WO1999024435A1

WO1999024435A1 - Azachromachalime derivatives having hypotensive activity

Info

Publication number: WO1999024435A1
Application number: PCT/HU1998/000095
Authority: WO
Inventors: Géza TIMÁRI; Zsuzsanna Riedl; Sándor BÁTORI; György Hajós; Anikó MIKLÓSNÉ KOVÁCS; Gábor SZÉNÁSI; Katalin IVANICSNÉ MEGYERI; János WELLMAN; András Egyed; Mária SZÉCSEYNÉ HEGEDU^'S; Ildikó NAGYNÉ GYÖNÖS; Szabolcs KERTÉSZ; Katalin Pallagi; Károly TIHANYI
Original assignee: EGIS Gyógyszergyár Rt.
Priority date: 1997-11-06
Filing date: 1998-11-06
Publication date: 1999-05-20
Also published as: HU9701865D0; HUP9701865A3; AU1253699A; HUP9701865A2

Abstract

The invention relates to new pyrano[3.2-c]pyridine derivatives of general Formula (IA), their quaternary derivatives of general Formula (IB), their unsaturated derivatives of general Formula (IC) and salts thereof (wherein R6 is amino, -CH¿2?COR or -N=CH-NR?IVRV; A-¿ is the anion of an organic or inorganic acid. R1 stands for a group of general formula (A), (B) or (C); R3 represents hydrogen, optionally substituted aralkyl or acyl; with the proviso that if in compounds of general Formula (ISA), R1 is a group of general Formula (A), R3 is other than hydrogen). The compounds of the invention may be used in therapy due to their valuable hypotensive properties.

Description

AZACHROMACHALBVIE DERIVATIVES HAVING HYPOTENSIVE ACTIVITY

This invention relates to new azachromachalime derivatives.

In principle there are four different types of so-called "azachromachalime ring moieties", namely the pyrano[2.3-c]pyridine, pyrano[3.2-c]pyridine, pyrano[2.3- bjpyridine and pyrano[3.2-b]pyridine ring. The present invention relates to new pyrano[3.2-c]pyridine derivatives.

The preparation of derivatives comprising a pyrano[3.2- c]pyridine ring structure was published in prior art [J. M. Evans, G. Stemp, Synth. Commun., 18, 1119, (1988); G. F. Hemmion, J. J. Sheehan, D. E. Maloney, J. Am. Chem. Soc, 72, 3542, (1950); J. Read, W. G. Reid, J. Chem. Soc, 1928, 1487]. Said derivatives were examined as so-called azachromachalime analogues. Thus derivatives containing a lactame ring in position 4 [G. Burrell, F. Cassidy, D. Lightowler, G. Stemp, J. Med. Chem., 33, 3023 (1990)], an acylated or alkylated hydroxy group in position 3 [G. Stemp et al., EPA-2-0 399 834] and an unsaturated bond in positions 3,4 [D. R. Buckle, J. R. S. Arch, A. E. Fenwick, C. S. V. Houge-Frydrych, I.L Pinto, D. G. Smith, S. G. Taylor es J. M. Tedder, J. Med. Chem., 33, 3028 (1990)] were described.

It has been found that compounds comprising a secondary amino group in position 4 of the pyrano[3.2- c]pyridine ring system, functional derivatives thereof formed by acylation or reaction with isocyanate (i.e. acylamido and urea derivatives, respectively) and derivatives comprising in the place of the hydroxy group an aralkyl group attached through an ether bond in position 3 are new and possess very favourable therapeutical properties. It has been found furtheron that derivatives quaternerized on the nitrogen atom of the pyridine ring by an amino or alkyl group are also new compounds having advantageous therapeutical activity. The present invention relates to

- the above new compounds;

- a process for the preparation of said new compounds;

- pharmaceutical compositions comprising said new compounds;

- use of said compounds for the preparation of hypotensive pharmaceutical compositions and for the treatment of high blood-pressure.

According to an aspect of the present invention there are provided pyrano[3.2-c]pyridine derivatives of the general Formula

quaternary derivatives of the general Formula

thereof, unsaturated derivatives of the general Formula

thereof and salts of said compounds.

In the above general Formula n is 3, 4 or 5;

A- is the anion of an organic or inorganic acid; R¹ stands for a group of the general Formula

R"

or R"

/

R"

R represents hydrogen, optionally substituted aralkyl or acyl; R⁶ is amino, -CH₂COR or -N=CH-NR^IVR^V; R stands for alkoxy, optionally substituted aryl or optionally substituted amino; R' and R" independently from each other stand for hydrogen, optionally substituted alkyl, cycloalkyl, aralkyl or aryl; R"' represents acyl or substituted carbamoyl; R^lv and R^v independently from each other stand for hydrogen, alkyl, aryl or aralkyl or -NR^IVR^V forms a 5-7 membered nitrogen-containing heterocycle; with the proviso that if in compounds of the general Formula IA R¹ is a group of the general Formula A, R³ is other than hydrogen.

The term "alkyl" used in the present patent specification relates to straight or branched chained saturated hydrocarbon groups having 1-6 carbon atoms, preferably 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, n-butyl, isobutyl, n-hexyl etc.). The term "alkoxy" relates to such alkyl groups as defined above attached through an oxygen atom. The term "aryl" relates to mono- or bicyclic aromatic hydrocarbon group (e.g. phenyl, naphthyl, anthryl etc.). The term "aralkyl" relates to alkyl groups as defined above substituted by one or two aryl group(s) (e.g. benzyl, beta-phenyl-ethyl, beta, beta-diphenyl- ethyl etc.).

The alkyl groups may be optionally substituted e.g. by halogen, hydroxy, alkanoyloxy or 5-7 membered nitrogen containing heterocyclic ring (e.g. acetoxymethyl, acetoxyethyl, hydroxy ethyl, pyrrolidino ethyl etc.). The aralkyl and aryl rings may optionally bear one or more substituents, e.g. halogen, alkoxycarbonyl, alkyl or alkanoyl (e.g. o-methyl-benzyl, p_- chloro-benzyl, o-chloro-benzyl, p_-ethoxycarbonyl-benzyl, ρ_- fluoro-benzyl, o-fiuoro-benzyl etc.),

The term "cycloalkyl" relates to 3-8-membered saturated cyclic hydrocarbon groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.).

The term "acyl" relates to acyl groups derived from aliphatic (e.g. acetyl, propionyl, butyryl etc.), aromatic (e.g. benzoyi or substituted benzoyi such as halogeno benzoyi) or heterocyclic (e.g. nicotinoyl) carboxylic acids.

The substituent of the "substituted carbamoyl" groups may be e.g. halogen (e.g. chlorine or fluorine), alkyl (e.g. methyl), or optionally substituted phenyl (e.g. phenyl substituted by fluorine, chlorine, alkyl or alkoxy).

The anion of an inorganic or organic acid (A-) may be e.g. a chloride, bromide, fluoroborate, mesylate, brosylate or tosylate anion.

The pharmaceutically acceptable salts of the compounds according to the present invention may be formed with inorganic or organic acids (e.g. hydrogen halides such as hydrochloric acid or hydrogen bromide; suifuric acid, phosphoric acid, acetic acid, tartaric acid, succinic acid, malic acid, maleic acid, fumaric acid, citric acid, lactic acid etc.). in a preferred group of the compounds of the present invention R¹ is a group of the general Formula A. n is preferably 4.

In preferred compounds R³ stands for o-methyl-benzyl.

Compounds of the general Formula IB are preferred in which R⁶ is amino, R³ stands for hydrogen or p_-chloro-benzyl and A" is bromide.

The following compounds of the general Formula IA and IB possess particularly advantageous properties: trans-3,4-dihydro-6-amino-2,2-dimethyl-3-hydroxy-4-(2- oxo-piperidine-1-yl)-2H-pyrano[3,2-c]-pyridinium-bromide; trans-3,4-dihydro-6-amino-2,2-dimethyl-3-(4'-chloro- benzyloxyl)-4-(2-oxo-piperidine-1-yl)-2H-pyrano[3,2-c]- pyridinium-bromide; trans-3,4-dihydro-2,2-dimethyl-3-(o-methyI-benzyloxy)- 4-(2-oxo-piperidine-1-yl)-2H-pyrano[3,2-c]-pyridine.

According to a further aspect of the present invention there is provided a process for the preparation of compounds of the general Formulae IA, IB and IC and salts thereof which comprises a) reacting a compound of the Formula

with an amine of the general Formula

HNR'R" (X) or b) quaternerizing a compound of the general Formula

with an agent capable of introducing an R⁶ group; or c) quaternerizing a compound of the general Formula

R¹

with an agent capable of introducing an R group; or d) aralkylating or acylating a compound of the general Formula IA or

in which R _3 : is hydrogen; or e) reacting a compound of the general Formula IB, wherein R⁶ stands for -CH₂COOAIkyl, with an amine of the general Formula X; or f) acylating a compound of the general Formula IA or IB wherein R¹ stands for a group of the general Formula

_{/ R}" — N_χ (C)

R' or g) reacting a compound of the general Formula IB, wherein R⁶ stands for amino, with a trialkyl ortho formate and an amine of the general Formula

HNR^IVR (XI) h) if desired carrying out anion-exchange in a compound of the general Formula IB; and/or i) if desired converting a compound of the general Formula IA, IB or IC into a salt thereof.

According to process a) a compound of the Formula IX is reacted with an amine of the general Formula X. In this reaction compounds of the general Formula IA are obtained wherein R¹ is a group of the general Formula C and R³ stands for hydrogen. The starting material of the Formula IX is known [J. M. Evans, G. Stemp, Synth. Commun., 18, 1119 (1988)]. The reaction may be carried out in a polar aprotic solvent (e.g. dimethyl formamide, acetonitrile, tetrahydrofurane, hexamethyl phosphoric acid triamide). The reaction may be performed under heating, preferably under reflux. The reaction time is 24- 48 hours.

