GB2078215A - N-(4-pyridylmethyl)benzamides and Their Production - Google Patents
N-(4-pyridylmethyl)benzamides and Their Production Download PDFInfo
- Publication number
- GB2078215A GB2078215A GB8116144A GB8116144A GB2078215A GB 2078215 A GB2078215 A GB 2078215A GB 8116144 A GB8116144 A GB 8116144A GB 8116144 A GB8116144 A GB 8116144A GB 2078215 A GB2078215 A GB 2078215A
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- United Kingdom
- Prior art keywords
- acid
- substituted
- carbon atoms
- substituted acid
- sulfonylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- VDJSXBBFSHLEHE-UHFFFAOYSA-N n-(pyridin-4-ylmethyl)benzamide Chemical class C=1C=CC=CC=1C(=O)NCC1=CC=NC=C1 VDJSXBBFSHLEHE-UHFFFAOYSA-N 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- -1 sulfonylamino, phenyl Chemical group 0.000 claims abstract description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 8
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
- 125000004442 acylamino group Chemical group 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 28
- 239000000047 product Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 4
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- UCAGLBKTLXCODC-UHFFFAOYSA-N carzenide Chemical compound NS(=O)(=O)C1=CC=C(C(O)=O)C=C1 UCAGLBKTLXCODC-UHFFFAOYSA-N 0.000 claims description 4
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 0.000 claims description 4
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 claims description 2
- CXKCZFDUOYMOOP-UHFFFAOYSA-N 3,5-dichlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC(Cl)=C1 CXKCZFDUOYMOOP-UHFFFAOYSA-N 0.000 claims description 2
- UMVOQQDNEYOJOK-UHFFFAOYSA-N 3,5-dimethylbenzoic acid Chemical compound CC1=CC(C)=CC(C(O)=O)=C1 UMVOQQDNEYOJOK-UHFFFAOYSA-N 0.000 claims description 2
- YAGOYAVZOJQMRT-UHFFFAOYSA-N 4-(benzenesulfonamido)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NS(=O)(=O)C1=CC=CC=C1 YAGOYAVZOJQMRT-UHFFFAOYSA-N 0.000 claims description 2
- YDIYEOMDOWUDTJ-UHFFFAOYSA-N 4-(dimethylamino)benzoic acid Chemical compound CN(C)C1=CC=C(C(O)=O)C=C1 YDIYEOMDOWUDTJ-UHFFFAOYSA-N 0.000 claims description 2
- QCXJEYYXVJIFCE-UHFFFAOYSA-N 4-acetamidobenzoic acid Chemical compound CC(=O)NC1=CC=C(C(O)=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-N 0.000 claims description 2
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 claims description 2
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 claims description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 claims description 2
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 claims description 2
- NNJMFJSKMRYHSR-UHFFFAOYSA-N 4-phenylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-N 0.000 claims description 2
- KDVYCTOWXSLNNI-UHFFFAOYSA-N 4-t-Butylbenzoic acid Chemical compound CC(C)(C)C1=CC=C(C(O)=O)C=C1 KDVYCTOWXSLNNI-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- XRKIHUXCUIFHAS-UHFFFAOYSA-N [4-(3-methoxy-3-oxopropyl)phenyl]boronic acid Chemical compound COC(=O)CCC1=CC=C(B(O)O)C=C1 XRKIHUXCUIFHAS-UHFFFAOYSA-N 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 claims description 2
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 claims description 2
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 2
- 239000003176 neuroleptic agent Substances 0.000 abstract description 2
- 125000003368 amide group Chemical group 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 5
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- JROSDBYIFZWPBP-UHFFFAOYSA-N 3,5-dimethyl-n-(pyridin-4-ylmethyl)benzamide Chemical compound CC1=CC(C)=CC(C(=O)NCC=2C=CN=CC=2)=C1 JROSDBYIFZWPBP-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 230000002903 catalepsic effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Anesthesiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Compounds of the formula <IMAGE> where X and Y, which may be the same or different, are hydrogen, halogen, hydroxyl, nitro, linear or branched alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms, acylamino having 1 to 4 carbon atoms, sulfonylamino, phenyl, trifluoromethyl and phenylsulfonylamino, which are neuroleptic agents, particularly useful in therapeutics, are prepared by formation of the amide group.
