is an unsubstituted pyridine, pyrimidine or phenyl ring; a pyridine, pyrimidine or phenyl ring which is monosubstituted by halo, trifluoromethyl, cyano, nitro or C
1-6
alkyl; an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C
1-6
alkyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C
1-6
alkyl; C
1-6
alkylcarbonyl; thienyl sulfonyl; unsubstituted benzothiazole; or a benzothiazole group which is substituted on the phenyl ring by halo or C
1-6
alkyl;
c) a group of the formula
where R
2
′
is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by halo or C
1-6
alkyl;
d) a group of the formula
where R
3
′
is an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C
1-6
alkyl; C
1-6
alkylcarbonyl; di-C
1-6
alkylaminocarbonyl; C
3-8
cycloalkylcarbonyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C
1-6
alkyl; unsubstituted phenylaminocarbonyl; phenylaminocarbonyl which is monosubstituted on the phenyl ring by halo or C
1-6
alkyl; a phenyl-substituted thiazole ring; or a phenyl-substituted thiazole ring wherein the phenyl ring is monosubstituted by halo or C
1-6
alkoxy;
e) a (4-pentylbicyclo[2.2.2]oct-1-yl)amine group; or
f) a group of the formula
where R
4
′
is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by halo, trifluoromethyl, cyano, nitro or C
1-6
alkyl; or an acid addition salt thereof.
More preferred compounds are those of formula Ib :
where Y″ is:
a) a group of the formula
where R″ is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is mono-substituted by halo, trifluoromethyl or cyano or di-substituted by halo; unsubstituted benzoyl; a benzoyl group which is mono-substituted by halo or C
1-4
alkyl; C
1-6
alkylcarbonyl; di-C
1-6
alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is monosubstituted on the phenyl ring by halo or C
1-4
alkyl;
b) a group of the f
Borovian Joseph J.
Liu Hong
Novartis AG
Shah Mukund J.
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