The reaction mixture may be worked up by usual methods. One may proceed by reacting the amine of the general Formula X at first with sodium hydride and reacting the sodium salt of the amine thus formed with the compound of the Formula IX.

According to process b) a compound of the general Formula IA is reacted with an agent capable of introducing an R⁶ group to yield a compound of the general Formula IB.

R⁶ as amino can be introduced into a compound of the general Formula IA advantageously by reaction with tosyl hydroxyl amine. The reaction may be carried out in an aprotic solvent (e.g. dichloro methane) at a temperature between -10°C and +20°C. The reaction time is between 20 minutes and 4 hours. The reaction mixture may be worked up by usual methods. One may proceed by filtering the reaction mixture and evaporating the filtrate. According to another method the tosylate anion of the compound of the general Formula IB obtained is replaced by a fluoroborate anion by reacting with fluoro boric acid. Thus fluoro borate salts are obtained which are more readily crystaliizable and can be purified more easily.

According to a further embodiment of process b) the group of the Formula -CH₂-COR (R⁶) is introduced by reacting a compound of the general Formula IA with a suitable agent such as ethyl bromo acetate or phenacyl bromide etc. Said agent is used preferably in a 1-2 molar excess. The reaction may be carried out in a polar aprotic solvent (e.g. acetonitrile, dimethyl formamide, tetrahydrofurane) at a temperature of 50-100°C. One may work preferably under reflux. The reaction time is 1-4 hours. The reaction mixture may be worked up by usual methods (e.g. evaporation).

According to process c) a compound of the general Formula VII is quatemerized with an agent capable of introducing an R⁶ group. Thus compounds of the general Formula IC are obtained. The reaction may be carried out as described in connection with process b).

According to process d) a compound of the general Formula IA or IB, wherein R³ is hydrogen, is aralkylated or acylated. Thus compounds of the general Formula IA or IB, respectively, are obtained, wherein R³ is optionally substituted aralkyl or acyl.

The aralkyl group is introduced by reacting a 3-hydroxy compound of the general Formula IA or IB preferably in the presence of a proton acceptor. The aralkyl group may be introduced with the aid of the corresponding aralkyl halide, preferably bromide. As proton acceptor e.g. sodium hydride or tertiary amines (e.g. triethyl amine) may be used. The reaction may be performed in an aprotic polar solvent (e.g. dimethyl formamide, tetrahydrofurane, acetonitrile). The reaction may be carried out at 0-40°C, preferably at room temperature. The reaction time is 2-8 hours, preferably about 4 hours. The alkylating agent may be used in an excess (2-10 molar excess). The reaction mixture may be worked up by conventional methods (e.g. pouring into water, extraction).

The 3-hydroxy compounds may be acylated by methods known per se by using conventional acylating agents. For this purpose e.g. acid chlorides, acid anhydrides or mixed anhydrides may be used.

According to process e) compounds of the general Formula IB, wherein R⁶ stands for a group of the Formula -CH₂-COOAIkyl, are reacted with an amine of the general Formula X to yield compounds of the general Formula IB, wherein R⁶ stands for a group of the Formula -CH₂-CONR'R". The reaction may be carried out in a polar aprotic solvent (e.g. acetonitrile, dimethyl formamide etc.). The reaction time is 1-3 days. One may work under heating, preferably under reflux.

According to process f) a compound of the general Formula IA or IB, wherein R¹ stands for a group of the Formula C, is acylated to yield a compound of the general Formula IA or IB, respectively, wherein R is a group of the Formula B. As starting material compounds of the general Formula IA or IB are used in which R' is hydrogen. Acylation may be carried out by methods known per se. As acylating agent preferably acid chlorides, acid anhydrides or mixed anhydrides may be used. Acylation with acid chlorides may be performed in the presence of an acid binding agent (e.g. tertiary amines, such as triethyl amine). The reaction may be accomplished in an apolar solvent (e.g. dichloro methane). By using an isocyanate as acylating agent, the corresponding urea derivative is obtained. The reaction of the amino compound and the isocyanate is carried out in an aprotic solvent (e.g. dichloro methane) under cooling (e.g. at 0-10°C). The reaction time is 2-6 hours. The reaction mixture may be worked up by known methods (e.g. evaporation).

According to process g) a compound of the general Formula IB, wherein R⁶ stands for amino, is reacted with a trialkyl ortho formate and an amine of the general Formula XI. Thus compounds of the general Formula IB are obtained, wherein R⁶ represents a group of the Formula -N=CH-NR^IVR^V. The reaction may be carried out in an organic solvent (e.g. acetonitrile) under heating, preferably under reflux. To the solution of the amino compound at first the trialkyl ortho formate (advantageously triethyl ortho formate) and thereafter under heating the amine of the general Formula XI is added. The reaction mixture may be worked up by conventional methods (e.g. cooling, filtration etc.).

According to process h) the anion exchange and according to process i) salt formation is carried out by methods known per se.

The starting material of the Formula IX is known and can be converted into a compound of the general Formula IA, where R¹ stands for a group of the Formula A and R³ represents hydrogen, by known methods [J. M. Evans, G. Stemp. Synth. Commun., 18, 1119, (1988)]. The starting materials of the general Formula VII are known too [D. R. Buckle, J. R. S. Arch, A. E. Fenwick, C. S. V. Houge-Frydrych, I. L. Pinto, D. G. Smith, S. G. Taylor and J. M. Tedder: J. Med. Chem., 33, 3028 (1990)].

The new azachromachalime derivatives of the invention have valuable hypotensive effect superior to that of chromachalime. The compounds of the invention increased heart rate to a lesser extent than chromachalime at doses that caused the same degree of hypotension as induced by chromachalime.

The compounds of the invention have valuable biological activity. Experiments in conscious rats showed that the compounds lowered blood pressure to a significantly greater extent than chromachalime. Moreover, they caused surprisingly less reflex tachycardia, that usually accompanies hypotension, than that observed after treatment with the reference compound. Considering their chemical structure, the compounds likely are ATP related K⁺-channel openers. Compounds having this mechanism of action may relax smooth muscle cells not only in blood vessel wall but also in other organs.

As to the above mentioned mechanism of action, the compounds of the invention may be suitable for treatment of diseases either caused by pathological smooth muscle contraction or which develop due to increased smooth muscle tone or spasm. The compounds decreased blood pressure by relaxing smooth muscle in blood vessels but the simultaneous increase in heart rate that is a general characteristic of vasorelaxant agents was small or absent. That is why the molecules may potentially be useful for the treatment of hypertension. In addition, their vasorelaxant effect may be suitable for the treatment of pulmonary hypertension either derived from the insufficient activity of the right ventricle or developed independently of that, and for the treatment of spasm of coronary vessels (angina pectoris), for treatment of brain vessel spasms of different origin and for acute or chronic neurodegenerative changes caused by them, for enhancing the insufficient blood flow originating from kidney diseases, or for treatment of other peripheral blood vessel diseases. Their smooth muscle relaxing effect may be used for relieving bronchus spasm caused by asthma and other pulmonary diseases, for counteracting increased activity of smooth muscle in the bowel such as in irritable bowel syndrome, diverticulitis, etc. or for other diseases in which increased smooth muscle activity of one or more organs play a role.

The efficacy of the compounds of the invention was proved in the following experiments.

Measurement of blood pressure and heart rate in conscious rats Protocol

Conscious rat experiments were performed with the aid of a telemetry system (Date Sciences International, USA). Previously, telemetry transmitters (type TL11 M2-C50-PXT), suitable for measuring of arterial blood pressure and heart rate, were implanted into the abdominal cavity under sterile conditions during pentobarbital anaesthesia (Nembutal inj., 60 mg/kg i.p.). The catheter of the transmitter that measured blood pressure was inserted into the abdominal aorta. Heart rate was determined by counting the aortic pulse waves. After surgery the animals were given penicillin injection (5000 IU ip.) and were allowed to recover for at least 3 days.

Radio signals emitted by the implanted transmitters were detected by RLA1000 type receivers. The data were collected and saved on the hard disk using the Dataquest IV Data Acquisition Computer System (Data Sciences). The collection of parameters was started 1.5 hours before the first treatment and was continued for 24 hours after the last treatment.

Animals were treated by gavage. The test substance was suspended in 0.4 % methyl cellulose solution and was given at the volume of 1 ml/kg. Doses applied were 0.1 ; 0.3 and 1.0 mg/kg. The selected 3 doses were given in increasing order on three consecutive days. That was followed by a control treatment day when the animals were given the vehicle at the same dosing volume as the test compound. Evaluation of data

Acquisition was set to sample the parameters for 10 seconds in every second minute during the experiment. 30 min averages of the 10 sec data samples were calculated running the "Sort Utility" of the Dataquest IV System. The upper and lower filters of the evaluating routine were set to exclude biologically improbable values. The data obtained were processed by Microsoft Excel programme. Individual values obtained after the treatment with the vehicle were subtracted from those obtained at the same times after the treatment with the test compound. A single mean value was calculated for the differences between the values measured in the control and treated groups during the 18 hours period after treatment. These mean values were used for evaluating the efficiency the compounds.

Results are shown in table I.

Table I

Absolute changes in blood pressure and heart rate caused by different doses of the test compounds and chromachalime relative to the vehicle treated group during the 18 hours period after oral treatment in conscious Wistar rats (n=6/dose).

