Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-19
2003-09-09
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S286000, C544S322000, C544S335000
Reexamination Certificate
active
06617340
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)-pyrrolidines, pharmaceutical compositions containing said compounds, and the use of said compounds in inhibiting dipeptidyl peptidase-IV.
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.
More recently, it was discovered that DPP-IV is responsible for inactivating glucagon-like peptide-1 (GLP-1). More particularly, DPP-IV cleaves the amino-terminal His-Ala dipeptide of GLP-1, generating a GLP-1 receptor antagonist, and thereby shortens the physiological response to GLP-1. Since the half-line for DPP-IV cleavage is much shorter than the half-life for removal of GLP-1 from circulation, a significant increase in GLP-1 bioactivity (5- to 10-fold) is anticipated from DPP-IV inhibition. 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).
Although a number of DPP-IV inhibitors have been described in the literature, all have limitations relating to potency, stability or toxicity. Accordingly, it is clear that a great need exists for novel DPP-IV inhibitors which are useful in treating conditions mediated by DPP-IV inhibition and which do not suffer from the above-mentioned limitations of known DPP-IV inhibitors.
DESCRIPTION OF THE PRIOR ART
WO 95/15309 discloses certain peptide derivatives which are inhibitors of DPP-IV and, therefore, are useful in treating a number of DPP-IV mediated processes.
WO 95/13069 discloses certain cyclic amine compounds which are useful in stimulating the release of natural or endogenous growth hormone.
European Patent 555,824 discloses certain benzimidazolyl compounds which prolong thrombin time and inhibit thrombin and serine-related proteases.
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.
Journal of Neurochemistry, Vol. 66, pgs. 2105-2112 (1996) discloses certain Fmoc-aminoacylpyrrolidine-2-nitriles which are useful in inhibiting prolyl oligopeptidase.
Bulletin of the Chemical Society of Japan, Vol. 50, No. 7, pgs. 1827-1830 (1977) discloses the synthesis of an aminohexapeptide, viz., Z-Val-Val-lmPro-Gly-Phe-Phe-OMe, and its related aminopeptides. In addition, the antimicrobial properties of said compounds were examined.
Bulletin of the Chemical Society of Japan, Vol. 51, No. 3, pgs. 878-883 (1978) discloses the synthesis of two known peptide antibiotics, viz., Bottromycins B
1
and B
2
according to the structures proposed by Nakamura, et al. However, since the resultant compounds were devoid of antimicrobial properties, it was concluded that the structures proposed by Nakamura, et al. were erroneous.
WO 90/12005 discloses certain amino acid compounds which inhibit prolylendopeptidase activity and, therefore, are useful in treating dementia or amnesia.
Derwent Abstract 95: 302548 discloses certain N-(aryl(alkyl)carbonyl) substituted heterocyclic compounds which are cholinesterase activators with enhanced peripheral selectivity useful in treating conditions due to the lowering of cholinesterase activity.
Chemical Abstracts 84: 177689 discloses certain 1-acyl-pyrrolidine-2-carbonitrile compounds which are useful as intermediates for proline compounds exhibiting angiotensin converting enzyme (ACE) inhibiting activity.
Chemical Abstracts 96: 116353 discloses certain 3-amino-2-mercapto-propyl-proline compounds which are Ras farnesyl-transferase inhibitors useful in treating various carcinomas or myeloid leukemias.
WO 95/34538 discloses certain pyrrolidides, phosphonates, azetidines, peptides and azaprolines which inhibit DPP-IV and, therefore, are useful in treating conditions mediated by DPP-IV inhibition.
WO 95/29190 discloses certain compounds characterized by a plurality of KPR-type repeat patterns carried by a peptide matrix enabling their multiple presentation to, and having an affinity for, the enzyme DPP-IV, which compounds exhibit the ability to inhibit the entry of HIV into cells.
WO 91/16339 discloses certain tetrapeptide boronic acids which are DPP-IV inhibitors useful in treating autoimmune diseases and conditions mediated by IL-2 suppression.
WO 93/08259 discloses certain polypeptide boronic acids which are DPP-IV inhibitors useful in treating autoimmune diseases and conditions mediated by IL-2 suppression.
WO 95/11689 discloses certain tetrapeptide boronic acids which are DPP-IV inhibitors useful in blocking the entry of HIV into cells.
East German Patent 158109 discloses certain N-protected peptidyl-hydroxamic acids and nitrobenzoyloxamides which are useful as, inter alia, DPP-IV inhibitors.
WO 95/29691 discloses, inter alia, certain dipeptide proline phosphonates which are DPP-IV inhibitors useful in the treatment of immune system disorders.
German Patent DD 296075 discloses certain amino acid amides which inhibit DPP-IV.
Biochimica et Biophysica Acta, Vol. 1293, pgs. 147-153 discloses the preparation of certain di- and tri-peptide p-nitroanilides to study the influence of side chain modifications on their DPP-IV and PEP-catalyzed hydrolysis.
Bioorganic and Medicinal Chemistry Letters, Vol. 6, No. 10, pgs. 1163-1166 (1996) discloses certain 2-cyanopyrrolidines which are inhibitors DPP-IV.
J. Med. Chem., Vol. 39, pgs. 2087-2094 (1996) discloses certain prolineboronic acid-containing dipeptides which are inhibitors of DPP-IV.
Diabetes, Vol. 44, pgs. 1126-1131 (September '96) is directed to a study which demonstrates that GLP-I amide is rapidly degraded when administered by subcutaneous or intravenous routes to diabetic and non-diabetic subjects.
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)-pyrrolidines 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)-pyrrolidine. 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)-pyrrolidine.
DETAILED DESCRIPTION OF THE INVENTION
The essence of the instant invention is the discovery that certain N-(substituted glycyl)-pyrrolidines are useful in inhibiting DPP-IV. In one embodiment, the present invention provides compounds of formula I:
wherein R is a group
an unsubstituted (C
3-7
)-cycloalkyl ring; a (C
3-7
)cycloalkyl ring substituted in the 1-position by a hydroxy(C
1-3
)alkyl group; a group &Parenopenst;CH
2
&Parenclosest;
2
R
2
; a group
a group &Parenopenst;CH
2
&Parenclosest;
3
R
4
; an isopropyl group; or an isopropyl group substituted in the 1-position by a hydroxy(C
1-3
)alkyl group;
R
1
is an unsubstituted pyridine ring; a pyridine ring mono- or di-substituted by halo, trifluoromethyl, cyano or nitro; an unsubstituted pyrimidine ring; or a pyrimidine ring monosubstituted by halo, trifluoromethyl, cyano or nitro;
R
2
is an unsubstituted phenyl ring; or a phenyl ring mono-, di- or tri-substituted by halo or (C
1-3
)alkoxy;
each R
3,
independently, is an unsubstituted phenyl ring; or a phenyl ring mono-substituted by halo or (C
1-3
)alkoxy; and
R
4
is a 2-oxopyrrolidine group or a (C
2-4
)alkoxy
Borovian Joseph J.
Novartis AG
Robinson Binta
Rotman Alan L.
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