HK1111994A

HK1111994A - Substituted benzoquinolizines as dpp-iv inhibitors for the treatment of diabetes

Info

Publication number: HK1111994A
Application number: HK08107085.3A
Authority: HK
Inventors: 马库斯‧伯林格; 丹尼尔‧洪齐格; 贝恩德‧库恩; 贝恩德‧米夏埃尔‧勒夫勒; 法比耶纳‧里克兰; 汉斯‧彼得‧魏斯
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2004-11-30
Filing date: 2005-11-21
Publication date: 2008-08-22

Description

Substituted benzoquinolizine derivatives as DPP-IV inhibitors for the treatment of diabetes

The present invention relates to novel pyrido [2, 1-a ] isoquinoline derivatives, their preparation and their use as pharmaceutical agents.

Specifically, the present invention relates to compounds of the general formula:

wherein

R¹Selected from hydrogen or methoxy;

R²selected from:

a hydroxyl group(s),

lower alkoxy, provided that at R¹In the case of methoxy, R²Is not a methoxy group, and is not a methoxy group,

lower alkoxy which is mono-or disubstituted with:

hydroxy, lower alkoxy, benzyloxy,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

the structure of the tetrazolyl group is,

-O-(CH₂)_m-C(O)-NR⁸R⁹wherein m is 1 or 2, and R⁸And R⁹Independently selected from: hydrogen, lower alkyl or tetrazolyl, or R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclic ring which may contain a further heteroatom selected from N, O or S and which may be substituted by lower alkyl,

-O-(CH₂)_n-COOR¹⁰wherein n is 1 or 2 and R¹⁰Is hydrogen or a lower alkyl group,

-O-(CH₂)_p-NH-C(O)-OR¹¹wherein p is 1 or 2, and R¹¹Is a lower alkyl group, and is,

-O-SO₂-R¹²wherein R is¹²Is a lower alkyl group, and is,

-NR¹³R¹⁴wherein R is¹³Is hydrogen or lower alkyl, and R¹⁴Is lower alkyl or benzyl, and

-NH-CO-(CH₂)_q-R¹⁵wherein q is 1 or 2, and R¹⁵Is lower alkyl or tetrazolyl;

R³selected from:

the presence of hydrogen in the presence of hydrogen,

a hydroxyl group(s),

a lower alkoxy group,

lower alkoxy which is mono-or disubstituted with:

a hydroxyl group, a benzyloxy group,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

tetrazolyl, and

-O-SO₂-R¹²wherein R is¹²Is a lower alkyl group, and is,

R⁴is composed of

Wherein

R⁵Selected from: lower alkyl, lower hydroxyalkyl, lower haloalkyl, halogen and cycloalkyl; or

At R²Selected from the group consisting of⁵It may also be hydrogen:

-(CH₂)_m-C(O)-NR⁸R⁹，-O-(CH₂)_p-NH-C(O)-OR¹¹，-O-SO₂-R¹²，

-NR¹³R¹⁴，

-NH-CO-(CH₂)_q-R¹⁵and lower alkoxy mono-or disubstituted with a group selected from: hydroxy, benzyloxy, amino, alkylamino, dialkylamino or cyano;

R⁶selected from: hydrogen, lower alkyl, lower alkoxy, lower hydroxyalkyl, lower haloalkyl, halogen and cycloalkyl;

R⁷selected from: lower alkyl, cycloalkyl, lower hydroxyalkyl, halogen-and lower haloalkyl; and pharmaceutically acceptable salts thereof.

The enzyme dipeptidyl peptidase IV (EC.3.4.14.5, hereinafter abbreviated as DPP-IV) is involved in the regulation of several hormonal activities. In particular, DPP-IV efficiently and rapidly degrades glucagon-like peptide 1(GLP-1), which is one of the most potent stimulators of insulin production and secretion. Inhibition of DPP-IV potentiates the action of endogenous GLP-1 and results in higher plasma insulin concentrations. In patients suffering from impaired glucose tolerance (impaired glucose tolerance) and type II diabetes, higher plasma insulin concentrations will moderate the risk of hyperglycemia, thus reducing the risk of tissue damage. Therefore, DPP-IV inhibitors have been proposed as candidates for the treatment of impaired glucose tolerance and type II diabetes (e.g. Villhauer, WO 98/19998). Further relevant prior art can be found in WO 99/38501, DE 19616486, DE 19834591, WO 01/40180, WO01/55105, US 6110949, WO 00/34241 and US 6011155.

In addition, DPP IV contributes to the generation and regulation of T cell immune responses. DPP IV (also known as CD26) has a fundamental role in immunomodulation as a modulator of T cell activation molecules and chemokine function, thus proposing a role for DPP-IV in the pathophysiology of immune-mediated and autoimmune diseases (Hosano O. et al, model Rheumatology 2003, 13(3), 199- "204). Abnormal expression of DPP-IV is found in autoimmune diseases, HIV-related diseases and cancer. In general, natural substrates for DPP-IV are involved in immunomodulation (immunomodulation), psycho/neuromodulation and physiological processes (Boonecker E.; VanNoorden C.J.F., European Journal of Cell Biology 2003, 82(2), 53-73). Furthermore, a correlation was found between DPP-IV and the key nuclear protein topoisomerase alpha (Aytacu., Dang, N.H., Current Drug Targets: Immune, Endocrine and Metabolic disorders 2004, 4(1), 11-18). Therefore, DPP-IV inhibitors can be used as medicaments for the treatment of various diseases associated with DPP-IV.

We have found novel DPP-IV inhibitors which are very effective in lowering plasma glucose levels. Accordingly, the compounds of the present invention are useful in the treatment and/or prevention of diabetes, particularly non-insulin dependent diabetes mellitus, and/or impaired glucose tolerance, as well as other conditions in which amplification of the action of peptides, which are normally inactivated by DPP-IV, produces therapeutic benefit. Furthermore, the compounds of the invention can be used for the treatment and/or prophylaxis of obesity, metabolic syndrome, beta-cytoprotection, autoimmune diseases such as inflammatory bowel disease, periaxial encephalitis, folliculitis and rheumatoid arthritis, ulcerative Colitis (Colitis Ulcerosa), Crohn's disease (Morbus Crohn), psoriasis, lichen planus and/or benign prostatic hypertrophy. The compounds of the invention can also be used for the prevention of AIDS (acquired immunodeficiency syndrome) or for the prevention of metastases, in particular of the metastasis of breast and prostate cancer to the lung. Furthermore, the compounds of the invention can also be used as diuretics and for the treatment and/or prophylaxis of hypertension.

Unexpectedly, the compounds of the present invention exhibit improved therapeutic and pharmacological properties, e.g. in terms of pharmacokinetics and bioavailability, compared to other DPP-IV inhibitors known in the art.

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts per se, as well as the compounds of formula I and their pharmaceutically acceptable salts as pharmaceutically active substances, their preparation, medicaments based on the compounds of formula I and their manufacture, as well as the use of the compounds of formula I according to the invention for the control or prevention of diseases of the aforementioned kind, and correspondingly, the use of the compounds of formula I according to the invention for the preparation of corresponding medicaments.

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.

In the present specification, the term "lower" is used to indicate a group consisting of 1 to 6, preferably 1 to 4, carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred. The most preferred halogen is chlorine.

The term "alkyl", alone or in combination with other groups, means a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms, more preferably 1 to 10 carbon atoms. The term "lower alkyl" alone or in combination with other groups means a branched or straight chain monovalent alkyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. The term is further exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl, and the like. Preferred lower alkyl residues are methyl and ethyl, with methyl being particularly preferred.

The term "lower haloalkyl" refers to a lower alkyl group wherein at least one hydrogen of the lower alkyl group is substituted with a halogen atom, wherein the halogen atom is preferably fluoro or chloro, most preferably fluoro. Preferred lower haloalkyl groups are trifluoromethyl, difluoromethyl, fluoromethyl and chloromethyl, with fluoromethyl and trifluoromethyl being particularly preferred.

The term "alkoxy" refers to a R '-O-group, wherein R' is an alkyl group. The term "lower alkoxy" refers to the group R '-O-, wherein R' is lower alkyl. Examples of lower alkoxy are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy being particularly preferred.

The term "lower hydroxyalkyl" refers to lower alkyl wherein at least one hydrogen of the lower alkyl is substituted with a hydroxy group. Among them, preferred lower hydroxyalkyl groups are hydroxymethyl, 2-hydroxyethyl, 2, 3-dihydroxypropyl and 1-hydroxymethyl-2-hydroxyethyl.

The term "cycloalkyl" refers to a monovalent carbocyclic group of 3 to 6, preferably 3 to 5, carbon atoms. The term is further exemplified by groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with cyclopropyl being preferred.

The term "R⁸And R⁹Taken together with the nitrogen atom to which they are attached to form a 5 or 6 membered heterocyclic ring which may contain another heteroatom selected from N, O or S means R⁸And R⁹Form a ring together with the nitrogen atom such as pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl, piperazinyl or thiomorpholinyl, with morpholinyl and piperazinyl being particularly preferred.

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, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, salicylic acid, p-toluenesulfonic acid and the like, which salts are non-toxic to living organisms. Preferred salts with acids are formates, maleates, citrates, hydrochlorides, hydrobromides and methanesulfonates, particularly preferably hydrochlorides.

In detail, the present invention relates to compounds of the general formula:

wherein

R¹Selected from hydrogen or methoxy;

R²selected from:

a hydroxyl group(s),

lower alkoxy which is mono-or disubstituted with:

hydroxy, lower alkoxy, benzyloxy,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

the structure of the tetrazolyl group is,

-O-SO₂-R¹²wherein R is¹²Is a lower alkyl group, and is,

R³selected from:

the presence of hydrogen in the presence of hydrogen,

a hydroxyl group(s),

a lower alkoxy group,

lower alkoxy which is mono-or disubstituted with:

a hydroxyl group, an alkoxy group, a benzyloxy group,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

tetrazolyl, and

-O-SO₂-R¹²wherein R is¹²Is a lower alkyl group, and is,

R⁴is composed of

Wherein

At R²Selected from the group consisting of⁵It may also be hydrogen:

-(CH₂)_m-C(O)-NR⁸R⁹，-O-(CH₂)_p-NH-C(O)-OR¹¹，-O-SO₂-R¹²，-NR¹³R¹⁴，

R⁷selected from: lower alkyl, cycloalkyl, lower hydroxyalkyl, halogen and lower haloalkyl; and pharmaceutically acceptable salts thereof.

The invention also includes all specific stereoisomers and enantiomers of the compounds of formula I.

In one embodiment, the invention relates to compounds of formula I as defined above, wherein R is⁴Is phenyl and R²Selected from: - (CH)₂)_m-C(O)-NR⁸R⁹，-O-(CH₂)_p-NH-C(O)-OR¹¹，-O-SO₂-R¹²，-NR¹³R¹⁴，-NH-CO-(CH₂)_q-R¹⁵And lower alkoxy mono-or disubstituted with a group selected from: hydroxy, benzyloxy, amino, alkylamino, dialkylamino or cyano, of which those compounds in which R is⁴Is phenyl, and R²Is- (CH)₂)_m-C(O)-NR⁸R⁹。

Preferred compounds of the formula I as defined above are those in which

R⁴Is composed of

And wherein

R⁵Selected from: lower alkyl, lower hydroxyalkyl, lower haloalkyl, halogen and cycloalkyl;

R⁶selected from: hydrogen, lower alkyl, lower alkoxy, lower hydroxyalkyl, lower haloalkyl, halogen and cycloalkyl; and is

R⁷Selected from: lower alkyl, cycloalkyl, lower hydroxyalkyl, halogen and lower haloalkyl.

Further preferred are compounds of formula I according to the invention, wherein R is²Selected from:

a hydroxyl group(s),

lower alkoxy which is mono-or disubstituted with:

hydroxy, lower alkoxy, benzyloxy,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

the structure of the tetrazolyl group is,

-O-SO₂-R¹²wherein R is¹²Is a lower alkyl group, and is,

-NH-CO-(CH₂)_q-R¹⁵wherein q is 1 or 2, and R¹⁵Is lower alkyl or tetrazolyl; and R is³Is hydrogen, hydroxy or lower alkoxy.

More preferred are compounds of formula I of the present invention, wherein R²Selected from:

a hydroxyl group(s),

lower alkoxy which is mono-or disubstituted with:

hydroxy, benzyloxy, amino, cyano, phenyl or tetrazolyl,

-O-SO₂-R¹²wherein R is¹²Is a lower alkyl group, and is,

-NH-CO-(CH₂)_q-R¹⁵wherein q is 1 or 2, and R¹⁵Is lower alkyl or tetrazolyl.

Within this group, preference is given to compounds of the formula I in which R is²Is hydroxy or lower alkoxy mono-or disubstituted with: hydroxy, benzyloxy, amino, cyano, phenyl or tetrazolyl.

Further preferred are compounds of formula I, wherein R is²Is composed of

-O-(CH₂)_m-C(O)-NR⁸R⁹Wherein m is 1 or 2, and R⁸And R⁹Independently selected from: hydrogen, lower alkyl or tetrazolyl, or R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclic ring which may contain a further heteroatom selected from N, O or S and which may be substituted by lower alkyl, wherein those compounds of formula I are those wherein R is²is-O- (CH)₂)_m-C(O)-NR⁸R⁹Wherein m is 1 or 2, and R⁸And R⁹Independently selected from: hydrogen, lower alkyl or tetrazolyl.

Also preferred are compounds of formula I, wherein R²is-O- (CH)₂)_n-COOR¹⁰Wherein n is 1 or 2 and R¹⁰Is hydrogen or lower alkyl.

Preference is furthermore given to compounds of the formula I in which R is²is-O-SO₂-R¹²Wherein R is¹²Is a lower alkyl group.

Further preferred are compounds of formula I, wherein R is²is-NH-CO- (CH)₂)_q-R¹⁵Wherein q is 1 or 2, and R¹⁵Is lower alkyl or tetrazolyl.

Particularly preferred are compounds of formula I, wherein R²As defined above, and R³Is hydrogen.

