wherein R1 and R2 are independently from each other hydrogen, lower alkyl,-(CH2) n-OH, -(CH2) n-N (R6) 2,-NR6C (O) C (0) 0-lower alkyl,-NR6-(CH2) n-OH, -NR6C(O)-lower alkyl, -NH-benzyl or NR6C (O)- (CH2)n-OH ; R6 is independently from each other hydrogen or lower alkyl R'is hydrogen or lower alkyl ; R3 is hydrogen or amino; R4 is hydrogen or lower alkyl ; R5 is hydrogen or halogen; or Rl and R'may be together with the carbon atoms to which they are attached the group -(CH2)4-; or R2 and R3 may be together with the carbon atoms to which they are attached the group -N(R6)-CH2-O-CH2-; n is 0, 1, 2 or 3 ; and to pharmaceutically acceptable acid addition salts thereof.

The compounds of formula I and their salts are distinguished by valuable therapeutic properties. Compounds of the present invention are NMDA (N-methyl-D-aspartate)-

receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.

Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death.

NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas.

Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors displaying different pharmaceutical properties. Possible therapeutic indications for NMDA NR-2B receptor subtype specific blockers include acute forms of neurodegeneration caused, e. g. , by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis), neurodegeneration associated with bacterial or viral infections, and, in addition, depression and chronic and acute pain.

Objects of the invention are the compounds of formula I and pharmaceutically acceptable acid addition salts thereof, the preparation of the compounds of formula I and salts thereof, medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, the manufacture of such medicaments and the use of the compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier, and, respectively, for the manufacture of corresponding medicaments.

The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.

As used herein, the term"lower allcyl"denotes a straight-or branched-chain alkyl group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. Preferred lower alkyl groups contain from 1 to 4 carbon atoms.

The term"halogen"denotes chlorine, iodine, fluorine and bromine.

The term"pharmaceutically acceptable acid addition salts"embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.

Preferred are compounds of formula IA.

Exemplarly preferred are those compounds of formula IA, wherein R2 is amino, for example the following compounds: 2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-4-yl-amine, Rac. -2- (4-methyl-3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl-amine, 2- (3, 4-dihydro-lH-isoquinolin-2-yl)-5-methyl-pyridin-4-yl-amine, 2-(3, 4-dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-4-yl-amine, 2- (3, 4-dihydro-lH-isoquinolin-2-yl)-6-ethyl-pyridin-4-yl-amine or [4-amino-6- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-2-yl]-methanol Further preferred compounds of formula IA are those, wherein R2 is -NH (CH2) 20H. Examples of these groups are, for example, the following: 2- [2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl-amino]-ethanol, 2- [2- (3, 4-dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-4-yl-amino]- ethanol or 2- [2- (3, 4-dihydro-lH-isoquinolin-2-yl)-5-methyl-pyridin-4-yl-amino]- ethanol.

Compounds of formula IA, wherein R2 is-NH-lower allcyl, are also preferred, for example the following compounds: [2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-4-yl]-methyl-am ine or [2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl]-dimethyl-amine.

Preferred are also compounds of formula IB.

Compounds of formula IB, wherein R is hydrogen, are preferred, for example the following: 2-pyridin-4-yl-1, 2,3, 4-tetrahydro-isoquinoline or 2- (2-methyl-pyridin-4-yl) -1, 2,3, 4-tetrahydro-isoquinoline.

Further preferred compounds of formula IB are those, wherein R2 is amino, for example the followings: 4-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-2-yl-amine or 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-pyridin-2-yl-am ine.

Compounds of formula IB, wherein R2 is-NHC (O) C (O) OCH2CH3 or -NH (CH2) 20H are further preferred, for example: N-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-pyridin-2-yl ]-oxalamic acid ethyl ester or 2- [4- (3, 4-dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-2-yl-amino]- ethanol The afore-mentioned compounds of formulae IA and IB can be manufactured in accordance with the invention by a) reacting a compound of formula

with a compound of formula to a compound of formula

wherein Rl-R5 and R'have the significances given above and hal is bromo or chloro, or b) reacting a compound of formula with a compound of formula

to a compound of formula wherein R3-Rs have the significances given above, or c) reacting a compound of formula

with C1C (O) C (O) OCH2CH3 to a compound of formula

wherein R1, R3-R5 and R'have the significances given above, or d) reducing a compound of formula with an reducing agent, such as AlLiH4/THF to a compound of formula or to a compound of formula

wherein Rl, R3-R5 and R'have the significances given above, or e) reacting a compound of formula

with C1C (O) OCH2CH3 or with CH3C (O) Cl or with ClC (O)-phenyl or with CHOOH/CH20, respectively to give a compound of formula or of formula or of formula or of formula wherein R1, R and R'have the significances given above, or f) reacting a compound of formulae

with HCOOH/CH20 to give a compound of formulae

wherein Rl, R4, Rs and R'have the significances given above, and if desired, converting the compound of formula I obtained into a pharmaceutically acceptable salt.

In the following the preparation of compounds of formula IA and IB are described in more detail: In accordance with the process variants, described above, and with schemes 1-12, described below, compounds of formula IA and IB may be prepared by known procedures, for example by the followings : A mixture of a compound of formula IIA or IIB, for example 2-bromo-pyridin-4-yl- amine or 4-bromo-pyridin-2-yl-amine, respectively, and a compound of formula III, such as 1,2, 3,4-tetrahydro-isoquinoline is stirred at 150 °C for about 3 hr. After extractive workup the organic phase is dried and concentrated to give the free base of a compound of general formulae IA or IB.

Compounds of formula IIA1 may be prepared as follow: To a solution of a compound of formula IIA, for example 2-bromo-6-ethyl-pyridine (S. G.

