Pyrido[2,1-A]Isoquinoline derivatives

Details Pyrido[2,1-A]Isoquinoline derivatives Pyrido[2,1-A]Isoquinoline derivatives

2002-12-17

2004-04-27

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S096000, C546S094000, C546S071000

Reexamination Certificate

active

06727261

ABSTRACT:

BACKGROUND OF THE INVENTION
The enzyme dipeptidyl peptidase IV (EC.3.4.14.5, abbreviated in the following as DPP-IV) is involved in the regulation of the activities of several hormones. In particular DPP-IV is degrading efficiently and rapidly glucagon like peptide 1 (GLP-1), which is one of the most potent stimulator of insulin production and secretion. Inhibiting DPP-IV would potentiate the effect of endogenous GLP-1, and lead to higher plasma insulin concentrations. In patients suffering from impaired glucose tolerance and type 2 diabetes mellitus, higher plasma insulin concentration would moderate the dangerous hyperglycaemia and accordingly reduce the risk of tissue damage. Consequently, DPP-IV inhibitors have been suggested as drug candidates for the treatment of impaired glucose tolerance and type 2 diabetes mellitus (e.g. Vilhauer, WO98/19998). Without disclosing any medical use, Buzas et al., Lab. Chim. Org. V, Fac. Sci., Orleans, Fr. Chim. Ther. (1992), 7(5), 404-7 describe synthesis of the compounds of Examples 41 and 42 below.
SUMMARY OF THE INVENTION
The compounds of the present invention are useful for the treatment and/or prophylaxis of diabetes or non-insulin dependent diabetes.
The present invention provides pyrido[2,1-a]isoquinoline derivatives in accordance with formula (I)
wherein
R
1
is lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or lower alkyl substituted by cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
R
2
, R
3
and R
4
are each independently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy or lower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl are optionally substituted by lower alkoxycarbonyl, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;
R
5
is hydrogen, fluorine, lower alkyl, aryl or substituted aryl;
R
6
is hydrogen, lower alkyl or hydroxy-lower alkyl, or
R
5
and R
6
together with the carbon atoms to which they are attached form a five or six membered saturated carbocyclic ring;
R
7
is hydrogen, fluorine or lower alkyl;
and pharmaceutically acceptable salts thereof;
with the exception of rac-3&bgr;-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b&bgr;-hexahydro-2H-pyrido[2,1-a]isoquinolin-2&bgr;-ylamine dihydrochloride and rac-3&bgr;-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b&bgr;-hexahydro-2H-pyrido[2,1-a]isoquinolin-2&agr;-ylamine dihydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
Novel DPP-IV inhibitors have been found that very efficiently lower plasma glucose levels. Consequently, the compounds of the present invention are useful for the treatment and/or prophylaxis of diabetes, particularly non-insulin dependent diabetes mellitus, and/or impaired glucose tolerance, as well as other conditions wherein the amplification of action of a peptide normally inactivated by DPP-IV gives a therapeutic benefit. Surprisingly, the compounds of the present invention can also be used in the treatment and/or prophylaxis of Bowl disease, Colitis Ulcerosa, Morbus Crohn, obesity and/or metabolic syndrome. Furthermore, the compounds of the present invention can be used as diuretic agents and for the treatment and/or prophylaxis of hypertension. Unexpectedly, the compounds of the present invention exhibit improved therapeutic and pharmacological properties compared to other DPP-IV inhibitors known in the art, such as e.g. in context with pharmacokinetics and bioavailability.
The present invention provides pyrido[2,1-a]isoquinoline derivatives in accordance with formula (I)
wherein
R
1
is lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or lower alkyl substituted by cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
R
2
, R
3
and R
4
are each independently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy or lower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl are optionally substituted by lower alkoxycarbonyl, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;
R
5
is hydrogen, fluorine, lower alkyl, aryl or substituted aryl;
R
6
is hydrogen, lower alkyl or hydroxy-lower alkyl, or
R
5
and R
6
together with the carbon atoms to which they are attached form a five or six membered saturated carbocyclic ring;
R
7
is hydrogen, fluorine or lower alkyl;
and pharmaceutically acceptable salts thereof;
with the exception of rac-3&bgr;-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b&bgr;-hexahydro-2H-pyrido[2,1-a]isoquinolin-2&bgr;-ylamine dihydrochloride and rac-3&bgr;-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b&bgr;-hexahydro-2H-pyrido[2,1-a]isoquinolin-2&agr;-ylamine dihydrochloride.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein. In this specification the term “lower” is used to mean a group consisting of one to six, preferably of one to four carbon atom(s).
The term “halogen” refers to fluorine, chlorine, bromine and iodine, preferably to chlorine.
The term “alkyl”, alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms.
The term “lower-alkyl”, alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to six carbon atoms, preferably one to four carbon atoms. This term is further exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl and the like.
The term “cycloalkyl” refers to a monovalent carbocyclic radical of three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with cyclopropyl being preferred.
The term “alkoxy” refers to the group R′—O—, wherein R′ is alkyl. The term “lower-alkoxy” refers to the group R′—O—, wherein R′ is lower-alkyl. Examples of lower-alkoxy groups are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy being especially preferred.
The term “lower alkoxycarbonyl” refers to the group R′—O—C(O)—, wherein R′ is lower alkyl.
The term “heterocyclyl” refers to a 5- or 6-membered aromatic or saturated N-heterocyclic residue, which may optionally contain a further nitrogen or oxygen atom, such as imidazolyl, pyrazolyl, thiazolyl, phenyl, pyridyl, pyrimidyl, morpholino, piperazino, piperidino or pyrrolidino, preferably pyridyl, thiazolyl or morpholino. The term “substituted heterocyclyl” refers to a heterocyclyl that is mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy, halo, cyano, azido, amino, di-lower alkyl amino or hydroxy. Preferable substituent is lower alkyl, with methyl being preferred.
The term “aryl” refers to an aromatic monovalent mono- or polycarbocyclic radical, such as phenyl or naphthyl, preferably phenyl. The term “substituted aryl” refers to an aryl that is mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy, halo, cyano, azido, amino, di-lower alkyl amino or hydroxy.
The term “heteroaryl” refers to a 5- or 6-membered, unsaturated aromatic monovalent cyclic radical containing one to three, preferably one or two, heteroatoms independently selected from nitrogen, sulfur and oxygen, with nitrogen being preferred. Examples of heteroaryl residues are pyrrolyl, pyridinyl and pyrimidinyl, with pyrrolyl and pyridinyl being preferred. The term “substituted heteroaryl” refers to a heteroalkyl that is mono-, di- or tri-substituted, independently, by halogen, amino, perfluoro-lower alkyl, lower alkyl or lower alkoxy.
The term “pharmaceutically acceptable salts” embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic

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