Test compound cfa g m blood change In heart

(dose) ^' - .pressure (mm Hg) rate (1 m n) chromachalime

0.1 mg/kg -3.2±0.5 11.8±3.9

0.3 mg/kg -4.1 ±0.6 22.3±2.6

1.0 mg/kg -8.4±1.6 40.3+4.5

Case 7

0.1 mg/kg -5.9±0.5 13.7+5.1

0.3 mg/kg -9.3±1.8 24.4±6.4

1.0 mg/kg -15.4±1.3 52.7±6.8

Case 27

0.1 mg/kg -2.2±0.9 -10.8±5.2

0.3 mg/kg -3.4±0.8 -6.4±4.6

1.0 mg/kg -7.9±1.0 12.6±7.1

Case 29

0.1 mg/kg -4.3±0.9 -0.7+4.3

0.3 mg/kg -6.4±1.1 12.2+7.2

1.0 mg/kg -9.9±1.6 25.4+6.5

Case 2

0.1 mg/kg -2.9±0.9 3.0±2.3

0.3 mg/kg -5.9±1.0 10.0±2.8

1.0 mg/kg -13.0±0.9 32.3±5.3 The reference substance chromachalime caused a dose-dependent decrease in blood pressure and increase in heart rate.

The compound of example 7 evoked greater hypotension than that caused by chromachalime at all 3 doses applied. The compound of example 2 was more effective than chromachalime at 0.3 and 1.0 mg/kg doses.

Azachromachalime derivatives, at doses that caused the same degree of hypotension as chromachalime, increased heart rate to a lesser extent than chromachalime. A blood pressure decrease of 8.4±1.6 mmHg caused by chromachalime was accompanied by 40.3±4.5 1/min increase in heart rate, whereas the increase in heart rate for the compound of example 7 was only 24.4±6.4 1/min in spite of a blood pressure decrease of more than 9.3±1.8 mmHg. The lack of tachycardia-inducing effect is especially obvious for the compound of example 27, which caused 12.6±7.1 1/min change in heart rate accompanied by 7.9 mmHg decrease in blood pressure.

In summary, in conscious rats azachromachalime derivatives of the invention caused greater decreases in blood pressure after oral treatment than chromachalime did. An unexpected feature of the azachromachalime derivatives was that they caused significantly less reflex tachycardia due to hypotension than that was induced by chromachalime or it was absent for some compounds. Tachycardia-inducing effect, a general characteristic of vasorelaxant substances, is disadvantageous from therapeutical point of view. Considering all the aforementioned, the application of azachromachalime derivatives for treatment of the human hypertension is potentially favourable.

According to the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of the general Formula IA, IB or IC or a salt thereof.

The pharmaceutical compositions according to the present invention may be prepared in forms suitable preferably for oral or parenteral administration. These are conventional pharmaceutical composition forms (e.g. tablets, dragees, capsules, injections) and can be prepared by methods of pharmaceutical industry known per se.

The daily dose of the compounds of the present inventions is generally between about 0.003 mg/kg and about 3 mg/kg, preferably between about 0.03 mg/kg and about 0.3 mg/kg.

Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples. Examples i

General process for the N-amination of 2,2-dimethyl-2H- pyrano-r3.2-c1pyridines

To a solution (or suspension) of 10 millimoles of a 4- substituted-2,2-dimethyl-2H-pyrano[3.2-c]-pyridine in 50 ml of dichloro methane a solution of 1.9 g (10 millimoles) of tosyl- hydroxile amine and 50 ml of dichloro methane is added under stirring and ice-cooling. The reaction mixture is stirred under ice-cooling for 30 minutes and at room temperature for 3 hours.

The reaction mixture may be worked up by two methods (A and B). Method A

The small amount of a substance precipitated from the reaction mixture is filtered, the mother-lye is evaporated to dryness and the residual oil is triturated with ethyl acetate. Thus tosylate salts are obtained which do not crystallize readily and can be purified only with difficulties. Method B

The reaction mixture is evaporated to dryness. The residue is dissolved in 20 ml of water, then admixed with 5 ml of a 50 % fluoro boric acid solution and extracted 5 times with 10 ml of nitro methane each.

The nitro methane solution is evaporated to dryness. The residue is triturated with ethyl acetate. The fluoroborate salts thus obtained readily crystallize and can be easily purified. On the reaction of the compound after addition of fluoro boric acid the fluoroborate salt precipitates from the solution in crystalline form. The salt is filtered and washed with water to yield the pure product.

Example 1

Trans-3,4-dihvdro-6-amino-2.2-dimethyl-3-(2'-methyl- benzyloxy -(2-oxo-pyrrolidine-1-yr)-2H-pyrano.3.2- clpyridinium-bromide

Mp.: 159-162°C

Analysis: for the Formula C₂₂H₂₈N₃O₃Br (462.4) calc: C 57.15 H 6.10 N 9.09 found: C 57.33 H 6.25 N 9.05

¹H-NMR (400 MHz, CDCI₃): 8.90 (s, 1H, H-5); 8.65 (d, 1H, H- 7); 7.2 (m, 4H, H-aryl); 7.04 (d, 1H, H-8); 5.10; 4.0 (d, 2H, H-4, H-3); 4.65; 4.52 (d, 2H, H-CH₂); 3.4; 2.5; 2.1 ; 1.9 (m, 6H, H-pyrrolidone), 2.30 (s, 3H, H- methyl-xylyl), 1.60; 1.35 (s, 6H, H-methyl). Example 2 Trans-3,4-dihvdro-6-amino-2,2-dimethyl-3-(4'-chloro- benzyloxy)-4-(2-oxo-piperidine-2-yl)-2H-pyranof3.2- clpyridinium-bromide This compound is prepared by the above N-amination procedure. Mp.: 72-75°C Analysis: for the Formula C₂ιH₂₃BrCIN₃O₂ (464.8) calc: C 54.27 H 4.99 N 9.04 found: C 54.10 H 4.77 N 8.93

NMR (400 MHz, CDCI₃):8.75 (s, 1H, H-5); 8.50 (d, 1 H, H- 7); 7.25 (d, 1 H, H-8); 4.75; 4.70 (d, 2H, H-CH₂); 4.25 (d, 1 H, H-4); 3.5; 3.0; 2.4; 1.8 (m, 8H, H-piperidone); 1.60; 1.30 (s, 6H, H-methyl). Example 3 Trans-S^-dihvdro-e-amino^^-dimethyl^-hvdroxy^-^-oxo- Pyrrolidine-1-vD-2H-pyranor3.2-c]pyridinium-flouroborate Yield 84 %; mp.: 243-245°C IR (KBr): 3340, 3280, 3140, 3090, 2940, 2880, 1640,

1620, 1540, 1480, 1060 cπr¹

Example 4

Trans-3,4-dihvdro-6-amino-2,2-dimethyl-3-hydroxy-4-(2-oxo- piperidine-1-yl)-2H-pyranor3.2-c1pyridinium-fluoroborate

Yield 83 %; mp.: 200-203°C

IR (KBr): 3340, 3280, 3140, 3090, 2940, 2880, 1640,

1620, 1540, 1480, 1060 cm"¹

Example 5

Trans-S^-dihvdro-e-amino^^-dimethyl-S-hvdroxy^-^-oxo-

2.3.4, 5.6.7-hexahvdroazepine-1-vn-2H-pyranor3.2- clpyridinium-tosylate

Yield 95 %; mp.: 160-165°C

IR (KBr): 3350, 3090, 3040, 3010, 2930, 2910, 2830,

2710, 2640, 1620, 1600, 1470, 1430, 1410,

1240 cm"¹ H General process for the preparation of bromide salts

To a solution of 10 millimoles of an N-amino- fluoroborate salt and 10 ml of warm water 1.2 g (10 millimoles) of potassium bromide are added. The reaction mixture is stirred at room temperature for 10 minutes, allowed to stand in a refrigerator for 2 hours, the precipitated crystals are filtered, washed twice with 2 ml of water each and the mother-lye is evaporated to dryness. The residue is dissolved in ethanol, filtered, evaporated to dryness and the residue is recrystallized from a mixture of ethanol and ether.

Example 6 Trans-3,4-dihvdro-6-amino-2,2-dimethyl-3-hvdroxy-4-(2-oxo- PVrrolidine-1-yl)-2H-pyranof3.2-c1pyridinium-bromide Yield 78 %; mp.: 201 -203°C Analysis: for the Formula Cι₄H₂₀BrN₃O₃ (358.25) calc: C 46.94 N 11.73 found: C 46.90 N 11.51

IR (KBr): 3280, 3120, 3050, 2980, 2920, 2840, 1650,

1480, 1430 cm"¹ NMR (DMSO): doubled signs; a 5:4 mixture of acid amide rotameters. 8.58 resp. 8.51 (d, 1 H, H-7); 8.46 (s, 1 H, H-5); 7.40 (d, 1 H, H-8); 5.05 (d, 1 H, H-4); J ₄.₅ = 10.4 Hz); 3.90 (d, 1 H, H-3); 1.54 and 1.31 (s, 3H, CH₃) Example 7

Trans-3,4-dihvdro-6-amino-2,2-dimethyl-3-hvdroxy-4-(2-oxo- piperidine-1-yl)-2H-pyranor3.2-c1pyridinium-bromide Yield 59 %; mp.: 208-210°C Analysis: for the Formula C₁₅H₂₂BrN₃O₃ (372.28) calc: C 48.40 N 11.29 found: C 48.19 N 11.02

IR (KBr): 3240, 3120, 3050, 2930, 2860, 1620, 1600,

1520, 1480 cm^"1 NMR (DMSO)-d₆: 8.60-8.40 (m, 2H, H-5.7); 7.38 (d, 1 H, H- 8); about 5.85 (broad band, 1 H, H-4); about 3.95 (broad band, 1 H, H-4); about 3.95 (broad band, 1 H, H-3); 1.52 and 1.28 (s, 3H, CH₃) Examples 8-9 Trans-3.4-dihvdro-6-amino-2,2-dimethyl-3-hvdroxy-4-(2-oxo- 2,3,4,5.6.7-hexahvdroazepine-1-yl)-2H-pyranor3.2- clpyridinium-bromide This compound is prepared according to a method other than the general process as follows:

A mixture of 4.8 g (10 millimoles) of the tosylate salt, 50 ml of ethyl acetate and 4.8 g (15 millimoles) of tetrabutyl ammonium bromide is heating to boiling, thereafter stirred at room temperature for a day. The precipitated crystals are filtered and washed with ethyl acetate. 3.45 g (92 %) of the crude product are obtained. After recrystallization from a mixture of aqueous ethanol and ethyl acetate 2.9 g of the title compound are obtained in the form of colouriess crystals, yield

77 %; mp.: 206-210°C.