Davies and M. R. Shipton, J. Chem. Soc., Perkin Trans. 1, 1991,3, 501) in acetic acid is added peracetic acid, maintaining T <50 °C. After complete addition the mixture is stirred at about 50 °C for 5 hr and then cooled to rt. Crushed ice is added and the pH is adjusted to pH 12 with aqueous KOH solution. After extraction the combined organic phases are

dried and evaporated to give the corresponding oxide of formula IVA. Then, with ice bath cooling HNOs is added dropwise, followed by H2SO4. The mixture is stirred at about 90 °C for 90 min and then cooled to rt. Crushed ice is added and the pH is adjusted to pH 12 with aqueous NaOH solution. After extraction the combined organic phases are dried and evaporated to give a compound of formula VA, wich is directly used in the next step. A solution of a compound of formula VA in acetic acid is treated with powdered iron. The mixture is slowly heated to 100 °C and kept for 1 hr at this temperature. Then the reaction mixture is cooled to rt and filtered. After evaporation of the solvent the residue is crystallized to yield a compound of formula IIA1.

The corresponding compounds of formula IA may be prepared as described above.

Furthermore, compounds of formula IIA2 may be prepared as follows: To a solution of a compound of formula VA1, for example 2-bromo-6-methyl-4-nitro- pyridine (A. Puszko, Pr. Nauk. Alcad. Ekon. im. Oskara Langego Wroclawiu, 1984,278, 169) in conc. H2SO4, CrO3 is added maintaining T <55 °C. After about 4 hr the mixture is heated to 70 °C for 30 min and then cooled to rt. Ice-cold water is added maintaining T <70 °C. The mixture is left overnight. A compound of formula VA2 is obtained. A corresponding solution of these compounds in THF is treated with borane/THF. The mixture is refluxed for 6 hr, then powdered iron is added, followed by acetic acid. Reflux is maintained for 6 hr, the mixture is filtered, evaporated, partitioned, dried and concentrated to give a compound of formula IIA2. The corresponding compounds of formulae IA may then be prepared as described above.

A compound of formula IIA3 may be prepared in the following way: With efficient ice bath cooling a compound of formula VI, for example 2-bromo-5,6, 7,8-tetrahydro- quinoline 1-oxide (S. Zimmermann et al., J. Am. Chem. Soc. , 1991,113, 183) is treated with conc. H2SO4, followed by conc. HN03. The resulting mixture is heated to about 90 °C for 90 min, cooled and poured on crushed ice. NaOH is added to reach pH 7 and the aqueous phase is extracted, dried and concentrated to yield a compound of formula VII.

A mixture of a compound of formula VII, for example 2-bromo-4-nitro-5,6, 7,8- tetrahydro-quinoline 1-oxide, powdered iron and acetic acid is heated to about 100 °C for 1 hr. After cooling the mixture is filtered, evaporated and the residue is partitioned. The organic phase is dried and concentrated to provide a compound of formula IIA3. The corresponding compounds of formulae IA1 may then be prepared as described above.

Furthermore, a compound of formulae IA3 or IB3 may be prepared by reaction of a compound of formula IA2 or IB2, with ethyl chlorooxoacetate. The obtained compound of formula IA3 or IB3 is then reacted with lithium aluminum hydride. After workup and chromatography the free base of a compound of formulae IA4 and IA5 or IB4 and IB5 may be obtained.

Compounds of formula IA9 or IB9 may be prepared as follows: A solution of a compound of formula IA2 or IB2, for example 2- (3, 4-dihydro-lH- isoquinolin-2-yl) -pyridin-4-yl-amine in formic acid is treated with aqueous formaldehyde solution. The mixture is refluxed for 1 hr followed by evaporation of the volatiles. The residue is partitioned and the organic phase is separated, dried and concentrated.

Compounds of formulae IA6, IB6, IA7, IB7, IA8 or IB8 may be obtained from a compound of formula IA2 or IB2 with ethyl chloroformate, acetylchloride or benzoyl chloride, respectively. These reactions are carried out in conventional manner.

In accordance with schemes 11 and 12, a compound of formula IAl1 or IB 11 or similar compounds may be prepared from a solution of a compound of formula IA10 or IB10, for example [2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl]-ethyl-amine, in formic acid This solution is treated with aqueous formaldehyde solution. The mixture is refluxed for 1 hr followed by evaporation of the volatiles. The residue is partitioned and the organic phase is separated, dried and concentrated to obtain a compound of formula IA11 or IBll.

Pharmaceutically acceptable salts can be manufactured according to methods which are known per se and familiar to any person skilled in the art. The acid addition salts of compounds of formula I are especially well suited for pharmaceutical use.

In the following schemes 1-12 are described processes for preparation of compounds of formula I, starting from known compounds, from commercial products or from compounds, which can be prepared in conventional manner.

The preparation of compounds of formulae IA and IB are described in more detail in working examples 1-35 Scheme 1 The substituents Rl to R5 and R are described above.

Scheme 2 The substituents R1 to R5 And R' are described above.

Scheme 3

The substituents Rl, R3 andR are described above.

Scheme 4

The substituents R1 and R3 are described above.

Scheme 5 %/0%/0- N N R. 1 R3 N N R3 H2SO4 R' R3 borane/THF HO Cr03 HO Fe/AcOH N Br 3 N Br N Br VA1 0 VA2 IIA2 VA1 y The substituents R'and R3 are described above.

Scheme 6

wherein R3 - R5 have the significances given above.

Scheme 7 The substituents RI, R3 - R5 and R'are described above.

Scheme 8 The substituents R1 and R3 - R5 are described above.

Scheme 9 The substituents R1 and R3 - R5 are described above.

Scheme 10 The substituents Rl, R3 - R5 and R'have been described above.

Scheme 11

The substituents Rl, R', R4, R5 and R6 have been described above.

Scheme 12

The substituents Rl, R4 and R5 are described above.

