WO1993016076A1 - 3-(1h^_-tetrazol-5-yl)-4h^_-pyrido[1,2-a^_]pyrimidine-4-ones, pharmaceutical compositions containing the same and the preparation thereof - Google Patents
3-(1h^_-tetrazol-5-yl)-4h^_-pyrido[1,2-a^_]pyrimidine-4-ones, pharmaceutical compositions containing the same and the preparation thereof Download PDFInfo
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- WO1993016076A1 WO1993016076A1 PCT/HU1993/000009 HU9300009W WO9316076A1 WO 1993016076 A1 WO1993016076 A1 WO 1993016076A1 HU 9300009 W HU9300009 W HU 9300009W WO 9316076 A1 WO9316076 A1 WO 9316076A1
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- Prior art keywords
- general formula
- tetrazol
- stands
- hydrogen
- pharmaceutically acceptable
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- 239000008194 pharmaceutical composition Substances 0.000 title claims 2
- 150000003839 salts Chemical class 0.000 claims abstract 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract 9
- 150000001875 compounds Chemical class 0.000 claims abstract 9
- 238000000034 method Methods 0.000 claims abstract 8
- 150000004677 hydrates Chemical class 0.000 claims abstract 6
- 230000002378 acidificating effect Effects 0.000 claims abstract 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 3
- 229910052739 hydrogen Inorganic materials 0.000 claims 9
- 239000001257 hydrogen Substances 0.000 claims 9
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 229910052736 halogen Inorganic materials 0.000 claims 5
- 150000002367 halogens Chemical class 0.000 claims 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- -1 nitro, carboxy Chemical group 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- OPOGBHGEIKNEJO-UHFFFAOYSA-N 3-(pyridin-2-ylamino)-2-(2h-tetrazol-5-yl)prop-2-enenitrile Chemical compound N1=NNN=C1C(C#N)=CNC1=CC=CC=N1 OPOGBHGEIKNEJO-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 3
- 125000005843 halogen group Chemical group 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 abstract 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract 1
- 230000003266 anti-allergic effect Effects 0.000 abstract 1
- 230000000767 anti-ulcer Effects 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the invention relates to partly new 3-(lH-tetrazol- -5-yl)-4H-pyrido[l,2-a]pyrimidin-4-ones of the general formula (I) and pharmaceutically acceptable salts and/or hydrates and the preparation thereof. These compounds possess significant antiallergic or antiulcer activity.
- 3-(lH-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4- -ones of general formula (I) where R represents hydrogenatom, are described in US-PS Nos. 4122274 and 4209620 as antiallergic agents, whereas in US-PS No. 4457932 as antiulcer agents.
- the basis of our invention is the unexpected dis ⁇ covery that the acrylnitriles of general formula (II) may be transformed in a simple manner, in good yield, and without the formation of by-products into the pyrido- [l,2-a]pyrimidines of general formula (I).
- R stands for hydrogenatom, C 1 _ 4 alkyl group, or c 6 - 10 ar Yl group
- R 1 stands for hydrogenatom, - ⁇ ⁇ _ % alkyl group, halogen- atom, hydroxyl group, nitro group, carboxyl group, C2-5 alkoxycarbonyl group or C ⁇ ⁇ i2 aralkoxy group
- R 2 represents hydrogenatom, C 1 -4 alkyl group, or halogenatom; and a process for the preparation thereof.
- C1--.4 alkyl group means - in itself or in moieties, for instance in alkoxy groups - straight or branched chain aliphatic saturated hydrocarbon groups having one to four carbon atoms (such as e.g. methyl, ethyl, n-propyl and tert.-butyl group).
- C 6 _ ⁇ o aryl group means phenyl group or naphthyl group, optionally bearing a ⁇ - ⁇ alkyl group.
- the present invention also relates to a process for the preparation of compounds of general formula (I) and pharmaceutically acceptable salts and/or hydrates thereof, which comprises cyclising a 3-(2-pyridylamino)- -2-(lH-tetrazol-5-yl)acrylnitrile of general formula (II)
- organic and inorganic acids may be applied. If desired, the reaction may be carried out in the presence of solvent, preferably in the presence of water. As for organic acids alkanecarboxylic acids and arylsulfonic acids may be used. For inorganic acids preferably hydrogenhalides, sulfonic acid and various acids of the phosphor may be applied.