Description
SPECIFICATION
N-(4-Pyridylmethyl)-Benzamides and Their Production
This invention relates to a method for the industrial production of N-(4-pyridylmethyl)benzamides, which are very powerful as neuroleptic agents, thus making them particularly useful in therapeutics.
These compound are of the formula:
where X and Y, which may be the same or different, are hydrogen, halogen, hydroxyl, nitro, linear or branched alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms, acylamino (e.g. alkanoylamino) having 1 to 4 carbon atoms, sulfonylamino, phenyl, trifluoromethyl or phenylsulfonylamino.
The method of the invention comprises the following operations: 1) reacting a substituted acid of the formula
where X and Y have the aforesaid meanings, with 4-aminomethyl-pyridine of the formula:
in the presence of a condensing agent in a suitable solvent and at temperatures between -800C and the boiling point of the solvent itself; 2) removing the solid by-products by filtration upon completion of the reaction; 3) evaporating the solvent to dryness, and 4) crystallizing the residue formed by the desired product in a suitable solvent.
If desired, the product may subsequently be converted into a salt, for example by treatment with an acid.
With the exception of the compound in which X and Y are methyl groups in the 3- and 5positions, the compounds of formula (I) and their physiologically acceptable acid addition salts are novel compounds.
In the compounds of formula (I), Y is preferably a hydrogen atom and Xis preferably a hydroxy, dialkylamino, alkanoylamino, sulfonylamino or phenyl sulfonylamino group, which may for example be in the 4-position. A particularly preferred group of compounds is those in which Y is a hydrogen atom and X is a hydroxy, dimethylamino, acetamido, sulfonylamino or phenylsulfonylamino group in the 4position.
The compounds of formula (I) may be formulated for use in conventional manner, for example with one or more pharmaceutical carriers.
Some examples which do not limit the scope of this invention are given below.
Example 1(X=3-CH,; Y=5-C H3) A mixture of 7.5 g (0.05 moles) of 3,5-dimethyl-benzoic acid, 5.4 g (0.05 moles) of 4aminomethylpyridine and 100 ml of methylene chloride is placed in a two-neck flask with a capacity of 250 ml, fitted with a thermometer, a calcium chloride tube, an ice bath and magnetic stirring. When the mixture is at 20C a solution of 10.3 g (0.05 moles) of dicyclohexylcarbodiimide in 25 ml of methylene chloride is added portionwise and while stirring. Stirring is maintained between 0 and 50C for 2 hours and the temperature is then allowed to rise until it reaches room temperature, leaving the reaction proceed under stirring overnight. The dicyclohexylurea formed is filtered and washed with two portions of 25 ml of methylene chloride each.The filtrate, together with the washing liquids, are evaporated to dryness and the solid residue is crystallized from ethyl acetate. The N-(4-pyridylmethyl)3,5-dimethylbenzamide has a m.p.=1 05-1060C.
Analysis
Calculated for C1sH16N2o C: 74.97; H: 6.71; N: 11.65
Found C: 74.85; H: 6.70; N: 11.65 Example 2 (X=3-CH3; Y=H) Operation is as in the preceding example, using 0.05 moles of m-toluic acid and acetonitrile as a solvent. M.p.=1 04-1 050C (dimethylformamide-water).
Analysis
Calculated for C14H,4N20
C: 74.31; H: 6.23; N: 12.38
Found C: 74.50; H: 6.19; N: 12.35
Example 3 (X=4-But; Y=H)
Operation is as in Example 1, using 0.05 moles of 4-tertbutylbenzoic acid and tetrahydrofuran as solvent. M.p.=1 29-1 300C (benzene).
Analysis
Calculated for C'7H20N20 C: 76.08; H: 7.51; N: 10.44
Found C: 75.81; H: 7.24; N: 10.15
Example 4 (X=4-CH3S; Y=H)
Operation is as in Example 1, using 0.05 moles of 4-thiomethoxybenzoic acid. M.p.=1 50- 1 520C (ethanol-water).
