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HK1057551B - Substituted 3.4-dihydro-pyrido[1,2-a]pyrimidines - Google Patents

Substituted 3.4-dihydro-pyrido[1,2-a]pyrimidines Download PDF

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Publication number
HK1057551B
HK1057551B HK04100342.1A HK04100342A HK1057551B HK 1057551 B HK1057551 B HK 1057551B HK 04100342 A HK04100342 A HK 04100342A HK 1057551 B HK1057551 B HK 1057551B
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HK
Hong Kong
Prior art keywords
alkyl
phenyl
branched
pyrido
dihydro
Prior art date
Application number
HK04100342.1A
Other languages
German (de)
French (fr)
Chinese (zh)
Other versions
HK1057551A1 (en
Inventor
Gerlach Matthias
Maul Corinna
Jagusch Utz-Peter
Original Assignee
Grunenthal Gmbh
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Priority claimed from DE10050662A external-priority patent/DE10050662A1/en
Application filed by Grunenthal Gmbh filed Critical Grunenthal Gmbh
Publication of HK1057551A1 publication Critical patent/HK1057551A1/en
Publication of HK1057551B publication Critical patent/HK1057551B/en

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Description

This notification concerns substituted 3,4-dihydro-pyridine[1,2-a]pyrimidines, their manufacturing processes, medicinal products containing these compounds, the use of these compounds in the manufacture of medicinal products for the treatment of pain, urinary incontinence, itching, tinnitus aureus and/or diarrhoea and pharmaceutical formulations containing these compounds.
The treatment of chronic and non-chronic pain conditions is of great importance in medicine, and there is a worldwide need for effective therapies for patient-centred and targeted treatment of chronic and non-chronic pain conditions, including successful and satisfactory pain management for the patient.
Traditional opioids such as morphine are effective in treating moderate to severe pain, but their use is limited by known side effects such as respiratory depression, vomiting, sedation, constipation and development of tolerance, and they are less effective in neuropathic or incidental pain, particularly in tumour patients.
The present invention is intended to provide analgesic compounds suitable for the treatment of pain, particularly chronic and neuropathic pain, and to avoid, if possible, the adverse effects commonly experienced with opioids with μ-receptor affinity such as morphine, such as nausea, vomiting, dependence, respiratory depression or constipation.
This task is solved by the compounds of general structure I, which are analgesic. In which R1 and R2independently H or phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or is single or multiple substitution of OH or OCH3 with H,R3 and R4independently H or C1-12 alkyl, where the C1-12 alkyl is straight or branched, where at least one residue of R3 and R4 is H,R5C3-8-cycloalkyl, where the cycloalkyl is saturated and unsubstituted or substituted with CO2ethyl, where the cycloalkyl is substituted with NO2,C=O11,C2H2 or Cl2H2 means R6 and R8 or R7R, where the C1-12 alkyl or branched alkyl is CO,R11 means C11R,R11 means C12R,R11 means C12R,R11 means C12R,R11 means C12R,R11 means C12R,R11 means C12R,R11 means C12R,R11 means C12R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R11R,R1R,R1R,R1R,R1R,R1R,R1R,R1R,R,R1R,R1R,R1R,R,R1R,R1R,R,R1R,R,R1R,R,R1R,R,R2R,R,R,R2R,R,R2R,R,R,R2R,R,R,R2R,R,R,R,R2R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R,R
Err1:Expecting ',' delimiter: line 1 column 57 (char 56)
Err1:Expecting ',' delimiter: line 1 column 56 (char 55)
Pharmaceutically acceptable salts for the purpose of this invention are those salts of the compounds of the invention according to general structure I which are physiologically acceptable for pharmaceutical use, particularly for use in mammals and/or humans.
Preferably, the pharmaceutically acceptable salts of the compounds of the invention according to the general structure I are formed with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, p-toluol sulphonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, amber acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. The salts formed are, inter alia, hydrochlorides, hydrobromide, phosphoric acid, carbon crystals, hydrogen carbonate, formic acid, acetylated acetic acid, oxalatin, sulphuric acid, faminic acid, glutamate and chlorine. In the case of salts which can be obtained by hydrolyzation of the solution, the solution must be water.
All compounds of the invention contain at least one centre of asymmetry, namely the carbon atom of structure I substituted by R5. Therefore, the compounds of general structure I of the invention may be present in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers or diastereomers, both in substance and as pharmaceutically acceptable salts of these compounds. The mixtures may be present in any mixing ratio of the stereoisomers.
The compounds of preference for the present invention are such 3,4-dihydro-pyrido[1,2-a]pyrimidines of general structure I, where one of the residues R1 and R2 means naphthyl or phenyl one or more times substituted with OH or OCH3, one of the residues R3 and R4 means H or C1-6 alkyl, and the other two residues R1, R2, R3 and R4 mean H, R5 C3-6 cycloalkyl, furanyl substituted with NO2, C=(O) R11 or CO2R12, R6 and R8 mean both Cl or fur, R7 H or C1-6 means alkyl, R9 H, R11 means phenyl and C121-6 means alkyl, and their pharmaceutical equivalents mean salts.
In particular, preference is given to compounds of general structure I, where one of the residues R1 and R2 means 24-hydroxyphenyl, 4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl or 2-naphthyl, one of the residues R3 and R4 means H or methyl, and the other two residues of R1, R2, R3 and R4 mean H, R5 means cyclopropyl, 2-(C=O) O-ethyl) -cyclopropyl, cyclohexyl, 5-nitro-furan-2-yl, C=(O) phenyl, or CO2Ethyl, R6 and R8 or both mean Cl, R7 means H or methyl and R9 means H and their pharmaceutically acceptable salts.
The most preferred compounds of the invention are those selected from: The following substances are to be classified in the immediate vicinity of the product: [7,9-dichlor-4- ((4-hydroxy-3-methoxyphenyl) -3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-2-yl]phenyl-methane,[7,9-dibromo-4-(4-hydroxyphenyl) -3,6-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-3,7-dimethyl-3,4-dihydroxyphenyl-pyridine-3,3-dibromo-3,4-dibromo-3,4-dibromo-3,4-dibromo-3,4-dibromo-3,4-dibromo-3,4-dibromo-3,4-dibromo-3,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,3-dibromo-2,3-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,4-dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,dibromo-2,
The invention also relates to a process for the manufacture of the compounds of structure I according to the invention in which the R1 and R2independently H or phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or is substituted one or more times with OH or OCH3, where at least one residue of R1 and R2 is H,R3 and R4independently H or C1-12 alkyl, where the C1-12 alkyl is straight or branched, where at least one residue of R3 and R4 is H,R5C3-8-cycloalkyl, where the cycloalkyl is saturated and unsubstituted or substituted with CO2ethyl, where the cycloalkyl is substituted with NO2, where C=O) R11-R11 or CO2R12-R6 and R8R or Bromide, where R7R1-H or C1-12 alkyl, where the alkyl or branched alkyl is R11-R11-R9R1 or its branched alkyl, means branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, branched, where the method is characterised by the production of a heteroarylamine of general structure II in which R6, R7, R8 and R9 are as defined above, with an aldehyde of general structure III wherein R5 is defined as above, an olefin of general structure IV and wherein R1, R2, R3 and R4 as defined above are converted in the presence of an acid.
Err1:Expecting ',' delimiter: line 1 column 98 (char 97)
The method of the invention may also be performed in semi- or fully automated form as a parallel synthesis of a group of compounds of general structure I according to the invention.
The acid used is an inorganic or organic protonic or Lewis acid, preferably in the presence of an organic acid, e.g. acetic acid, trifluoric acetic acid or methan sulfonic acid, especially trifluoric acetic acid.
The manufacturing process of the invention can be carried out in any suitable solvent in which the reactants dissolve sufficiently, and organic solvents, e.g. dichloromethane or especially acetonitrile, are preferred as solvents.
The manufacture of the compounds of general structure I according to the invention is conveniently carried out at a temperature of 0 to 100 °C, in particular 15 to 40 °C. The reaction time is preferably 15 minutes to 12 hours and can be adapted to the needs of the individual.
The heteroarylamines of general structure II, the aldehydes of general structure III and the olefins of general structure IV used in the inventive process are available commercially (from Acros, Yellow; Avocado, Port of Heysham; Aldrich, Deisenhofen; Fluka, Seelze; Lancaster, Mülheim; Maybridge, Tintagel; Merck, Darmstadt; Sigma, Deisenhofen; TCl, Japan) or may be produced by generally known processes.
The compounds of general structure I according to the invention can be isolated as both a free base and a salt. The free base of the compound of general structure I is usually obtained after transformation according to the above-mentioned method and subsequent conventional treatment. The base obtained can then be obtained, for example, by transformation with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanosulphonic acid, p-toluol sulphonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, corticosteroic acid, oxalic acid, trimeric acid, bernoxylic acid, trimeric acid, citric acid, glutamic acid or aspartic acid. It can also be soluble in organic solvents, especially in hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid
Insofar as the compounds of general structure I are obtained in the manufacturing process of the invention as racemates or as mixtures of their various enantiomers and/or diastereomers, these mixtures may be separated by methods well known to the present state of the art. Suitable methods include chromatographic separation methods, in particular liquid chromatography at normal or increased pressure, preferably the MPLC and HPLC methods, and fractionated salinization methods. In particular, individual enantiomers may be separated from each other e.g. by HPLC at the chiral phase or by the chiral separation of crystalline acids, such as (+) crystalline acid, crystalline acid or (+) -10 sulphuric acid, when the salts are dissolved.
In addition, a medicinal product which contains at least one of the compounds of general structure I, as defined above, and their pharmaceutically acceptable salts, may be present in the medicinal product as isomeric pure compounds, in particular enantiomeric pure compounds or diastereomeric pure compounds, but also as a racemic or nonracemic mixture.
The invention also relates to the use of at least one compound of general structure I, including its diastereomers or enantiomers, whether or not in the form of a racemate or enantiomeric mixture in the form of a free base or a salt formed with a physiologically compatible acid, in particular hydrochloride salt, to produce a medicinal product for the treatment of pain.