- the reaction may be accomplished, if desired, at elevated temperature. The temperature may be chosen according to the properties of the acidic agent and, if the reaction is carried out in the presence of solvent, according to the properties of the solvent. The reaction is preferably carried out at a temperature different from room temperature.
- the compound of general formula (I) obtained in the reaction precipitates from the reaction mixture after dilution with water or after adjusting the pH of the reaction mixture to neutral and may be recovered for instance by filtration.
- Compounds of general formula (I) may be converted into their pharmaceutically acceptable salts and/or hydrates on the effect of acids or bases. From the salts the bases may be liberated and, if desired, converted into another salt thereof.
- acid addition salts with e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, acetic acid, citric acid ets. may favourably be prepared, as well as the sodium, potassium and calcium salts.
- the compound of general formula (I) or its pharma- ceutically acceptable salts may therapeutically be used in the form of pharmaceutical compositions containing the active ingredient in an admixture with inert non- toxic solid or liquid diluents and carriers.
- compositions may be formulated as solids (tablet, capsule, dragee) or as liquids (solution, suspension, emulsion) .
- the usual materials such as e.g. talc, calcium carbonate, magnesium stearate, water, poly(ethylene glycol) may be used.
- the preparations may contain supplementary materials such as e.g. emulsifying agents, or dissolution materials.
- Example 1 53 . 3 g ( 0. 25 mol) of 3- ( 2-pyridylamino) -2- ( 1H- -tetrazol-5-yl)-acrylnitrile are heated in 500 ml of cone, hydrochloric acid under reflux conditions for 1 hour. After 10-15 mins of heating the original crystals dissolve, and the crystals of the product appear. The resulting suspension is cooled, diluted with 1000 ml of water, and neutralized with 25 % aqueous ammonia solution. The crystals are collected, washed with water.
- Example 5 ⁇ 2.47 g (0.01 mol) of 3-[ (5-chloro-2-pyridyl)- -amino]-2-(lH-tetrazol-5-yl)acrylnitrile are added under stirring to 12 g of polyphosphoric acid at 60 °C.
- the mixture is granulated with the help of 150 g of Endragit-lac solution, then it is dried at 40 °C and re- granulated.
- the granulatum is homogenized with a powder mixture consisting of 20 g of talc and 20 g of magnesium stearate, then in a method known per se, with the help of the appropriate pressure tools, it is pressed into tablets of 50, 100, 200 and 400 mg.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to partly new 3-(1H^_-tetrazol-5-yl)-4H^_-pyrido[1,2-a^_]pyrimidin-4-ones of general formula (I) and pharmaceutically acceptable salts and/or hydrates and the preparation thereof. These compounds possess significant antiallergic or antiulcer activity. The subjects of our invention are compounds of general formula (I) and pharmaceutically acceptable salts and/or hydrates thereof, wherein R stands for hydrogenatom, C1-4 alkyl group, or C6-10 aryl group; R1 stands for hydrogenatom, C¿1-4? alkyl group, halogenatom, hydroxyl group, nitro group, carboxyl group, C2-5 alkoxycarbonyl group or C7-12 aralkoxy group; R?2¿ represents hydrogenatom, C¿1-4? alkyl group, or halogenatom; and a process for the preparation thereof. The invention also relates to a process for the preparation of compounds of general formula (I) and pharmaceutically acceptable salts and/or hydrates thereof, which comprises cyclising a 3-(2-pyridylamino)-2-(1H^_-tetrazol-5-yl)acrylnitrile of general formula (II), (wherein the meanings of R, R?1 and R2¿ are the same as defined above) in acidic media and converting the compound of general formula (I) thus obtained into a pharmaceutically acceptable salt thereof or, if desired, liberating the base from its salt, or converting it into another salt thereof in a way known per se.
Description
3-(lH-tetrazol-5-y1)-4H-pyrido[1,2- ] yrimidine-4-ones , pharmaceutical compositions containing the same and the preparation thereof
The invention relates to partly new 3-(lH-tetrazol- -5-yl)-4H-pyrido[l,2-a]pyrimidin-4-ones of the general formula (I) and pharmaceutically acceptable salts and/or hydrates and the preparation thereof. These compounds possess significant antiallergic or antiulcer activity. 3-(lH-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4- -ones of general formula (I) , where R represents hydrogenatom, are described in US-PS Nos. 4122274 and 4209620 as antiallergic agents, whereas in US-PS No. 4457932 as antiulcer agents.