Analysis
Calculated for C14H,4N20S
C: 65.10; H: 5.46; N: 10.84; S: 12.41
Found C: 65.19; H: 5.23; N: 10.61; S: 12.21
Example 5 (X=Y=H)
Operation is as in Example 1, using 0.05 moles of benzoic acid. M.p.=1 14-11 60C (ethanolwater).
Analysis
Calculated for C13H'3N20 C: 73.58; H: 5.66; N: 13.20
Found C: 73.23; H: 5.71; N: 13.40
Example 6 (X=4-CH3; Y=H)
Operation is as in Example 1, using 0.05 moles of p-toluic acid. M.p.=1 30-1 31 OC (water).
Analysis
Calculated for C14H14N20
C: 74.31; H: 6.23; N: 12.38
Found C: 74.09; H: 6.22; N:12.21 Example 7 (X=2-CH3; Y=H) Operation is as in Example 1, using 0.05 moles of o-toluic acid. M.p.=1 46-1 480C (water).
Analysis
Calculated for C14H'4N20 C: 74.31; H: 6.23; N: 12.38
Found C: 74.08; H: 6.31; N: 12.49 Example 8 (X=4-OCH3; Y=H) Operation is as in Example 1, using 0.05 moles of anisic acid. M.p.=l 38-140"C (water).
Analysis
Calculated for C14H14N202
C: 69.57; H: 5.85; N: 11.45
Found C: 69.40; H; 5.80; N: 11.56
Example 9 (X=4-OH; Y=H)
Operation is as in Example 1, using 0.05 moles of 4-hydroxybenzoic acid. M.p. 2600C (dimethylformamide-water).
Analysis
Calculated for Ca3H12N202 C: 68.40; H: 5.29; N: 12.27
Found C: 68.46; H: 5.15; N: 12.14 Example 10 (X=4-NO2; Y=H) Operation is as in Example 1, using 0.05 moles of 4-nitrobenzoic acid. M.p.=1 98-2000C (ethanol-water).
Analysis
Calculated for C13H1,N303
C: 60.69; H: 4.31; N: 16.33
Found C: 60.42; H: 4.18; N: 16.06
Example 11 (X=4-N(CH3)2; Y=H)
Operation is as in Example 1, using 0.05 moles of 4-dimethylaminobenzoic acid. M.p.=206- 2070C (dimethylformamide-water).
Analysis
Calculated for C1sH,7N30 C: 70.56; H: 6.71; N: 16.45
Found C: 70.31; H: 6.48; N: 16.22
Example 12 (X=4-CH3CONH;Y=H)
Operation is as in Example 1, using 0.05 moles of 4-acetylaminobenzoic acid. M.p.=233- 2350C (water).
Analysis
Calculated for C,5H,5N302
C: 66.89; H: 5.61; N: 15.60
Found C: 66.70; H: 5.34; N: 15.48
Example 13 (X=4-SO2NH 2;Y=H) Operation is as in Example 1, using 0.05 moles of 4-sulfamoylbenzoic acid. M.p.=235-2370C (water).
Analysis
Calculated for C,3H,3N303S C: 53.60; H: 4.49. N: 14.42; S: 10.90
Found C: 53.74; H: 4.61; N: 14.61; S: 10.64 Example 14 (X=4-C6H5; Y=H) Operation is as in Example 1, using 0.05 moles of 4-phenylbenzoic acid. M.p.=l 93-194"C (methanol-water).
Analysis
Calculated for CrgH,6N20 C: 79.14; H: 5.59; N: 9.71
Found C: 79.10; H: 5.74; N: 9.59
Example 15 (X=4-CI; Y=H)
Operation is as in Example 1, using 0.05 moles of 4-chlorobenzoic acid. M.p.=l 33--1 340C (dimethylformamide-water).
Analysis
Calculated for C,3H,1N20CI C: 63.31; H: 4.46; N: 11.36 Cl: 14.36
Found C: 63.29; H: 4.61; N: 11.12; Cl: 14.44
Example 16 (X=3-CI; Y=H) Operation is as in Example 1, using 0.05 moles of 3-chlorobenzoic acid. M.p.=88-900C (ethanol-water).
