Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-24
2001-01-09
Owens, Amelia (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S146000
Reexamination Certificate
active
06172081
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the area of dipeptidyl peptidase-IV (DPP-IV) inhibition. 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-life for DPP-IV cleavage is much shorter than the half-life for removal of GLP-l 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).
SUMMARY OF THE INVENTION
The instant invention relates to novel tetrahydroisoquinoline 3-carboxamide derivatives of formula I
and pharmaceutically acceptable salts thereof. As used in formula I, and throughout the specification, the symbols have the following meanings:
X is
(a) CH
2
;
(b) S;
(c) O; or
(d) C(CH
3
)
2
;
R
1
and R
2
are independently
(a) hydrogen;
(b) hydroxy;
(c) alkyl;
(d) alkoxy;
(e) aralkoxy; or
(f) halogen.
Compounds of formula I are DPP-IV inhibitors which are effective in treating conditions mediated by DPP-IV.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds. Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances either individually or as part of a larger group).
The term “alkyl” refers to optionally substituted straight or branched chain hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 5 carbons. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, the various branched chain isomers thereof, such as isopropyl, t-butyl, isobutyl, isohexyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl and the like. Substituted alkyl groups include said alkyl groups substituted by one or more substituents selected from halogen, alkoxy, cycloalkyl, hydroxy, carboxy, —CONR
3
R
4
, —NR
3
R
4
(where R
3
and R
4
are independently hydrogen or alkyl), nitro, cyano or thiol.
The term “alkoxy” refers to any of the above alkyl groups linked to an oxygen atom.
The term “cycloalkyl” refers to saturated cyclic hydrocarbon groups containing 3 to 7 ring carbons with cyclopropyl, cyclopentyl and cyclohexyl being preferred.
The term “halogen” or “halo” refers to chlorine, bromine and fluorine.
The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl or biphenyl groups, each of which may optionally be substituted by one to four substituents such as alkyl, halo, hydroxy, alkoxy, amino, thiol, nitro, cyano, carboxy and the like.
The term “aralkoxy” refers to an aryl group bonded to an alkoxy group.
The compounds of formula I can exist in free form or in acid addition salt form. Salt forms may be recovered from the free form in known manner and vice-versa. Acid addition salts may e.g. be those of pharmaceutically acceptable organic or inorganic acids. Although the preferred acid addition salts are the trifluoroacetate, the hydrochloric, lactic or acetic acid may also be utilized.
The compounds of the invention may exist in the form of optically active isomers or diastereoisomers and can be separated and recovered by conventional techniques, such as chromatography.
A preferred group of compounds of the invention is the compounds of formula I wherein.
X is CH
2
; and
R
1
and R
2
are independently hydrogen, hydroxy, or alkoxy.
More preferred compounds of the invention are those compounds of formula I wherein
X is CH
2
;
R
1
is alkoxy; and
R
2
is hydrogen.
The compounds of formula I may be prepared as illustrated for the compounds of formula I where X is CH
2
and one of R
1
or R
2
is hydroxy or alkoxy according to scheme 1 below:
The Boc amino acid derivative (1) is silylated using a silating agent such as t-butyl dimethyl chlorosilane to form compounds of formula (2), where Y is H or a protecting group such as trialkylsilyl, arylalkylsilyl, arylsilyl or t-butyl ester, The silyl derivative (2) is condensed with prolineamide (2A; commercially available) mediated by an activating agent such as EDCI and HOAt in a solvent such as DMF. The resulting amide (3) is dehydrated to the nitrile (4) using a dehydrating agent such as phosphorus oxychloride. The nitrile (4) is then desilylated and alkylated using an alkylating agent such as an alkyl halide of the formula RaX (where Ra is an alkyl or arylalkyl group such as methyl or benzyl and X is a halogen such as iodine, bromine or chlorine) without isolation of the phenol, to form the ether (5). Alternatively, compound (5) can be prepared by alkylating the nitrile (4) with an alcohol subsequent to desilylation via a Mitsunobu-type reaction (via intermediates (6)).
In all cases, the final step is the removal of the Boc group using an acid such as trifluoroacetic acid in an organic solvent such as acetonitrile, preferably in the presence of a scavenger such as 1,3-dimethoxybenzene to give compound (7) which are compounds of formula I where R
2
is hydrogen and R
1
is alkoxy.
For compounds of formula I where R
2
is other than hydroxy condensation with a prolineamide is carried out using the Boc amino acid derivative (1) directly.
The Boc amino acid derivative(1) is commercially available or can be derived using known methods.
Compounds of formula I where X is other than CH
2
can be prepared in a similar fashion using the appropriate analog of proline as a starting material. Proline analogs where X═S or O are commercially available and can be used with standard methods of converting the carboxylic acid functionality to a nitrile via the primary amide. In the case where X represents —C(CH
3
)
2
, the requisite proline analog may be prepared as described in either of two literature references: J. Ezquerra, C. Pedregal, A. Rubio, and J. B. Deeter,
Journal of Organic Chemistry
1994, 59,4327 or F. Soucy, D. Wernic and P. Beaulieu,
JCS Perkin I,
1991, 2885.
The compounds of the invention may be isolated from the reaction mixture and purified in conventional manner, e.g. by chromatography.
Insofar as its preparation is not particularly described herein, a compound used as starting material is known or may be prepared from known compounds in known manner or analogously to known methods or analogously to methods described in the Examples.
The instant invention also includes pharmaceutical compositions useful in inhibiting DPP-IV comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof
In still another embodiment, the instant invention provides a method of inhibiting DPP-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof.
In a further embodiment, the instant invention provides a method of treating conditions mediated by DPP-IV inhibition comprising administering to a mammal in need of such treatment a therapeutically effecti
Borovian Joseph J.
Novartis AG
Owens Amelia
LandOfFree
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