Surprisingly, the compounds of general structure I have been found to be very suitable for further indications, in particular for the treatment of urinary incontinence, itching, tinnitus aureus and/or diarrhoea.
In addition, the present invention also covers pharmaceutical compositions containing at least one compound of the general structure I defined above or one of its pharmaceutically acceptable salts and one or more pharmaceutical excipients.
The medicinal products and pharmaceutical formulations of the invention may be presented and administered in liquid, semi-solid or solid forms, and may be in the form of solutions for injection, drops, juices, syrups, sprays, suspensions, granules, tablets, pellets, transdermal therapeutic systems, capsules, patches, ointments, ointments, creams, lotions, gels, emulsions or aerosols, and may contain, in addition to at least one compound of the general structure of the invention, pharmaceutical excipients, such as carrier acid, drops, juices, tablets, tablets, tablets, transdermal therapeutic systems, capsules, patches, ointments, ointments, lotions, gels, emulsions or aerosols, and may be modified by: acetic acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochlor
The choice of excipients and the amounts to be used depend on whether the product is to be administered orally, subcutaneously, parenterally, intravenously, vaginally, pulmonally, intraperitoneally, transdermally, intramuscularly, nasally, buccally, rectally or topically, for example to treat skin, mucous membranes and eye infections. For oral application, preparations in the form of tablets, drops, capsules, granules, drops, juices and syrups, for parenteral, topical and inhalative application, suspensions, easily reconstitutable solutions for oral administration and sprays.
Err1:Expecting ',' delimiter: line 1 column 298 (char 297)
For example, for a solid formulation such as a tablet, the active substance of the medicinal product, i.e. a compound of general structure I or one of its pharmaceutically acceptable salts, may be granulated to form a solid composition containing a polymeric composition or a polymeric composition thereof in pharmaceutical dosage distribution, e.g. conventional tablet ingredients such as cornstarch, lactose, sucrose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable rubber, and pharmaceutical diluents such as water. A homogeneous composition is obtained by distributing the composition of the composition in a homogeneous way, such that the composition of the composition is more uniformly distributed over a wide range of solids, such as tablets or tablets, or in a more homogeneous form, such as tablets or tablets, or in a form which is more uniformly distributed over a large range of substances, such as tablets or tablets, and/or tablets, and/or tablets, such as tablets or tablets.
The amount of active substance to be administered to the patient varies according to the weight, age and medical history of the patient, the type of application, the indication and the severity of the disease, and is usually between 0.1 and 5000 mg/kg, in particular between 1 and 500 mg/kg, preferably between 2 and 250 mg/kg bodyweight, of at least one compound of the general structure I of the invention.
The following examples are intended to illustrate the present invention.
Examples
The chemicals and solvents used were commercially purchased from one of the following suppliers: Acros, Geel; Avocado, Port of Heysham; Aldrich, Deisenhofen; Fluka, Seelze; Lancaster, Mülheim; Maybridge, Tintagel; Merck, Darmstadt; Sigma, Deisenhofen; TCl, Japan; or produced by generally known state-of-the-art processes.
The chromatographic cleaning was carried out on an HPLC-RP-18 column of the Macherey nail; material NUCLEOSIL 100-3 C18-HD. approximately 100 mm (VarioPrep), 21 mm in diameter; solvent water/methanol, gradient: 50-100% in about 18 min., flow: 10 ml/min.; detection: UV, Beckman 168 PDA.
The general working rules AAV (semi-automated synthesis)
A round glass tube with thread (diameter 16 mm, length 125 mm) was fitted with a stirrer and closed with a screw cap with septum. The tube was placed in the stirrer block, which had been tempered to 20 °C. The following reagents were then added in succession: 1 ml of a solution of trifluoroacetic acid, 0,1 M, and heteroarylamine component II, 0,1 M, in acetonitrile;1 ml of a solution of 0,11 M of aldehyde III in acetonitrile;1 ml of a solution of 0,3 M of olefin IV in acetonitrile.
The reaction mixture was stirred at 20 °C in one of the stirring blocks for 10 h. The reaction solution was then filtered and the tube was rinsed twice with 1.5 ml of 7.5% NaHCO3 solution.
The rack containing the samples was placed manually on the treatment plant. The reaction mixture was placed and shaken on a pre-treatment vessel with 2 ml of ethyl acetate. The phase boundary was centrifuged briefly in the centrifuge to form the phase boundary. The phase boundary was optically detected and the organic phase was sampled. The aqueous phase was again placed with 2 ml of ethyl acetate, shaken, centrifuged and the organic phase sampled. The combined organic phases were dried over 2.4 gSO Mg4 (granulated). The solvent was removed in a vacuum centrifuge.
Each sample was characterised by ESI-MS and/or NMR. Mass spectrometric studies (ESI-MS) were performed with a mass spectrometer from Fa. Finnegan, LCQ Classic. 1H-NMR studies of the compounds of the invention were performed with a 300 MHz DPX Advance NMR apparatus from Fa. Bruker.
The AAV indicated was used to produce examples of the invention (*) and reference examples 1-131 (see Table 1). HPLC cleared.