As mentioned earlier, the compounds of formula I and their pharmaceutically usable acid addition salts possess valuable pharmacodynamic properties. They are NMDA- receptor subtype 2B selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.

The compounds were investigated in accordance with the test given hereinafter.

Test method <BR> <BR> <BR> 3H-Ro 25-6981 binding (Ro 25-6981 is [R-(R*, S*)]-cc-(4-Hydroxy-phenyl)-ß-methyl-4-<BR> <BR> <BR> <BR> <BR> (phenyl-methyl)-1-piperidine propanol) Male Fullinsdorf albino rats weighing between 150-200 g were used. Membranes were prepared by homogenization of the whole brain minus cerebellum and medulla oblongata with a Polytron (10.000 rpm, 30 seconds), in 25 volumes of a cold Tris-HCl 50 mM, EDTA 10 mM, pH 7.1 buffer. The homogenate was centrifuged at 48, 00. 0 g for 10 minutes at 4 °C. The pellet was resuspended using the Polytron in the same volume of buffer and the homogenate was incubated at 37 °C for 10 minutes. After centrifugation the pellet was homogenized in the same buffer and frozen at-80 °C for at least 16 hours but not more than 10 days. For the binding assay the homogenate was thawed at 37 °C, centrifuged and the pellet was washed three times as above in a Tris-HCl 5 mM, pH 7.4 cold buffer. The final pellet was resuspended in the same buffer and used at a final concentration of 200 mg of protein/ml.

3H-Ro 25-6981 binding experiments were performed using a Tris-HCl 50 mM, pH 7.4 buffer. For displacement experiments 5 nM of 3H-Ro 25-6981 were used and non specific binding was measured using 10 mM of tetrahydroisoquinoline and usually it accounts for 10 % of the total. The incubation time was 2 hours at 4 °C and the assay was stopped by filtration on Whatmann GF/B glass fiber filters (Unifilter-96, Packard, Zürich, Switzerland). The filters were washed 5 times with cold buffer. The radioactivity on the

filter was counted on a Packard Top-count microplate scintillation counter after addition of 40 mL of microscint 40 (Canberra Packard S. A., Zürich, Switzerland).

The effects of compounds were measured using a minimum of 8 concentrations and repeated at least once. The pooled normalized values were analyzed using a non-linear regression calculation program which provide ICso with their relative upper and lower 95% confidence limits.

The IC50(µM) of preferred compounds of formula I, tested in accordance with the above mentioned methods, is < 0.02 µM. In the table below are shown some IC50 values of prefrred compounds: Example No. ICso (llM) 1 0.008 3 0.011 4 0.014 5 0.0053 6 0. 011 9 0.006 10 0.011 30 0.004 31 0.02 32 0.011 33 0.02 35 0. 004

The compounds of formula I and their salts, as herein described, can be incorporated into standard pharmaceutical dosage forms, for example, for oral or parenteral application with the usual pharmaceutical adjuvant materials, for example, organic or inorganic inert carrier materials, such as, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene-glycols and the like. The pharmaceutical preparations can be employed in a solid form, for example, as tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions. Pharmaceutical adjuvant materials can be added and include preservatives stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. The pharmaceutical preparations can also contain other therapeutically active substances.

The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in the range of about 0.1 mg per dosage to about 1000 mg per day of a compound of general formula I although the upper limit can also be exceeded when this is shown to be indicated.

The following examples illustrate the present invention in more detail. However, they are not intended to limit its scope in any manner. All temperatures are given in degree Celsius.

Example 1 2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl-amine 1: 1 hydrochloride A mixture of 2-bromo-pyridin-4-yl-amine (0.50 g, 2.9 mmol) and 1,2, 3,4-tetrahydro- isoquinoline (1. 1 g, 8.7 mmol) was stirred at 150 °C for 3 hr. After extractive workup (AcOEt/HzO) the organic phase was dried (Na2SO4), concentrated and chromatographed (Si02 with CH2Cl2/CH3OH/NH40H = 140/10/1) to give the free base of the title compound (0.39 g, 60 %) as a colorless oil. Treatment with hydrogen chloride gave white crystals. Mp. 252 °C (dec. ) (isopropanol/AcOEt), MS: m/e= 226 (M+H+).

Example 2 Rac. -2- (4-Methyl-3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl-amine 1 : 1 fumarate Following the general method described in example 1, the title compound was obtained as a white crystalline material by reaction of 2-bromo-pyridin-4-yl-amine with rac.-4-methyl- 1,2, 3, 4-tetrahydro-isoquinoline (G. Grunewald et al. , J. Med. Chem. , 1988,31, 433) and crystallization of the free base as the fumarate salt. Mp. 178-179 °C (MeOH/Et20), MS: m/e= 239 (M+).

Example 3 2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-5-methyl-pyridin-4-yl-amine 1: 1 fumarate Following the general method described in example 1, the title compound was obtained as a white crystalline material by reaction of 2-bromo-5-methyl-pyridin-4-yl-amine (A.

Puszko, Z. Talik, Pr. Nauk. Akad. Ekon. im. Oskara Langego Wroclawiu, 1980,167, 177) with 1,2, 3,4-tetrahydro-isoquinoline and crystallization of the free base as the fumarate salt. Mp. 110 °C (dec. ) (MeOH/Et2O), MS: m/e= 240 (M+H).

Example 4 2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-4-yl-amine 1 : 1 fumarate Following the general method described in example 1, the title compound was obtained as a white crystalline material by reaction of 2-bromo-6-methyl-pyridin-4-yl-amine (A.

Puszko, Pr. Nauk. Akad. Ekon. im. Oskara Langego Wroclawiu, 1984,278, 169) with 1,2, 3,4-tetrahydro-isoquinoline and crystallization of the free base as the fumarate salt. Mp.

110 °C (dec. ) (MeOH/Et2O), MS: m/e= 239 (Mt).