Analysis: for the Formula Ci₆H₂₄BrN₃O₃ (386.31) calc: C 49.75 N 10.88 found: C 49.50 N 10.59 ]r (KBr): 3300, 3160, 3140, 3060, 2970, 2930, 2840,

1650, 1610, 1510, 1480, 1440, 1360, 1320 cm"¹ NMR (TFA): 8.76 (s, 1 H, H-5); 8.62 (d, 1 H, H-7); 7.39 (d, 1H, H-8); 6.30 (d, 1 H, H-4); 4.34 (d, 1H, H-3); 3.64 (m, 2H, CH₂-CO); 3.0 (m, 2H, CH₂-N); 1.93 (m, 6H, 4', 5', 6'-CH₂); 1.81 (s, 3H, CH₃); 1.54 (s, 3H, CH₂) ppm

Example 10

Trans-3.4-dihvdro-2,2-dimethyl-3-(2'-methyl-benzyloxy)-6- amino-4-(2-oxo-piperidine-1-yl)-2H-pyrano[3.2-c]pyridinium- bromide Mp.: 186-192°C Analysis: for the Formula C₂₃H3oBrN₃θ3 (476.4) calc: C 57.99 H 6.35 N 8.82 found: C 58.20 H 6.48 N 8.93

NMR (400 MHz, DMSO-CDCI₃): 8.75 (s, 1 H, H-5); 8.50 (d, 1H, H-7); 7.25 (d, 1H, H-8); 4.75; 4.70 (d, 2H, H- CH₂); 4.25 (d, 1 H, H-4); 3.5; 3.0; 2.4; 1.8 (m, 8H, H-piperidone); 2.30 (s, 3H, H-methyl-xylyl); 1.60; 1.30 (s, 6H, H-methyl). ϋl General process for the preparation of derivatives alkylated on the pyridine ring

To a suspension of 2 millimoles of the corresponding starting material and 10 ml of anhydrous acetonitrile 3 millimoles of p- bromo-phenacyl bromide or ethyl bromo acetate, respectively, are added. The reaction mixture is refluxed for 2 hours. The solution thus formed is evaporated and the residue is treated with a mixture of ethyl acetate and ether. The colourless precipitate thus obtained is recrystallized from a mixture of ethanol and ether.

Example 11

Trans-3,4-dihvdro-2.2-dimethyl-3-hydroxy-6-(p-bromo- phenacyl)-4-(2-oxo-pyrrolidine-1-yl)-2H-pyranor3.2- clpyridinium-bromide

Mp.: 150-154°C

Analysis: for the Formula C₂₂H₂₇Br₂N O (543.3) calc: C 48.64 H 5.01 N 5.16 found: C 48.78 H 5.28 N 5.26

NMR (400 MHz), DMSO): 8.70 (d, 1 H- H-7); 8.62 (s, 1 H, H-5); 8.02; 7.9 (dd, 4H, H-aryl); 7.6 (d, 1 H, H-8); 6.4 (m, 2H, H-CH₂); 6.10 (br, 1 H, H-OH); 5.15 (d, 1H, H-4); 4.0 (d, 1 H, H-3); 3.5; 3.2; 2.4; 2.05 (m, 6H, H- pyrrolidone); 1.62; 1.42 (s, 6H, H-methyl). Example 12

Trans-3.4-dihvdro-2,2-dimethyl-3-hvdroxy-6-(p-bromo- phenacyl)-4-(2-oxo-2,3,4,5,6,7-hexahvdroazepine-1-yl)-2H- pyranof3.2-c]pyridinium-bromide Mp.: 253-255°C Analysis: for the Formula C₂₄H₂₈Br₂N₂O (568.3) calc: C 50.72 H 4.97 N 4.93 found: C 50.78 H 5.18 N 5.23

NMR (400 MHz, DMSO): 8.63 (d, 1 H, H-7); 8.57 (s, 1 H, H- 5); 8.05; 7.92 (dd, 4H, H-aryl); 7.58 (d, 1 H, H-8); 6.3 (m, 2H, H-CH₂); 5.9 (br, 1 H, H-OH); 3.9 (br, 1 H, H-3); 3.2; 2.7; 1.7 (m, 10H, H-azepine); 1.62; 1.35 (s, 6H, H-methyl).

Example 13

Trans-3,4-dihydro-2,2-dimethyl-3-(4'-chloro-benzyloxy)-6-(p- bromo-phenacyl)-4-(2-oxo-piperidine-1-yl)-2H-pyranof3.2- clpyridinium-bromide

Mp.: 222-228°C

Analysis: for the Formula C₂₉H₃₂Br₂CIN₂O₄ (667.9) calc: C 52.16 H 4.83 N 4.19 found: C 52.28 H 4.98 N 4.23

NMR (400 MHz, DMSO): 8.6 (m, 2H, H-7, H-5); 8.05; 7.75 (dd, 4H, H-p-Br-aryl); 7.3 (m, 5H, H-8, H-p-CI-aryl); 6.35 (m, 2H, H-CH₂); 6.2 (br, 1 H, H-4); 4.7 (br, 2H, H-CH₂); 4.1 (br, 1H, H-3); 3.2; 2.8; 1.7 (m, 8H, H- piperidone); 1.7; 1.4 (s, 6H, H-methyl). Example 14

Trans-3.4-dihvdro-2,2-dimethyl-3-hvdroxy-6-(carbethoxy- methvO-4-(2-oxo-pyrrolidine-1-yl)-2H-pyranor3.2-c]pyridinium- bromide

Mp.: 73-79°C

Analysis: for the Formula Cι₈H₂₅BrN₂O₅ (429.3) calc: C 50.36 H 5.87 N 6.53 found: C 50.28 H 5.98 N 6.65

NMR (400 MHz, DMSO): 8.75 (d, 1 H, H-7); 7.68 (s, 1 H, H- 5); 7.60 (d, 1H, H-8); 6.08; 5.12 (d, 2H, H-3, H-4); 6.55 (m, 2H, H-CH₂); 4.25 (m, 2H, H-CH₂-ethyl); 3.9; 3.45; 3.1 ; 2.45; 2.05 (m, 6H, H-pyrrolidone); 1.6; 1.4 (s, 6H, H-methyl); 1.3 (t, 3H, H-methyl-ethyl). Example 15

Trans-3,4-dihydro-2₁2-dimethyl-3-(4'-carbethoxy-benzyloxy)-6-

(carbethoxy-methyl)-4-(2-oxo-pyrrolidine-1-vπ-2H-pyranor3.2- clpyridinium-bromide

Mp.: 198-202°C

Analysis: for the Formula C ₈H₃₅BrN₂O₇ (591.5) calc: C 56.86 H 5.96 N 4.74 found: C 56.88 H 5.98 N 4.65

NMR (400 MHz, DMSO): 8.75 (m, 2H, H-7, H-5); 8.65 (d, 1 H, H-8); 8.0; 7.5 (m, 4H, H-aryl); 5.51 (m, 2H, H- CH₂); 5.36; 4.2 (d, 2H, H-3, H-4); 4.95; 4.78 (m, 2H, H-CH₂-aryl); 4.40; 4.25 (m, 4H, H-CH₂-ethyl); 3.45; 3.1 ; 2.45; 2.2 (m, 6H, H-pyrrolidone); 1.7; 1.45 (s, 6H-H-methyl); 1.4; 1.3 (t, 6H-H-methyl-ethyl). Example 16

Trans-3,4-dihvdro-2.2-dimethyl-3-(4'-chloro-benzyloxy)-6- (carbethoxy-methvπ-4-(2-oxo-piperidine-1-vπ-2H-pyranor3.2- clpyridinium-bromide Mp.: 204-208°C Analysis: for the Formula C₂₆H₃2BrCIN₂O₅ (567.9) calc: C 54.99 H 5.68 N 4.93 found: C 55.14 H 5.76 N 5.05

NMR (400 MHz, DMSO-CDCI₃): 8.8 (m, 2H, H-7, H-5); 7.3 (m, 5H, H-8, H-aryl); 5.6 (m, 2H, H-CH₂); 6.1 ; 4.1 (d, 2H, H-3, H-4); 4.7 (m, 2H, H-CH₂-aryl); 4.25 (m, 2H, H-CH₂-ethyl); 3.9; 3.2; 2.9; 2.4; 2.2; 1.8 (m, 8H, H- piperidone), 1.7; 1.4 (s, 6H, H-methyl); 1.3 (t, 3H, H- methyl-ethyl).

Example 17

Trans-3,4-dihvdro-2,2-dimethyl-3-(2'-methyl-benzyloxy)-6-

(carbethoxy-methyl)-4-(2-oxo-2,3,4,5,6,7-hexahvdro-azepine-

1-yl)-2H-pyranor3.2-c]pyridinium-bromide Mp.: 218-222°C Analysis: for the Formula C₂₈H₃₇BrN₂O₅ (561.5) calc: C 59,89 H 6,64 N 4,99 found: C 59,94 H 6,76 N 5,15

NMR (400 MHz, DMSO): 8.75 (d, 1 H, H-7); 8.65 (s, 1 H, H- 5); 7.55 (d, 1H, H-8); 7.3 (m, 4H, H-aryl); 5.6 (m, 2H, H-CH₂); 4.75 (m, 2H, H-CH₂-aryl); 4.3 (m, 2H, H-CH₂- ethyl); 3.4; 2.6; 1.7 (m, 10H, H-azepine); 2.35 (s, 3H, H-methyl-aryl); 1.7; 1.4 (s, 6H, H-methyl); 1.3 (t, 3H, H-methyl-ethyl).

!Y General process for the conversion of the N-carbethoxymethyl function into an acid amide

To a suspension of 2 millimoles of the suitable starting material and 10 ml of anhydrous acetonitrile 10 millimoles of the corresponding amine are added. The reaction mixture is refluxed for 24 hours; a solution is formed. The reaction is monitored by thin layer chromatography; the spot of the starting material completely disappears. The solution is evaporated, the residue is treated with ethyl acetate. The colourless crystals obtained may be recrystallized from a mixture of ethanol and ether.

Example 18

Trans-3.4-dihvdro-2.2-dimethyl-3-hvdroxy-6-(benzylamido- methyl)-4-(2-oxo-pyrrolidine-1-yl)-2H-pyranor3.2-c]pyridinium- bromide Mp.: 88-95°C Analysis: for the Formula C₂₃H₂₈BrN₃O₄ (490.4) calc: C 56.33 H 5.76 N 8.57 found: C 56.23 H 5.88 N 8.55

NMR (400 MHz, DMSO-CDCI₃): 8.9 (br, 1H, NH); 8.65 (d, 1 H, H-7); 8.55 (s, 1 H, H-5); 7.30 (m, 6H, H-8, H-aryl); 5.4 (m, 2H, H-CH₂); 5.12; 3.9 (d, 2H, H-3, H-4); 4.35 (m, 2H, H-CH₂); 3.5; 3.1 ; 2.45; 2.05 (m, 6H, H- pyrrolidone); 1.6; 1.4 (s, 6H, H-methyl). Example 19

Trans-3,4-dihvdro-2,2-dimethyl-3-(4'-chloro-benzyloxy)-6- (benzylamido-methyl)-4-(2-oxo-piperidine-1-yl)-2H-pyranof3.2- clpyridinium-bromide Mp.: 210-218°C Analysis: for the Formula C₃ιH₃₅BrCIN₃O₄ (629.0) calc: C 59.20 H 5.61 N 6.68 found: C 59.32 H 5.78 N 6.55

NMR (400 MHz, DMSO-CDCI₃): 9.1 (br, 1 H, NH); 8.85 (s,

1 H, H-5); 8.65 (d, 1 H, H-7); 7.30 (m, 6H, H-8, H-aryl);

5.6 (m, 2H, H-CH₂); 4.7 (m, 2H, H-CH₂); 3.5; 3.3;

2.45; 1.9 (m, 8H, H-piperidone); 1.6; 1.4 (s, 6H, H- methyl).

General process for O-alkylation

To a solution of 4 millimoles of the starting material and 10 ml of anhydrous dimethyl formamide 0.15 g of pure sodium hydride are added. The mixture is stirred at room temperature for an hour whereupon 5 millimoles of the alkylating agent are added. The reaction mixture is stirred for 4 hours, whereby the precipitate goes into solution. The mixture is poured onto a five-fold amount of water, extracted with dichloro methane and the organic phase is evaporated to dryness. The residue may be recrystallized from cyclohexane to yield the pure ether. Example 20

Trans-3.4-dihvdro-2,2-dimethyl-3-(2'-methyl-benzyloxy)-4-(2- oxo-2.3,4.5.6.7-hexahvdro-azepine-1-vπ-2H-pyranof3.2- clpyridine Mp.: 286-290°C Analysis: for the Formula C₂ H₃₀N₂O₃ (366.5) calc: C 73.07 H 7.66 N 7.10 found: C 73.28 H 7.75 N 7.15

NMR (400 MHz, CDCI₃): 8.25 (m, 2H, H-7, H-5); 7.2 (m, 4H, H-xylyl); 6.7 (d, 1H, H-8); 6.20 (d, 1H, H-4), 4.70 (d, d, 2H, H-methylene); 3.65 (d, 1 H, H-3, J3.4=10 Hz); 2.95; 2.70; 2.4; 1.7; 1.4 (m, 10H, H-azepine); 2.34 (s, 3H, H-methyl-xylyl); 1.55; 1.25 (s, 6H, H- methyl).

Example 21

Trans-3,4-dihvdro-2,2-dimethyl-3-(4'-chloro-benzyloxy)-4-(2- oxo-2.3,4, 5,6, 7-hexahvdro-azepine-1-vπ-2H-pyrano[3.2- cl pyridine Mp.: 180-184°C Analysis: for the Formula C₂₃H27CIN₂O₃ (414.9) calc: C 66.58 H 6.56 N 6.75 found: C 66.68 H 6.43 N 6.88

NMR (400 MHz, CDCI₃): 8.25 (m, 2H, H-7, H-5); 7.27 (m, 4H, H-aryl); 6.72 (d, 1 H, H-8); 6.12 (d, 1 H, H-4); 4.60 (d, d, 2H, H-methylene); 3.55 (d, 1 H, H-3); 3.05; 2.9; 2.65; 2.5; 1.7; 1.4 (m, 10H, H-azepine); 1.56; 1.28 (s, 6H, H-methyl). NMR (400 MHz, CDCI₃): 8.28 (d, 1 H, H-7); 8.10 (s, 1 H, H- 5); 6.70 (d, 1 H, H-8); 5.4 (d, 1 H, H-4); 3.6 (m, 2H, H- butyl-methylene); 3.48 (d, 1 H, H-3); 3.3; 3.15; 2.5; 2.2; 2.1 ; 1.4 (m, 10H, H-pyrrolidone, H-butyl); 1.5; 1.27 (s, 6H, H-methyl); 0.9 (t, 3H, H-butyl). Example 22 Trans-3,4-dihvdro-2,2-dimethyl-3-(4'-carbethoxy-benzyloxy)-4-

(2-oxo-pyrrolidine-1-vπ-2H-pyranor3.2-c]pyridine Mp.: 88-90°C Analysis: for the Formula C₂ H₂₈N₂0₅ (424.5) calc: C 67.91 H 6.65 N 6.60 found: C 67.88 H 6.77 N 6.85

NMR (400 MHz, CDCI₃): 8.28 (d, 1H, H-7); 8.10 (s, 1H, H- 5); 8.05; 7.40 (m, 4H, H-aryl), 6.70 (d, 1 H, H-8); 5.45 (d, 1 H, H-4); 4.75 (m, 2H, H-CH₂-aryl); 4.35 (m, 2H, H-CH₂-ethyl); 3.7 (d, 1 H, H-3); 3.1 ; 2.45; 2.3; 1.95; 1.8 (m, 6H, H-pyrrolidone); 1.55; 1.32 (s, 6H, H- methyl); 1.35 (t, 3H, H-methyl-ethyl). Example 23 Trans-3,4-dihvdro-2,2-dimethyl-3-(4'-fluoro-benzyloxy)-4-(2- oxo-2, 3,4, 5,6, 7-hexahvdro-azepine-1-vD-2H-pyranor3.2- clpyridine Mp.: 152-155°C Analysis: for the Formula C₂₃H₂7N₂FO₃ (398.5) calc: C 69.33 H 6.83 N 7.03 found: C 69.48 H 6.77 N 6.95 NMR (400 MHz, CDCI₃): 8.25 (m, 2H, H-7, H-5); 7.3; 7.05 (m, 4H, H-aryl); 6.70 (d, 1 H, H-8); 6.10 (d, 1 H, H-4); 4.7 (m, 4H; H-methylene); 3.55 (d, 1 H, H-3); 3.05; 2.9; 2.65; 2.6; 1.7; 1.6 (m, 10H, H-azepine); 1.5; 1.2 (s, 6H, H-methyl).

Example 24

Trans-3,4-dihvdro-2,2-dimethyl-3-(2'-fluoro-benzyloxy)-4-(2- oxo-2,3,4.5,6,7-hexahvdro-azepine-1-yl)-2H-pyranor3.2- clpyridine Mp.: 133-136°C Analysis: for the Formula C₂₃H₂₇N₂FO3 (398.5) calc: C 69.33 H 6.83 N 7.03 found: C 69.48 H 6.87 N 7.09

NMR (400 MHz, CDCI₃): 8.25 (m, 2H, H-7, H-5); 7.45; 7.3; 7.2; 7.05 (m, 4H, H-aryl); 6.70 (d, 1 H, H-8); 6.10 (d, 1 H, H-4); 4.7 (m, 4H, H-methylene); 3.6 (d, 1 H, H-3); 3.05; 2.9; 2.65; 2.6; 1.7; 1.6 (m, 10H, H-azepine); 1.5; 1.25 (s, 6H, H-methyl). Example 25 Trans-3,4-dihvdro-2,2-dimethyl-3-(2'-fluoro-benzyloxy)-4-(2- oxo-pyrrolidine-1-yl)-2H-pyranof3.2-c1pyridine Mp.: 104-106°C Analysis: for the Formula C₂₁H₂₃FN2O3 (370.4) calc: C 68.09 H 6.26 N 7.56 found: C 68.33 H 6.37 N 7.69

NMR (400 MHz, CDCI₃): 8.27 (d, 1 H, H-7); 8.10 (s, 1 H, H- 5); 7.4; 7.3; 7.15; 7.05 (m, 4H, H-aryl); 6.70 (d, 1 H, H-8); 5.45 (m, 1 H, H-4); 4.7 (m, 2H, H-methylene); 3.65 (d, 1 H, H-3); 3.05; 2.5; 2.45; 2.0; 1.85 (m, 6H, H-pyrrolidone); 1.5; 1.3 (s, 6H, H-methyl). Example 26 Trans-3 , 4-d ihvd ro-2 ,2-d imethyl-3-(2'-methyl-benzyloxy)-4-(2- oxo-Pyrrolidine-l-vP^H-pyranoβ^-clpyridine

Mp.: 118-20°C

Analysis: for the Formula C₂₂H₂₆N₂O₃ (366.5) calc: C 72.11 H 7.15 N 7.64 found: C 72.58 H 7.25 N 7.55

¹H-NMR (400 MHz, CDCI₃): 8.28 (d, 1H, H-7); 8.06 (s, 1H, H- 5); 7.2 (m, 4H, H-xylyl); 6.72 (d, 1 H, H-8); 5.43 (d, 1 H, H-4); 4.78; 4.59 (d, d, 2H, H-methylene); 3.65 (d, 1H, H-3, J3.4=10 Hz); 2.90; 2.80; 2.30; 1.8 (m, 6H, H-pyrrolidone); 2.36 (s, 3H, H-methyl-xylyl); 1.55; 1.30 (s, 6H, H-methyl).