1 400,78 401,2/403,2 9-Chlor-4-(4-methoxy-phenyl)-3-methyl-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
2 428,83 429,2/430,1 9-Chlor-4-(4-methoxy-phenyl)-3-methyl-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäureethylester
3 411,28 411,1/413,1 7,9-Dichlor-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäureethylester
4 500,19 499,1/501,0/503,0 7,9-Dibrom-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäureethylester
5 387,39 388,2 4-(3,4-Dimethoxy-phenyl)-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäureethylester
6 381,25 381,1/383,0 7,9-Dichlor-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäureethylester
7 357,36 358,2 4-(4-Methoxy-phenyl)-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäureethylester
8 383,23 383,2/385,0 7,9-Dichlor-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
9 486,16 485,1/487,0/488,9 7,9-Dibrom-4-(3,4-dimethoxy-phenyl)-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
10 359,33 360,1 4-(3,4-Dimethoxy-phenyl)-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
11 353,2 353,1/355,0 7,9-Dichlor-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
12 329,31 330,1 4-(4-Methoxy-phenyl)-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
13 408,21 408,1/410,1 7-Brom-4-(4-methoxy-phenyl)-9-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
14 450,27 450,2/452,1 7,9-Dichlor-4-(3,4-dimethoxy-phenyl)-2-(5-nitro- furan-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
15 539,18 538,1/540,1/542,0 7,9-Dibrom-4-(3,4-dimethoxy-phenyl)-2-(5-nitro-furan-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
16 426,38 427,2 4-(3,4-Dimethoxy-phenyl)-7-nitro-2-(5-nitro-furan-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
17 420,25 420,2/422,1 7,9-Dichlor-4-(4-methoxy-phenyl)-2-(5-nitro-furan-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
18 419,35 419,3/421,1 2-[7,9-Dichlor-4-(2,4-dimethyl-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
19 452,9 453,3 2-[9-Chlor-4-(2,4-dimethyl-phenyl)-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
20 540,26 539,3/541,1/543,1 2-[7,9-Dibrom-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
21 421,32 421,1/423,1 2-[7,9-Dichlor-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
22 510,23 509,1/511,0/513,0 2-[7,9-Dibrom-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
23 454,87 455,2/456,0/457,1 2-[9-Chlor-4-(4-methoxy-phenyl)-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
24 397,43 398,2 2-[4-(4-Methoxy-phenyl)-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
25 357,36 358,2 4-(4-Hydroxy-phenyl)-3-methyl-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2- carbonsäureethylester
26 355,24 355,1/357,0 7,9-Dichlor-4-phenylsulfanyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
27 331,34 332,1 7-Nitro-4-phenylsulfanyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
28 383,23 383,1/385,1 7,9-Dichlor-4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
29 472,14 471,0/473,0/475,0 7,9-Dibrom-4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
30 486,16 485,0/487,0/488,9 7,9-Dibrom-4-(4-hydroxy-3-methoxy-phenyl)-3,6-dimethyl-34-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
31 416,78 417,1/419,1 9-Chlor-4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
32 367,23 367,1/369,1 7,9-Dichlor-4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
33 456,14 455,0/457,0/459,0 7,9-Dibrom-4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
34 470,17 469,0/471,0/472,9 7,9-Dibrom-4-(4-methoxy-phenyl)-3,6-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
35 400,78 401,1/403,1 9-Chlor-4-(4-methoxy-phenyl)-3-methyl-7-trifluormethyl-3,4-dihydro-2H-pyrido[12-a]pyrimidin-2-carbonsäure
36 343,33 344,2 4-(4-Methoxy-phenyl)-3-methyl-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
37 422,23 422,1/424,0 7-Brom-4-(4-methoxy-phenyl)-3-methyl-9-nitro-34-dihydro-2H-pyrido[12-a]pyrimidin-2-carbonsäure
38 353,2 353,1/355,1 7,9-Dichlor-4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
39 456,14 455,0/457,0/459,0 7,9-Dibrom-4-(4-hydroxy-phenyl)-3,6-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
40 383,23 383,1/385,1 7,9-Dichlor-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
41 472,14 471,0/473,0/475,0 7,9-Dibrom-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
42 486,16 485,0/487,0/489,0 7,9-Dibrom-4-(3,4-dimethoxy-phenyl)-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
43 416,78 417,1 9-Chlor-4-(3,4-dimethoxy-phenyl)-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2- carbonsäure
44 359,33 360,2 4-(3,4-Dimethoxy-phenyl)-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
45 285,3 286,2 4-(4-Methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2-a]pyrimidin-2-carbonsäure
46 353,2 353,1/355,1 7,9-Dichlor-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pycido[1,2-a]pyrimidin-2-carbonsäure
47 442,11 441,0/443,0/445,0 7,9-Dibrom-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