Example 5 2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-6-ethyl-pyridin-4-yl-amine 1: 1 fumarate a) 2-Bromo-6-ethyl-pyridine 1-oxide To a solution of 2-bromo-6-ethyl-pyridine (15.4 g, 82.8 mmol) (S. G. Davies and M. R.

Shipton, J. Chem. Soc., Perkin Trans. 1, 1991, 3,501) in acetic acid (15 ml) was added peracetic acid (26 ml of a 39 % solution) maintaining T <50 °C. After complete addition the mixture was stirred at 50 °C for 5 hr and then cooled to rt. Crushed ice (40 g) was added and the pH was adjusted to pH 12 with 40 % aqueous KOH solution. After extraction with CHCl3 (6 x 60 ml) the combined organic phases were dried (Na2CO3) and evaporated to give 20.0 g (>100 %) of the title compound, MS: m/e= 201 (M-,-) as a yellow oil. b) 2-Bromo-6-ethyl-4-nitro-pyridine 1-oxide With ice bath cooling HNO3 (100 %, 25 ml) was added dropwise to 2-bromo-6-ethyl- pyridine 1-oxide (example 5a) (20.0 g, 99 mmol), followed by H2SO4 (98 %, 17 ml). The mixture was stirred at 90 °C for 90 min and then cooled to rt. Crushed ice (500 g) was added and the pH was adjusted to pH 12 with 28% aqueous NaOH solution. After extraction with AcOEt (4 x 250 ml) the combined organic phases were dried (Na2CO3) and

evaporated to give 15.9 g (65 %) of a yellow solid mass which was directly used in the next step c) 2-Bromo-6-ethyl-pyridin-4-ylamine A solution of2-bromo-6-ethyl-4-nitro-pyridine 1-oxide (example 5b) (15.9 g, 69 mmol) in acetic acid (310 ml) was treated with powdered iron (25.8 g, 462 mmol). The mixture was slowly heated to 100 °C and kept for 1 hr at this temperature. Then the reaction mixture was cooled to rt and filtered. After evaporation of the solvent the residue was crystallized to yield the title compound as a beige material (88 %). Mp. 75-77 °C (pentane), MS: m/e= 200 (M). d) 2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-6-ethyl-pyridin-4-yl-amine 1 : 1 fumarate Following the general method described in example 1, the title compound was obtained as a white crystalline material by reaction of 2-bromo-6-ethyl-pyridin-4-yl-amine (example 5c) with 1,2, 3,4-tetrahydro-isoquinoline and crystallization of the free base as the fumarate salt. Mp. 140-141 °C (AcOEt), MS: m/e= 254 (M+H+).

Example 6 [4-Amino-6- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-2-yl]-methanol a) 6-Bromo-4-nitro-pyridine-2-carboxylic acid To a solution of 2-bromo-6-methyl-4-nitro-pyridine (17.8 g, 82.0 mmol) (A. Puszko, Pr.

Nauk. Akad. Ekon. im. Oskara Langego Wroclawiu, 1984,278, 169) in conc. H2SO4 (100 ml) Cr03 (32. 8 g, 328 mmol) was added maintaining T <55 °C. After 4 hr the mixture was heated to 70 °C for 30 min and then cooled to rt. Ice-cold water (500 ml) was added maintaining T <70 °C. The mixture was left overnight. The title compound crystallized as a beige material (76 %). Mp. 173-175 °C (H2O), MS: m/e= 246 (M+). b) (4-Amino-6-bromo-pyridin-2-yl)-methanol A solution of 6-bromo-4-nitro-pyridine-2-carboxylic acid (example 6a) (6.60 g, 29.1 mmol) in THF (150 ml) was treated with borane/THF (87 ml of a IM solution). The mixture was refluxed for 6 hr, then powdered iron (16.3 g, 291 mmol) was added, followed by acetic acid (150 ml). Reflux was maintained for 6 hr, the mixture was filtered, evaporated and partitioned (AcOEt/NaHCO3-solution). The organic phase was dried (Na2SO4), concentrated and chromatographed (Si02 with CH2Cl2/MeOH = 93/7) to provide 2.0 g (34 %) of (4-amino-6-bromo-pyridin-2-yl)-methanol as a white solid material. Mp. 144-145 °C (AcOEt), MS: m/e= 202 (M+).

c) (4-Amino-6- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-2-vll-methanol Following the general method described in example 1, the title compound was obtained as an off-white crystalline material by reaction of (4-amino-6-bromo-pyridin-2-yl)-methanol (example 6b) with 1,2, 3,4-tetrahydro-isoquinoline. Mp. 183-184 °C (AcOEt), MS: m/e= 255 (M-'-).

Example 7 2- (3, 4-Dihydro-1H-isoquinolin-2-yl)-5, 6,7, 8-tetrahydro-quinolin-4-yl-amine 1: 1 hydrochloride a) 2-Bromo-4-nitro-5, 6, 7, 8-tetrahydro-quinoline 1-oxide With efficient ice bath cooling 2-bromo-5,6, 7, 8-tetrahydro-quinoline 1-oxide (8.0 g, 35 mmol) (S. Zimmermann et al., J. Am. Chem. Soc. , 1991,113, 183) was treated with conc.