Example 27

Trans-3,4-dihvdro-2,2-dimethyl-3-(2'-methyl-benzyloxy -4-(2- oxo-piperidine-1-vπ-2H-pyranor3.2-c]pyridine

Mp.: 131-33°C

Analysis: for the Formula C₂₃H₂sN₂O3 (380.5) calc: C 72.61 H 7.42 N 7.36 found: C 72.68 H 7.43 N 7.45

¹H-NMR (400 MHz, CDCI₃): 8.25 (d, 1 H, H-7); 8.12 (s, 1 H, H- 5); 7.2 (m, 4H, H-xylyl); 7.70 (d, 1H, H-8); 6.22 (d, 1 H, H-4); 4.76; 4.66 (d, d, 2H, H-methylene); 3.68 (d, 1 H, H-3, J3.4=10 Hz); 2.8; 2.55; 2.40; 1.8 (m, 8H, H- piperidone); 2.32 (s, 3H, H-methyl-xylyl); 1.55; 1.32 (s, 6H, H-methyl).

Example 28

Trans-3,4-dihvdro-2.2-dimethyl-3-(2'-chloro-benzyloxy)-4-(2- oxo-pyrrolidine-1-vO-2H-pyranor3.2-clpyridine

Mp.: 146-48°C

Analysis: for the Formula C₂ιH₂ N₂O₃CI (387.9) calc: C 65.03 H 6.24 N 7.22 found: C 65.30 H 6.25 N 7.35

¹H-NMR (400 MHz, CDCI₃): 8.26 (d, 1 H, H-7); 8.10 (s, 1 H, H- 5); 7.32; 7.24 (m, 4H, H-p-chlorophenyl); 6.70 (d, 1 H, H-8); 5.45 (d, 1 H, H-4); 4.70; 4.58 (d, d, 2H, H- methylene); 3.65 (d, 1 H, H-3, J3.4=10 Hz); 3.05; 2.45; 2.30; 1.95; 1.80 (m, 6H, H-pyrrolidone), 1.54; 1.30 (s, 6H, H-methyl).

Example 29

Trans-3,4-dihvdro-2,2-dimethyl-3-(4'-chloro-benzyloxy)-4-(2- oxo-piperidine-1-yl)-2H-pyranor3.2-c]pyridine

Mp.: 132-35X

Analysis: for the Formula C₂₂H₂₆N₂O₃CI (401.9) calc: C 65.75 H 6.52 N 7.64 found: C 65.88 H 6.57 N 7.85

¹H-NMR (400 MHz, CDCI₃): 8.28 (d, 1H, H-7); 8.12 (s, 1 H, H- 5); 7.32; 7.24 (m, 4H, H-p-chlorophenyl); 6.70 (d, 1 H, H-8); 6.24 (d, 1 H, H-4); 4.75; 4.60 (d, d, 2H, H- methylene); 3.62 (d, 1 H, H-3, J3.4=10 Hz); 2.9; 2.55; 2.40; 1.8; 1.6 (m, 8H, H-piperidone); 1.55; 1.30 (s, 6H, H-methyl). i

General process for the preparation of cyclic amidrazones

To a solution of 10 millimoles of an N-amino-substituted bromide salt and 50 mi of anhydrous acetonitrile 3 ml of triethyl formate are added and the mixture is refluxed for 4 hours. The homogenous solution thus formed is cooled, 2 ml of the corresponding amine are added and the reaction mixture is refluxed for 10 minutes. The mixture is cooled, the precipitated crystalline product is filtered and the product is purified by precipitation from a mixture of acetonitrile and ethyl acetate. Thus crystalline bromide salts are obtained.

Example 30

Trans-3₁4-dihvdro-6-f(pyrrolidino-metheno)-amino1-2,2- dimethyl-3-hvdroxy-4-(2-oxo-pyrrolidine-1-yl)-2H-pyranor3.2- clpyridinium-bromide

Mp.: 204-206°C

Analysis: for the Formula C₁₉H₂₇N₄O₃Br (439.4) calc: C 51.94 H 6.19 N 12.75 found: C 52.08 H 6.28 N 12.66

NMR (400 MHz, CD₃CN): 8.25 (m, 1 H, H-7); 8.17 (s, 1H, H-formyl); 8.11 (m, 1H, H-5); 7.18 (d, 1H, H-8, J7.8=7Hz); 5.13 (d, 1 H, H-4 J3.4=10 Hz); 3.97 (d, 1 H, H-3); 3.6; 3.36; 3.2; 2.48; 2.30; 2.10 (m, 14H, H- pyrrolidine and H-pyrrolidone); 1.60; 1.36 (s, 6H, H- methyl). Example 31

Trans-3,4-dihvdro-6-[(pyrrolidino-metheno)-amino]-2,2- dimethyl-3-hvdroxy-4-(2-oxo-piperidine-1-yl)-2H-pyranor3.2- clpyridinium-bromide Mp.: >250°C Analysis: for the Formula C₂oH₂₉N₄O₃Br (453.4) calc: C 52.98 H 6.45 N 12.36 found: C 52.78 H 6.38 N 12.33 H-NMR (400 MHz, CD₃CN-D₂O): 8.22 (d, 1 H, H-7); 8.15 (s, 1 H, H-formyl); 8.08 (s, 1 H, H-5); 7.28 (d, 1 H, H-8); 4.1 (br, 1 H, H-3); 3.55; 3.35; 3.2; 2.6; 2.45; 1.9 (m, 16H, H-pyrrolidine and H-piperidone); 1.56; 1.32 (s, 6H, H-methyl). yπ

General process for the preparation of amines

The epoxide compound of the Formula IX is admixed with 5 equivalents of the corresponding amine. The reaction mixture is stirred for 24-48 hours. To the resulting slurry acetonitrile is added. The crystalline product precipitates.

Example 32 Trans-3,4-dihvdro-2,2-dimethyl-3-hvdroxy-4-ethanolamino-2H- pyranof3.2-c]pyridine Mp.: 85-87°C Analysis: for the Formula Cι₂Hι₈N₂O₃ (238.3) calc: C 60.49 H 7.61 N 11.76 found: C 60.80 H 7.79 N 11.88 NMR (400 MHz, CDCI₃): 8.65 (s, 1H, H-5); 8.20 (d, 1H, H- 7); 6.70 (d, 1H, H-8); 3.85 (d, 1H, H-3); 3.65 (d, 1H, H-4); 3.71 (m, 2H, H-CH₂); 2.85; 2.70 (m, 2H, H-CH₂); 1.50; 1.20 (s, 6H, H-methyl). Example 33

Trans-3.4-dihvdro-2,2-dimethyl-3-hvdroxy-4-benzylamino-2H- Pyranof3.2-c]pyridine

Mp.: 140-41°C

Analysis: for the Formula d₇H₂₀N₂O₂ (284.4) calc: C 71.81 H 7.09 N 9.85 found: C 72.06 H 6.98 N 9.97

NMR (400 MHz, CDCI₃): 8.60 (s, 1H, H-5); 8.25 (d, 1H, H- 7); 7.3 (m, 5H, H-phenyi); 6.70 (d, 1H, H-8); 3.87 (d, 1H, H-3); 3.66 (d, 1H, H-4); 3.76 (m, 2H, H-CH₂); 1.50; 1.20 (s,6H, H-methyl). Example 34 Trans-3,4-dihvdro-2,2-dimethyl-3-hvdroxy-4-isopropylamino- 2H-pyrano[3.2-c1pyridine

Mp.: 108-10°C

Analysis: for the Formula Cι₃H₂oN₂O₂ (236,3) calc: C 66,07 H 8,53 N 11,85 found: C 66,15 H 8,67 N 11,76

NMR (400 MHz, CDCI₃): 8,50 (s, 1H, H-5); 8,24 (d, 1H, H- 7); 6,68 (d, 1H, H-8); 3,82 (s, 1H, H-NH); 3,64 (d, 1H, H-3); 3,34 (d, 1H, H-4); 3,35 (m, 1H, H-CH); 1,52; 1,20 (s, 6H, H-methyl); 1,21; 1,14 (d, 6H, H-iPr). Example 35

Trans-3,4-dihvdro-2,2-dimethyl-3-hvdroxy-4-rβ-(N-pyrrolidinyl)- ethvn-amino-2H-pyrano[3.2-c]pyridine

Mp.: 104-107°C

Analysis: for the Formula Ci₆H₂₅N₃θ₂ (291.4) calc: C 65.95 H 8.65 N 14.42 found: C 66.12 H 8.45 N 14.62

NMR (400 MHz, CDCI₃): 8.54 (s, 1H, H-5); 8.24 (d, 1H, H- 7); 6.92 (s, 1 H, H-NH); 6.68 (d, 1 H, H-8); 3.68 (d, 1 H, H-3); 3.45 (d, 1 H, H-4); 3.08; 2.95 (m, 2H, H-CH₂); 2.72; 2.60 (m, 2H, H-CH₂); 2.59; 1.82 (m, 8H, H- pyrrolidine-CH₂); 1.51 ; 1.21 (s, 6H, H-methyl). Example 36

Trans-3,4-dihvdro-2,2-dimethyl-3-hydroxy-4-cvclopropylamino- 2H-pyranor3.2-c]pyridine

Mp.: 117-118°C

Analysis: for the Formula C₁₃H₁₈N₂0₂ (234.3) calc: C 66.64 H 7.74 N 11.96 found: C 66.50 H 7.86 N 12.02

NMR (400 MHz, CDCI₃): 8.60 (s, 1 H, H-5); 8.26 (d, 1 H, H- 7); 6.71 (d, 1H, H-8); 3.54 (s, 1 H, H-NH); 3.76 (d, 1H, H-3); 3.63 (d, 1H, H-4); 2.39 (m, 1H, H-CH); 1.53; 1.25 (s, 6H, H-methyl); 0.54-0.36 (m, 4H, H- cyclopropyl). Example 37

Trans-3,4-dihvdro-2,2-dimethyl-3-hvdroxy-4-(γ-dimethylamino- propylamino)-2H-pyranor3.2-c]pyridine-hvdrochloride Mp.: 135°C (decomp.) Analysis: for the Formula C₁₅H₂₇CIN₃O₂ (316.86) calc: C 56.86 H 8.59 N 13.26 found: C 57.06 H 8.77 N 13.10

NMR (400 MHz, CDCI₃-DMSO): 9.80 (s, 1 H, H-5); 8.6 (d, 1 H, H-7); 7.32 (d, 1 H, H-8); 4.68; 4.4 (d, 2H, H-3, H- 4); 2.4 (m, 6H, H-CH₂); 2.8 (s, 6H, H-N-Me); 1.53; 1.25 (s, 6H, H-methyl). VIII General process for the preparation of derivatives substituted by an acetylated amino group To a mixture of 2.1 ml of acetic anhydride and 0.82 g of sodium acetate 2 millimoles of the corresponding amino compound are added under cooling with icecold water. The reaction mixture is stirred for 24 hours, admixed with icecold water and extracted with chloroform. The organic phase is neutralized with a saturated sodium hydrogen carbonate solution, dried and evaporated. The product may be generally isolated in the form of a syrup from which the crystalline hydrochloride may be recovered by treatment with ether containing hydrogen chloride. Example 38

Trans-3,4-dihvdro-2,2-dimethyl-3-acetoxy-4-(N-acetyl-3- acetoxyethylamino)-2H-pyrano[3.2-c]pyridine-hydrochloride Mp.: 219-222°C Analysis: for the Formula Cι₈H₂₅CIN₂O₆ (400.8) calc: C 53.93 H 6.29 N 6.99 found: C 56.07 H 6.45 N 7.11

NMR (400 MHz, CDCI₃): 8.50 (s, 1 H, H-5); 8.26 (d, 1H, H- 7); 7.10 (d, 1 H, H-8); 4.4-4.2 (m, 4H, H-CH₂); 3.93; 3.69 (m, 2H, H-3.4); 2.1 (s, 9H, H-acetyl); 1.49; 1.41 (s, 6H, H-methyl).

Example 39 Trans-S^-dihvdro^^-dimethyl-S-acetoxy^-fN-acetyl- benzylamino)-2H-pyranor3.2-c1pyridine-hydrochloride Mp.: 140-42°C Analysis: for the Formula C₂₁H₂₅CIN₂O₄ (404.8) calc: C 62.30 H 6.22 N 6.92 found: C 62.50 H 6.11 N 6.85

NMR (400 MHz, CDCI₃): 8.15 (s, 1 H, H-5); 8.28 (d, 1 H, H- 7); 7.05 (d, 1H, H-8); 7.2-7.6 (m, 5H, H-phenyl); 4.5; 4.7 (m, 2H, H-CH₂); 5.8; 4.8 (m, 2H, H-3.4); 2.3; 2.05 (s, 6H, H-acetyl); 1.49; 1.31 (s, 6H, H-methyl). Example 40 Trans-3,4-dihvdro-2,2-dimethyl-3-hvdroxy-4-(N-acetyl- isopropylamino)-2H-pyranof3.2-c]pyridine Mp.: 90-92°C Analysis: for the Formula Cι₅H₂₂N₂O₃ (278.3) calc: C 64.73 H 7.97 N 10.06 found: C 64.87 H 8.05 N 10.35

NMR (400 MHz, CDCI₃): 8.52 (s, 1H, H-5); 8.26 (d, 1 H, H- 7); 6.69 (d, 1 H, H-8); 3.76 (d, 1 H, H-3); 5.02 (d, 1 H, H-4); 3.17 (m, 1 H, H-CH); 2.1 (s, 3H, H-acetyl); 1.44; 1.33 (s, 6H, H-methyl); 1.17; 1.08 (d, 6H, H-iPr). Example 41 Trans-3,4-dihvdro-2,2-dimethyl-3-acetoxy-4-(N-acetyl- cvclopropylamino)-2H-pyranof3.2-c1pyridine

Mp.: 158-160°C

Analysis: for the Formula C₁₇H₂₂N₂O₄ (234.3) calc: C 64.13 H 6.97 N 8.80 found: C 64.32 H 7.08 N 8.63

NMR (400 MHz, CDCI₃): 8.10 (s, 1H, H-5); 8.26 (d, 1 H, H- 7); 6.71 (d, 1 H, H-8); 5.6 (d, 1 H, H-3); 5.9 (d, 1 H, H- 4); 2.6 (m, 1 H, H-CH); 2.3; 2.1 (s, 6H, H-acetyl); 1.43; 1.29 (s, 6H, H-methyl); 0.84-0.36 (m, 4H, H- cyclopropyl).

JX

General process for the preparation of derivatives substituted by an acylated amino group

To a solution of 10 millimoles of the corresponding amino compound and anhydrous dichloro methane 1 equivalent of triethyl amine is added. The mixture is cooled with a mixture of ice and salt to 0°C, whereupon 1 equivalent of the corresponding acid chloride is added dropwise. The reaction mixture is stirred at room temperature for 24 hours, admixed with icecold water and extracted with chloroform. The organic phase is neutralized with a saturated sodium hydrogen carbonate solution, dried and evaporated. The product may be generally isolated as a syrup from which the crystalline hydrochloride can be recovered by treatment with ether containing hydrochloric acid.

Example 42

Trans-3,4-dihvdro-2.2-dimethyl-3-hvdroxy-4-rN-(O-chloro- benzovD-hvdroxyethylaminol-2H-pyranor3.2-c1pyridine- hydrochloride Mp.: 226-228°C Analysis: for the Formula Cι₉H₂₂Cl₂N₂O₄ (413.3) calc: C 55.22 H 5.37 N 6.78 found: C 55.54 H 5.23 N 6.42

NMR (400 MHz, CDCI₃-DMSO): 9.78 (s, 1 H, H-5); 8.55 (d, 1H, H-7); 7.26 (d, 1 H, H-8); 8.11 ; 7.5-7.38 (m, 3H, H- phenyl); 4.8-3.65 (m, 4H, H-CH₂); 4.37; 4.72 (m, 2H, H-3.4); 1.63; 1.31 (s, 6H, H-methyl). Example 43 Trans-3.4-dihvdro-2,2-dimethyl-3-hvdroxy-4-rN-(p-chloro- benzovD-benzylaminol-2H-pyranor3.2-clpyridine Mp.: 154-57°C Analysis: for the Formula C₂ H₂₃CIN₂O₃ (422.9) calc: C 68.16 H 5.48 N 6.62 found: C 68.24 H 5.52 N 6.55

NMR (400 MHz, CDCI₃): 8.40 (s, 1H, H-5); 8.31 (d, 1 H, H- 7); 6.72 (d, 1 H, H-8); 7.3-7.16 (m, 5H, H-phenyl); 7.35; 7.52 (m, 4H, H-pCI-phenyl); 5.4; 5.02 (m, 2H, H-CH₂); 3.71 ; 3.95 (m, 2H, H-3.4); 1.41 ; 1.13 (s, 6H, H-methyl).

X General process for the preparation of substituted urea derivatives To a solution of 10 millimoles of the corresponding amino compound and anhydrous dichloro methane 1 equivalent of the corresponding isocyanate is added at a temperature below 10°C. The reaction mixture is stirred at room temperature for 3-4 hours and evaporated. The residue is treated with a mixture of ether and petrolether. The urea derivative is isolated in crystalline form.

Example 44 1-(m-fluoro-phenvD-3-hvdroxyethylamino-3-rtrans-3,4-dihvdro-

2,2-dimethyl-3-hvdroxy-2H-pyranor3.2-clPyridine-4-yl1-urea Mp.: 175-78°C Analysis: for the Formula Cι₉H₂₂FN₃O₄ (375.4) calc: C 60.79 H 5.91 N 11.19 found: C 60.33 H 5.78 N 11.08

NMR (400 MHz, CDCI₃-DMSO): 8.3 (s, 1H, H-5); 8.3 (d, 1 H, H-7); 6.7 (d, 1 H, H-8); 7.5-7.1 (m, 4H, H-phenyl); 4.0-3.65 (m, 4H, H-CH₂); 5.58; 3.68 (m, 2H, H-3.4); 1.54; 1.31 (s, 6H, H-methyl). Example 45

1-(m-fluoro-phenyl)-3-isopropylamino-3-rtrans-3,4-dihvdro-2,2- dimethyl-3-hvdroxy-2H-pyranor3.2-clpyridine-4-yl1-urea Mp.: 180-83°C Analysis: for the Formula C₂oH2₄FN₃θ3 (373.4) calc: C 64.33 H 6.48 N 11.25 found: C 64.11 H 6.60 N 11.32

NMR (400 MHz, CDCI₃-DMSO): 8.5 (s, 1 H, H-5); 8.25 (d,

1 H, H-7); 6.4 (d, 1 H, H-8); 7.3-6.9 (m, 4H, H-phenyl);

5.1 ; 3.8 (m, 2H, H-3.4); 2.9 (m, 1H, H-iPr); 1.53; 1.25

(s, 6H, H-methyl); 1.43 (d, 6H, H-methyl-iPr).