48 456,14 455,0/457,0/459,0 7,9-Dibrom-4-(4-methoxy-phenyl)-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
49 386,75 387,1 9-Chlor-4-(4-methoxy-phenyl)-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
50 329,31 330,1 4-(4-Methoxy-phenyl)-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
51* 443,32 441,2/443,1/445,1 [7,9-Dichlor-4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2- yl]-phenyl-methanon
52 532,24 533,0 [7,9-Dibrom-4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
53 546,26 545,0/547,0/549,0 [7,9-Dibrom-4-(4-hydroxy-3-methoxy-phenyl)-3,6-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
54 419,43 420,2 [4-(4-Hydroxy-3-methoxy-phenyl)-3-methyl-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
55 403,43 404,2 [4-(4-Methoxy-phenyl)-3-methyl-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
56* 516,24 515,0/517,0/519,0 [7,9-Dibrom-4-(4-hydroxy-phenyl)-3,6-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
57 443,32 443,11445,1 [7,9-Dichlor-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
58 532,24 531,1/533,1 [7,9-Dibrom-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
59 546,26 545,1/547,0 [7,9-Dibrom-4-(3,4-dimethoxy-phenyl)-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
60 476,88 477,1 [9-Chlor-4-(3,4-dimethoxy-phenyl)-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
61 419,43 420,2 [4-(3,4-Dimethoxy-phenyl)-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
62 389,41 390,2 [4-(4-Methoxy-phenyl)-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-phenyl-methanon
63 303,18 303,1/305,1 2-(7,9-Dichlor-2-cyclopropyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-4-yloxy)-ethanol
64 392,1 391,0/393,01395,0 2-(7,9-Dibrom-2-cyclopropyl-3,4-dihydro-2H- pyrido[1,2-a]pyrimidin-4-yloxy)-ethanol
65 336,74 337,1/339,1 2-(9-Chlor-2-cyclopropyl-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-4-yloxy)-ethanol
66 279,29 280,1 2-(2-Cyclopropyl-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-4-yloxy)-ethanol
67 412,83 413,1 9-Chlor-2-cyclopropyl-4-(3,4-dimethoxy-phenyl)-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
68 438,17 439,0 7,9-Dibrom-2-cyclopropyl-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
69 382,81 383,1/385,1 9-Chlor-2-cyclopropyl-4-(4-methoxy-phenyl)-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
70 325,36 326,2 2-Cyclopropyl-4-(4-methoxy-phenyl)-7-nitro-3,4-dihydro-2H-pyrida[1,2-a]pyrimidin
71 345,26 345,1/347,1 2-(7,9-Dichlor-2-cyclohexyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-4-yloxy)-ethanol
72 434,18 433,1/435,1/437,0 2-(7,9-Dibrom-2-cyclohexyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-4-yloxy)-ethanol
73 448,2 447,1/449,0/451,0 2-(7,9-Dibrom-2-cyclohexyl-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-4-yloxy)-ethanol
74 378,82 379,2/381,2 2-(9-Chlor-2-cyclohexyl-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-4-yloxy)-ethanol
75 321,37 322,2 2-(2-Cyclohexyl-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-4-yloxy)-ethanol
76 421,36 421,1/423,1 7,9-Dichlor-2-cyclohexyl-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
77* 391,34 391,1/393,1 7,9-Dichlor-2-cyclohexyl-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
78* 480,25 479,1/481,1/483,0 7,9-Dibrom-2-cyclohexyl-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
79 424,89 425,2/427,2 9-Chlor-2-cyclohexyl-4-(4-methoxy-phenyl)-7- trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
80 484,19 485,0/487,0 7,9-Dibrom-4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäureethylester
81 456,14 457,4/459,5 7,9-Dibrom-4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-carbonsäure
82 523,19 522,4/524,3/526,2 7,9-Dibrom-4-(4-methoxy-phenyl)-3-methyl-2-(5-nitro-furan-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
83 524,26 525,2 2-[7,9-Dibrom-4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
84* 553,21 554,2/555,2/556,2 7,9-Dibrom-4-(3,4-dimethoxy-phenyl)-6-methyl-2-(5-nitro-furan-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
85 396,35 397,1 4-(4-Methoxy-phenyl)-7-nitro-2-(5-nitro-furan-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
86 508,26 509,1 2-[7,9-Dibrom-4-(2,4-dimethyl-phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropan-carbonsäureethylester
87 554,28 553,2/555,1/557,1 2-[7,9-Dibrom-4-(3,4-dimethoxy-phenyl)-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
88 484,9 485,5 2-[9-Chlor-4-(3,4-dirnethoxy-phenyl)-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
89* 524,26 525,1/527,2 2-[7,9-Dibrom-4-(4-methoxy-phenyl)-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl)-cyclopropancarbonsäureethylester
90 399,42 400,2 2-[4-(4-Fluor-phenyl)-4-methyl-7-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-yl]-cyclopropancarbonsäureethylester
91 393,51 291,3 (M+H-OBenzyl) 9-Benzyloxy-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
92 346,41 347,3 8-Methyl-7-nitro-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
93 356,28 356,2/358,2 7,9-Dichlor-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