H2SO4 (65 ml), followed by conc. HNO3 (10 ml). The resulting mixture was heated to 90 °C for 90 min, cooled and poured on crushed ice (200 g). NaOH (28 %) was added to reach pH 7 and the aqueous phase extracted with AcOEt. The organic phase was dried (Na2SO4) and concentrated to yield 7.9 g (83 %) of the title compound as a yellow oil. MS: m/e= 272 (M+). b) 2-Bromo-5, 6, 7, 8-tetrahydro-quinolin-4-yl-amine A mixture of 2-bromo-4-nitro-5, 6,7, 8-tetrahydro-quinoline 1-oxide (example 7a) (7.9 g, 28.9 mmol), powdered iron (13.3 g, 238 mmol) and acetic acid (160 ml) was heated to 100 °C for 1 hr. After cooling the mixture was filtered and evaporated and the residue was partitioned (AcOEt/NaHC03-solution). The organic phase was dried (Na2SO4), concentrated and chromatographed (SiO2 with CH2Cl2/MeOH = 98/2) to provide 2.4 g (37 %) of the title compound as a brown solid material. MS: m/e= 226 (M+). c) 2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-5, 6, 7, 8-tetrahydro-quinolin-4-yl-amine 1 : 1 hydrochloride Following the general method described in example 1, the title compound was obtained as an off-white crystalline material by reaction of 2-bromo-5, 6,7, 8-tetrahydro-quinolin-4- ylamine (example 7b) with 1,2, 3,4-tetrahydro-isoquinoline and crystallization of the free base as the hydrochloride salt. Mp. 109-110 °C (MeOH/Et2O), MS: m/e= 279 (M').

Example 8 N- [2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-4-yl]-oxalam ic acid ethyl ester With ice bath cooling, a solution of ethyl chlorooxoacetate (2. 0 g, 14. 6 mmol) in THF (25 ml) was dropwise added to a solution of 2-(3, 4-dihydro-lH-isoquinolin-2-yl)-6-methyl- pyridin-4-yl-amine (example 4) (2.9 g, 12.1 mmol) in pyridine (40 ml). The mixture was stirred at 75 °C for lhr, evaporated and partitioned (AcOEt/NaHCO3-solution). The organic phase was dried (Na2SO4), concentrated and crystallized yielding 3.1 g (75 %) of the title compound as light brown solid. Mp. 128-129 °C (AcOEt), MS: m/e= 340 (M+H+).

Example 9 2- [2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl-amino]-ethanol 1: 1 hydrochloride a) N- [2-(3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yll-oxalamic acid ethyl esterl : 1 hydrochloride Following the general method described in example 8, the title compound was obtained as a white crystalline material by reaction of 2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4- ylamine (example 1) with ethyl chlorooxoacetate followed by crystallization of the hydrochloride salt. Mp. >187 °C (dec. ) (EtOH/Et2O), MS: m/e= 326 (M+H+). b) 2-l2-(3n4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl-aminol-e thanol 1: 1 hydrochloride A solution of N-[2-(3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl]-oxalamic acid ethyl ester (example 9a) (1.3 g, 4.1 mmol) in THF (41 ml) was cooled in an ice bath and lithium aluminum hydride (0.31 g, 8.2 mmol) was added in 5 portions. The mixture was refluxed for 2 hr, quenched with saturated aqueous Seignette-salt solution and diluted with AcOEt (200 ml). The organic phase was separated, dried (Na2SO4) and concentrated. After chromatography (SiO2 with CH2Cl2/CH3OH/NH4OH = 140/10/1) the free base of the title compound was obtained as a colorless oil (0.79 g, 72 %). Treatment with hydrogen chloride and triturating with hexane gave the title compound as a white hygroscopic foam.

MS: m/e= 270 (M+H+).

Example 10 2- [2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-4-yl-amino]- ethanol 1: 1 hydrochloride Following the general method described in example 9, N- [2- (3, 4-dihydro-lH-isoquinolin- 2-yl) -6-methyl-pyridin-4-yl] -oxalamic acid ethyl ester (example 8) was reacted with

lithium aluminum hydride. After workup and chromatography the free base of the title compound was treated with an aliquot of 0.1 N hydrochloric acid, filtered and freeze-dried.

MS: m/e= 284 (M+H+).

Example 11 2- [2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-5-methyl-pyridin-4-yl-amino]- ethanol 1: 1 fumarate a) N-F2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-5-methyl-pvridin-4-yll-oxalam ic acid ethyl ester Following the general method described in example 8, the title compound was obtained as a white crystalline material by reaction of 2- (3, 4-dihydro-lH-isoquinolin-2-yl)-5-methyl- pyridin-4-yl-amine (example 3) with ethyl chlorooxoacetate. Mp. 110-111 °C (AcOEt), MS: m/e= 340 (M+H+). b) 2-F2-(3, 4-Dihydro-lH-isoquinolin-2-yl)-5-methyl-pyridin-4-yl-aminol- ethanol 1 : 1 fumarate Following the general method described in example 9, N- [2- (3, 4-dihydro-lH-isoquinolin- 2-yl) -5-methyl-pyridin-4-yl] -oxalamic acid ethyl ester (example 11a) was reacted with lithium aluminum hydride. After workup and chromatography the free base of the title compound was treated with an aliquot of fumaric acid and crystallized as the white salt.

Mp. 232-233 °C (MeOH/EtzO), MS: m/e= 284 (M+H+).

Example 12 [2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl]-methyl-amine 1 : 1 fumarate a) (2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yll-carbamic acid ethyl ester 1: 1 hydrochloride In analogy to the general method described in example 8, the title compound was obtained by reaction of 2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl-amine (example 1) with ethyl chloroformate followed by crystallization of the white hydrochloride salt. Mp. >213 °C (dec) (MeOH/Et2O), MS: m/e= 298 (M+H+). b) 02-(3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yll-methyl-amine l : l fumarate Following the general method described in example 9, [2-(3,4-dihydro-1H-isoquinolin-2- yl) -pyridin-4-yl] -carbamic acid ethyl ester (example 12a) was reacted with lithium aluminum hydride. After workup and chromatography the free base of the title compound was treated with an aliquot of fumaric acid to yield a white crystalline material. Mp. 171- 172 °C (MeOH/Et20), MS: m/e= 239 (M+).