The starting materials and the methods applied in the above patent specifications, however, are not very favourable for the preparation of the compounds of general formula (I) , where R stands for hydrogen, as they result very low yields even lower than shown in the description and/or they use hazardeous reactants, such as the aluminium chloride-sodium azide 1:3 mixture in tetra- hydrofuran.
The reactants and the reaction conditions given in US-PS No. 4474953 are more favourable, but the yields of 60-70 % given in the examples do not relate to pure (1H- -tetrazol-5-yl)-4H-pyrido[l,2-a]pyrimidin-4-ones of general formula (I) , wherein R stands for hydrogen. After repeating the process we identified and isolated from the product, in about 30 % yield, an isomeric mixture consisting of the 3-(2-ethyl-tetrazol-5-yl) derivative of general formula (III), and the 3-(l-ethyl-tetrazol-5-yl) derivative of general formula (IV) . These isomers may be separated from each other by crystallisation. Identification of the compound of general formula (IV)
was accomplished by X-ray diffractometry. The formation of these compounds may be explained by an ethylation reaction where the ethanol resulting from the ring closure reaction of the ethyl-[3-(2-pyridylamino)-2-(lH- tetrazol-5-yl)acrylates] of general formula (V) in polyphosphoric acid, alkylates the products of the ring closure, i.e. the compounds of general formula (I) , wherein R stands for hydrogen. Thus, beside the compound of general formula (I) , significant amount of compounds of general formulae (III) and (IV) are also obtained.
The basis of our invention is the unexpected dis¬ covery that the acrylnitriles of general formula (II) may be transformed in a simple manner, in good yield, and without the formation of by-products into the pyrido- [l,2-a]pyrimidines of general formula (I).
The subjects of our invention are compounds of general formula (I)
and pharmaceutically acceptable salts and/or hydrates thereof, wherein R stands for hydrogenatom, C1_4 alkyl group, or c 6-10 arYl group; R1 stands for hydrogenatom, -\~_% alkyl group, halogen- atom, hydroxyl group, nitro group, carboxyl group, C2-5 alkoxycarbonyl group or Cη^i2 aralkoxy group; R2 represents hydrogenatom, C1-4 alkyl group, or halogenatom; and a process for the preparation thereof.
As used herein, the term "C1--.4 alkyl group" means - in itself or in moieties, for instance in alkoxy groups - straight or branched chain aliphatic saturated hydrocarbon groups having one to four carbon atoms (such as e.g. methyl, ethyl, n-propyl and tert.-butyl group). As used herein the term "C6_ιo aryl group" means phenyl group or naphthyl group, optionally bearing a ^-^ alkyl group.
Compounds of general formula (I) may give equilibrium mixture with compounds of general formula (IA) as demonstrated on Scheme A.
Scheme A The present invention also relates to a process for the preparation of compounds of general formula (I) and pharmaceutically acceptable salts and/or hydrates thereof, which comprises cyclising a 3-(2-pyridylamino)- -2-(lH-tetrazol-5-yl)acrylnitrile of general formula (II)
(wherein the meanings of R, R1 and R2 are the same as defined above) in acidic media and converting the com¬ pound of general formula (I) thus obtained into a pharma¬ ceutically acceptable salt thereof or, if desired, liberating the base from its salt, or converting it into
- A -
another salt thereof in a way known per se.
The application of compounds of general formula (II) implies the application of compounds of general formula (IIA) (wherein R, R1 and R2 are the same as defined above) which constitute tautomeric equilibrium mixtures with the compounds of general formula (II) (see Scheme B) , as well as the tetrazole ring tautomers of the compounds of general formulae (II) and (IIA) , and the E-Z geometric isomerε of the compounds of general formula (II).
As acidic agents, organic and inorganic acids may be applied. If desired, the reaction may be carried out in the presence of solvent, preferably in the presence of water. As for organic acids alkanecarboxylic acids and arylsulfonic acids may be used. For inorganic acids preferably hydrogenhalides, sulfonic acid and various acids of the phosphor may be applied. The reaction may be accomplished, if desired, at elevated temperature. The temperature may be chosen according to the properties of the acidic agent and, if the reaction is carried out in the presence of solvent, according to the properties of the solvent. The reaction is preferably carried out at a temperature different from room temperature. The compound of general formula (I) obtained in the reaction precipitates from the reaction mixture after dilution with water or after adjusting the pH of the reaction mixture to neutral and may be recovered for instance by filtration. Compounds of general formula (I) , if desired, may be converted into their pharmaceutically acceptable salts and/or hydrates on the effect of acids or bases. From the salts the bases may be liberated and, if desired, converted into another salt thereof. By this method acid addition salts with e.g. hydrochloric acid, hydrobromic
acid, sulphuric acid, acetic acid, citric acid ets. may favourably be prepared, as well as the sodium, potassium and calcium salts.