94 389,83 390,3/392,2 9-Chlor-4-phenyl-2-pyridin-2-yl-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
95 346.41 347,1 8-Methyl-9-nitro-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
96 332,38 333,2 7-Nitro-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
97 332,38 333,2 9-Nitro-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
98 411,28 413,1/416,2 7-Brom-9-nitro-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
99 459,2 458,1/460,0/462,0 7,9-Dibrom-6-methyl-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
100 445,18 444,2/446,1/448,0 7,9-Dibrom-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
101 363,44 364.2 4-Phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-carbonsäure
102 333.45 334,2 7-Methyl-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
103 425,55 426,2 9-Benzyloxy-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
104 378,45 379,2 8-Methyl-7-nitro-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
105 398,87 399,1/400,0 6-Chlor-9-nitro-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
106 388,32 388,2/390,1 7,9-Dichlor-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
107 421,88 422,2/424,1/425,1 9-Chlor-4-phenylsulfanyl-2-pyridin-2-yl-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2- a]pyrimidin
108 378,45 379,2 8-Methyl-9-nitro-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
109 364,42 365,2 7-Nitro-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
110 398,33 398,1/400,1/401,1 7-Brom-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
111 364,42 365,2 9-Nitro-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
112 412,36 414,1/415,1 7-Brom-9-methyl-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
113 412,36 414,1 4-Phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-ol
114 335,43 7-Chlor-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
115 335,43 336,2 4-Phenylsulfanyl-6-propyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
116 491,25 492,1 7,9-Dibrom-6-methyl-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
117 387,43 388,2 4-Phenylsulfanyl-2-pyridin-2-yl-7-trifluormethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
118 477,23 476,11478,0/480,0 7,9-Dibrom-4-phenylsulfanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin
119 385,49 386,2 1-Phenylsulfanyl-3-pyridin-2-yl-2,3-dihydro-1H-pyrimido[1,2-a]chinolin-10-ol
120 289,39 288,4 2-Methyl-6-pyridin-2-yl-7,10-methano-6a,7,10,10a-tetrahydro-6H-pyrido[1,2-a]chinazolin
121 344,26 2,4-Dichlor-6-pyridin-2-yl-7,10-methano-6a,7,10,10a-tetrahydro-6H-pyrido[1,2-a]chinazolin
122 377,81 4-Chlor-6-pyridin-2-yl-2-trifluormethyl-7,10-methano-6a,7,10,10a-tetrahydro-6H-pyrido[1,2-a]chinazolin
123 320,35 2-Nitro-6-pyridin-2-yl-7,10-methano-6a,7,10,10a-tetrahydro-6H-pyrido[1,2-a]chinazolin
124 320,35 4-Nitro-6-pyridin-2-yl-7,10-methano-6a,7,10,10a-tetrahydro-6H-pyrido[1,2-a]chinazolin
125 309,81 2-Chlor-6-pyridin-2-yl-7,10-methano-6a,7,10,10a-tetrahydro-6H-pyrido[1,2-a]chinazolin
126 317,45 1-Propyl-6-pyridin-2-yl-7,10-methano-6a,7,10,10a-tetrahydro-6H-pyrido[1,2-a]chinazolin
127 447,18 446,2/448,2/450,1 2,4-Dibrom-1-methyl-6-pyridin-2-yl-7,10-methano-6a,7,10,10a-tetrahydro-6H-pyrido[1,2-a]chinazolin
128 343,36 6-Pyridin-2-yl-2-trifluormethyl-7,10-methano-6a,7,10,10a-tetrahydro-6H-pyrido[1,2-a]chinazolin
129 341,43 324,1 1,4-Methano-5-pyridin-2-yl-1,4a,5,12c-tetrahydro-4H-6,12b-diaza-benzo[c]phenathren-12-ol
130 325,42 324,2 1,4-Methano-5-pyridin-2-yl-1,4a,5,12c-tetrahydro-4H-6,12b-diaza-benzo[c]phenathren
131 325,42 324,2 6-Pyridin-2-yl-7,10-methano-6a,7,10,10a-tetrahydro-6H-isochino[2,1-a]chinazolin
Pharmaceutical studies The following information is provided in the Annex to Regulation (EC) No 396/2005 for the determination of the toxicity of the active substance:
Err1:Expecting ',' delimiter: line 1 column 184 (char 183)
The following characteristics were determined for the NA transporter: The test shall be carried out on the test vessel. (N = 4 each, i.e. mean ± independent series of tests carried out in triple parallel tests).
A detailed description of the methodology can be found in the literature (M. Ch. Frink, H.-H. Hennies, W. Engelberger, M. Haurand and B. Wilffert (1996) Pharmaceutical research/drug Res. 46 (III), 1029-1036).
For the compound of the invention 2-[7,9-dibromo-4-(4-methoxyphenyl)-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-2-yl]-cyclopropancarbonic acid ethyl ester as described in Example 89, a significant inhibition of noradrenaline reuptake (10 μmol/l) of 53% was measured. This result, as well as the results for other compounds of the invention, are given in the following table.
51 33 %
56 35 %
77 30 %
78 43%
84 33%
89 53 %
Pharmaceutical formulation of a medicinal product of the invention
1 g of hydrochloride of 4-(3,4-dimethoxyphenyl) -7-nitro-3.4-dihydro-2H-pyrido[1,2-a]pyrimidine-2-carbonic acid was dissolved in 1 l of water for injection at room temperature and then adjusted to isotonic conditions by addition of sodium chloride.