Example 46

1-(m-fluoro-phenvπ-3-rβ-(N-pyrrolidinvπ-ethvπ-3-l^'trans-3,4- dihvdro-2,2-dimethyl-3-hvdroxy-2H-pyranor3.2-c]pyridine-4-vπ- urea Mp.: 125-28°C Analysis: for the Formula C₂₃H₂₉FN₄O3 (428.5) calc: C 64.47 H 6.82 N 13.07 found: C 64.63 H 6.90 N 12.98

NMR (400 MHz, CDCI₃): 8.18 (s, 1H, H-5); 8.17 (d, 1H, H- 7); 6.7 (d, 1 H, H-8); 7.3-6.9 (m, 4H, H-phenyl); 6.1 ; 5.1 (m, 2H, H-3.4); 3.2-2.9 (m, 4H, H-CH₂); 2.6; 1.8 (m, 8H, H-pyrrolidine); 1.47; 1.28 (s, 6H, H-methyl). Example 47 1-(m-fluoro-phenv0-3-cvclopropylamino-3-.trans-3,4-dihvdro- 2.2-dimethyl-3-hvdroxy-2H-pyranof3.2-c]pyridine-4-vπ-urea Mp.: 120-22°C Analysis: for the Formula C₂₀H₂₂FN₃O₃ (371.4) calc: C 64.68 H 5.97 N 11.31 found: C 64.88 H 5.76 N 11.22

Example 48

1-(p-fluoro-phenyl)-3-hvdroxyethylamino-3-rtrans-3,4-dihydro-

2,2-dimethyl-3-hvdroxy-2H-pyranof3.2-c]pyridine-4-yl1-urea

Mp.: 184-85°C

Analysis: for the Formula Cι₉H₂₂FN₃O (375.4) calc: C 60.79 H 5.91 N 11.19 found: C 60.30 H 5.87 N 11.05

NMR (400 MHz, CDCI₃): 8.35 (s, 1H, H-5); 8.2 (d, 1 H, H- 7); 6.7 (d, 1 H, H-8); 7.3-6.91 (m, 4H, H-phenyl); 4.0- 3.65 (m, 4H, H-CH₂); 5.1; 3.7 (m, 2H, H-3.4); 1.54; 1.18 (s, 6H, H-methyl).

Example 49

1-(m-chloro-phenyl)-3-hvdroxyethylamino-3-[trans-3,4-dihvdro- 2,2-dimethyl-3-hvdroxy-2H-pyranor3.2-c]pyridine-4-vπ-urea

Mp.: 110-12°C

Analysis: for the Formula Cι₉H₂₂CIN₃O (391.8) calc: C 58.24 H 5.66 N 10.72 found: C 58.11 H 5.52 N 10.35

NMR (400 MHz, CDCI₃): 8.35 (s, 1 H, H-5); 8.2 (d, 1 H, H- 7); 6.7 (d, 1 H, H-8); 7.3-6.91 (m, 4H, H-phenyl); 4.0- 3.65 (m, 4H, H-CH₂); 5.5; 3.7 (m, 2H, H-3,4); 1.54; 1.18 (s, 6H, H-methyl). Example 50

1-(m-anvsylV3-hvdroxyethylamino-3-.trans-3,4-dihvdro-2.2- dimethyl-3-hvdroxy-2H-pyranor3.2-c1pyridine-4-yl1-urea Mp.: 116-119°C Analysis: for the Formula C₂oH₂ N₃O₅ (387.4) calc: C 62.16 H 6.26 N 10.87 found: C 62.22 H 6.11 N 10.53

NMR (400 MHz, CDCI₃): 8.35 (s, 1 H, H-5); 8.2 (d, 1 H, H- 7); 6.7 (d, 1 H, H-8); 7.3-6.91 (m, 4H, H-phenyl); 4.0- 3.65 (m, 4H, H-CH₂); 5.5; 3.7 (m, 2H, H-3.4); 3.7 (s, 3H, H-methoxy); 1.54; 1.18 (s, 6H, H-methyl). Example 51 1-(m-chloro-phenyl)-3-rβ-(N-pyrrolidinyl)-ethyl1-3-ftrans-3,4- dihvdro-2.2-dimethyl-3-hvdroxy-2H-pyranor3.2-c]pyridine-4-vπ- urea Mp.: 204-206°C Analysis: for the Formula C2₃H25.CIN.As (444.97) calc: C 62.08 H 6.57 N 12.59 found: C 61.95 H 6.67 N 12.33

NMR (400 MHz, CDCI₃): 8.26 (s, 1 H, H-5); 8.27 (d, 1 H, H- 7); 6.7 (d, 1 H, H-8); 7.3-6.9 (m, 4H, H-phenyl); 5.6; 3.61 (m, 2H, H-3.4); 3.3-2.9 (m, 4H, H-CH₂); 2.6; 1.92 (m, 8H-H-pyrrolidine); 1.53; 1.29 (s, 6H, H- methyl). XI

Example 52

6-amino-2,2-dimethyl-3-hvdroxy-4-(2-oxo-piperidine-1-yl)-2H- pyranof3.2-c]pyridinium-bromide The title compound is prepared from the corresponding unquaternarized derivative by reacting with tosyl hydroxyl amine. The crude tosylate salt is first converted into the fluoroborate which is transformed into the title bromide salt by treatment with an aqueous potassium bromide solution. The unquaternarized starting material is prepared by methods described in prior art. Mp.: 230-35°C Analysis: for the Formula Ci₅H₂oBrN₃O2 (354.2) calc: C 50.86 H 5.69 N 11.86 found: C 50.79 H 5.71 N 11.42

NMR (400 MHz, CDCI3-TFA): 9.55 (s, 2H, H-NH₂); 8.45 (d, 1H, H-7); 8.42 (s, 1H, H-5); 7.1 (d, 1H, H-8); 5.95 (s, 1H, H-3); 3.5; 2.8; 2.6; 2.0 (m, 8H, H-piperidone); 1.65; 1.60 (s, 6H, H-methyl).

Claims

What we claim is,

1) Pyrano[3.2-c]pyridine derivatives of the general Formula

R

their quaternary derivatives of the general Formula

their unsaturated derivatives of the general Formula

and salts thereof

(wherein n is 3, 4 or 5;

(CH₂)_n (A), R"

^■ N (B)

R"

O or

R"

/

- (C);

R'

R³ represents hydrogen, optionally substituted aralkyl or acyl; R⁶ is amino, -CH₂COR or -N=CH-NR^IVR^V; R stands for alkoxy, optionally substituted aryl or optionally substituted amino; R' and R" independently from each other stand for hydrogen, optionally substituted alkyl, cycloalkyl, aralkyl or aryl; R'" represents acyl or substituted carbamoyl; R^ιv and R^v independently from each other stand for hydrogen, alkyl, aryl or aralkyl or -NR^IVR^V forms a 5-7 membered nitrogen-containing heterocycle; with the proviso that if in compounds of the general Formula IA R¹ is a group of the general Formula A, R³ is other than hydrogen).

2) Compounds according to Claim 1 wherein R¹ stands for a group of the Formula A and n is 4. 3) Compounds of the general Formulae IA and IB according to Claim 1 wherein R³ is o-methyl-benzyl.

4) Compounds of the general Formulae IA and IB according to Claim 1 wherein R⁶ is amino; R³ stands for hydrogen or p-chloro-benzyl and A^" is a bromide ion.

5) The following compounds according to Claim 1 : trans-3,4-dihydro-6-amino-2,2-dimethyl-3-hydroxy-4-(2-oxo- piperidine-1-yl)-2H-pyrano[3,2-c]-pyridinium-bromide; trans-3,4-dihydro-6-amino-2,2-dimethyl-3-(4'-chloro- benzyloxyl)-4-(2-oxo-piperidine-1-yl)-2H-pyrano[3,2-c]- pyridinium-bromide; trans-3,4-dihydro-2,2-dimethyl-3-(o-methyl-benzyloxy)-4-(2- oxo-piperidine-1-yl)-2H-pyrano[3,2-c]-pyridine.

6) Process for the preparation of compounds of the general Formulae IA, IB and IC according to Claim 1 and salts thereof

(wherein R¹, R³, R⁶, R, R', R", R , R^ιv, R^v, A" and n have the same meaning as stated in Claim 1) w h i c h c o m p r i s e s a) reacting a compound of the Formula

with an amine of the general Formula

HNR'R" (X) or b) quaternerizing a compound of the general Formula

with an agent capable of introducing an R⁶ group; or d) aralkylating or acylating a compound of the general Formula IA or

wherein R is hydrogen; or e) reacting a compound of the general Formula IB, wherein R⁶ stands for -CH₂COOAIkyl, with an amine of the general Formula X; or f) acylating a compound of the general Formula IA or IB wherein R¹ stands for a group of the general Formula

.R"

^•N (C)

\

HNR^1VR^V (XI) h) if desired carrying out anion-exchange in a compound of the general Formula IB; and/or i) if desired converting a compound of the general Formula IA, IB or IC into a salt thereof.

7) Pharmaceutical composition comprising as active ingredient at least one compound of the general Formula IA, IB or IC according to Claim 1 or a pharmaceutically acceptable salt thereof in admixture with suitable inert pharmaceutical carriers and/or diluents.

8) Pharmaceutical composition according to Claim 7 having hypotensive effect.

9) Process for the preparation of pharmaceutical compositions according to Claim 7 or 8 which comprises admixing a compound of the general Formula IA, IB or IC or a pharmaceutically acceptable salt thereof with suitable inert pharmaceutical carriers or diluents and finishing the mixture in galenic form. 10) Compounds of the general Formula IA, IB or IC according to Claim 1 or pharmaceutically acceptable salts thereof for use as pharmaceutical active ingredient.

11) Use of compounds of the general Formula IA, IB or IC according to Claim 1 or pharmaceutically acceptable salts thereof for the preparation of pharmaceutical compositions having hypotensive effect.

12) Method for the treatment of high blood pressure which comprises administering to the patient in need of such treatment an effective amount of a compound of the general Formula IA, IB or IC according to Claim 1 or a pharmaceutically acceptable salt thereof.