Example 13 [2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl]-dimethyl-amine 1 : 1 fumarate A solution of 2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-y-lamine (example 1) (2.3 g, 10.0 mmol) in formic acid (16 ml) was treated with aqueous formaldehyde solution (8ml of a 40 % solution). The mixture was refluxed for 1 hr followed by evaporation of the volatiles. The residue was partitioned (AcOEt/NaHCO3-solution) and the organic phase was separated, dried (Na2SO4) and concentrated. After chromatography (SiO2 with CH2CI2/CH3OH/NH4OH = 300/10/1) the free base of the title compound was obtained as a colorless oil (1.44 g, 57 %). It was crystallized as the white fumarate salt. Mp. 177-178 °C (MeOH/Et2O), MS: m/e= 254 (M+H+).

Example 14 5- (3, 4-Dihydro-lH-isoquinolin-2-yl)-l-methyl-1, 4-dihydro-2H-pyrido [4,3- d] [1, 3] oxazine 1 : 1 hydrochloride The free base of the title compound was obtained as a minor (less polar) product (0.54 g, 19 %) in the synthesis of [2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl]-dimethyl- amine (example 13). It was crystallized as the white hydrochloride salt. Mp. 220-221 °C (MeOH/Et2O), MS: m/e= 282 (M+H'-).

Example 15 N- [2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl]-acetamide 1 : 1 hydrochloride In analogy to the general method described in example 8, the title compound was obtained by reaction of 2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-ylamine (example 1) with acetyl chloride followed by crystallization of the white hydrochloride salt. Mp. 229-230 °C (MeOH/Et2O), MS: m/e= 267 (M+).

Example 16 [2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl]-ethyl-amine 1: 1 fumarate Following the general method described in example 9, N- [2- (3, 4-dihydro-lH-isoquinolin- 2-yl)-pyridin-4-yl]-acetamide (example 15) was reacted with lithium aluminum hydride.

After workup and chromatography the free base of the title compound was treated with an aliquot of fumaric acid and crystallized as the white salt. Mp. 73-74 °C (MeOH/Et2O), MS: m/e= 254 (M+).

Example 17 Benzyl- [2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl]-amine a) N-f2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-4-yll-benzamide In analogy to the general method described in example 8, the title compound was obtained by reaction of 2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl-amine (examplel) with benzoyl chloride followed by crystallization of the free base. Mp. 139-140 °C (AcOEt/iPr2O), MS: m/e= 330 (M+H+). b) Benzyl- [2- (3. 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yll-amine Following the general method described in example 9, N- [2- (3, 4-dihydro-lH-isoquinolin- 2-yl)-pyridin-4-yl]-benzamide (example 17a) was reacted with lithium aluminum hydride.

After workup and chromatography the free base of the title compound was treated with hydrogen chloride and triturated with Et2O/pentane. The title compound was obtained as white amorphous material. MS: m/e= 315 (M+).

Example 18 6-(3, 4-Dihydro-lH-isoquinolin-2-yl)-4-methyl-pyridin-2-yl-amine 1: 1 hydrochloride Following the general method described in example 1, the title compound was obtained as a white crystalline material by reaction of 6-bromo-4-methyl-pyridin-2-yl-amine (F.

Johnson et al. , J. Org. Chem. , 1962,27, 2473) with 1,2, 3,4-tetrahydro-isoquinoline and crystallization of the free base as the hydrochloride salt. Mp. 196-197 °C (MeOH/Et2O), MS: m/e= 240 (M+H+).

Example 19 6- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-2-yl-amine 1: 1 hydrochloride Following the general method described in example 1, the title compound was obtained as a light brown crystalline material by reaction of 6-bromo-pyridin-2-yl-amine with 1,2, 3,4- tetrahydro-isoquinoline and crystallization of the free base as the hydrochloride salt. Mp.

177-178 °C (MeOH/EtzO), MS: m/e= 225 (M+).

Example 20 2- (4-Methyl-pyridin-2-yl)-1, 2,3, 4-tetrahydro-isoquinoline 1: 1 hydrochloride Following the general method described in example 1, the title compound was obtained as a white crystalline material by reaction of 2-bromo-4-methyl-pyridine with 1,2, 3,4-

tetrahydro-isoquinoline and crystallization of the free base as the hydrochloride salt. Mp.

142-143 °C (MeOH/Et2O), MS: m/e= 224 (M+).

Example 21 2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-3-yl-amine 1: 1 hydrochoride a) 2- (3-Nitro-pyridin-2-yl)-1, 2, 3, 4-tetrahydro-isoquinoline A suspension of 2-chloro-5-nitro-pyridine (1.58 g, 10 mmol) in isopropanol (30 ml) was treated at rt with 1,2, 3,4-tetrahydro-isoquinoline (2.6 g, 20 mmol). The resulting mixture was stirred for 3 hr. The precipitate was filtered, partitioned (AcOEt/H2O) and the organic phase dried (Na2SO4). After evaporation of the solvent the title compound was obtained as a yellow solid mass (1.4 g, 55 %), MS: m/e= 256 (M+H+). b) 2- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-3-yl-amine 1: 1 hydrochoride To a solution of 2- (3-nitro-pyridin-2-yl)-1, 2,3, 4-tetrahydro-isoquinoline (example 21a) (1.4 g, 5.5 mmol) in methanol (50 ml) palladium on carbon (10 %, 140 mg) was added and the resulting mixture was hydrogenated for 24 hr. After filtration of the catalyst, the reaction mixture was concentrated and chromatographed (SiO2 with hexane/AcOEt = 4/1) to yield the free base of the title compound (0.64 g, 52 %) as a brown oil. Treatment with hydrogen chloride gave white crystals. Mp. 195-196 °C (MeOH/Et20), MS: m/e= 225 (M+).