Claims (15)

  1. Substituted 3,4-dihydropyrido[1,2-a]pyrimidines of the general structure I in which
    R1 and R2   mutually independently mean H or phenyl or naphthyl, wherein phenyl or naphthyl are unsubstituted or mono- or polysubstituted with OH or OCH3, wherein at least one residue of R1 and R2 is H,
    R3 and R4   mutually independently mean H or C1-12 alkyl, wherein C1-12 alkyl is linear or branched, wherein at least one residue of R3 and R4 is H,
    R5   means C3-8 cycloalkyl, wherein cycloalkyl is saturated and is unsubstituted or substituted with CO2ethyl, or means furanyl substituted with NO2, C(=O)R11 or CO2R12,
    R6 and R8   both mean Cl or Br,
    R7   means H or C1-12 alkyl, wherein alkyl is linear or branched,
    R9   means H,
    R11   is phenyl,
    R12   means C1-8 alkyl, wherein alkyl is linear or branched,
    and the pharmaceutically acceptable salts thereof.
  2. Compounds of the general structure I and the pharmaceutically acceptable salts thereof according to claim 1 in the form of the racemates thereof, in the form of the pure enantiomers or in the form of mixtures of the enantiomers or diastereomers in any desired mixing ratio.
  3. Compounds of the general structure I according to one of claims 1 or 2 and the pharmaceutically acceptable salts thereof, wherein one of the residues R1 and R2 means naphthyl or means phenyl mono- or polysubstituted with OH or OCH3, one of the residues R3 and R4 means H or C1-6 alkyl, and the other two residues of R1, R2, R3 and R4 mean H, R5 means C3-6 cycloalkyl, furanyl substituted with NO2, C(=O)R11 or CO2R12, R6 and R8 both mean Cl or Br, R7 means H or C1-6 alkyl, R9 means H, R11 means phenyl and R12 means C1-6 alkyl.
  4. Compounds of the general structure I according to claim 3 and the pharmaceutically acceptable salts thereof, wherein one of the residues R1 and R2 means 4-hydroxyphenyl, 4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl or 2-naphthyl, one of the residues R3 and R4 means H or methyl, and the other two residues of R1, R2, R3 and R4 mean H, R5 means cyclopropyl, 2-(C(=O)O-ethyl)-cyclopropyl, cyclohexyl, 5-nitro-2-furanyl, C(=O)phenyl or CO2ethyl, R6 and R8 both mean Cl or Br, R7 means H or methyl and R9 means H.
  5. Compounds of the general structure I according to one of claims 1 to 4 and the pharmaceutically acceptable salts thereof, wherein the compounds are selected from among:
    [7,9-dichloro-4-(4-hydroxy-3-methoxyphenyl)-3-methyl-3,4-dihydro-2H-pyrido[1,2-a]-2-pyrimidinyl]-phenylmethanone,
    [7,9-dibromo-4-(4-hydroxyphenyl)-3,6-dimethyl-3,4-dihydro-2H-pyrido[1,2-a]-2-pyrimidinyl]-phenylmethanone,
    7,9-dichloro-2-cyclohexyl-4-(4-methoxyphenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine,
    7,9-dibromo-2-cyclohexyl-4-(4-methoxyphenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine,
    7,9-dibromo-4-(3,4-dimethoxyphenyl)-6-methyl-2-(5-nitro-2-furanyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine,
    2-[7,9-dibromo-4-(4-methoxyphenyl)-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]-2-pyrimidinyl]-cyclopropane carboxylic acid ethyl ester.
  6. A process for the production of substituted 3,4-dihydropyrido[1,2-a]pyrimidines of the general structure I and the pharmaceutically acceptable salts thereof, in which
    R1 and R2   mutually independently mean H or phenyl or naphthyl, wherein phenyl or naphthyl are unsubstituted or mono- or polysubstituted with OH or OCH3, wherein at least one residue of R1 and R2 is H,
    R3 and R4   mutually independently mean H or C1-12 alkyl, wherein C1-12 alkyl is linear or branched, wherein at least one residue of R3 and R4 is H,
    R5   means C3-8 cycloalkyl, wherein cycloalkyl is saturated and is unsubstituted or substituted with CO2ethyl, or means furanyl substituted with NO2, C(=O)R11 or CO2R12,
    R6 and R8   both mean Cl or Br,
    R7   means H or C1-12 alkyl, wherein alkyl is linear or branched,
    R9   means H,
    R11   is phenyl,
    R12   means C1-8 alkyl, wherein alkyl is linear or branched,
    characterised in that a heteroarylamine of the general structure II in which R6, R7, R8 and R9 are defined as above, is reacted in the presence of an acid with an aldehyde of the general structure III in which R5 is defined as above, and an olefin of the general structure IV    in which R1, R2, R3 and R4 are defined as above.
  7. A process according to claim 6, characterised in that the reaction of the heteroarylamine of the general structure II with the aldehyde of the general structure III and the olefin of the general structure IV is performed in a single-vessel reaction.
  8. A process according to either of claims 6 or 7, characterised in that the acid is trifluoroacetic acid.
  9. A process according to one of claims 6 to 8, characterised in that the reaction is performed in an organic solvent at a temperature of 0 to 100°C and a reaction time of 0.25 to 12 h.
  10. A process according to one of claims 6 to 9, characterised in that the reaction is performed at a temperature of 15 to 40°C.
  11. A process according to one of claims 6 to 10, characterised in that the organic solvent is acetonitrile.
  12. A pharmaceutical preparation containing at least one compound of the general structure I or a pharmaceutically acceptable salt thereof in which
    R1 and R2   mutually independently mean H or phenyl or naphthyl, wherein phenyl or naphthyl are unsubstituted or mono- or polysubstituted with OH or OCH3, wherein a residue of R1 and R2 is H,
    R3 and R4   mutually independently mean H or C1-12 alkyl, wherein C1-12 alkyl is linear or branched, wherein at least one residue of R3 and R4 is H,
    R5   means C3-8 cycloalkyl, wherein cycloalkyl is saturated and is unsubstituted or substituted with CO2ethyl, or means furanyl substituted with NO2, C(=O)R11 or CO2R12,
    R6 and R8   both mean Cl or Br,
    R7   means H or C1-12 alkyl, wherein alkyl is linear or branched,
    R9   means H,
    R11   means phenyl and
    R12   means C1-8 alkyl, wherein alkyl is linear or branched.
  13. Use of a compound of the general structure I or a pharmaceutically acceptable salt thereof in which
    R1 and R2   mutually independently mean H or phenyl or naphthyl, wherein phenyl or naphthyl are unsubstituted or mono- or polysubstituted with OH or OCH3, wherein at least one residue of R1 and R2 is H,
    R3 and R4   mutually independently mean H or C1-12 alkyl, wherein C1-12 alkyl is linear or branched, wherein at least one residue of R3 and R4 is H,
    R5   means C3-8 cycloalkyl, wherein cycloalkyl is saturated and is unsubstituted or substituted with CO2ethyl, or means furanyl substituted with NO2, C(=O)R11 or CO2R12,
    R6 and R8   both mean Cl or Br,
    R7   means H or C1-12 alkyl, wherein alkyl is linear or branched,
    R9   means H,
    R11   is phenyl,
    R12   means C1-8 alkyl, wherein alkyl is linear or branched,
    for the production of a pharmaceutical preparation for the treatment of pain.
  14. Use of a compound of the general structure I or a pharmaceutically acceptable salt thereof in which
    R1 and R2   mutually independently mean H or phenyl or naphthyl, wherein phenyl or naphthyl are unsubstituted or mono- or polysubstituted with OH or OCH3, wherein at least one residue of R1 and R2 is H,
    R3 and R4   mutually independently mean H or C1-12 alkyl, wherein C1-12 alkyl is linear or branched, wherein at least one residue of R3 and R4 is H,
    R5   means C3-8 cycloalkyl, wherein cycloalkyl is saturated and is unsubstituted or substituted with CO2ethyl, or means furanyl substituted with NO2, C(=O)R11 or CO2R12,
    R6 and R8   both mean Cl or Br,
    R7   means H or C1-12 alkyl, wherein alkyl is linear or branched,
    R9   means H,
    R11   is phenyl,
    R12   means C1-8 alkyl, wherein alkyl is linear or branched,
    for the production of a pharmaceutical preparation for the treatment of urinary incontinence, pruritus, tinnitus and/or diarrhoea.
  15. A pharmaceutical composition, which contains at least one compound of the general structure I or a pharmaceutically acceptable salt thereof in which
    R1 and R2   mutually independently mean H or phenyl or naphthyl, wherein phenyl or naphthyl are unsubstituted or mono- or polysubstituted with OH or OCH3, wherein at least one residue of R1 and R2 is H,
    R3 and R4   mutually independently mean H or C1-12 alkyl, wherein C1-12 alkyl is linear or branched, wherein at least one residue of R3 and R4 is H,
    R5   means C3-8 cycloalkyl, wherein cycloalkyl is saturated and is unsubstituted or substituted with CO2ethyl, or means furanyl substituted with NO2, C(=O)R11 or CO2R12,
    R6 and R8   both mean Cl or Br,
    R7   means H or C1-12 alkyl, wherein alkyl is linear or branched,
    R9   means H,
    R11   is phenyl,
    R12   means C1-8 alkyl, wherein alkyl is linear or branched,
    together with at least one pharmaceutical auxiliary substance.
HK04100342.1A 2000-10-13 2001-10-10 Substituted 3.4-dihydro-pyrido[1,2-a]pyrimidines HK1057551B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10050662A DE10050662A1 (en) 2000-10-13 2000-10-13 New substituted dihydropyrido-pyrimidine derivatives, useful for treating e.g. pain, urinary incontinence and tinnitus
DE10050662.3 2000-10-13
PCT/EP2001/011700 WO2002030933A1 (en) 2000-10-13 2001-10-10 Substituted 3.4-dihydro-pyrido[1,2-a]pyrimidines

Publications (2)

Publication Number Publication Date
HK1057551A1 HK1057551A1 (en) 2004-04-08
HK1057551B true HK1057551B (en) 2005-12-09

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