Furthermore, preference is given to compounds of the formula I according to the invention in which R³Selected from:

a hydroxyl group(s),

a lower alkoxy group,

lower alkoxy which is mono-or disubstituted with:

a hydroxyl group, an alkoxy group, a benzyloxy group,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

tetrazolyl, and

-O-(CH₂)_m-C(O)-NR⁸R⁹wherein m is 1 or 2, and R⁸And R⁹Independently selected from: hydrogen, lower alkyl or tetrazolyl, or R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclic ring which may contain a further heteroatom selected from N, O or S and which may be substituted by lower alkyl, and

R²is hydroxy or lower alkoxy.

Within this group, preference is given to compounds of the formula I in which R is³Is hydroxy or lower alkoxy mono-or disubstituted with: hydroxy, alkoxy, benzyloxy or phenyl.

Also preferred are compounds of formula I, wherein R³is-O- (CH)₂)_m-C(O)-NR⁸R⁹Wherein m is 1 or 2, and R⁸And R⁹Independently selected from: hydrogen, lower alkyl or tetrazolyl, or R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring which may contain a further heteroatom selected from N, O or S and which may be substituted by lower alkyl.

a hydroxyl group(s),

a lower alkoxy group,

lower alkoxy which is mono-or disubstituted with:

a hydroxyl group, an alkoxy group, a benzyloxy group,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

tetrazolyl, and

and R is²Is methoxy.

Furthermore, preference is given to compounds of the formula I according to the invention in which R⁴Is composed of

R⁵Selected from: lower alkyl, lower hydroxyalkyl, lower haloalkyl, halogen and cycloalkyl; and

R⁶selected from: hydrogen, lower alkyl, lower alkoxy, lower hydroxyalkyl, lower haloalkyl, halogen and cycloalkyl, wherein R is particularly preferred⁵Is lower alkyl or lower haloalkyl, and R⁶Those which are hydrogen or lower alkyl.

Also preferred are compounds of formula I according to the invention, wherein R⁴Is composed of

And R is⁷Selected from: lower alkyl, cycloalkyl, lower hydroxyalkyl, halogen and lower haloalkyl, wherein R is particularly preferred⁷Those which are lower alkyl.

Preferred compounds of formula I are those selected from the group consisting of:

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-amino-ethoxy) -3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - {2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -ethyl } -carbamic acid tert-butyl ester,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -3- (2, 5-dimethyl-phenyl) -10-methoxy-9- [2- (1H-tetrazol-5-yl) -ethoxy ] -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -3- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propionitrile,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -methanesulfonic acid 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ester hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -ethanol hydrochloride

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -N- (1H-tetrazol-5-yl) -acetamide hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetamide hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -N-methyl-acetamide hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -N- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ] -2- (1H-tetrazol-5-yl) -acetamide hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -N9-benzyl-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinoline-2, 9-diamine hydrochloride,

(2S, 3R, 11RS) -and (2R, 3S, 11bS) -N9-benzyl-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinoline-2, 9-diamine,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -10-methoxy-9-methylamino-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinoline-2, 9-diamine hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -N- (2H-tetrazol-5-yl) -acetamide hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -methanesulfonic acid 2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ester,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -ethanol,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-benzyloxy-ethoxy) -10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-amino-ethoxy) -10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -N-methyl-acetamide,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -N, N-dimethyl-acetamide,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -acetamide,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-benzyloxy-ethoxy) -10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -ethanol,

(2R, 3S, 11bS) -and (2S, 3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

(2R, 3S, 11bS) -and (2S, 3R, 11bR) -2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -acetamide hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -1-morpholin-4-yl-ethanone hydrochloride,

(2R, 3S, 11bS) -and (2S, 3R, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

(2S, 3S, 11bS) and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol,

(2R, 3S, 11bS) -and (2S, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-benzyloxy-ethoxy) -10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -ethanol,

(2S, 3S, 11bS) -and (2R, 3R, 11bR)) -9- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propane-1, 3-diol,

(S) -3- [ (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propane-1, 2-diol,

(R) -3- [ (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propane-1, 2-diol,

(2R, 3S, 11bS) -and (2S, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -1-morpholin-4-yl-ethanone hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -1-morpholin-4-yl-ethanone hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1a ] isoquinolin-9-yloxy ] -acetamide hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-3- (4-fluoromethyl-pyridin-2-yl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid methyl ester,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine, and pharmaceutically acceptable salts thereof.

Furthermore, preferred compounds of formula I are those selected from the group consisting of:

rac- (2S, 3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine,

rac- (2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-ol,

rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -acetamide, (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereomers,

rac-2- ((2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -1-morpholin-4-yl-ethanone,

rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -1- (4-methyl-piperazin-1-yl) -ethanone, (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereomers,

rac-2- ((2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -N, N-dimethyl-acetamide,

rac-9-methoxy-8- (2-methoxy-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine, the (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereomers,

rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -ethanol, the (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereomers, and pharmaceutically acceptable salts thereof.

More preferred compounds of formula I are those selected from the group consisting of:

Particularly preferred compounds of the formula I are those selected from the group consisting of:

rac-2- ((2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -N, N-dimethyl-acetamide, and pharmaceutically acceptable salts thereof.

Compounds of formula I have three or more asymmetric carbon atoms and may exist in the form as follows: optically pure enantiomers, mixtures of diastereomers, racemates, or mixtures of diastereomeric racemates. The present invention encompasses all of these forms.

In a preferred embodiment, R¹With pyrido [2, 1a]The hydrogen in position 11b of the isoquinoline backbone is in the cis configuration, while pyrido [2, 1a ]]The amino group in position 2 of the isoquinoline backbone is in the trans configuration, i.e.

In another preferred embodiment, R¹Pyrido [2, 1a ]]The amino group at the 2-position and the hydrogen at the 11-b-position of the isoquinoline backbone are both in the cis-configuration, i.e.

It will be appreciated that the compounds of general formula (I) of the present invention may be derivatised at functional groups to give derivatives which are capable of conversion back to the parent compound in vivo.

The present invention also relates to a process for the preparation of a compound of formula I, which process comprises:

a) converting a compound of formula II:

wherein X is hydrogen or tert-butyloxycarbonyl, X₂is-OH or-NH₂，R¹And R⁴As defined above, the above-mentioned,

and R is³To hydrogen, to a compound of formula I:

wherein R is¹，R²And R⁴As defined above, and R³Is hydrogen, or alternatively,

b) reacting a compound of formula III:

wherein R is^XIs hydrogen or benzyl, and R¹To R⁴As defined above, the above-mentioned,

to a compound of formula I:

wherein R is¹To R⁴As defined above, the above-mentioned,

and optionally converting the compound of formula I into a pharmaceutically acceptable salt.

More specifically, the compounds of formula I can be prepared by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are commercially available or can be prepared by methods similar to those given below or in the examples or by methods known in the art.

The compounds of formula I of the present invention may be prepared as shown in schemes 1 and 2 below:

pyrido [2, 1-a ] of formula 5]The synthesis of isoquinoline derivatives is shown in scheme 1 and can be achieved using appropriately substituted 2-phenylethylamines of formula 1 using compounds well known in the art. Amines of formula I can be converted to carboxamides by reaction with formic acid and employing a coupling agent such as N, N '-Carbonyldiimidazole (CDI) or N, N' -dicyclohexyl-carbodiimide (DCC). The carboxamides may then be reacted with POCl₃Or with oxalyl chloride and FeCl₃Reacting to obtain the 3, 4-dihydroisoquinoline derivative of the formula 2.

At X₁In the case of Br, over a palladium (0) catalyst such as tris (dibenzylideneacetone) dipalladium (0) (Pd₂(dba)₃) The compound of formula 2 can be converted to the corresponding benzylamino derivative with the help of rac-2, 2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl (BINAP) and sodium tert-butoxide.

Subsequent reaction of 2 with 4-dimethylamino-2-butanone hydrochloride or 4-dimethylamino-3-phenyl-2-butanone hydrochloride, respectivelyTo obtain wherein R⁴Ketones of formula 3 which are hydrogen or phenyl. Wherein R is⁴The compound of formula 3, which is a substituted phenyl or pyridyl group, can be obtained by: under suitable conditions (base, oxygen scavenging) and over a palladium catalyst such as palladium acetate or tris (dibenzylideneacetone) dipalladium (0) (Pd)₂(dba)₃) With the aid of BINAP, in which R is⁴The compound of formula 3 is reacted with a suitable benzene or pyridine.

The ketones of formula 3 are then converted into amino functions by known methods. One possibility is: the keto group is converted to the oxime of formula 4 using hydroxylamine hydrochloride and sodium or ammonium acetate in a solvent such as ethanol. Oximes can be reduced to amines of formula 5, wherein X is₂Is hydroxyl or amino. For example, the hydrogenation may be carried out in the presence of a catalyst such as Raney nickel, platinum or palladium in an inert solvent such as ethanol at a temperature of about 20 to 80 ℃.

The 2 α, 3 β, 11b β isomers are usually the major products and are readily separated from the other stereoisomers by chromatography.

Separation of the mixture of enantiomers in the chiral component can be achieved by chiral phase chromatography.

Wherein R is²Compounds of formula I representing other residues than hydroxyl or amino groups may be prepared from compounds of formula 5 by subsequent side chain transformation. Such side chain transformations are, for example, the formation of ethers. The synthesis of ethers is widely described in the literature and is well known to those skilled in the art. This transformation can be carried out by employing the reaction conditions usually employed in the so-called "Mitsunobu reaction".

The present inventors have found that a phosphine such as trialkylphosphine such as tributylphosphine ((n-Bu) is used in a solvent such as Tetrahydrofuran (THF), toluene, dichloromethane, etc₃P), triphenylphosphine (Ph)₃P) and the like and coupling agents such as di-tert-butyl-azodicarboxylate, diethyl-azodicarboxylate (DEAD), diisopropyl-azodicarboxylate (DIAD) (optionally polymer-bound), tetramethyl azodicarboxylateConveniently, the compound of formula 5 or the amino-protected derivative of formula 6 (whichever is more suitable) is reacted with an alcohol HO-R under conditions such as dimethylamide^YCoupling to give a compound of formula 7 or 8, wherein X₃represents-O-R^Y。

Scheme 1

Alcohol HO-R^Y(R^YRepresents a group selected from: lower alkyl, lower hydroxyalkyl, lower cyanoalkyl, lower aminoalkyl, lower alkylaminoalkyl, lower dialkylaminoalkyl, lower alkyl substituted by phenyl (said phenyl being optionally substituted by 1 to 3 groups selected from lower alkyl, lower alkoxy, halogen or lower haloalkyl), lower alkyl substituted by tetrazolyl, - (CH)₂)_m-C(O)-NR⁸R⁹(wherein m is 1 or 2, and R⁸And R⁹Independently selected from: hydrogen, lower alkyl or tetrazolyl, or R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclic ring which may contain a further heteroatom selected from N, O or S and which may be substituted by lower alkyl-₂)_n-COOR¹⁰(wherein n is 1 or 2 and R¹⁰Is hydrogen or lower alkyl), or- (CH)₂)_p-NH-C(O)-OR¹¹(wherein p is 1 or 2, and R¹¹Lower alkyl) are commercially available or can be obtained by methods described in the literature references or by methods well known in the art.

An amino-protected derivative of the compound of formula 5, such as a tert-butyloxycarbonyl (Boc) derivative 6, can be easily prepared by known methods. Further preferred amino protecting groups are benzyloxycarbonyl (Z) and 9-fluorenylmethoxycarbonyl (Fmoc). Deprotection may be carried out by methods known in the art, for example, the Boc group may be cleaved by employing acidic conditions such as hydrochloric acid in a solvent such as dioxane or THF.

Yet another side chain transformation is: in the presence of a base such as Hunig's base (N, N-diisopropylethylamine, DIPEA), wherein X₂Reaction of a compound of formula 6, which is-OH, with an alkylsulfonyl chloride to give a compound of formula 8, wherein X is₃is-O-SO₂-R¹²Wherein R is¹²Is a lower alkyl group.

Another side chain transformation is: through which X₂is-NH₂With a suitable carboxylic acid to give a compound of formula 8, wherein X₃is-NH-CO- (CH)₂)_q-R¹⁵Wherein q is 1 or 2, and R¹⁵Is lower alkyl or tetrazolyl. This reaction can be carried out under basic conditions, for example by using a base such as triethylamine in an inert solvent such as dichloromethane with the aid of a reagent for activating the carboxyl group such as bis (2-oxo-3-oxazolidinyl) phosphonium chloride (BOP-Cl). Yet another side chain formation is: wherein X₂is-NH₂To a compound of formula 6 to give a compound of formula 8, wherein X₃is-NR¹³R¹⁴Wherein R is¹³Is hydrogen or lower alkyl, and R¹⁴Is lower alkyl or benzyl.

Wherein R is³The synthesis of compounds of formula I according to the invention, which are groups other than hydrogen, is shown in scheme 2.

Scheme 2

Y is C or N, R' represents a substituent R as defined above⁵，R⁶And R⁷，X₄Is hydrogen or benzyl and R-X is a suitably substituted alkyl halide, such as methyl bromoacetate, 2-bromoethyl-benzyl ether or 2-chloroethyl-methyl ether. These alkyl halides are commercially available or can be prepared by known methods.

In analogy to the procedure as described in scheme 1, ketones of formula 13 or formula 16 can be converted into amines of formula 15.

Alternatively, the reaction of ketones of formula 16 with O-benzylhydroxylamine and sodium or ammonium acetate gives O-benzyl-oxime derivatives of formula 17. The compound of formula 17 is then reacted with a suitable alkyl halide and a strong base such as potassium tert-butoxide in an inert solvent such as Dimethylformamide (DMF) to give the 8-RO-substituted O-benzyl oxime derivative of formula 18 wherein RO represents the group R as defined above³Or wherein RO can be converted into the group R by side chain transformation^*O, radical R^*O corresponds to a radical R as defined above³. Finally, the O-benzyl oxime derivatives of formula 18 can be reduced, for example by catalytic hydrogenation, to amines of formula 19, wherein Y is C or N and R' represents a substituent R as defined above⁵，R⁶And R⁷And RO or R^*O corresponds to R as defined above³. For example, the hydrogenation may be carried out in the presence of a catalyst such as Raney nickel, platinum such as palladium, in an inert solvent such as ethanol at a temperature of about 20 to 80 ℃.