The compound of general formula (I) or its pharma- ceutically acceptable salts may therapeutically be used in the form of pharmaceutical compositions containing the active ingredient in an admixture with inert non- toxic solid or liquid diluents and carriers.
These pharmaceutical compositions may be formulated as solids (tablet, capsule, dragee) or as liquids (solution, suspension, emulsion) .
For carriers the usual materials (such as e.g. talc, calcium carbonate, magnesium stearate, water, poly(ethylene glycol) may be used. The preparations, if desired, may contain supplementary materials such as e.g. emulsifying agents, or dissolution materials.
The starting materials of general formulae (II) and (IIA) forming tautomeric equilibrium mixtures (see Scheme B) ,
(π) (ΠA)
Scheme B may be prepared from the malonitriles of general formula (VI)
(wherein R, R1 and R2 are the same as defined above) giving tautomeric equilibrium mixtures with the 3-cyano- -4-imino-4H-pyrido[l,2-a]pyrimidines of general formula (VIA) (see Scheme C)
(VI) (VIA)
Scheme C by reacting them with ammonium azide.
Compounds of general formulae (VI) and (VIA) may be synthetized in a simple way known from the literature [Journal of Organic Chemistry, 1986, 5i, 2988] by the reaction of 2-amino-pyridines, malonitrile and orthoesters which are available on the market.
The invention is illustrated in detail by the following non-limiting Examples.
Examples Example 1 53 . 3 g ( 0. 25 mol) of 3- ( 2-pyridylamino) -2- ( 1H-
-tetrazol-5-yl)-acrylnitrile are heated in 500 ml of cone, hydrochloric acid under reflux conditions for 1 hour. After 10-15 mins of heating the original crystals dissolve, and the crystals of the product appear. The resulting suspension is cooled, diluted with 1000 ml of water, and neutralized with 25 % aqueous ammonia solution. The crystals are collected, washed with water. Product: 41.48 g (87.9 %) of 3-(lH-tetrazol-5-yl)-4-oxo- -4H-pyrido[1,2-a]pyrimidine. Mp.: 316 °C (decomp.) Analysis for CgHgNgO calculated: C 50.47 %; H 2.82 %; N 39.24 %; found: C 49.73 %; H 2.77 ; N 39.48 %.
Example 2
23.7 g (0.1 mol) of 3-[ (3-methyl-2-pyridyl)amino]- -2-(lH-tetrazol-5-yl)acrylnitrile are heated n 200 ml of cone, hydrochloric acid under reflux conditions for 1 hour. After 10-15 mins. of heating the original crystals dissolve, and the crystals of the product appear. The resulting suspension is cooled, diluted with 400 ml of water, and neutralized with 25 % aqueous ammonia solution
(pH = 6.5). The crystals are collected, washed with water. Product: 19.57 g (85.76 %) of 3-(lH-tetrazol-5-yl)-9- methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine. Mp.: 312 °C decomp. (diroethylformamide) Analysis for CioHgNgO calculated: C 52.62 %; H 3.53 %; N 36.83 %; found: C 52.66 %; H 3.44 %; N 37.27 %.
Example 3
13.3 g (0.059 mol) of 3-[ (6-methy1-2-pyridyl)- -amino]-2-(lH-tetrazol-5-yl)acrylnitrile are added under stirring to 70 g of polyphosphoric acid at 60 °C. The
reaction mixture is heated and stirred in a 130-140 °C oil bath for 2 hours, then it is cooled to 30-40 °C, cautiously diluted with 210 ml of water and neutralized under ice cooling with 75 ml of 25 % aqueous ammonia solution (pH = 6.5-7). The precipitated crystals are collected, washed with water. Product: 12.7 g (94.8 %) of 3-(lH-tetrazol-5-yl)-6-methyl-4-oxo-4H-pyrido[l,2-a]pyri- midine.
Mp: 286 °C decomp. (dimethyIformamide) Analysis for C]_oH 8 N 6 0 calculated: C 52.62 %; H 3.53 %; N 36.83 %; found: C 52.80 %; H 3.48 %; N 37.01 %.
Example 4 2.41 g (0.01 mol) of 3-methyl-3-[ (6-methyl-2- -pyridyl)-amino]-2-(lH-tetrazol-5-yl)acrylnitrile are added under stirring to 20 g of polyphosphoric acid at 60 °C. The reaction mixture is heated and stirred in a 130-140 °C oil bath for 4 hours, then it is cooled to 50-60 °C, cautiously diluted with 28 ml of water and neutralized under ice cooling with 28 ml of 25 % aqueous ammonia solution (pH = 7) . The precipitated crystals are collected, washed with water. Product: 1.47 g (60.8 %) of 3-(lH-tetrazol-5-yl)-2,6- -dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine. Mp: 258-260 °C decomp. (dimethylformamide) Analysis for
calculated: C 54.54 %; H 4.16 %; N 34.70 %; found: C 54.58 %; H 4.12 %; N 34.33 %.
Example 5 ■ 2.47 g (0.01 mol) of 3-[ (5-chloro-2-pyridyl)- -amino]-2-(lH-tetrazol-5-yl)acrylnitrile are added under stirring to 12 g of polyphosphoric acid at 60 °C. The reaction mixture is heated and stirring in a 130-140 °C
oil bath for 1 hour, then it is cooled to 50-60 °C, cautiously diluted with 50 ml of water and neutralized under ice cooling with 25 ml of 25 % aqueous ammonia solution (pH = 6.5-7). The precipitated crystals are collected, washed with water. Product: 1.7 g (68.6 %) of 3-(lH-tetrazol-5-yl)-7-chloro-4-oxo-4H-pyrido[1,2-a]pyri- midine. Mp: 304 °C decomp. Analysis for C9H5N6OCI calculated: C 43.48 %; H 2.03 %; N 33.80 %; Cl 14.26 %; found: C 43.71 %; H 2.50 %; N 33.53 %; Cl 14.60 %.
Example 6
2.27 g (0.01 mol) of 3-[ (5-methy1-2-pyridyl)- -amino]-2-(lH-tetrazol-5-yl)-acrylnitrile are added under stirring to 12 g of polyphosphoric acid at 60 °C. The reaction mixture is heated and stirred on a 140 °C oil bath for 1 hour, then it is cooled to room temperature, cautiously diluted with 50 ml of water and neutralized under ice cooling with 20 ml of 25 % aqueous ammonia sol- ution. The precipitated crystals are collected, washed with water.
Product: 2.3 g (93.5 %) of 3-(lH-tetrazol-5-yl)-7-methyl- -4-oxo-4H-pyrido[l,2-a]pyrimidine monohydrate. Mp: 297 °C decomp. Analysis for CιoH 8 N 6°'H2° calculated: C 48.78 %; H 4.09 %; N 34.13 %; found: C 49.34 %; H 4.18 %; N 34.57 %.
Example 7 2.27 g (0.01 mol) of 3-[ (4-methyl-2-pyridyl)- -amino]-2-(lH-tetrazol-5-yl)acrylnitrile are added under stirring to 20 g of polyphosphoric acid at 60 °C. The reaction mixture is heated and stirred on a 140 °C oil bath for 1 hour, then it is cooled to room temperature, cautiously diluted with 60 ml of water and neutralized
under ice cooling with 28 ml of 25 % aqueous ammonia solution (pH = 6.5-7). The precipitated crystals are collected, washed with water. Product: 2.24 g (94.5 %) of 3-(lH-tetrazol-5-yl)-8-methyl-4-oxo-4H-pyrido[1,2-a]- pyrimidine hemihydrate. Mp: 288 °C decomp. Analysis for C10H8N6O' H2O calculated: C 50.63 %; H 3.82 %; N 35.42 %; found: C 50.26 %; H 3.90 %; N 35.38 %.
Example 8
2.41 g (0.01 mol) of 3-[ (4,6-dimethyl-2-pyridyl)- -amino]-2-(lH-tetrazol-5-yl)acrylnitrile are added under stirring to 12 g of polyphosphoric acid at 60 °C. The reaction mixture is heated and stirred in a 140 °C oil bath for 1 hour, then it is cooled to room temperature, cautiously diluted with 50 ml of water and neutralized under ice cooling with 18 ml of 25 % aqueous ammonia solution. The precipitated crystals are collected, washed with water. Product: 1.43 g (59.1 %) of 3-(lH-tetrazol-5- -yl)-6,8-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine. Mp: 350 °C decomp. Analysis for CnHioNδ 0 calculated: C 54.54 %; H 4.16 %; N 34.69 %; found: C 54.35 %; H 4.21 %; N 33.94 %.
Example 9
2.3 g (0.01 mol) of 3-[ (3-hydroxy-2-pyridyl)amino]- -2-(lH-tetrazol-5-yl)acrylnitrile is heated in 20 ml of cone, hydrochloric acid under reflux conditions for 1 hour. The reaction mixture is cooled to room temperature and poured on 30 ml of water, and the pH adjusted to 6.5 with 10 ml of 25 % aqueous ammonia solution. The crystals are collected, washed with water. Product: 2.4 g (90.2 %) of 3-(lH-tetrazol-5-yl)-9-hydroxy-4-oxo-4H-pyrido[1,2-a]- pyrimidine hydrochloride salt.
Mp. : 324 °C decomp.
Analysis for C9H6N6θ2'HCl calculated: C 40.54 %; H 2.65 %; N 31.52 %; found: C 40.82 %; H 2.78 %; N 31.26 %.
Example 10
1.1 g (0.004 mol) of 3-[ (3,5-dichloro-2-pyridyl)-
-amino]-2-(lH-tetrazol-5-yl)-acrylnitrile are added under stirring to 12 g of polyphosphoric acid at 60 °C. The reaction mixture is heated and stirred in a 130-140
°C oil bath for 30 minutes, then it is cooled to 60 °C, cautiously diluted with 50 ml of water and neutralized under ice cooling with 15 ml of 25 % aqueous ammonia solution (pH *= 7) . The precipitated crystals are collected, washed with water. Product: 1.04 g (90.4 %) of
3-(lH-tetrazol-5-yl)-dichloro-4-oxo-4H-pyrido[1,2-a]- pyrimidine.
Mp: 291 °C decomp. (dimethyIformamide) .
Analysis for C9H4N6CI2O calculated: C 38.19 %; H 1.42 %; N 29.69 %; Cl 25.05 %; found: C 37.80 %; H 1.58 %; N 29.77 %; Cl 25.02 %.
Example 11
1.25 g (4 mmol) of 3-(5-bromo-2-pyridylamino)-2- -(lH-tetrazol-5-yl)-acrylnitrile are heated in 10 ml of cone, hydrochloric acid under reflux conditions for 1 hour. The reaction mixture is cooled to room temperature and poured on 30 ml of water, and neutralized with 10 ml of 25 % aqueous ammonia solution (pH = 7) . The crystals are collected, washed with water.
Product: 1.25 g (99.0 %) of 3-(lH-tetrazol-5-yl)-7-bromo- -4-oxo-4H-pyrido[l,2-a]pyrimidine. Mp: 298-300 °C decomp. Analysis for C9H5N6BrO calculated: C 36.88 %; H 1.72 %; N 28.67 %; Br 27.26 %; found: C 36.76 %; H 1.62 %; N 28.86 %; Br 27.13 %.
Example 12
1.41 g (4.6 mmol) of 3-phenyl-[ (6-methyl-2- -pyridyl)-amino]-2-(lH-tetrazol-5-yl)-acrylnitrile are added under stirring to 12 g of polyphosphoric acid at 60 °C. The reaction mixture is heated and stirred in a 130-140 °C oil bath for 1 hour, then it is cooled to 60 °C, cautiously diluted with 60 ml of water and neutralized under ice cooling with 14 ml of 25 % aqueous ammonia solution (pH = 7) . The precipitated crystals are collected, washed with water.
Product: 1.05 g (75.0 %) of 3-(lH-tetrazol-5-yl)-2- -phenyl-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine. Mp.: 280 °C decomp. (dimethylformamide)
Analysis for £16^12^6° calculated: C 63.15 %; H 3.97 %; N 27.62 %; found: C 63.39 %; H 3.66 %; N 27.72 %.
Example 13
0.65 g (2.5 mmol) of 3-(3-nitro-2-pyridylamino)-2- -(lH-tetrazol-5-yl)acrylnitrile are heated in 10 ml of cone, hydrochloric acid under reflux conditions for 1 hour. The reaction mixture is cooled to room temperature and poured on 35 ml of water, and neutralized with 9 ml of 25 % aqueous ammonia solution (pH = 7) . The crystals are collected, washed with water.
Product: 0.49 g (75.0 %) of 3-(lH-tetrazol-5-yl)-9-nitro- -4-oxo-4H-pyrido[l,2-a]pyrimidine. Mp. : 283-285 °C decomp.
Analysis for C9H5N7O3 calculated: C 41.71 %; H 1.94 %; N 37.83 %; found: C 41.20 %; H 2.30 %; N 38.20 %.
Example 14
1.4 g (0.005 mol) of 3-[ (-ethoxycarbonyl-2-pyri- -dyl)-amino]-2-(lH-tetrazol-5-yl)acrylnitrile are added
under stirring to 12 g of polyphosphoric acid at 60 °C. The reaction mixture is heated and stirred in a 130-140 °C oil bath for 1 hour, then it is cooled to 60 °C, cautiously diluted with 50 ml of water and neutralized under ice cooling with 16 ml of 25 % aqueous ammonia solution (pH = 7) . The precipitated crystals are collected, washed with water.
Product: 3-(lH-tetrazol-5-yl)-9-ethoxycarbonyl-6-methyl- -4-oxo-4H-pyrido[1,2-a]pyrimidine. Mp. : 247-250 °C decomp.
Analysis for C^H^NβO calculated: C 50.35 %; H 3.52 %; N 29.36 %; found: C 50.12 %; H 3.45 %; N 29.87 %.
Example 15
Preparation of 50, 100, 200 and 400 mg tablets. 750 mg of 3-(lH-tetrazol-5-yl)-2,6-dimethyl-4-oxo- -4H-pyrido]l,2-a]pyrimidine potassium salt are homogenized with 1050 g of crystalline cellulose and 15 g of arnidopectine.
The mixture is granulated with the help of 150 g of Endragit-lac solution, then it is dried at 40 °C and re- granulated. The granulatum is homogenized with a powder mixture consisting of 20 g of talc and 20 g of magnesium stearate, then in a method known per se, with the help of the appropriate pressure tools, it is pressed into tablets of 50, 100, 200 and 400 mg.
Claims
1. Compounds of the general formula (I)
or pharmaceutically acceptable salts and/or hydrates thereof, wherein
R stands for hydrogen, C1_4 alkyl or Cg_ιo aryl group; R1 stands for hydrogen, C1_4 alkyl, halogen, hydroxy, nitro, carboxy, C2_s alkoxycarbonyl or c7-12 aralkoxy, R2 stands for hydrogen, -_..^ alkyl or halogen with the proviso that if R stands for hydrogen, R1 is different from hydrogen, C1--.4 alkyl or halogen.
2. Pharmaceutical composition which comprises as active ingredient a compound of general formula (I) or pharmaceutically acceptable salts and/or hydrates thereof wherein R, R1 and R2 are the same as defined in claim 1.
3. Process for the preparation of a compound of general formula (I)
or pharmaceutically acceptable salts and/or hydrates thereof, wherein
R stands for hydrogen, C1_4 alkyl or C6_10 aryl group;
R1 stands for hydrogen, C^ ^ alkyl, halogen, hydroxy, nitro, carboxy, C2-5 alkoxycarbonyl or c7-12 aralkoxy,
R2 stands for hydrogen, C^-4 alkyl or halogen which c o m p r i s e s cyclising a 3-(2-pyridyl-amino)-2-(lH-tetrazol-5-yl)- -acrylnitrile - wherein the meaning of R, R1 and R2 are defined above - in acidic media, and converting the compound of the general formula (I) thus obtained into a pharmaceutically acceptable salt and/or hydrate thereof, or liberating the base from the salt and converting it into another salt by methods known per se.
4. Process according to claim 3 which c o m p r i s e s applying as acidic media organic or inorganic acids, e.g. alkanecarboxylic acid, arylsulfonic acid, hydrogen halogenide, sulfuric acid or phosphoric acid.
5. Process according to claims 3-4, which c o m p r i s e s carrying out the cyclisation of the compound of general formula (II)
6. Process according to claim 5, which c o m p r i s e s applying water as solvent.
7. Process according to claims 3-6, which c o m p r i s e s carrying out the cyclisation at a temperature between 25-50 °C.