Analysis
Calculated for C13H11N20CI
C: 63.31; H: 4.46; N: 11.36; Cl: 14.36
Found C: 63.19; H: 4.51; N: 11.16; Cl: 14.63
Example 17 (X=2-CL; Y=H)
Operation is as in Example 1, using 0.05 moles of 2-chlorobenzoic acid. M.p.=98-990C (ethanol-water).
Analysis
Calculated for C13H11N20CI
C: 63.31; H: 4.46; N: 11.36; Cl: 14.36
Found C: 63.12; H: 4.56; N: 11.16; Cl: 14.46
Example 18 (X=Y=3,5-Cl2) Operation is as in Example 1, using 0.05 moles of 3,5-dichlorobenzoic acid. M.p.=1 44-1 460C (dimethylformamide-water).
Analysis
Calculated for C13H1oN2ocl2 C: 55.51; H: 3.55; N: 9.96; Cl: 25.26
Found C: 55.42; H: 3.36; N: 10.07; Cl: 25.54
Example 19 (X=4-F; Y=H)
Operation is as in Example 1, using 0.05 moles of 4-fluorobenzoic acid. M.p.=88--90"C (ethylacetate-petroleum ether).
Analysis
Calculated for C13H11N20F
C: 67.82; H: 4.85; N: 12.17
Found C: 67.73; H: 4.79; N: 11.89
Example 20 (X=4-CF3; Y=H)
Operation is as in Example 1, using 0.05 moles of 4-trifluoromethylbenzoic acid. M.p.=1 67-1 690C (methanol)
Analysis
Calculated for C14H11N20F3
C: 60.00; H: 3.92; N: 10.00
Found C: 60.27; H: 4.25; N: 10.05
Example 21 (X=4-C6H5-SO2NH; Y=H)
Operation is as in Example 1, using 0.05 moles of 4-phenylsulfonylaminobenzoic acid.
M.p.=1 80-181 OC (ethyl acetate).
Analysis
Calculated for C19H17N303S
C: 62.11; H: 4.66; N: 11.43; S: 8.72
Found C: 62.22; H: 4.60; N: 11.45; S: 8.96
Pharmacological Studies
The product of Example 1 of this patent application has evidenced a pharmacological activity spectrum similar to that of neuroleptics. characterized by a reduction in motile activity which is accomplished by loss of reactivity as the dose is increased and by cataleptic immobilization at even higher doses. For this reason, the measurement selected for comparing the potency of the products of the examples of this patent application was the reduction in motile activity at a standardized dose for all of them.
Acute Toxicity
Swiss l.C.R. albino mice were used. The products were administered intraperitoneally and the observation time was 72 hours, following which the death rate was evaluated in the different batches, calculating the LD50 from these data. The results obtained are given in the following table.
Product
of
Example LD50Fi.p.) mg/kg
1 266
2 271
3 114.7
4 259.3
5 417.8
6 364.4
7 510
8 345.7
9 1,277.7
Product
of
Example LD50fi.p.) mg/kg
10 350
11 300
12 1,333.8
13 1,314.1
14
15
16 219
17
18 113
19 339.1
20
21 > 1,500
Reduction in Motile Activity
Swiss I.C.R. albino mice were used. The products were administered intraperitoneally at the dose of 72 mg/kg, motile activity control measurements having been taken previously. Fresh motile acitivity measurements are taken thirty minutes after administration of the products and when compared with the control measurements they enable us to calculate the percentage of reduction in motile activity. All the measurements were taken with an automatic actinometer supplied by the Panlab company, taking at least six control measurements for each product and six measurements after administering the product, calculating the reduction in motile activity from the difference between the corresponding averages. The results obtained are given in the following table.
Product % Reduction in Motile
of Activity at the Dose
Example of 72 mglkg (i.p.)
1 99.6
2 97.5
3 97.5
4 87.6
5
6 56.3
7 90.4
8 72.9
9 98.3
10 85.1
11 93.6
12 99.8
13 90.2
14
15 95.3
16 99.2
17
18
19 97.6
20
21 98.7
Claims (33)
1. N-(4-pyridylmethyl)-benzamides of the general formula:
where X and Y, which may be the same or different, are hydrogen, halogen, hydroxyl, nitro, linear or branched alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms,dialkylamino having 1 to 4 carbon atoms, acylamino having 1 to 4 carbon atoms, sulfonylamino, phenyl, trifluoromethyl or phenylsulfony!amino, (excluding the compound in which X and Y represent methyl in positions 3 and 5), and the physiologically acceptable acid addition salts thereof.