Separation of diastereomers can generally be carried out by chromatography. Separation of the mixture of enantiomers in the chiral component can be achieved by chiral phase chromatography.

The invention also relates to compounds of formula I as defined above, prepared according to the process as defined above.

As mentioned above, the compounds of formula I according to the invention can be used as medicaments for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, in particular non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, ulcerative colitis, crohn's disease, obesity, and/or metabolic syndrome or beta-cytoprotection, preferably non-insulin dependent diabetes mellitus and/or impaired glucose tolerance. Furthermore, the compounds of the invention can be used as diuretics or for the treatment and/or prophylaxis of hypertension.

The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.

Furthermore, the present invention relates to compounds as defined above for use as therapeutically active substances, in particular as therapeutically active substances for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, in particular non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, ulcerative colitis, crohn's disease, obesity, and/or metabolic syndrome or beta-cytoprotection, preferably for use as therapeutically active substances for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus and/or impaired glucose tolerance. Furthermore, the present invention relates to compounds as defined above for use as a diuretic or as therapeutically active substances for the treatment and/or prophylaxis of hypertension.

In another embodiment, the present invention relates to a method for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, in particular non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, ulcerative colitis, crohn's disease, obesity, and/or metabolic syndrome or beta-cell protection, preferably for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus and/or impaired glucose tolerance, which method comprises administering a compound as defined above to a human being or animal. Furthermore, the present invention relates to a method of treatment and/or prevention as defined above, wherein said disease is hypertension or a disease wherein a diuretic has a beneficial effect.

The invention also relates to the use of a compound as defined above for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, in particular non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, ulcerative colitis, crohn's disease, obesity, and/or metabolic syndrome or beta-cell protection, preferably for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus and/or impaired glucose tolerance. Furthermore, the invention relates to the use as defined above, wherein the disease is hypertension or to the use as a diuretic.

Furthermore, the present invention relates to the use of a compound as defined above for the preparation of a medicament for the treatment and/or prevention of diseases which are associated with DPP-IV, such as diabetes, in particular non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, ulcerative colitis, crohn's disease, obesity, and/or metabolic syndrome or beta-cytoprotection, preferably for the treatment and/or prevention of non-insulin dependent diabetes mellitus and/or impaired glucose tolerance. These medicaments comprise a compound as defined above. Furthermore, the invention relates to the use as defined above, wherein the disease is hypertension, or for the preparation of a diuretic.

With regard to the methods and uses as defined above, the following diseases are related to preferred embodiments: diabetes, in particular non-insulin dependent diabetes mellitus, impaired glucose tolerance, obesity, and/or metabolic syndrome or beta-cell protection, preferably non-insulin dependent diabetes mellitus and/or impaired glucose tolerance.

The following assays were performed to determine the activity of the compounds of formula I.

DPP-IV inhibitor activity is tested with native human DPP-IV derived from human plasma pools or with recombinant human DPP-IV. Human citrate plasma from different donors was pooled, filtered through a 0.2 micron membrane under sterile conditions, and 1ml aliquots were shock frozen and stored at-120 ℃ until use. In a total test volume of 100. mu.l, 5 to 10. mu.l of human plasma were used in the colorimetric DPP-IV assay and 1.0. mu.l of human plasma was used as the enzyme source in the fluorometric assay. The cDNA of the human DPP-IV sequence, limited to amino acids 31-to 766 of the N-terminal and transmembrane domains, was cloned into Pichia pastoris. Human DPP-IV is expressed and purified from the culture medium using conventional column chromatography, including size exclusion and anion and cation chromatography. The final enzyme preparation was > 95% pure by Coomassie blue SDS-PAGE. 20ng of recombinant human DPP-IV was used in the colorimetric DPP-IV assay and 2ng of recombinant human DPP-IV was used as enzyme source in the fluorescence assay, with a total assay volume of 100. mu.l.

In fluorescence assays, Ala-Pro-7-acylamino was used-4-trifluoromethylcoumarin (Calbiochem No 125510) as substrate. 20mM of 10% DMF/H₂Stock solutions in O were stored at-20 ℃ until use. In IC₅₀In the assay, a final substrate concentration of 50. mu.M was used. In the determination of kinetic parameters such as K_m、V_max、K_iThe substrate concentration varied between 10. mu.M and 500. mu.M in the assay of (1).

In the colorimetric assay, H-Ala-Pro-pNA. HCl (Bachem L-1115) was used as a substrate. 10mM of 10% MeOH/H₂Stock solutions in O were stored at-20 ℃ until use. In IC₅₀In the assay, a final substrate concentration of 200. mu.M was used. In the determination of kinetic parameters such as K_m、V_max、K_iThe substrate concentration varied between 100. mu.M and 2000. mu.M in the assay of (1).

Fluorescence was measured every 15 seconds using a Perkin Elmer Luminescence Spectrometer LS 50B at an excitation wavelength of 400nm and an emission wavelength of 505nm for 10-30 minutes in succession. The initial velocity constant is calculated by best fit linear regression.

The absorbance of pNA released from the colorimetric substrate was measured at 405nm using a Packard SpectraCount, every 2 minutes for a total of 30 to 120 minutes. The initial velocity constant is calculated by best fit linear regression.

DPP-IV activity assays were performed in 96-well plates at 37 ℃ in a total assay volume of 100. mu.l. The assay buffer consisted of 50mM Tris/HCl pH7.8 and 100mM NaCl containing 0.1mg/ml BSA. Test compounds were dissolved in 100% DMSO, 10% DMSO/H₂O is diluted to the desired concentration. The final DMSO concentration in the assay was 1% (v/v). At this concentration, DMSO inactivated the enzyme < 5%. The compounds and enzymes were either preincubated (10 min at 37 ℃) or not. The substrate was added and immediately mixed to start the enzymatic reaction.

Test Compound IC₅₀Is determined by calculation using a non-linear best fit regression of the DPP-IV inhibition for at least 5 different compound concentrations. The kinetic parameters of the enzymatic reaction are at least 5 differentAnd at least 5 different concentrations of test compound.

As shown in the following table, the compounds of the present invention exhibited IC₅₀The value is 0.1nM to 10. mu.M, more preferably 0.1-100 nM.

Examples	IC₅₀[μM]
Examples	IC₅₀[μM]	8	0.0001
13	0.0011	8	0.0001
13	0.0011	48	0.0003

The compounds of formula I and/or their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They may be administered, for example, orally in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions; rectal administration, such as in the form of suppositories; parenteral administration, e.g. in the form of injections or infusions; or topically, such as in the form of an ointment, cream, or oil. Oral administration is preferred.

Pharmaceutical preparations can be prepared in a manner familiar to the skilled worker by bringing the compounds of the formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, nontoxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, customary pharmaceutical auxiliaries.

Suitable support materials are not only inorganic support materials but also organic support materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active ingredient, soft gelatine capsules may not require a carrier). Suitable carrier materials for the preparation of solutions or syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical formulations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

The use of customary stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavoring agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants is conceivable as pharmaceutical auxiliary agents.

The dosage of the compounds of the formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients, a daily dosage of about 1 to 1000mg, in particular about 1 to 100mg, is contemplated. Depending on the severity of the disease and the precise pharmacokinetic profile, the compounds may be administered in 1 or several daily dosage units, for example in 1 to 3 dosage units.

The pharmaceutical preparations generally contain from about 1 to 500mg, preferably from 1 to 100mg, of a compound of formula I.

The following examples serve to illustrate the invention in more detail. However, they are not intended to limit the scope of the present invention in any way.

Example (b):

example 1

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-amino-ethoxy) -3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

a) (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one

Palladium acetate (0.41g), sodium tert-butoxide (5.4g) and rac-9-benzyloxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]A mixture of isoquinolin-2-ones (CAS 68360-33-8; 6.18g) was dried under high vacuum at 80 ℃ and flushed with argon three times. Degassed tetrahydrofuran (65ml) was added at rt under argon. The reaction mixture was stirred at room temperature for 10 minutes, cooled, and tri-tert-butylphosphine (0.51g) and 1-bromo-2, 5-dimethylbenzene (4.3g) were added simultaneously with a syringe. The reaction mixture was stirred at 0 ℃ for 1h under argon and at ambient temperature for another 3 h. The crude reaction mixture was poured onto ice/water and washed with CH₂Cl₂And (4) extracting. The organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, AcOEt/heptane, 3/2) to give (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] -pyridine]Isoquinolin-2-one (1.9g) as a white solid.

MS：442.4(M+H)⁺

b) (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinoline-2-one oxime

A suspension of (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (218mg), hydroxylamine hydrochloride (100mg) and sodium acetate (100mg) in ethanol (10ml) was stirred at room temperature for 4 h. The mixture was evaporated and the residue crystallized from methanol/water to give (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (186mg) as a white solid.

MS：457.6(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol

(3S, 11bS) -and (3R, 11bR) -9-benzyloxy-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] are reacted at room temperature under an atmosphere of H2]Isoquinoline-2-one oxime (100mg), Raney Nickel (500mg) and 1ml NH₄A suspension of OH in 5ml of methanol and 5ml of THF is stirred for 18 h. The reaction mixture was filtered, evaporated and chromatographed (silica gel, AcOEt/heptane, 1/1) to give a white solid (32 mg).

MS：353.0(M+H)⁺

d) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - {2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -ethyl } -carbamic acid tert-butyl ester

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol (48mg), triphenylphosphine (66mg), di-tert-butyl-azodicarboxylate (62mg) and Boc-ethanolamine (50mg) in 4ml THF were stirred at room temperature for 18H. The reaction mixture was concentrated and chromatographed (silica gel, ethyl acetate/heptane, 1/1) to give the product (42 mg).

MS：496.4(M+H)⁺

e) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-amino-ethoxy) -3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - {2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] -in 1ml TFA]Isoquinolin-9-yloxy]-Ethyl } -carbamic acid tert-butyl ester (36mg) was stirred at 0 ℃ for 1h, then evaporated and chromatographed (silica gel, CH)₂Cl₂/MeOH/NH₄OH, 10/1/0.1) to afford the title compound as a white solid (24 mg).

MS：396.3(M+H)⁺

Example 2

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -3- (2, 5-dimethyl-phenyl) -10-methoxy-9- [2- (1H-tetrazol-5-yl) -ethoxy ] -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine hydrochloride

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [3- (2, 5-dimethyl-phenyl) -9-hydroxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

Reacting (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-9-ol (1.5g) and di-tert-butyl-dicarbonate (1.11g) in 50ml CH₂Cl₂The solution in (a) was stirred at room temperature for 18h, evaporated and chromatographed (silica gel, ethyl acetate (AcOEt)/heptane, 1/1) to give the product as a yellow solid (1.5 g).

MS：453.3(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - {3- (2, 5-dimethyl-phenyl) -10-methoxy-9- [2- (1H-tetrazol-5-yl) -ethoxy ] -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl } -carbamic acid tert-butyl ester

To a solution of (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [3- (2, 5-dimethyl-phenyl) -9-hydroxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (113mg) in 10ml THF was added 5- (2-chloro-ethyl) -1H-tetrazole (40mg) and sodium tert-butoxide (29 mg). During 22h, the reaction mixture was refluxed, diluted with AcOEt, washed with water and brine. The aqueous layer was extracted with AcOEt, the organic extracts were dried over magnesium sulfate, evaporated and chromatographed (silica gel, AcOEt/MeOH). Precipitation from methanol/AcOEt gave the product as a brown solid (45 mg).

MS：549.5(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -3- (2, 5-dimethyl-phenyl) -10-methoxy-9- [2- (1H-tetrazol-5-yl) -ethoxy ] -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine; hydrochloride salt

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - {3- (2, 5-dimethyl-phenyl) -10-methoxy-9- [2- (1H-tetrazol-5-yl) -ethoxy ] -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl } -carbamic acid tert-butyl ester (45mg) in 3ml dioxane and 1ml 4M HCl/dioxane were stirred at room temperature for 4 days, precipitated with diethyl ether and filtered to give the title compound as a white solid (18 mg).

MS：449.1(M+H)⁺

Example 3

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -3- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propionitrile

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [9- (2-bromo-ethoxy) -3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

Mixing (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [3- (2, 5-dimethyl-phenyl) -9-hydroxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-2-yl]Suspension of tert-butyl-carbamate (100mg) in 1, 2-dibromo-ethane (1ml) and NaOH 1M (2ml) with several Bu₄N⁺Br^-The crystals were stirred vigorously at 60 ℃ for 36 h. The reaction mixture was cooled, diluted with AcOEt, washed with water and brine. The aqueous layer was extracted with AcOEt, the organic extracts were dried over magnesium sulfate, evaporated and chromatographed (silica gel, AcOEt/MeOH) to give 84mg as a white solid.

MS：559.5(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [9- (2-cyano-ethoxy) -3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

To a solution of (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-bromo-ethoxy) -3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (100mg) in 5ml DMF under argon and ice cooling was added NaCN (23mg) and tetrakis (triphenylphosphine) palladium (10 mg). The reaction mixture was cooled, poured onto 1M NaOH/ice, and extracted with AcOEt. The organic extracts were washed with water and brine, dried over magnesium sulfate, evaporated and chromatographed (silica gel, AcOEt/heptane) to give 54 mg.

MS：506.5(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -3- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propionitrile

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [9- (2-cyano-ethoxy) -3- (2, 5-diMethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a]Isoquinolin-2-yl]-carbamic acid tert-butyl ester (80mg) was prepared according to a similar method to that described in example 2c, but followed by basic workup and chromatography (silica gel, CH)₂Cl₂/MeOH/NH₄OH, 10/1/0.1) to give the product as a white solid (14 mg).

MS：406.5(M+H)⁺

Example 4

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -methanesulfonic acid 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ester; hydrochloride salt

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -methanesulfonic acid 2-tert-butoxycarbonylamino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ester

To a solution of (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [3- (2, 5-dimethyl-phenyl) -9-hydroxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (200mg) in 5ml THF under ice-cooling was added Hunig' S base (0.51ml) and methanesulfonyl chloride (0.078ml) successively. The reaction mixture was stirred at 0 ℃ for 1h, held at 4 ℃ for 18h, diluted with AcOEt and washed with brine. The aqueous layer was extracted with AcOEt, the combined organic extracts were dried over magnesium sulfate, evaporated and chromatographed (silica gel, AcOEt/MeOH). Precipitation from AcOEt/heptane gave the product as a white solid (217 mg).

MS：531.4(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -methanesulfonic acid 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ester; hydrochloride salt

Following the procedure described in example 2c, (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ methanesulfonic acid 2-tert-butoxycarbonylamino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ester (210mg) were converted to the title compound as a white solid (70 mg).

MS：431.4(M+H)⁺

Example 5

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [9- (2-benzyloxy-ethoxy) -3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

In analogy to example 1d, (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [3- (2, 5-dimethyl-phenyl) -9-hydroxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (144mg) were converted into the title compound to yield 135mg of a white solid.

MS：587.6(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -ethanol, hydrochloride

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [9- (2-benzyloxy-ethoxy) -3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] in 10ml MeOH and 2ml 4M HCl/dioxane]Isoquinolin-2-yl]Tert-butyl-carbamate (110mg) was hydrogenated with Pd/C10% followed by chromatography (silica gel, CH)₂Cl₂/MeOH/NH₄OH, 10/1/0.1) provided a solid which was treated with 4M HCl/dioxane to give the title compound as a white salt (15 mg).

MS：397.4(M+H)⁺

Example 6

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid; hydrochloride salt

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-tert-Butoxycarbonylamino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid methyl ester

To a solution of (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [3- (2, 5-dimethyl-phenyl) -9-hydroxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (110mg) in 1ml THF at 0 deg.C were added tBuONa (28mg) and methyl bromoacetate (0.030 ml). The reaction mixture was stirred at 0 ℃ for 1h, at room temperature for 2h, diluted with AcOEt and washed with brine. The aqueous layer was extracted with AcOEt and the organic extracts were dried over magnesium sulphate, evaporated and chromatographed (silica gel, AcOEt/heptane) to give (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-tert-butoxycarbonylamino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid methyl ester as a yellow solid (100 mg).

MS：525.3(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-tert-Butoxycarbonylamino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-tert-Butoxycarbonylamino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H pyrido [2, 1a ] isoquinolin-9-yloxy ] -acetic acid methyl ester (380mg) were saponified with lithium hydroxide (125mg) in 5ml THF/1ml water at room temperature and treated acidic to give the title compound as an oil (153 mg).

MS：511.3(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid hydrochloride

An analogous procedure to that described in example 2c, but using (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-tert-butoxycarbonylamino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid (17mg) and crystallizing (AcOEt/tBuOMe) gave the title compound as a white solid (18 mg).

MS：411.3(M+H)⁺

Example 7

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -N- (1H-tetrazol-5-yl) -acetamide hydrochloride

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - {3- (2, 5-dimethyl-phenyl) -10-methoxy-9- [ (1H-tetrazol-5-ylcarbamoyl) -methoxy ] -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl } -carbamic acid tert-butyl ester

A solution of (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-tert-butoxycarbonylamino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid (153mg), Hunig' S base (0.17ml), EDCI (96mg) and aminotetrazole (85mg) in 5ml acetonitrile was stirred at ambient temperature for 18H. The reaction mixture was diluted with AcOEt, washed with water and brine. The aqueous layer was extracted with AcOEt and the organic extracts were dried over magnesium sulphate, evaporated and chromatographed (silica gel, AcOEt/heptane) to give (2S, 3S, 11bS) -and (2R, 3R, 11bR) - {3- (2, 5-dimethyl-phenyl) -10-methoxy-9- [ (1H-tetrazol-5-ylcarbamoyl) -methoxy ] -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl } -carbamic acid tert-butyl ester as a yellow oil (32 mg).

MS：578.3(M+H)⁺

b) (2S, 3S, 11bS) and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -N- (1H-tetrazol-5-yl) -acetamide hydrochloride

The compound was prepared in analogy to example 2c, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - {3- (2, 5-dimethyl-phenyl) -10-methoxy-9- [ (1H-tetrazol-5-ylcarbamoyl) -methoxy ] -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl } -carbamic acid tert-butyl ester (32mg) to give the title compound as white solid (30 mg).

MS：478.5(M+H)⁺

Example 8

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetamide, hydrochloride

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-carbamoylmethoxy-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

Will be in 1ml NH₃(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-tert-Butoxycarbonylamino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] in MeOH]Isoquinolin-9-yloxy]Methyl acetate (50mg) was stirred at room temperature for 20h, evaporated and chromatographed (silica gel, AcOEt/heptane, 1/1) to give the product as a yellow oil (35 mg).

MS：510.8(M+H)⁺

b) (2S, 3S, 11bS) and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetamide hydrochloride

Following the procedure described in example 2c, (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetamide hydrochloride was obtained after crystallization (AcOEt/diethyl ether) as a white solid (28 mg).

MS：410.6(M+H)⁺

Example 9

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -N-methyl-acetamide; hydrochloride salt

In analogy to examples 8a and 8b, the title compound was obtained as white solid (40 mg).

MS：424.5(M+H)⁺

Example 10

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -N- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ] -2- (1H-tetrazol-5-yl) -acetamide hydrochloride

a) N- [2- (3-bromo-4-methoxy-phenyl) -ethyl ] -carboxamide

To a solution of 1, 1' -carbonyl-diimidazole (7.27g) in THF (146ml) was added dropwise formic acid (1.7ml) in THF (44 ml). The reaction mixture was stirred at room temperature for 30min, after which 10.32g of 2- (3-bromo-4-methoxy-phenyl) -ethylamine (J.Med.chem.1994, 37, 4317-4328) in THF (140ml) were added dropwise to the mixture over 40 min. The solution was stirred for 18 h. AcOEt was added and the mixture was washed with 1N HCl and brine. The organic layer was washed with MgSO₄Drying, filtering, and concentrating. To obtain N- [2- (3-bromo-4-methoxy-phenyl) -ethyl]Formamide as a white solid (9.42 g).

MS：257.8/259.8(M+H)⁺

b) 6-bromo-7-methoxy-3, 4-dihydro-isoquinoline

To N- [2- (3-bromo-4-methoxy-phenyl) -ethyl]Formamide (9.00g) in CH₂Cl₂To the solution in (350ml), oxalyl chloride (3.25ml) was added dropwise, and the reaction mixture was stirred at room temperature for 40min, then cooled to-20 ℃. At this temperature, FeCl was added in one portion₃(6.79 g). The mixture was slowly warmed to room temperature and stirred during 18 h. 1N aqueous HCl (0.7l) was added to quench the reaction. The mixture was stirred well at room temperature for 1h and the layers were separated. The organic layer was washed with brine, over MgSO₄Drying, filtering and evaporating. The residue was taken up in MeOH-concentrated H₂SO₄(19: 1, 248ml) was slurried and the mixture heated to reflux for 2 h. The mixture was cooled and the volatiles were evaporated under vacuum. Water and AcOEt were added. The organic layer was washed twice with 1N HCl. The combined aqueous layers were basified to pH 11. The product is treated with CH₂Cl₂And (4) extracting. The organic layer was washed with brine, over MgSO₄Dried, filtered, and evaporated. The resulting oil was chromatographed (silica gel, AcOEt) to give 6-bromo-7-methoxy-3, 4-dihydro-isoquinoline (5.29 g).

MS：239.1/241.0(M+H)⁺

c) Benzyl- (7-methoxy-3, 4-dihydro-isoquinolin-6-yl) -amine

To a solution of 6-bromo-7-methoxy-3, 4-dihydro-isoquinoline (4.44g) in 106ml of toluene was added benzylamine (2.4ml), tris (benzylideneacetone) dipalladium (0) (0.071g), rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (0.132g) and sodium tert-butoxide (2.49 g). The mixture was heated at 100 ℃ for 1.4h under argon and cooled. Tert-butyl methyl ether and water were added. The aqueous layer was extracted with tert-butyl methyl ether. The organic layer was successively washed with water and NaHCO₃And washed with water, over MgSO₄Dried, filtered, and concentrated to give an orange oil (4.93 g).

MS：267.2(M+H)⁺

d) (3R, 11bS) -and (3S, 11bR) -9-benzylamino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one

Benzyl- (7-methoxy-3, 4-dihydro-isoquinolin-6-yl) -amine (454mg) and 4- (dimethylamino) -2-butanone hydrochloride (387mg) in H₂A solution in O/THF 3: 4(7ml) was stirred at room temperature for 1 day. Ethyl acetate (AcOEt) was added and the mixture was washed with water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed successively with water and MgSO₄Dried, filtered, and concentrated. Chromatography (silica gel, AcOEt) gave an orange solid (428 mg).

209mg of the above-obtained intermediate was dissolved in toluene (10ml) under argon. After addition of 2-bromo-4-methyl-pyridine (127mg), tris (dibenzylideneacetone) dipalladium (0) (2.5mg), rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (4.4mg) and sodium tert-butoxide (84mg), the mixture was heated at 83 ℃ for 4 h. The mixture was poured onto ice/water and extracted with tert-butyl methyl ether. The aqueous layer was back-extracted with tert-butyl methyl ether. The combined organic layers were successively washed with water and NaHCO₃And washed with water, over MgSO₄Dried, filtered, and concentrated. Chromatography (silica gel, AcOEt/MeOH, 19/1) gave an orange oil (16 mg).

MS：428.5(M+H)⁺

e) (3R, 11bS) -and (3S, 11bR) - (Z or E) -9-benzylamino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime

To (3R, 11bS) -and (3S, 11bR) -9-benzylamino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]To a suspension of isoquinolin-2-one (0.4338g) in 20ml EtOH was added anhydrous sodium acetate (0.0916g) and hydroxylamine hydrochloride (0.0776 g). Will be mixed withThe mixture was stirred at room temperature for 17 h. 13ml of water and 13ml of NaHCO are then added₃And (4) saturated solution. The solvent was partially evaporated. The precipitated solid was filtered off and washed with water and heptane. To give (3R, 11bS) -and (3S, 11bR) - (Z or E) -9-benzylamino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]Isoquinoline-2-one oxime as a yellow solid (0.45 g).

MS：443.5(M+H)⁺

f) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -N9-benzyl-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinoline-2, 9-diamine hydrochloride and (2S, 3R, 11RS) -and (2R, 3S, 11bS) -N9-benzyl-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinoline-2, 9-diamine.

To a suspension of raney nickel (0.65g) in 6.5ml EtOH and 6.5ml dioxane were added (3R, 11bS) -and (3S, 11bR) - (9-benzylamino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] -c]Isoquinoline-2-one oxime (0.17g) and concentrated ammonium hydroxide solution (0.65 ml). Mixing the mixture in H₂Stir at rt for 22 h. The catalyst was filtered over dicalite and the filtrate was evaporated. The yellow solid obtained is chromatographed (silica gel, CH)₂Cl₂/MeOH/NH₄OH, 9/1/0.05) to give two racemic compounds, (2S, 3S, 11bS) -and (2R, 3R, 11bR) -N9-benzyl-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] respectively]Isoquinoline-2, 9-diamine (30mg) and (2S, 3R, 11RS) -and (2R, 3S, 11bS) -N9-benzyl-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] -2]Isoquinoline-2, 9-diamine (152 mg). Further treatment of the 2, 3-trans-isomer with 4M HCl/dioxane provided the salt as a yellow solid (0.15 g).

MS：429.6(M+H)⁺

g) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - ([ 9-benzylamino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

To (2S, 3S, 11bS) -and (2R, 3R, 11bR) -N9-benzyl-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinoline-2, 9-diamine (250mg) in 2.5ml CH₂Cl₂Adding Boc into the solution₂O (128 mg). The reaction mixture was stirred at room temperature for 2h, evaporated and chromatographed (SPE Isolute Flash NH)₂AcOEt/heptane, 2/1) to give the product as a white solid (210 mg).

MS：529.3(M+H)⁺

h) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-benzylamino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] -are reacted under hydrogen at room temperature]Isoquinolin-2-yl]-tert-butyl carbamate (0.1962g) and palladium on charcoal (10% Pd, 0.325g) in 6ml MeOH and 4ml CH₂Cl₂The suspension in (1) was stirred for 22 h. The mixture was filtered over dicalite under argon, the filtrate was evaporated and chromatographed (silica gel, AcOEt/MeOH, 4/1) to give (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] -2]Isoquinolin-2-yl]-carbamic acid tert-butyl ester (66 mg).

MS：439.4(M+H)⁺

i) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -N- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ] -2- (1H-tetrazol-5-yl) -acetamide hydrochloride

The reaction was carried out at 0 deg.C (2S, 3S,11bS) -and (2R, 3R, 11bR) - [ 9-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) 1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-2-yl]To a solution of tert-butyl carbamate (17mg), 1H-tetrazole-5-acetic acid (6mg) and triethylamine (0.013ml) in dichloromethane (1ml) was added bis (2-oxo-3-oxazolidinyl) phosphonium chloride (12 mg). After 36h at room temperature, the solvent was evaporated. HPLC (RP-8(Lichroprep, 40-63 μm, Merck), H₂O/MeCN) provided a white solid by evaporation.

This residue (31mg) was dissolved in 3ml dioxane and treated with 4 MHCl/dioxane at room temperature during 18 h. The reaction mixture was evaporated and purified by HPLC (Combi HT SBC18, 50mm, 5mm, H)₂O/NEt₃/MeCN). The residue was lyophilized and treated with 4M HCl/dioxane to provide (2S, 3S, 11bS) -and (2R, 3R, 11bR) -N- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] -c]Isoquinolin-9-yl]-2- (2H-tetrazol-5-yl) -acetamide hydrochloride as a white solid (4 mg).

MS：449.2(M+H)⁺

Example 11

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -10-methoxy-9-methylamino-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinoline-2, 9-diamine hydrochloride

Following the procedure described in example 2c, (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 10-methoxy-9-methylamino-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (17mg) obtained as a by-product in example 10H were treated to give the title compound as a white solid (9 mg).

MS：353.4(M+H)⁺

Example 12

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid, hydrochloride salt

a) (3R, 11bS) -and (3S, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one

The compound was synthesized from rac-9-benzyloxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (CAS 68360-33-8; 30g) and 2-bromo-4-methylpyridine according to the procedure described in example 1a to give a yellow solid (9.9 g).

MS：429.6(M+H)⁺

b) (3R, 11bS) -and (3S, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime

(3R, 11bS) -and (3S, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (8.2g) were treated under the same conditions as described in example 1b to give the title compound as a white solid (8.59 g).

MS：444.0(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

(3R, 11bS) -and (3S, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (2.55g) were treated under the same conditions as described in example 1c to give the title compound as a foam (1.08 g).

MS：430.4(M+H)⁺

d) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

Using the procedure described for example 2a, (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine (1.08g) were converted to the title compound as a white solid (520 mg).

MS：530.4(M+H)⁺

e) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-hydroxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

A suspension of (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (440mg) and palladium on activated carbon (10% Pd, 0.060g) in 15ml MeOH and 15ml AcOEt was stirred at room temperature under hydrogen for 3H. The mixture was filtered over dicalite under argon and the filtrate was evaporated to give (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-hydroxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester as a white solid (327 mg).

MS：440.4(M+H)⁺

f) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid hydrochloride

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid hydrochloride were prepared according to the procedure described in examples 6a to 6c, but starting with (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-hydroxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester. The product obtained was a white solid (38 mg).

MS(ISN)：396.2(M-H)^-

Example 13

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -N- (2H-tetrazol-5-yl) -acetamide hydrochloride

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -10-methoxy-3- (4-methyl-pyridin-2-yl) -9- [ (2H-tetrazol-5-ylcarbamoyl) -methoxy ] -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl } -carbamic acid tert-butyl ester

The procedure described in example 7a, but using (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-tert-butoxycarbonylamino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid (160mg) gave (2S, 3S, 11bS) -and (2R, 3R, 11bR) -10-methoxy-3- (4-methyl-pyridin-2-yl) -9- [ (2H-tetrazol-5-ylcarbamoyl) -methoxy ] -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl } -carbamic acid tert-butyl ester as a yellow solid (37 mg).

MS：565.5(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -N- (2H-tetrazol-5-yl) -acetamide hydrochloride

The title compound was prepared according to the procedure described in example 7b to give a yellow solid (29 mg).

MS：465.4(M+H)⁺

Example 14

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -methanesulfonic acid 2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ester

a) (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one

A suspension of 6-benzyloxy-7-methoxy-3, 4-dihydro-isoquinoline (CAS 68360-22-5, 4g) and phenethylammonium-. beta. -acetyl-N, N, N-trimethyl-iodide (CAS 31034-99-8; 7.48g) in 100ml ethanol and 0.75ml NaOH 1M was heated under reflux during 2 h. On cooling, the product precipitated as a yellow solid (3.07 g).

MS：414.2(M+H)⁺

b) (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime

Treatment of (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (358mg) as described in example 1b provided the title compound as a white solid (358 mg).

MS：429.6(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine and (2R, 3S, 11bS) -and (2S, 3R, 11bR) -9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

Reacting (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]Isoquinoline-2-one oxime (350mg) was hydrogenated under the same conditions as described in example 1 c. Two diastereoisomers by chromatography (silica gel, CH)₂Cl₂/MeOH/NH₄OH, 9/1/0.05) separation, (2S, 3S, 11bS) -and (2R,3R, 11bR) -9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-2-ylamine (171mg, 50%, R)_f0.25) and (2R, 3S, 11bS) -and (2S, 3R, 11bR) -9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-2-ylamine (27mg, 8%, R)_f＝0.5)。

MS：415.5(M+H)⁺

d) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine (200mg) were converted to the title compound using the procedure described in example 2 a. To give (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester as a white solid (243 mg).

MS：515.5(M+H)⁺

e) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester

Starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (2.6g) and using the same procedure as compound 2c, the title compound was obtained as a yellow solid (1.58 g).

MS：425.5(M+H)⁺

f) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -methanesulfonic acid 2-tert-butoxycarbonylamino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ester

To (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] under ice-cooling]To a solution of isoquinolin-2-yl) -carbamic acid tert-butyl ester (130mg) in 5ml THF was added potassium tert-butoxide (51mg) and methanesulfonyl chloride (0.031ml) successively. The reaction mixture was stirred at reflux for 18h with CH₂Cl₂Diluting with NaHCO₃And a brine wash. The aqueous layer is replaced by CH₂Cl₂The organic extracts were dried over magnesium sulfate, evaporated and precipitated from tBuOMe to give the product as a yellow solid (148 mg).

MS：503.4(M+H)⁺

g) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -methanesulfonic acid 2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yl ester

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -methanesulfonic acid 2-tert-butoxycarbonyl-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] in 2ml 4M HCl/dioxane]Isoquinolin-9-yl ester (140mg) was stirred at room temperature for 2 days. Evaporating the mixture with CH₂Cl₂And 1M NaOH dilution. The aqueous layer is replaced by CH₂Cl₂The organic extracts were dried over magnesium sulfate, evaporated and precipitated from tBuOMe to give the product as a yellow solid (76 mg).

MS：403.5(M+H)⁺

Example 15

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -ethanol

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [9- (2-benzyloxy-ethoxy) -10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

During 20H, (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a)]A suspension of isoquinolin-2-yl) -carbamic acid tert-butyl ester (100mg), benzyl 2-bromoethyl ether (0.044ml) and potassium tert-butoxide (39mg) in 4ml THF was refluxed. Subjecting the mixture to CH₂Cl₂And NaHCO₃And (6) diluting. The aqueous layer is replaced by CH₂Cl₂The organic extracts were dried over magnesium sulphate, evaporated and precipitated from tBuOMe to give the product as a yellow solid (57 mg).

MS：559.7(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-benzyloxy-ethoxy) -10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - [9- (2-benzyloxy-ethoxy) -10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (50mg) were treated according to the procedure described in example 14g to afford the product as a yellow solid (19 mg).

MS：459.6(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -ethanol

During 3H, (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [9- (2-benzyloxy-ethoxy) -10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a)]Isoquinolin-2-yl]-solution of tert-butyl carbamate (280mg) in 7ml methanol in H₂Treated with HCl/dioxane and Pd/C10% under an atmosphere. The reaction mixture was filtered (dicalite), evaporated and chromatographed (silica gel, AcOEt/MeOH/NH)₄OH, 95/4/1) to yield a yellow solid (107 mg).

MS：369.4(M+H)⁺

Example 16

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-amino-ethoxy) -10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [9- (2-tert-Butoxycarbonylamino-ethoxy) -10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

This compound was prepared according to the method described in example 15a starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (300mg) and 2-boc-amino-ethylbromide to give a white solid (203 mg).

MS：568.6(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-amino-ethoxy) -10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

This compound was prepared according to the method described in example 14g starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (190mg) to give an orange solid (86 mg).

MS：368.4(M+H)⁺

Example 17

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -N-methyl-acetamide

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (10-methoxy-9-methylcarbamoylmethoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester

The compound was synthesized in analogy to example 14f, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (200mg) and 2-chloro-N-methyl-acetamide to yield a yellow solid (160 mg).

MS：496.3(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -N-methyl-acetamide

The compound was synthesized in analogy to example 14g, starting from (2S, 3S, 11bS) and (2R, 3R, 11bR) - (10-methoxy-9-methylcarbamoylmethoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (150mg) to yield a light brown solid (96 mg).

MS：396.3(M+H)⁺

Example 18

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -N, N-dimethyl-acetamide

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-Dimethylcarbamoylmethoxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester

This material was obtained as described in example 14f starting from (2S, 3S, 11bS) and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (180mg) and 2-chloro-N, N-dimethylacetamide to give a yellow solid (190 mg).

MS：510.5(M+H)⁺

b) (2S, 3S, 11bS) and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -N, N-dimethyl-acetamide

The title compound was obtained starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-dimethylcarbamoylmethoxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (180mg) as described in example 14 g. It was isolated as a yellow solid (59 mg).

MS：410.6(M+H)⁺

Example 19

(2S, 3S, 11bS) and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -acetamide

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (2-tert-Butoxycarbonylamino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -acetic acid methyl ester

This compound was synthesized according to the procedure described in example 14f starting from (2S, 3S, 11bS) and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (300mg) and methyl bromoacetate to give a yellow solid (337 mg).

MS：497.2(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-carbamoylmethoxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester

The reaction mixture of (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (2-tert-butoxycarbonylamino-10-methoxy-3-phenyl-1, 3,4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-9-yloxy) -acetic acid methyl ester (250mg) in 5ml NH₃The suspension in/MeOH was stirred at room temperature for 72h, then precipitated from tBuOMe and heptane to give the title compound as a yellow solid (106 mg).

MS：482.6(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -acetamide

This compound was prepared according to the procedure described in example 14g starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-carbamoylmethoxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (96mg) to afford a yellow solid (50 mg).

MS：382.3(M+H)⁺

Example 20

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

a) (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydropyrido [2, 1-a ] isoquinolin-2-one

This compound was prepared in analogy to example 1a, starting from rac-9-benzyloxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (2.05g) and 3-bromotoluene (1.08g) to give (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (0.53g) as a light yellow foam.

MS(ISP)：428.5(M+H)⁺

b) (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydropyrido [2, 1-a ] isoquinolin-2-one oxime

The compound is analogous to example 1b, starting from (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (0.52g), hydroxylamine hydrochloride (0.093g) and sodium acetate (0.11g), prepared in ethanol (15mL) to give (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (0.52g) as an off-white solid.

MS(ISP)：443.4(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

To a solution of (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (0.52g) in ethanol/dioxane (60mL) was added raney Ni (3.5 g). Air was removed from the reaction mixture and replaced with hydrogen. Concentrated ammonium hydroxide (2.0mL) was added by syringe and the reaction mixture was stirred at room temperature for 3 hours. The suspension was passed through a microfilter. The filtrate was concentrated and the residue was chromatographed on silica gel using dichloromethane/methanol/concentrated ammonium hydroxide as eluent to give (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine (0.21g) as a light yellow solid. This product was second eluted during chromatography (comparative example 21).

MS(ISP)：429.4(M+H)⁺

Example 21

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol

The compound was prepared in analogy to example 20c, starting from (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (0.52 g). It was obtained as a pale red solid (0.182 g). This product was fourth eluted during chromatography (comparative example 20c)

MS(ISP)：339.4(M+H)⁺

Example 22

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-benzyloxy-ethoxy) -10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

A solution of triphenylphosphine (0.36g) in anhydrous THF (10mL) was cooled to 0 ℃, diethyl ethyl azodicarboxylate (0.32g) was added dropwise over 2 minutes, and the reaction mixture was stirred at 0-5 ℃ for 30 minutes. A mixture of (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol (0.155g) and benzyloxyethanol (0.28g) in anhydrous THF (10mL) was added in one portion. The reaction mixture was stirred at room temperature overnight, concentrated, and the residue was chromatographed on silica gel using dichloromethane/methanol/concentrated ammonium hydroxide as eluent to give (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-benzyloxy-ethoxy) -10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine (0.18g) as a light yellow solid.

MS(ISP)：473.4(M+H)⁺

Example 23

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -ethanol

To a solution of (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-benzyloxy-ethoxy) -10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine (0.125g) in dioxane/ethanol 1: 1(12mL) was added 10% Pd/C (0.05g) and 1N HCl (0.4 mL). The reaction mixture was hydrogenated at room temperature and 1.1 bar for 2h and then filtered. The filtrate was concentrated and the residue was chromatographed on silica gel using dichloromethane/methanol/concentrated ammonium hydroxide as eluent to give the title compound (0.075g) as a light yellow foam.

MS(ISP)：383.3(M+H)⁺

Example 24

(2R, 3S, 11bS) -and (2S, 3R, 11bR) -9-benzyloxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

This product was obtained as pale red crystals eluting as the first compound (0.048g) in the final chromatography described in example 20 c.

MS(ISP)：429.4(M+H)⁺

Example 25

(2R, 3S, 11bS) -and (2S, 3R, 11bR) -2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol

The title compound was obtained as a red solid eluting in the final chromatography described in example 20c as third compound (0.019 g).

MS(ISP)：339.3(M+H)⁺

Example 26

((2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -acetamide hydrochloride

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester

To a solution of (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol (0.34g, comparative example 21) in dichloromethane (25mL) was added di-tert-butyl-dicarbonate (0.24 g). The reaction mixture was stirred at reflux for 2h, concentrated and chromatographed on silica gel (25g) using dichloromethane/methanol 19: 1 as the eluent to give the desired compound (0.43g) as a yellow foam.

MS(ISP)：439.3(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (2-tert-Butoxycarbonylamino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -acetic acid methyl ester

The product was prepared in analogy to example 6a, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (0.40g), potassium tert-butoxide (0.123g) and methyl bromoacetate (0.167g) to give the desired compound (0.34g) as colorless crystals.

MS(ISP)：511.5(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-carbamoylmethoxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester

The product was prepared in analogy to example 8a, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (2-tert-butoxycarbonyl-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -acetic acid methyl ester (0.30g) and 20% NH3/MeOH to give the desired compound (0.25g) as colorless crystals.

MS(ISP)：496.5(M+H)⁺

d) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -acetamide hydrochloride

A suspension of (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-carbamoylmethoxy-10-methoxy-3-M-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (0.105g) in dioxane (5mL) was treated with 6M HCl/dioxane (0.5mL) and stirred at room temperature for 60 hours. Diethyl ether (10mL) was added, and the precipitate was filtered, washed with diethyl ether, and dried to give the title compound (0.09g) as a colorless powder.

MS(ISP)：396.5(M+H)⁺

Example 27

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -1-morpholin-4-yl-ethanone hydrochloride

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 10-methoxy-9- (2-morpholin-4-yl-2-oxo-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

The product was prepared in analogy to example 26a, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - (9-hydroxy-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl) -carbamic acid tert-butyl ester (0.43g), potassium tert-butoxide (0.132g) and 4-2- (chloroacetyl) morpholine (0.192g) to give the desired compound (0.47g) after chromatography as colorless crystals.

MS(ISP)：566.5(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -1-morpholin-4-yl-ethanone hydrochloride

The product was prepared in analogy to example 26d, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 10-methoxy-9- (2-morpholin-4-yl-2-oxo-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (0.10g) and 4N HCl/dioxane (0.5mL) in dioxane to give the title compound (0.085g) as a colorless powder.

MS(ISP)：466.4(M+H)⁺

Example 28

(2R, 3S, 11bS) -and (2S, 3R, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

The product was prepared in analogy to example 20c, starting from (3S, 11bS) and (3R, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (0.49g) to give, after chromatography, the title compound (0.064g) as a yellow foam. The product was first eluted during chromatography.

MS(ISP)：430.5(M+H)⁺

Example 29

(2S, 3S, 11bS) and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol

The product was prepared in analogy to example 20c from (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (7.2g) to give the title compound (1.90g) as a pink solid. The product was fourth eluted during chromatography (comparative example 28)

MS(ISP)：340.5(M+H)⁺

Example 30

(2R, 3S, 11bS) -and (2S, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol

The product was prepared in analogy to example 20c, starting from (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (3.9g) to give the title compound (0.49g) as an orange foam. The product was third eluted during chromatography (comparative example 28)

MS(ISP)：340.3(M+H)⁺

Example 31

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-benzyloxy-ethoxy) -10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

The product was prepared in analogy to example 22, starting from (2S, 3S, 11bS) and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol (0.34g), triphenylphosphine (1.05g), benzyloxyethanol (0.76g) and di-tert-butyl azodicarboxylate (0.92g) to give the title compound (0.43g) as an orange foam.

MS(ISP)：474.5(M+H)⁺

Example 32

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -ethanol

The product was prepared in analogy to example 23, starting from (2S, 3S, 11bS) and (2R, 3R, 11bR) -9- (2-benzyloxy-ethoxy) -10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine (0.34g) to give the title compound (0.205g) as a light brown foam.

MS(ISP)：384.1(M+H)⁺

Example 33

(2S, 3S, 11bS) -and (2R, 3R, 11bR)) -9- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

The product was prepared in analogy to example 22, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol (0.325g), triphenylphosphine (1.26g), 1, 3-bis-benzyloxy-2-propanol (1.30g) and diisopropyl azodicarboxylate (0.97g) to give the title compound (0.54g) as an orange foam.

MS(ISP)：594.3(M+H)⁺

Example 34

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propane-1, 3-diol

The product was prepared in analogy to example 23, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine (0.30g) to give the title compound (0.18g) as a light brown foam.

MS(ISP)：414.6(M+H)⁺

Example 35

(S) -3- [ (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propane-1, 2-diol

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- ((R) -2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

The product was prepared in analogy to example 22, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol (0.339g), triphenylphosphine (1.05g), [ (R) -2, 2-dimethyl- [1, 3] -dioxolan-4-yl ] -methanol (0.66g) and di-tert-butyl azodicarboxylate (0.92g) to give the desired compound (0.345g) as a light brown foam.

MS(ISP)：454.6(M+H)⁺

b) (S) -3- [ (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propane-1, 2-diol

To a solution of (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- ((R) -2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine (0.325g) in tetrahydrofuran (30mL) was added 2NHCl (10.0 mL). The reaction mixture was stirred at room temperature for 20h and then filtered over an Amberlite IRA-400 column. The filtrate was evaporated and the residue was chromatographed on silica gel using ethyl acetate/methanol/concentrated ammonium hydroxide 8: 2: 0.2 as eluent to give the title compound (0.029g) as a light brown foam.

MS(ISP)：414.5(M+H)⁺

Example 36

(R) -3- [ (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propane-1, 2-diol

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- ((S) -2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

The product was prepared analogously to example 35a, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol (0.339g), triphenylphosphine (1.05g), [ (S) -2, 2-dimethyl- [1, 3] -dioxolan-4-yl ] -methanol (0.66g) and di-tert-butyl azodicarboxylate (0.92g), giving the desired compound (0.322g) as an orange foam.

MS(ISP)：454.8(M+H)⁺

b) (R) -3- (2S, 3S, 11bS) and (2R, 3R, 11bR) -3- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -propane-1, 2-diol

The product was prepared in analogy to example 35b, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) -9- ((S) -2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine (0.29g) to give, after chromatography, the title compound (0.042g) as a light brown foam.

MS(ISP)：414.6(M+H)⁺

Example 37

(2R, 3S, 11bS) -and (2S, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -1-morpholin-4-yl-ethanone hydrochloride

a) (2R, 3S, 11bS) -and (2S, 3R, 11bR) - [ 9-hydroxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

The product was prepared in analogy to example 2a, starting from (2R, 3S, 11bS) -and (2S, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol (1.22g) to give the desired compound (0.74g) after chromatography as a light yellow foam.

MS(ISP)：440.5(M+H)⁺

b) (2R, 3S, 11bS) -and (2S, 3R, 11bR) - [ 10-methoxy-3- (4-methyl-pyridin-2-yl) -9- (2-morpholin-4-yl-2-oxo-ethoxy) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

The compound was prepared in analogy to example 27a, starting from (2R, 3S, 11bS) -and (2S, 3R, 11bR) - [ 9-hydroxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (0.445g) to give the desired compound (0.17g) after chromatography as a light yellow foam.

MS(ISP)：567.5(M+H)⁺

c) (2R, 3S, 11bS) -and (2S, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -1-morpholin-4-yl-ethanone hydrochloride

The product was prepared in analogy to example 26d, starting from (2R, 3S, 11bS) -and (2S, 3R, 11bR) - [ 10-methoxy-3- (4-methyl-pyridin-2-yl) -9- (2-morpholin-4-yl-2-oxo-ethoxy) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (0.15g) to give the title compound (0.132g) as an amorphous powder.

MS(ISP)：467.1(M+H)⁺

Example 38

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -1-morpholin-4-yl-ethanone hydrochloride

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-hydroxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

The product was prepared in analogy to example 26a, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol (0.34g) and di-tert-butyl dicarbonate (0.24g) to give the desired compound (0.405g) as a light yellow foam.

MS(ISP)：440.4(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 10-methoxy-3- (4-methyl-pyridin-2-yl) -9- (2-morpholin-4-yl-2-oxo-ethoxy) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

The product was prepared in analogy to example 27a, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-hydroxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (0.24g), potassium tert-butoxide (0.075g) and 4-2-chloroacetyl) morpholine (0.107g) to give the desired compound (0.267g) as a colorless foam after chromatography

MS(ISP)：567.5(M+H)⁺

c) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -1-morpholin-4-yl-ethanone hydrochloride

The title compound was prepared in analogy to example 26d, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 10-methoxy-3- (4-methyl-pyridin-2-yl) -9- (2-morpholin-4-yl-2-oxo-ethoxy) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (0.24g) to give the desired compound (0.21g) as an amorphous powder.

MS(ISP)：467.0M+H)⁺

Example 39

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1a ] isoquinolin-9-yloxy ] -acetamide hydrochloride

a) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 9-carbamoylmethoxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester

The product was prepared in analogy to example 8a, starting from (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-tert-butoxycarbonyl-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid methyl ester (comparative example 12f) (0.19g) to give the desired compound (0.18g) as a colorless solid.

MS(ISP)：497.5(M+H)⁺

b) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1a ] isoquinolin-9-yloxy ] -acetamide hydrochloride

The title compound was prepared in analogy to example 26d, starting from (2S, 3S, 11bS) and (2R, 3R, 11bR) - [ 9-carbamoylmethoxy-10-methoxy-3- (4-methyl-pyridin-2-yl) -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl ] -carbamic acid tert-butyl ester (0.16g) to give the desired product (0.135g) as a colorless powder.

MS(ISP)：397.3(M+H)⁺

Example 40

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-3- (4-fluoromethyl-pyridin-2-yl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid methyl ester

a) 2-bromo-4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridine

To a solution of 2-bromo-4- (hydroxymethyl) pyridine (Lancaster, [ CAS 118289-16-0]) (7.3g) and imidazole (2.65g) in dichloromethane (80ml) was added dropwise a solution of tert-butyldimethylsilyl chloride (5.85g) in dichloromethane (20ml) at 0-5 ℃ over 15 minutes. The reaction mixture was stirred at 0-5 ℃ for 3h, poured onto ice/water and extracted with dichloromethane. The organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated. The crude compound was filtered through silica gel (200g) using dichloromethane as eluent. The product-containing fractions were evaporated to dryness to give 2-bromo-4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridine (10.3g) as a colourless liquid.

b) (3R, 11bS) -and (3S, 11bR) -9-benzyloxy-3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one

The compound was synthesized in analogy to example 1a, starting from rac-9-benzyloxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (1g) and 2-bromo-4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridine to give a yellow oil (606 mg).

MS：559.5(M+H)⁺

c) Z/E- (3R, 11bS) -and (3S, 11bR) -9-benzyloxy-3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime

The title compound was obtained as a yellow foam (469mg) from (3R, 11bS) and (3S, 11bR) -9-benzyloxy-3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (600mg) after chromatography (silica gel, AcOEt/MeOH, 19/1) using the same procedure as described in example 1 b.

MS：574.5(M+H)⁺

d) Z/E- (3R, 11bS) -and (3S, 11bR) -3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -9-hydroxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime

The compound was synthesized in analogy to example 15c, starting from Z/E- (3R, 11bS) -and (3S, 11bR) -9-benzyloxy-3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (400mg) to give a yellow foam (327 mg).

MS：484.6(M+H)⁺

e) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol are according to the procedure described in example 14g, starting with Z/E- (3R, 11bS) -and (3S, 11bR) -3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -9-hydroxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (400mg) to give a red foam (83 mg).

MS：470.4(M+H)⁺

f) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - {3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -9-hydroxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl } -carbamic acid tert-butyl ester

Following the procedure described in example 2a, (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol (80mg) were processed to give the title compound as a yellow foam (97 mg).

MS：570.5(M+H)⁺

g) (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-tert-Butoxycarbonylamino-3- (4-hydroxymethyl-pyridin-2-yl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid

(2S, 3S, 11bS) -and (2R, 3R, 11bR) - {3- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl ] -9-hydroxy-10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-yl } -carbamic acid tert-butyl ester (100mg) were dissolved in DMF. Using the procedure described in example 6a, the title product was obtained as a white solid (68 mg).

MS：528.3(M+H)⁺

h) (2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-3- (4-fluoromethyl-pyridin-2-yl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -acetic acid methyl ester

Reacting (2S, 3S, 11bS) -and (2R, 3R, 11bR) - [ 2-tert-butoxycarbonylamino-3- (4-hydroxymethyl-pyridin-2-yl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-9-yloxy]-acetic acid (65mg) was dissolved in 2ml of dichloromethane under ice-cooling. Diethylaminosulfur trifluoride (59mg) was added to the solution, and the solution was stirred at 0 ℃ for 2 hours. The reaction mixture was poured onto crashed ice/NaHCO₃And with CH₂Cl₂And (4) extracting. The combined organic layers were dried over magnesium sulfate, evaporated and chromatographed (silica gel, CH)₂Cl₂/MeOH/NH₄OH, 9/1/0.05). The residue was dissolved in 2ml dioxane and 0.5ml 4M HCl/dioxane, stirred at room temperature for 4h, precipitated with diethyl ether and filtered to give the title compound as a yellow solid (14 mg).

MS：431.0(M+H)⁺

EXAMPLE 41

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -9-benzyloxy-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

(3S, 11bS) -and (3R, 11bR) -9-benzyloxy-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime were dissolved in methanol. Using the procedure described in example 1c and reducing the reaction time to 1h, the title product was obtained as a white solid.

MS：443.4(M+H)⁺

Example 42

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2-amino-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-ol

The compound was synthesized according to the procedure described in example 1c, starting from (3S, 11bS) -and (3R, 11bR) -9-benzyloxy-10-methoxy-3-phenyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]Isoquinoline-2-ketoxime. By chromatography (silica gel, CH)₂Cl₂/MeOH/NH₄OH, 10/1/0.1) gave an orange solid.

MS：325.5(M+H)⁺

Example 43

rac- (2S, 3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

a) N- [2- (2-benzyloxy-3-methoxy-phenyl) -ethyl ] -carboxamide

Carbonyldiimidazole (CDI, 662mg) was dissolved in THF (15mL) under nitrogen, and a solution of formic acid (0.15mL) in THF (5mL) was added slowly over 5 minutes. The resulting mixture was stirred at room temperature for 30 minutes and then a solution of 2- (2-benzyloxy-3-methoxy-phenyl) -ethylamine (1.0g, prepared according to Chim. Ther.1973, 8(3), 308-) 313 in THF (10mL) was added dropwise over a period of 10 minutes. The mixture was stirred and TLC analysis confirmed that the starting material was completely consumed after 30 minutes. The reaction mixture was concentrated in vacuo, diluted with dichloromethane (100mL), washed with aqueous HCl (1M, 100mL) and brine, dried, and evaporated to give the crude product as a yellow oil. The residue was purified by flash chromatography (50g silica gel, gradient heptane in ethyl acetate (50% to 0%) and the fractions containing the desired product were combined and evaporated to give a colourless oil which solidified upon standing (0.96g, 87%).

¹H NMR(δ，CDCl₃)：8.00(s，1H)，7.45-7.35(m，5H)，7.04-6.98(m，1H)，6.86(dd，1H)，6.77(dd，1H)，5.80(br s，1H)，5.03(s，2H)，3.91(s，3H)，3.46(q，2H)，2.76(t，2H)。MS(ESI)：303.2(MNH₄ ⁺)。

b) 5-benzyloxy-6-methoxy-3, 4-dihydro-isoquinoline, hydrochloride and free base

Under argon, freshly distilled POCl₃(2.03mL) was added to CH₃CN (60 mL). In the course of 2 hours, N- [2- (2-benzyloxy-3-methoxy-phenyl) -ethyl]Formamide (2.5g) in CH₃A solution in CN (15mL) was added by syringe pump and the resulting mixture was stirred for another 3 hours. Methanol (60mL) was added carefully and the mixture was stirred for 30 minutes. The solution was concentrated in vacuo, and ethyl acetate (50mL) was added to the residue with stirring. The precipitated product is filtered, washed with a little ethyl acetate, andand dried in vacuo to give a colorless solid (0.65 g). The filtrate was evaporated and precipitated from ethyl acetate/diethyl ether 1: 1 to give a second crop of product (0.27 g).

¹H NMR(δ，DMSO-D₆)：13.18(br s，1H)，9.01(s，1H)，7.76(d，1H)，7.44-7.36(m，5H)，7.28(d，1H)，5.01(s，2H)，4.02(s，3H)，3.74(t，2H)，2.94(t，2H)。MS(ESI)：268.4(MH⁺)。

Liberation of the free base: 5-benzyloxy-6-methoxy-3, 4-dihydro-isoquinoline, hydrochloride (5.0g) was treated with 3N NaOH (200mL) and the aqueous layer was extracted with ethyl acetate (2X 250 mL). The organic layer was washed with brine, over MgSO₄Drying, evaporation and vacuum drying gave 5-benzyloxy-6-methoxy-3, 4-dihydro-isoquinoline as a pale brown oil (3.12 g).

¹H NMR(δ，CDCl₃)：8.21(t，1H)，7.42-7.32(m，5H)，7.04(d，1H)，6.84(d，1H)，4.99(s，2H)，3.93(s，3H)，3.58(td，2H)，2.59(t，2H)。

c) 4-dimethylamino-3-m-tolyl-butan-2-one hydrochloride

3-Methylphenylacetone (1.0g), dimethylamine hydrochloride (0.825g) and paraformaldehyde (0.304g) were added to anhydrous ethanol (5mL) and 4 drops of concentrated HCl were added. The mixture was heated to reflux for 24 hours, cooled, and concentrated in vacuo. Acetone (10mL) was added to the residue under stirring and the suspension was kept at 0 ℃ for 1 hour. The solid was filtered and dried under vacuum overnight (0.972 g). This material was used without further purification.

¹H NMR(δ，DMSO-D₆)：10.28(br s，1H)，7.31(t，1H)，7.18-7.10(m，3H)，4.51(dd，1H)，3.81(dd，1H)，3.25-3.10(m，1H)，2.71(s，6H)，2.31(s，3H)，2.07(s，3H)。MS(ESI)：206.3(MH⁺)。

d) rac- (3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one

5-benzyloxy-6-methoxy-3, 4-dihydro-isoquinoline (3.65g) and 4-dimethylamino-3-m-tolyl-butan-2-one hydrochloride (8.24g) were dissolved in THF (25mL) and water (25mL), and the mixture was stirred at room temperature for 36 hours. The mixture was poured into ice, saturated NaHCO₃And brine, and extracted with ethyl acetate. The organic layer was washed with brine and Na₂SO₄Dried and evaporated in vacuo. The crude product was purified by flash chromatography using a gradient of ethyl acetate in hexane. Fractions containing the desired product were combined, evaporated and dried in vacuo to yield: rac- (3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]Isoquinolin-2-one (4.06g) as a light yellow foam.

MS(ESI)：428.8(MH⁺)。

e) rac- (3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime

Rac- (3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (0.135g) was dissolved in anhydrous methanol (5mL) and water (2mL), and ammonium acetate (64mg) and hydroxylamine hydrochloride (65mg) were added. The mixture was heated to reflux for 4 hours and the resulting suspension was cooled to room temperature and evaporated. After addition of water (8mL) and methanol (0.5mL), the mixture was filtered and the solid was dried in vacuo overnight to give rac- (3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (126mg) as a white solid.

MS(ESI)：443.5(MH⁺)。

f) rac- (2S, 3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine

Subjecting rac- (3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]Isoquinoline-2-one oxime (108mg) was dissolved in methanol (5mL) and THF (5mL) and concentrated NH was added₄OH (25%, 1 mL). Raney nickel (500mg) was added and the reaction solution was degassed by repeated cycles of air/H₂Introduction of H₂-an atmosphere. The mixture was hydrogenated overnight and-in addition to a large amount of starting material-new products were observed. The mixture was evaporated and the residue was chromatographed on silica gel using a column containing 0.5% NH₄A gradient of methanol in dichloromethane of OH was used as eluent. In addition to the starting material (84mg), the desired reduced product rac- (2S, 3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] was obtained]Isoquinolin-2-ylamine as a light yellow foam (10 mg).

MS(ESI)：429.6(MH⁺)。

Example 44

rac- (2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-ol

a) rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one

Subjecting rac- (3S, 11bS) -8-benzyloxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]Isoquinolin-2-one (0.486mg, from example 43d) was dissolved in anhydrous methanol (7mL) and anhydrous THF (7mL) and 10% Pd on charcoal (85mg) were added. By repeatedly pumping out/H₂Introduction of H₂-an atmosphere. Stirring was continued for 18 hours. The reaction mixture was filtered through celite, and the filter cake was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography to give rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]Isoquinolin-2-one (0.148g) as a light yellow solid.

MS(ESI)：338.1(MH⁺)。

In a similar amount, the by-product rac- (3S, 11bS) -9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinoline-2, 8-diol (0.178g) is isolated as a mixture of diastereomers.

MS(ESI)：340.4(MH⁺)。

b) rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime

To rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one (80mg) dissolved in methanol (4mL) and water (2mL) was added ammonium acetate (48mg) and hydroxylamine hydrochloride (49 mg). The colorless suspension was heated to 60 ℃ overnight, cooled to RT, and evaporated in vacuo. Water (8mL) and methanol (0.5mL) were added and the suspension was stirred for 45 minutes. The solid was filtered off, washed with water, and dried in vacuo. Rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one oxime (72mg) was obtained as a white solid.

MS(ESI)：353.3(MH⁺)。

c) rac- (2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-ol

Mixing rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]Isoquinoline-2-one oxime (65mg) was dissolved in ethanol (3mL) and dioxane (3mL) and raney nickel (1.5mL of ethanol suspension) was added. By repeatedly pumping out/H₂Introduction of H₂-atmosphere, then addition of concentrated NH₄OH (25% aqueous, 0.5 mL). The mixture was stirred vigorously at 60 ℃ for 2 hours and then filtered through celite. The filter cake was washed well with ethyl acetate and the filtrate was evaporated in vacuo. The residue was washed with water and brine0.5% concentrated NH₄OH) as eluent. The appropriate fractions were combined and evaporated to give the desired product rac- (2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-8-ol (40mg) as a white solid.

MS(ESI)：339.4(MH⁺)。

Example 45

rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -acetamide, (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereomers

a) rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one-O-benzyl-oxime

Mixing rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]Isoquinolin-2-one (0.2g from example 44a), O-benzylhydroxylamine (0.365g) and sodium acetate (0.255g) were added to ethanol/water 1: 1(12 mL). The resulting suspension was heated to 60 ℃ for 12 hours. The mixture was poured onto ice/saturated NaHCO saturated with NaCl₃The mixture was extracted with ethyl acetate. The organic layer was washed with brine and Na₂SO₄Dried and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane as eluent. Fractions containing the desired product were combined and evaporated to give a viscous yellow solid which was treated with n-hexane at 0 ℃ for 60 min. The suspension was filtered, the solid washed with hexane and dried in vacuo to give rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]isoquinolin-2-one-O-benzyl-oxime (0.164g) as a white solid.

MS(ESI)：443.4(MH⁺)。

b) rac- { (3S, 11bS) -2- [ (E) and/or (Z) -benzyloxyimino ] -9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy } -acetic acid methyl ester

Under argon, rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]isoquinolin-2-one-O-benzyl-oxime (75mg) was dissolved in DMF (4mL) and cooled to 0 ℃. One part of potassium tert-butoxide (22mg) was added, and the mixture was stirred at 0 ℃ for 30 minutes. Methyl bromoacetate (0.02mL) was added dropwise and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured onto ice/saturated NaHCO saturated with NaCl₃The solution was washed with brine, and extracted with ethyl acetate. The organic layer was washed with brine and Na₂SO₄Dried and evaporated. The residue was purified by flash chromatography using a gradient of ethyl acetate in heptane as eluent. Fractions containing the desired product were combined and evaporated to yield, after vacuum drying: rac- { (3S, 11bS) -2- [ (E) and/or (Z) -benzyloxyimino group]-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-8-yloxy } -acetic acid methyl ester (59mg) as a light yellow foam.

MS(ESI)：515.5(MH⁺)。

c) rac-2- { (3S, 11bS) -2- [ (E) and/or (Z) -benzyloxyimino ] -9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy } -acetamide

At room temperature, rac- { (3S, 11bS) -2- [ (E) and/or (Z) -benzyloxyimino group]-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-8-yloxy } -acetic acid methyl ester (50mg) with NH₃Saturated methanol (3.5mL) was treated for 3 hours. The mixture was evaporated in vacuo to give rac-2- { (3S, 11bS) -2- [ (E) and/or (Z) -benzyloxyimino group]-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-8-yloxy } -acetamide (48mg), used without further purification.

MS(ESI)：500.5(MH⁺)。

d) rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -acetamide, (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereomers

Subjecting rac-2- { (3S, 11bS) -2- [ (E) -benzyloxyimino group to solid phase chromatography]-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-8-yloxy } -acetamide (45mg) was dissolved in anhydrous ethanol (2mL) and dioxane (2mL) and raney nickel (1mL of ethanol suspension) was added. By repeatedly pumping out/H₂Introduction of H₂-an atmosphere. Adding concentrated NH₄OH (25%, 0.35mL), and the reaction was stirred vigorously at 60 ℃ for 2 hours. The mixture was filtered through celite and the filter cake was washed well with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography to give rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-8-yloxy) -acetamide, as the (2R, 3S, 11bS) diastereomer (6 mg); ms (esi): 396.5 (MH)⁺) And the (2S, 3S, 11bS) diastereomer (23 mg); ms (esi): 396.5 (MH)⁺)。

Example 46

rac-2- ((2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -1-morpholin-4-yl-ethanone

a) rac- (3S, 11bS) -9-methoxy-8- (2-morpholin-4-yl-2-oxo-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one O-benzyl-oxime

Morpholine (17mg, 0.02mL) was added to toluene (3.5mL) at room temperature, and a solution of trimethylaluminum in toluene (2M, 0.06mL) was added via syringe. The mixture was stirred for 1 hour, and rac- { (3S, 11bS) -2- [ (E) -benzyloxyimino group was then added]-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]A solution of isoquinolin-8-yloxy } -acetic acid methyl ester (50mg, obtained in example 45 b) in toluene (2mL) was added, after which the mixture was heated at 110 ℃. TLC confirmed complete consumption of starting material after 1 hour; stirring was continued at RT overnight. The mixture was poured into ice-cold water, and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine and Na₂SO₄Dried and evaporated. The residue was washed with water and dried in DCM (containing 0.5% concentrated NH)₄OH) as eluent. The fractions containing the desired product were combined and evaporated to give rac- (3S, 11bS) -9-methoxy-8- (2-morpholin-4-yl-2-oxo-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] -pyridine]Isoquinolin-2-one O-benzyl-oxime (50mg) as a yellow foam.

MS(ESI)：570.7 MH⁺)。

b) rac-2- ((2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -1-morpholin-4-yl-ethanone

The compound is obtained in analogy to example 45d by hydrogenating rac- (3S, 11bS) -9-methoxy-8- (2-morpholin-4-yl-2-oxo-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one O-benzyl-oxime (25mg) to yield rac-2- ((2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -1-morpholin-4-yl-ethanone, as a single diastereomer (13 mg).

MS(ESI)：466.6(MH⁺)。

Example 47

rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -1- (4-methyl-piperazin-1-yl) -ethanone, (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereomers

a) rac- (3S, 11bS) -9-methoxy-8- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethoxy ] -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one-O-benzyl-oxime

This compound is obtained in analogy to example 46a from rac- { (3S, 11bS) -2- [ (E) and/or (Z) -benzyloxyimino ] -9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy } -acetic acid methyl ester (100mg) and N-methylpiperazine (40mg) to rac- (3S, 11bS) -9-methoxy-8- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethoxy ] -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one-O-benzyl-oxime (95 mg).

MS(ESI)：583.5(MH⁺)。

b) rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -1- (4-methyl-piperazin-1-yl) -ethanone, (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereomers

The compound is obtained in analogy to example 46b from rac- (3S, 11bS) -9-methoxy-8- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethoxy]-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]isoquinolin-2-one-O-benzyl-oxime (85mg) was obtained by hydrogenation to rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-8-yloxy) -1- (4-methyl-piperazin-1-yl) -ethanone as (2R, 3S, 11bS) -diastereomer (6 mg); ms (esi): 479.4 (MH)⁺) And (2S, 3S, 11bS) -diastereomer (22 mg). Ms (esi): 479.8 (MH)⁺)。

Example 48

rac-2- ((2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -N, N-dimethyl-acetamide

a) rac-2- { (3S, 11bS) -2- [ (E) and/or (Z) -benzyloxyimino ] -9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy } -N, N-dimethyl-acetamide

This compound is obtained in analogy to example 45b from rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one-O-benzyl-oxime (0.2g) by treatment with potassium tert-butoxide (58mg) and 2-chloro-N, N-dimethylacetamide (0.06mL) to give rac-2- { (3S, 11bS) -2- [ (E) and/or (Z) -benzyloxyimino ] -9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2 ], 1-a ] isoquinolin-8-yloxy } -N, N-dimethyl-acetamide (161 mg).

MS(ESI)：528.5(MH⁺)。

b) rac-2- ((2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -N, N-dimethyl-acetamide

This compound is obtained in analogy to example 45d from rac-2- { (3S, 11bS) -2- [ (E) and/or (Z) -benzyloxyimino ] -9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy } -N, N-dimethyl-acetamide (156mg) by hydrogenation to rac-2- ((2S, 3S, 11bS) -2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -N, n-dimethyl-acetamide (82mg), as a single diastereoisomer.

MS(ESI)：424.5 MH⁺.

Example 49

rac-9-methoxy-8- (2-methoxy-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine, (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereomers

a) rac- (3S, 11bS) -9-methoxy-8- (2-methoxy-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one-O-benzyl-oxime

This compound was obtained as described in example 45b from rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one-O-benzyl-oxime (200mg) by treatment with potassium tert-butoxide (90mg) and 2-chloroethyl-methyl ether (0.09mL) in DMF (6mL) to give rac- (3S, 11bS) -9-methoxy-8- (2-methoxy-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one-O-benzyl-oxime (88mg), is a yellow gum.

MS(ESI)：501.5MH⁺)。

b) rac-9-methoxy-8- (2-methoxy-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-2-ylamine, (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereomers

The compound is prepared from rac- (3S, 11bS) -9-methoxy-8- (2-methoxy-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]Isoquinolin-2-one O-benzyl-oxime (81mg) was obtained by hydrogenation as described in example 45d to give rac-9-methoxy-8- (2-methoxy-ethoxy) -3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-2-ylamine as (2R, 3S, 11bS) diastereomer (6mg, not characterized), and (2S, 3S, 11bS) diastereomer (35 mg); ms (esi): 397.4 MH⁺。

Example 50

rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -ethanol, (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereoisomers

a) rac- (3S, 11bS) -8- (2-benzyloxy-ethoxy) -9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one-O-benzyl-oxime

This compound was obtained as described in example 45b from rac- (3S, 11bS) -8-hydroxy-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one O-benzyl-oxime (105mg) by treatment with potassium tert-butoxide (31mg) and 2-bromoethyl-benzyl ether (0.05mL) in DMF (4mL) to give rac- (3S, 11bS) -8- (2-benzyloxy-ethoxy) -9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ] isoquinolin-2-one-O-benzyl-oxime (113mg), is a yellow gum.

MS(ESI)：577.4(MH⁺)。

b) rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-8-yloxy) -ethanol, (2S, 3S, 11bS) and (2R, 3S, 11bS) diastereoisomers

The compound is prepared from rac- (3S, 11bS) -8- (2-benzyloxy-ethoxy) -9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-pyrido [2, 1-a ]]isoquinolin-2-one-O-benzyl-oxime (105mg), obtained by hydrogenation as described in example 45d, to give rac-2- (2-amino-9-methoxy-3-m-tolyl-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ]]Isoquinolin-8-yloxy) -ethanol, being (2R, 3S, 11bS) -diastereomer (8 mg); ms (esi): 383.3 (MH)⁺) And (2S, 3S, 11bS) -diastereomer (43 mg). Ms (esi): 383.3 (MH)⁺)。

Galenic preparation examples

Example A

Film-coated tablets containing the following ingredients can be prepared in a conventional manner:

composition (I) Each sheet is

And (3) nucleus:

10.0mg 200.0mg of compound of formula (I)

Microcrystalline cellulose 23.5mg 43.5mg

Lactose hydrate 60.0mg 70.0mg

Polyvinylpyrrolidone K3012.5mg 15.0mg

Sodium starch glycolate 12.5mg 17.0mg

Magnesium stearate 1.5mg 4.5mg

(nuclear weight) 120.0mg 350.0mg

Film coating:

hydroxypropyl methylcellulose 3.5mg 7.0mg

Polyethylene glycol 60000.8 mg 1.6mg

Talc 1.3mg 2.6mg

Iron oxide (yellow) 0.8mg 1.6mg

Titanium dioxide 0.8mg 1.6mg

The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules were mixed with sodium starch glycolate and magnesium stearate and extruded to give cores weighing 120 or 350mg respectively. The core is coated with the aqueous solution/suspension of the film coating described above.

Example B

Capsules containing the following ingredients can be prepared in a conventional manner:

composition (I) Each capsule

25.0mg of the Compound of formula (I)

Lactose 150.0mg

Corn starch 20.0mg

Talc 5.0mg

The components are sieved and mixed, and then filled into capsules No. 2.

Example C

The injection solution may have the following composition:

composition (I)

3.0mg of a Compound of formula (I)

Polyethylene glycol 400150.0 mg

Acetic acid in appropriate amount to pH5.0

Adding water for injection to 1.0ml

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0ml by adding the balance of water. Using the appropriate excess of the solution, it is filtered, filled into vials and sterilized.

Example D

Soft gelatin capsules containing the following ingredients may be prepared in a conventional manner:

composition (I)

Capsule content

5.0mg of a Compound of formula (I)

Yellow wax 8.0mg

Hydrogenated Soybean oil 8.0mg

Partially hydrogenated vegetable oil 34.0mg

Soybean oil 110.0mg

The content of the capsule weighed 165.0mg

Gelatin capsule

Gelatin 75.0mg

Glycerol 85% 32.0mg

Karion 838.0mg (dry matter)

Titanium dioxide 0.4mg

Iron oxide yellow 1.1mg

The active ingredient is dissolved in a warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of suitable size. The filled soft gelatin capsules are processed according to conventional procedures.

Example E

Sachets containing the following ingredients may be prepared in a conventional manner:

composition (I)

50.0mg of a compound of formula (I)

Lactose, fine powder 1015.0mg

Microcrystalline cellulose (AVICEL PH102) 1400.0mg

Sodium carboxymethylcellulose 14.0mg

Polyvinylpyrrolidone K3010.0mg

Magnesium stearate 10.0mg

Flavoring additive 1.0mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone and water. The granules were mixed with magnesium stearate and flavouring additives and filled into sachets.

Claims

1. A compound of the formula

Wherein

R¹Selected from hydrogen or methoxy;

R²selected from:

a hydroxyl group(s),

lower alkoxy, provided that at R¹In the case of methoxyUnder the condition of R²Is not a methoxy group, and is not a methoxy group,

lower alkoxy which is mono-or disubstituted with:

hydroxy, lower alkoxy, benzyloxy,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

the structure of the tetrazolyl group is,

-O-SO₂-R¹²wherein R is¹²Is a lower alkyl group, and is,

R³selected from:

the presence of hydrogen in the presence of hydrogen,

a hydroxyl group(s),

a lower alkoxy group,

lower alkoxy which is mono-or disubstituted with:

a hydroxyl group, an alkoxy group, a benzyloxy group,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

tetrazolyl, and

-O-(CH₂)_m-C(O)-NR⁸R⁹wherein m is 1 or 2, and R⁸And R⁹Independently selected from:

hydrogen, lower alkyl or tetrazolyl, or R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclic ring which may contain a further heteroatom selected from N, O or S and which may be substituted by lower alkyl,

-O-SO₂-R¹²wherein R is¹²Is a lower alkyl group, and is,

R⁴is composed of

Or

Wherein

At R²Selected from the group consisting of⁵It may also be hydrogen:

-(CH₂)_m-C(O)-NR⁸R⁹，-O-(CH₂)_p-NH-C(O)-OR¹¹，-O-SO₂-R¹²，

-NR¹³R¹⁴，

-NH-CO-(CH₂)_q-R¹⁵and lower alkoxy mono-or disubstituted by a group selected from

Base: hydroxy, benzyloxy, amino, alkylamino, dialkylamino or cyano;

R⁶selected from: hydrogen, lower alkyl, lower alkoxy, lower hydroxyalkyl, lower alkyl halide

Alkyl, halo and cycloalkyl;

2. A compound of formula I according to claim 1, wherein

R⁴Is composed of

Or

And wherein

R⁶selected from: hydrogen, lower alkyl, lower alkoxy, lower hydroxyalkyl, lower haloalkyl, halogen and cycloalkyl; and

3. Compounds of formula I according to claims 1 or 2, wherein R²Selected from:

a hydroxyl group(s),

lower alkoxy which is mono-or disubstituted with:

hydroxy, lower alkoxy, benzyloxy,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

the structure of the tetrazolyl group is,

-O-SO₂-R¹²wherein R is¹²Is a lower alkyl group, and is,

-NH-CO-(CH₂)_q-R¹⁵wherein q is 1 or 2, and R¹⁵Is lower alkyl or tetrazolyl; and R is³Selected from: hydrogen, hydroxy and lower alkoxy.

4. Compounds of formula I according to any one of claims 1 to 3, wherein R²Selected from:

a hydroxyl group(s),

lower alkoxy which is mono-or disubstituted with:

hydroxy, benzyloxy, amino, cyano, phenyl or tetrazolyl,

-O-SO₂-R¹²wherein R is¹²Is a lower alkyl group, and is,

5. Compounds of formula I according to any one of claims 1 to 4, wherein R²Is hydroxy or lower alkoxy mono-or disubstituted with: hydroxy, benzyloxy, amino, cyano, phenyl or tetrazolyl.

6. Compounds of formula I according to any one of claims 1 to 4, wherein R²is-O- (CH)₂)_m-C(O)-NR⁸R⁹Wherein m is 1 or 2, and R⁸And R⁹Independently selected from: hydrogen, lower alkyl or tetrazolyl, or R⁸And R⁹To which nitrogen atoms are attachedTogether, the substituents form a 5-or 6-membered heterocyclic ring which may contain a further heteroatom selected from N, O or S and which may be substituted by lower alkyl.

7. Compounds of formula I according to claim 6, wherein R²is-O- (CH)₂)_m-C(O)-NR⁸R⁹Wherein m is 1 or 2, and R⁸And R⁹Independently selected from: hydrogen, lower alkyl or tetrazolyl.

8. Compounds of formula I according to any one of claims 1 to 4, wherein R²is-O- (CH)₂)_n-COOR¹⁰Wherein n is 1 or 2 and R¹⁰Is hydrogen or lower alkyl.

9. Compounds of formula I according to any one of claims 1 to 4, wherein R²is-O-SO₂-R¹²Wherein R is¹²Is a lower alkyl group.

10. Compounds of formula I according to any one of claims 1 to 4, wherein R²is-NH-CO- (CH)₂)_q-R¹⁵Wherein q is 1 or 2, and R¹⁵Is lower alkyl or tetrazolyl.

11. Compounds of formula I according to any one of claims 1 to 10, wherein R³Is hydrogen.

12. Compounds of formula I according to claims 1 or 2, wherein R³Selected from:

a hydroxyl group(s),

a lower alkoxy group,

lower alkoxy which is mono-or disubstituted with:

a hydroxyl group, an alkoxy group, a benzyloxy group,

amino, alkylamino, dialkylamino, cyano,

unsubstituted phenyl, phenyl substituted with 1 to 3 groups selected from:

lower alkyl, lower alkoxy, halogen or lower haloalkyl,

tetrazolyl, and

hydrogen, lower alkyl or tetrazolyl, or R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclic ring which may contain a further heteroatom selected from N, O or S and which may be substituted by lower alkyl, and

R²is hydroxy or lower alkoxy.

13. Compounds of formula I according to claims 1, 2 or 12, wherein R³Is hydroxy or lower alkoxy mono-or disubstituted with: hydroxy, alkoxy, benzyloxy or phenyl.

14. Compounds of formula I according to claims 1, 2 or 12, wherein R³is-O- (CH)₂)_m-C(O)-NR⁸R⁹Wherein m is 1 or 2, and R⁸And R⁹Independently selected from: hydrogen, lower alkyl or tetrazolyl, or R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring which may contain a further heteroatom selected from N, O or S and which may be substituted by lower alkyl.

15. Compounds of formula I according to any one of claims 1, 2 or 12 to 14, wherein R²Is methoxy.

16. Compounds of formula I according to any one of claims 1 to 15, wherein R⁴Is composed of

R⁶selected from: hydrogen, lower alkyl, lower alkoxy, lower hydroxyalkyl, lower haloalkyl, halogen and cycloalkyl.

17. Compounds of formula I according to any one of claims 1 to 16, wherein R⁵Is lower alkyl or lower haloalkyl, and R⁶Is hydrogen or lower alkyl.

18. Compounds of formula I according to any one of claims 1 to 15, wherein R⁴Is composed of

And R is⁷Is lower alkyl, cycloalkyl, lower hydroxyalkyl, halogen or lower haloalkyl.

19. Compounds of formula I according to any one of claims 1 to 15 or 18, wherein R⁷Is a lower alkyl group.

20. Compounds of formula I according to any one of claims 1 to 19, selected from:

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- [ 2-amino-3- (2, 5-dimethyl-phenyl) -10-methoxy-1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy ] -ethanol hydrochloride,

(2S, 3S, 11bS) -and (2R, 3R, 11bR) -2- (2-amino-10-methoxy-3-phenyl, -1, 3, 4, 6, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-9-yloxy) -N-methyl-acetamide,

21. Compounds of formula I according to any one of claims 1 to 20, selected from:

22. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 21, which process comprises:

a) converting a compound of formula II:

wherein X is hydrogen or tert-butyloxycarbonyl, X₂is-OH or-NH₂，R¹And R⁴As defined in claim 1, and R³To hydrogen, to a compound of formula I:

wherein R is¹，R²And R⁴As defined in claim 1, and R³Is hydrogen, or alternatively,

b) reacting a compound of formula III:

wherein R is^XIs hydrogen or benzyl, and R¹To R⁴As defined in claim 1, to a compound of formula I:

wherein R is¹To R⁴As defined in claim 1, wherein the first and second groups are,

23. Compounds according to any one of claims 1 to 21, when manufactured by a process according to claim 22.

24. Pharmaceutical compositions comprising a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable carrier and/or adjuvant.

25. Compounds according to any one of claims 1 to 21 for use as therapeutically active substances.

26. Compounds according to any one of claims 1 to 21 for use as therapeutic active substances for the treatment and/or prophylaxis of diseases which are associated with DPP-IV.

27. A method for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, periaxial encephalitis, folliculitis, rheumatoid arthritis, ulcerative colitis, crohn's disease, psoriasis, lichen planus, benign prostatic hypertrophy, hypertension, diseases in which diuretics are of beneficial effect, obesity, and/or metabolic syndrome or beta-cytoprotection, which method comprises administering a compound according to any of claims 1 to 21 to a human being or animal.

28. The use of compounds according to any one of claims 1 to 21 for the treatment and/or prophylaxis of: diabetes, non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, periaxial encephalitis, folliculitis, rheumatoid arthritis, ulcerative colitis, crohn's disease, psoriasis, lichen planus, benign prostatic hypertrophy, hypertension, diseases in which diuretics have a beneficial effect, obesity, and/or metabolic syndrome or beta-cell protection.

29. The use of compounds according to any of claims 1 to 21 for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are associated with DPP-IV.

30. Use according to claim 29 for the preparation of a medicament for the treatment and/or prophylaxis of diabetes, non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, periaxial encephalitis, folliculitis, rheumatoid arthritis, ulcerative colitis, crohn's disease, psoriasis, lichen planus, benign prostatic hypertrophy, hypertension, diseases in which diuretics have a beneficial effect, obesity, and/or metabolic syndrome or beta-cell protection.

31. The novel compounds, processes and methods as well as the use of such compounds substantially as described herein before.