SUBSTITUTE SHEET ISA/EP
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9200432A HUT64064A (en) | 1992-02-13 | 1992-02-13 | Process for producing puyrido/1,2-a/pyrimidine derivatives and pharmaceutical compositions comprising same as active ingredient |
| HUP9200432 | 1992-02-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993016076A1 true WO1993016076A1 (en) | 1993-08-19 |
Family
ID=10981335
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU1993/000009 WO1993016076A1 (en) | 1992-02-13 | 1993-02-12 | 3-(1h^_-tetrazol-5-yl)-4h^_-pyrido[1,2-a^_]pyrimidine-4-ones, pharmaceutical compositions containing the same and the preparation thereof |
Country Status (7)
| Country | Link |
|---|---|
| CN (1) | CN1080289A (en) |
| AU (1) | AU3573793A (en) |
| HU (1) | HUT64064A (en) |
| IL (1) | IL104706A0 (en) |
| MX (1) | MX9300779A (en) |
| SI (1) | SI9300075A (en) |
| WO (1) | WO1993016076A1 (en) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20030014619A (en) * | 2001-08-10 | 2003-02-19 | 디나미테 디파르마 에스.피.아. | A process for the preparation of high purity Pemirolast |
| WO2007093184A2 (en) * | 2006-02-13 | 2007-08-23 | Astion Pharma A/S | Treatment of mmp-mediated dermatological diseases with pemirolast |
| EP1818058A3 (en) * | 2006-02-13 | 2007-11-07 | Astion Pharma A/S | Treatment of mmp-mediated dermatological diseases with pemirolast |
| EP2210892A3 (en) * | 2002-10-04 | 2010-10-27 | Prana Biotechnology Limited | Neurologically-active compounds |
| US8940752B2 (en) | 2009-06-29 | 2015-01-27 | Incyte Corporation | Pyrimidinones as PI3K inhibitors |
| US9062055B2 (en) | 2010-06-21 | 2015-06-23 | Incyte Corporation | Fused pyrrole derivatives as PI3K inhibitors |
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| US9988401B2 (en) | 2015-05-11 | 2018-06-05 | Incyte Corporation | Crystalline forms of a PI3K inhibitor |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU209793B (en) * | 1990-09-25 | 1994-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for the production of pyrido[1,2-a]pyrimidine-derivatives and pharmaceutical compositions containing the same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0462834A1 (en) * | 1990-06-21 | 1991-12-27 | Wako Pure Chemical Industries, Ltd | Process for producing pyrido [1,2-a]pyrimidine derivative |
-
1992
- 1992-02-13 HU HU9200432A patent/HUT64064A/en unknown
-
1993
- 1993-02-12 IL IL104706A patent/IL104706A0/en unknown
- 1993-02-12 SI SI19939300075A patent/SI9300075A/en unknown
- 1993-02-12 AU AU35737/93A patent/AU3573793A/en not_active Withdrawn
- 1993-02-12 MX MX9300779A patent/MX9300779A/en unknown
- 1993-02-12 WO PCT/HU1993/000009 patent/WO1993016076A1/en active Application Filing
- 1993-02-13 CN CN93102959.7A patent/CN1080289A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0462834A1 (en) * | 1990-06-21 | 1991-12-27 | Wako Pure Chemical Industries, Ltd | Process for producing pyrido [1,2-a]pyrimidine derivative |
Non-Patent Citations (1)
| Title |
|---|
| CHEMICAl ABSTRACTS, Twelfth Collective Index, Volumes 106-115, 1987-1991, page 80, 214CS; & CHEMICAL ABSTRACTS 111:89 703n, YAKURI TO CHIRYO, 1989, 17(4), 14727-32, (Japan). * |
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| KR20030014619A (en) * | 2001-08-10 | 2003-02-19 | 디나미테 디파르마 에스.피.아. | A process for the preparation of high purity Pemirolast |
| EP2210892A3 (en) * | 2002-10-04 | 2010-10-27 | Prana Biotechnology Limited | Neurologically-active compounds |
| WO2007093184A2 (en) * | 2006-02-13 | 2007-08-23 | Astion Pharma A/S | Treatment of mmp-mediated dermatological diseases with pemirolast |
| WO2007093184A3 (en) * | 2006-02-13 | 2007-10-25 | Astion Pharma As | Treatment of mmp-mediated dermatological diseases with pemirolast |
| EP1818058A3 (en) * | 2006-02-13 | 2007-11-07 | Astion Pharma A/S | Treatment of mmp-mediated dermatological diseases with pemirolast |
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Also Published As
| Publication number | Publication date |
|---|---|
| MX9300779A (en) | 1993-09-30 |
| AU3573793A (en) | 1993-09-03 |
| HU9200432D0 (en) | 1992-04-28 |
| SI9300075A (en) | 1993-09-30 |
| IL104706A0 (en) | 1993-06-10 |
| CN1080289A (en) | 1994-01-05 |
| HUT64064A (en) | 1993-11-29 |
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