2. Compounds as claimed in claim 1 in which Y is a hydrogen atom.
3. Compounds as claimed in claim 1 or claim 2 in which X is hydroxy, dialkylamino, alkanoylamino, sulfonylamino or phenylsulfonylamino.
4. Compounds as claimed in claim 1 in which Y is a hydrogen atom and X is a hydroxy, dimethylamino, acetamido sulfonylamino or phenylsulfonylamino group in the 4-position.
5. A compound as claimed in claim 1, said compound being the product of any one of Examples 2 to 21.
6. A pharmaceutical composition comprising a compound as claimed in claim 1 together with one or more pharmaceutical carriers.
7. a method for the industrial production of N-(4-pyridylmethyl)-benzamides of the general formula
where X and Y, which may be the same or different, are hydrogen, halogen, hydroxyl, nitro, linear or branched alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms, acylamino having 1 to 4 carbon atoms, sulfonylamino, phenyl, trifluoromethyl, and phenylsulfonylamino, which comprises: 1) reacting a substituted acid of the general formula:
where X and Y have the aforesaid meanings, with 4-aminomethylpyridine of the formula:
in the presence of a condensing agent in a suitable solvent and at temperatures between -800C and the boiling point of the solvent itself; 2) removing the solid by-products by filtration upon completion of the reaction; 3) evaporating the solvent to dryness, and 4) crystallizing the residue formed by the desired product in a suitable solvent.
8. a method according to claim 7 in which dicyclohexylcarbodiimide is used as condensing agent.
9. A method according to claim 7 or claim 8 in which the solvent used is methylene chloride.
10. A method according to claim 7 or claim 8 in which the solvent used is acetonitrile.
11. A method according to claim 7 or claim 8 the solvent used is tetrahydrofuran.
12. A method according to any one of claims 7 to 11 in which the substituted acid is 3,5dimethylbenzoic acid.
1 3. a method according to any one of claims 7 to 11 in which the substituted acid is m-toluic acid.
14. A method according to any one of claims 7 to 11 in which the substituted acid is 4-tertbutylbenzoic acid.
1 5. A method according to any one of claims 7 to 11 in which the substituted acid is 4thiomethoxybenzoic acid.
1 6. A method according to any one of claims 7 to 11 in which the substituted acid is benzoic acid.
1 7. A method according to any one of claims 7 to 11 in which the substituted acid is p-toluic acid.
1 8. A method according to any one of claims 7 to 11 in which the substituted acid is o-toluic acid.