Example 22 C- [6- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-2-yl]-methylamine hydrochloride (1: 2) a) 6- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridine-2-carboxylic acid amide Following the general method described in example 1, the title compound was obtained as a light yellow crystalline material by reaction of 6-chloro-pyridine-2-carboxylic acid amide with 1,2, 3,4-tetrahydro-isoquinoline and crystallization of the free base. Mp. 145-150 °C (AcOEt/hexane), MS: m/e= 253 (M+). b) C-f6- (3, 4-Dihydro-1 H-isoquinolin-2-yl)-pyridin-2-yll-methylamine hydrochloride ( 1: 2) Following the general method described in example 9, 6- (3, 4-dihydro-lH-isoquinolin-2- yl)-pyridine-2-carboxylic acid amide (example 22a) was reacted with lithium aluminum hydride. After workup and chromatography the free base of the title compound was treated with hydrogen chloride and crystallized as the off white salt. Mp. 192-195 °C (iPr20), MS: m/e= 239 (M+).

Example 23 5- (3, 4-Dihydro-lH-isoquinolin-2-yl)-l-ethyl-1, 4-dihydro-2H-pyrido [4, 3-d] [1, 3] oxazine 1 : 1 hydrochloride A solution of [2- (3, 4-dihydro-lH-isoquinolin-2-yl)-pyridin-4-yl]-ethyl-amine (example 16) (0.8 g, 3.1 mmol) in formic acid (16 ml) was treated with aqueous formaldehyde solution (8ml of a 40 % solution). The mixture was refluxed for 1 hr followed by evaporation of the volatiles. The residue was partitioned (AcOEt/NaHC03-solution) and the organic phase was separated, dried (Na2S04) and concentrated. After chromatography (SiOz with CH2CI2/CH30H/NH40H = 400/10/1) the free base of the title compound was obtained as a colorless oil (0.74 g, 81 %). It was crystallized as the white hydrochloride salt.

Mp. 197-198 °C (MeOH/Et2O), MS: m/e= 295 (Mt).

Example 24 2-Pyridin-4-yl-1,2, 3,4-tetrahydro-isoquinoline A mixture of 4-chloro-pyridine 1 : 1 hydrochloride (24.5 g, 163 mmol) and 1,2, 3,4- tetrahydro-isoquinoline (65.3 g, 490 mmol) was slowly heated to 150 °C. After 30 min the reaction mixture was cooled to rt, H2O (700 ml) and 2N NaOH (82 ml) was added followed by extraction with AcOEt (5 times 300 ml). The combined organic phases were dried (Na2SO4), and the solvent was evaporated. After trituration with pentane and recrystallization the title compound (30.2 g, 88 %) was obtained as a light brown crystalline material. Mp. 95-96 °C (AcOEt), MS: m/e= 210 (Mt).

Example 25 5-Chloro-2-pyridin-4-yl-1, 2,3, 4-tetrahydro-isoquinoline 1 : 1 hydrochloride A mixture of 4-bromo-pyridine 1: 1 hydrochloride (0.95 g, 4.9 mmol), 5-chloro-1, 2,3, 4- tetrahydro-isoquinoline (C. Kaiser et al., J. Med. Chem. , 1980,23, 506) (0.99 g, 4.9 mmol) and Na2CO3 (1.8 g, 17 mmol) in N-methyl-pyrrolidinone (15 ml) was stirred at 170 °C for 3.5 hr. All volatiles were evaporated (at 50 °C, 0. 01 mbar) and the residue was partitioned (AcOEt/H2O). The organic phase was dried (Na2SO4), concentrated and chromatographed (Si02 with CH2CI2/CH3OH/NH40H = 250/10/1). The free base of the title compound was obtained as a light brown crystalline material (0.71 g, 59 %). It was crystallized as the white hydrochloride salt. Mp. 258-259 °C (MeOH/Et20), MS: m/e= 244 (M+).

Example 26 8-Chloro-2-pyridin-4-yl-1, 2,3, 4-tetrahydro-isoquinoline 1 : 1 fumarate Following the general method described in example 25, the free base of the title compound was obtained by reaction of 4-bromo-pyridine 1: 1 hydrochloride with 8-chloro-1, 2,3, 4- tetrahydro-isoquinoline (C. Kaiser et al. , J. Med. Chem. , 1980,23, 506) and Na2CO3 in N-

methyl-pyrrolidinone. It was crystallized as the light yellow fumarate salt. Mp. 178-179 °C (MeOH), MS: m/e= 244 (Mt).

Example 27 6-Chloro-2-pyridin-4-yl-1, 2,3, 4-tetrahydro-isoquinoline 1: 1 hydrochlorid Following the general method described in example 25, the free base of the title compound was obtained by reaction of 4-bromo-pyridine 1 : 1 hydrochloride with 6-chloro-1, 2,3, 4- tetrahydro-isoquinoline (C. Kaiser et al. , J. Med. Chem. , 1980, 23, 506) and Na2CO3 in N- methyl-pyrrolidinone. It was crystallized as the light brown hydrochloride salt. Mp. >250 °C (MeOH/Et20), MS: m/e= 245 (M+H).

Example 28 7-Chloro-2-pyridin-4-yl-1,2, 3,4-tetrahydro-isoquinoline In analogy to the general method described in example 25, the title compound was obtained as a white crystalline material by reaction of 4-chloro-pyridine 1: 1 hydrochloride with 7-chloro-1, 2,3, 4-tetrahydro-isoquinoline (C. Kaiser et al. , J. Med. Chem. , 1980,23, 506) and Cs2CO3 in DMF. Mp. 100-101 OC (AcOEt/pentane), MS: m/e= 244 (M+).

Example 29 rac.-4-Methyl-2-pyridin-4-yl-1, 2,3, 4-tetrahydro-isoquinoline 1: 1 hydrochloride Following the general method described in example 25, the free base of the title compound was obtained by reaction of 4-bromo-pyridine 1: 1 hydrochloride with rac.-1-methyl- 1,2, 3,4-tetrahydro-isoquinoline (G. Grunewald et al. , J. Med. Chem. , 1988,31, 433) and Na2CO3 in N-methyl-pyrrolidinone. It was crystallized as the off-white hydrochloride salt.

Mp. 224-227 °C (MeOH/Et2O), MS: m/e= 224 (M+).

Example 30 4- (3, 4-Dihydro-lH-isoquinolin-2-yl)-pyridin-2-yl-amine Following the general method described in example 24,4-bromo-pyridin-2-yl-amine (H. J. den Hertog, Recl. Trav. Chim. Pays-Bas, 1945, 64,85) was reacted with 1,2, 3,4-tetrahydro- isoquinoline. The crude product was chromatographed (SiO2 with CH2C12/CH30H/NH40H = 200/10/1) and crystallized to yield the title compound as an off-white crystalline material. Mp. 160-161 °C (CH3CN), MS: m/e= 226 (M+H+).

Example 31 2- (2-Methyl-pyridin-4-yl) -1, 2,3, 4-tetrahydro-isoquinoline 1 : 1 fumarate Following the general method described in example 24,4-bromo-2-methyl-pyridine (S.

Ochiai, Pharm. Bull. , 1954,2, 147) was reacted with 1,2, 3,4-tetrahydro-isoquinoline. The

crude product was chromatographed (SiOz with CH2Cl2/CH30H/NH40H = 200/10/1) and crystallized as the white fumarate salt. Mp. 155-156 °C (MeOH/Et20), MS: m/e= 225 (M+H+).

Example 32 4-(3, 4-Dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-2-yl-amine 1: 1 fumarate a) 4-Bromo-6-methyl-pyridin-2-yl-amine A mixture of 2, 4-dibromo-6-methyl-pyridine (J. Bernstein et al. , J. Amer. Chem. Soc., 1947,69, 1147) (22.6 g, 90 mmol) and aqueous ammonia (25 %, 260 ml) was stirred in an autoclave at 160 °C for 4 hr. The reaction mixture was cooled to rt and extracted with Et20.

The organic phase was dried (Na2SO4), concentrated and chromatographed (Si02 with AcOEt/hexane/NEt3 = 10/30/1) to yield the title compound as a white crystalline material (4.0 g, 6%). NMR (250 MHz, DMSO): 6 = 3.33 (s, 3H, CH3), 6.13 (s, broad, 2H, NH2), 6.44 (s, 1H, arom-H), 6.54 (s, 1H, arom-H). b) 4- (3, 4-Dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-2-yl-amine 1 : 1 fumarate Following the general method described in example 24,4-bromo-6-methyl-pyridin-2-yl- amine (example 32a) was reacted with 1,2, 3,4-tetrahydro-isoquinoline. The crude product was chromatographed (SiO2 with CH2Cl2/CH3OH/NH4OH = 200/10/1) and crystallized as the white fumarate salt. Mp. >270 °C (MeOH), MS: m/e= 240 (M+H+).

Example 33 N- [4- (3, 4-Dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-2-yl]-oxalam ic acid ethyl ester 1 : 1 hydrochloride Following the general method described in example 8, the title compound was obtained as a light yellow crystalline material by reaction of4- (3, 4-dihydro-lH-isoquinolin-2-yl)-6- methyl-pyridin-2-yl-amine (example 32) with ethyl chlorooxoacetate followed by <BR> <BR> <BR> crystallization of the hydrochloride salt. Mp. >160 °C (dec. ) (EtOH/Et2O), MS: m/e= 340<BR> <BR> <BR> <BR> <BR> <BR> (M+H+).

Example 34 N- [4- (3, 4-Dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-2-yl]-2-hydr oxy-acetamide A solution of N- [4- (3, 4-dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-2-yl]-oxalam ic acid ethyl ester (example 33) (0.43 g, 1.3 mmol) in THF (20 ml) was cooled in an ice bath and lithium aluminum hydride (0.12 g, 3.2 mmol) was added in. The mixture was stirred at rt for 2 hr, quenched with saturated aqueous Seignette-salt solution and filtered. The organic phase was dried (Na2SO4) and concentrated. After chromatograpy (Si02 with

CH2C12/CH3OH/NH4OH = 200/10/1) the title compound was obtained as a colorless oil (0.18 g, 47 %). Mp. 160-162 °C (AcOEt), MS: m/e= 296 (M-H-).

Example 35 2- [4- (3, 4-Dihydro-lH-isoquinolin-2-yl)-6-methyl-pyridin-2-yl-amino]- ethanol 1 : 1 fumarate Following the general method described in example 9, N- [4- (3, 4-dihydro-lH-isoquinolin- 2-yl) -6-methyl-pyridin-2-yl] -oxalamic acid ethyl ester (example 33) was reacted with lithium aluminum hydride. After workup and chromatography the free base of the title compound was treated with an aliquot of fumaric acid and crystallized as the white salt.

Mp. 160 °C (MeOH), MS: m/e= 284 (M+H'').

Example A Tablet Formulation (Wet Granulation) Item Ingredients mg/tablet 5 mg 25 mg 100mg 500mg 1. Compound of formula 1 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1111 Total 167 167 167 831 Manufacturing Procedure 1 Mix items 1, 2,3 and 4 and granulate with purified water.

2. Dry the granulation at 50 °C.

3. Pass the granulation through suitable milling equipment.

4. Add item 5 and mix for three minutes; compress on a suitable press.

Example B Capsule Formulation Item Ingredients mg/capsule 5 mg 25mg 100mg 500mg 1. Compound of formula 1 5 25 100 500 2. Hydrous Lactose 159 123 148--- 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600 Manufacturing Procedure 1 Mix items 1,2, and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

4. Add item 5 and mix for three minutes; compress on a suitable press.