19. A method according to any one of claims 7 to 11 in which the substituted acid is anisic acid.
20. A method according to any one of claims 7 to 11 in which the substituted acid is 4hydroxybenzoic acid.
21. A method according to any one of claims 7 to 11 in which the substituted acid is 4nitrobenzoic acid.
22. A method according to any one of claims 7 to 11 in which the substituted acid is 4dimethylaminobenzoic acid.
23. A method according to any one of claims 7 to 11 in which the substituted acid is 4acetylaminobenzoic acid.
24. A method according to any one of claims 7 to 11 in which the substituted acid is 4sulfamoylbenzoic acid.
25. A method according to any one of claims 7 to 11 in which the substituted acid is 4phenylbenzoic acid.
26. A method according to any one of claims 7 to 11 in which the substituted acid is 4chlorobenzoic acid.
27. A method according to any one of claims 7 to ii in which the substituted acid is 3chlorobenzoic acid.
28. A method according to any one of claims 7 to 11 in which the substituted acid is 2chlorobenzoic acid.
29. A method according to any one of claims 7 to 11 in which the substituted acid is 3,5dichlorobenzoic acid.
30. A method according to any one of claims 7 to 11 in which the substituted acid is 4fluorobenzoic acid.
31. A method according to any one of claims 7 to 11 in which the substituted acid is 4trifluoromethylbenzoic acid.
32. A method according to any one of claims 7 to 11 in which the substituted acid is 4phenylsulfonylaminobenzoic acid.
33. A method as claimed in any one of claims 7 to 32 in which the product is subsequently converted into a salt.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES492686A ES8200663A1 (en) | 1980-06-23 | 1980-06-23 | N-(4-pyridylmethyl)benzamides and Their Production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2078215A true GB2078215A (en) | 1982-01-06 |
| GB2078215B GB2078215B (en) | 1984-06-06 |
Family
ID=8480664
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8116144A Expired GB2078215B (en) | 1980-06-23 | 1981-05-27 | N-(4-pyridylmethyl)-benzamides and their production |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5732266A (en) |
| CH (1) | CH651298A5 (en) |
| DE (1) | DE3122700A1 (en) |
| ES (1) | ES8200663A1 (en) |
| FR (1) | FR2485008A1 (en) |
| GB (1) | GB2078215B (en) |
| PT (1) | PT73147B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0077534A3 (en) * | 1981-10-15 | 1984-03-07 | Chugai Seiyaku Kabushiki Kaisha | Benzamide derivatives, a process for preparing the same, and pharmaceutical compositions containing the same |
| US4595780A (en) * | 1984-01-06 | 1986-06-17 | Shionogi & Co., Ltd. | Sulfonamido-benzamide derivatives |
| US7388018B2 (en) | 2003-09-18 | 2008-06-17 | Basf Aktiengesellschaft | 4-Piridinylmethylsulphonamide derivatives as fungicidal plant protein agents |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9300083D0 (en) * | 1993-01-05 | 1993-03-03 | Roussel Lab Ltd | Chemical compounds |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1073961A (en) * | 1964-04-22 | 1967-06-28 | Far Eastern Detailers Ltd | Pyridine derivatives and their preparation |
| NL7416176A (en) * | 1973-12-26 | 1975-06-30 | Upjohn Co | PROCESS FOR PROMOTING THE PRODUCTION OF ENDOGENIC PROSTAGLANDINS BY MAMMALS, AND PROCESS FOR THE PREPARATION OF PREPARATIONS FOR USE THEREIN. |
| DE2417763A1 (en) * | 1974-04-11 | 1975-10-30 | Bayer Ag | CARBON ACID AMIDE, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT |
| DE2428673A1 (en) * | 1974-06-14 | 1976-01-02 | Bayer Ag | CARBON ACID AMIDE, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT |
-
1980
- 1980-06-23 ES ES492686A patent/ES8200663A1/en not_active Expired
-
1981
- 1981-05-27 GB GB8116144A patent/GB2078215B/en not_active Expired
- 1981-06-05 PT PT73147A patent/PT73147B/en unknown
- 1981-06-06 DE DE19813122700 patent/DE3122700A1/en not_active Withdrawn
- 1981-06-19 FR FR8112173A patent/FR2485008A1/en not_active Withdrawn
- 1981-06-22 CH CH4122/81A patent/CH651298A5/en not_active IP Right Cessation
- 1981-06-22 JP JP9644281A patent/JPS5732266A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0077534A3 (en) * | 1981-10-15 | 1984-03-07 | Chugai Seiyaku Kabushiki Kaisha | Benzamide derivatives, a process for preparing the same, and pharmaceutical compositions containing the same |
| US4595780A (en) * | 1984-01-06 | 1986-06-17 | Shionogi & Co., Ltd. | Sulfonamido-benzamide derivatives |
| US7388018B2 (en) | 2003-09-18 | 2008-06-17 | Basf Aktiengesellschaft | 4-Piridinylmethylsulphonamide derivatives as fungicidal plant protein agents |
Also Published As
| Publication number | Publication date |
|---|---|
| ES492686A0 (en) | 1981-06-01 |
| FR2485008A1 (en) | 1981-12-24 |
| DE3122700A1 (en) | 1982-04-22 |
| PT73147A (en) | 1981-07-01 |
| GB2078215B (en) | 1984-06-06 |
| PT73147B (en) | 1982-07-16 |
| CH651298A5 (en) | 1985-09-13 |
| ES8200663A1 (en) | 1981-06-01 |
| JPS5732266A (en) | 1982-02-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |