AU700602B2 - Novel 1-ar(alk)yl-imidazolin-2-ones containing a disubstituted amine radical in the 4th position, having an anti-convulsive effect, and process for their production - Google Patents
Novel 1-ar(alk)yl-imidazolin-2-ones containing a disubstituted amine radical in the 4th position, having an anti-convulsive effect, and process for their production Download PDFInfo
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- AU700602B2 AU700602B2 AU67375/96A AU6737596A AU700602B2 AU 700602 B2 AU700602 B2 AU 700602B2 AU 67375/96 A AU67375/96 A AU 67375/96A AU 6737596 A AU6737596 A AU 6737596A AU 700602 B2 AU700602 B2 AU 700602B2
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- Prior art keywords
- chlorophenyl
- morpholinoimidazolin
- phenyl
- alkyl
- imidazolin
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- 238000000034 method Methods 0.000 title claims description 9
- 230000002082 anti-convulsion Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 238000011282 treatment Methods 0.000 claims 2
- QYLBODXDNLFDFJ-UHFFFAOYSA-N 1-benzyl-4-morpholin-4-ylimidazolidin-2-one Chemical compound O=C1NC(N2CCOCC2)CN1CC1=CC=CC=C1 QYLBODXDNLFDFJ-UHFFFAOYSA-N 0.000 claims 1
- NSUITYVMTIPQNG-UHFFFAOYSA-N 4-(azepan-1-yl)-1-(4-chlorophenyl)imidazolidin-2-one Chemical compound ClC1=CC=C(C=C1)N1C(NC(C1)N1CCCCCC1)=O NSUITYVMTIPQNG-UHFFFAOYSA-N 0.000 claims 1
- MDYHGFXQHSAJQB-UHFFFAOYSA-N 4-morpholin-4-yl-1-phenylimidazolidin-2-one Chemical compound O=C1NC(N2CCOCC2)CN1C1=CC=CC=C1 MDYHGFXQHSAJQB-UHFFFAOYSA-N 0.000 claims 1
- SNNKKBGIRKSPGT-UHFFFAOYSA-N ClC1=CC=C(C=C1)N1C(NC(C1)NCC1CCCCC1)=O.CC1=CC=C(C=C1)N1C(NC(C1)N1CCOCC1)=O.ClC1=CC=C(C=C1)N1C(NC(C1)N1CCN(CC1)C)=O Chemical compound ClC1=CC=C(C=C1)N1C(NC(C1)NCC1CCCCC1)=O.CC1=CC=C(C=C1)N1C(NC(C1)N1CCOCC1)=O.ClC1=CC=C(C=C1)N1C(NC(C1)N1CCN(CC1)C)=O SNNKKBGIRKSPGT-UHFFFAOYSA-N 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000001037 epileptic effect Effects 0.000 claims 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- -1 1- (4-chlorophenyl) (4-methylpiperazino) imidazolin-2one 1- (4-methylphenyl) -4-morpholinoimidazolin-2-one Chemical compound 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241001484259 Lacuna Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000010457 zeolite Substances 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- XTMGVSBOILYKAA-UHFFFAOYSA-N 1-(4-bromophenyl)-4-morpholin-4-ylimidazolidin-2-one Chemical compound C1=CC(Br)=CC=C1N1C(=O)NC(N2CCOCC2)C1 XTMGVSBOILYKAA-UHFFFAOYSA-N 0.000 description 1
- ADOLLNOHUDQRCE-UHFFFAOYSA-N 1-(4-chlorophenyl)-4-morpholin-4-ylimidazolidin-2-one Chemical compound C1=CC(Cl)=CC=C1N1C(=O)NC(N2CCOCC2)C1 ADOLLNOHUDQRCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- JIYXHCMRGZVYMA-UHFFFAOYSA-N dimethylcarbamic acid;n-methylmethanamine Chemical compound C[NH2+]C.CN(C)C([O-])=O JIYXHCMRGZVYMA-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
According to the present invention, these novel compounds are 1-ar(alk)ylimidazolin-2-ones of the general formula 1 I, pki~ ii it AMENDED SHEET 2
(CH
2
H
0- NN m=O, 1, 2,3,4,5 in which X hydrogen, Cl-C 4 -alkyl, Cl-C 4 -alkoxy, trifluoronethyl or halogen
R
1 and R 2 =Cl-0 4 -alkyl, cycloalkyl or heteroalkyl where the alkyl group in each case contains 5-7 carbon atoff [sic] atoms or
R
1 and R 2 together are an alkylene group having 2-6 carbon atoms in which a -CR 2 group can be replaced by oxygen,- nitrogen or sulfur.
The number of CH 2 groups is either 0 (1-arylimidazolin- 2-ones) or 1 (l-aralkylimidazolin-2-ones).
Examples of compounds of the general formula I [sic] which may be mentioned are: l-phenyl-4 -morpholinoimidazolin-2-one 1- (4-methoxy) -4-piperidinoimidazolin-2-one 1- (4-chlorophenyl) -4-morpholinoimidazolin-2-one 1- (4-chlorophenyl) -4-piperidinoimidazolin-2-one 1- (4-chlorophenyl) -4-dimethylaminoimidazolin-2-one 1- (4-bromophenyl) -4-morpholinoimidazolin-2-one 1- (3-chiorophenyl) -4-morpholinoimidazolin-2-one 1- (4-chiorophenyl) -4-hexamethyleneiminoimidazolin-2-one 1- (4-chlorophenyl) (4-methylpiperazino) imidazolin-2one 1- (4-methylphenyl) -4-morpholinoimidazolin-2-one 1- (4-chiorophenyl) (cyclohexylmethylamino) imidazolin- 2-one 1- (4-fluorophenyl) -4-morpholinoimidazolin-2-one l-benzyl-4-morpholinoimidazolin-2-one x AMENDED SHEET WO 97/09314 PCT/EP96/03295 According to the present invention, the compounds of the general formula 1 can be prepared by a novel process by reaction of the compounds of the general formula 2
H
N.H n 0,1 (X)m m= 0,1,2,3,4,5 in which X hydrogen, Ci-C 4 -alkyl, Ci-C 4 -alkoxy, trifluoromethyl or halogen, with a secondary amine.
The preparation of the compounds of the formula 1 can alternatively be carried out in a solvent or in excess secondary amine at temperatures between 50 0 C and 160 0
C.
Suitable solvents are preferably aromatic hydrocarbons, for example benzene, toluene, chlorobenzene or dichlorobenzene.
The reaction is preferably carried out in the presence of water-binding substances such as zeolites or sodium sulfate. The reaction can be accelerated by addition of generally customary condensation catalysts such as 4-toluenesulfonic acid.
The compounds according to the invention are suitable for the preparation of pharmaceutical compositions. The pharmaceutical compositions can contain one or more of the compounds according to the invention. The customary pharmaceutical excipients and auxiliaries can be used to prepare the pharmaceutical preparations.
The medicaments can be administered parenterally (for example intravenously, intramuscularly or subcutaneous- Sly) or orally.
i l WO 97/09314 4 PCT/EP96/03295 The administration forms can be prepared by processes which are generally known and customary in pharmaceutical practice.
The compounds according to the invention have strong anticonvulsive actions.
They were tested for their anticonvulsive action in vivo after i.p. administration to mice or rats (p.o.
administration) according to the internationally customary standard (Pharmac. Weekblad, Sc.Ed. 14, 132 (1992) and Antiepileptic Drugs, Third Ed., Raven Press, New York (1989) (Table 1).
For example, for the compound 2 (1-(4-chlorophenyl)-4morpholinoimidazolin-2-one) in the rat the EDso for the maximum electroshock was determined to be 21 mg/kg, the ED 50 in the s.c. pentetrazole test was determined to be 16 mg/kg and the NT 50 for the neurotoxicity was determined to be 400 mg/kg. In comparison to this, known antiepileptics are active either in the maximum electroshock model or in the pentetrazole test or, in the case of relatively high activity, are severely neurotoxic in the PTZ test.
i~v'W/; 4 WO 97/09314 Table 1 PCT/EP96/03295 Comp ound tcordn Log p 2 Test 3)Dose 4 Action 5 Examples MES 100 1 0.64 100 MES 300 2 1.48 30 MES 100 100 3 2.29 PTZ 100 100 MES 300 4 0.48 PTZ 300 MES 300 100 2.17 300 100 MES 300 100 6 1.61 100 MES 300 100 7 1.53 PTZ 100 100 MES 300 8 1.45 PTZ 100 100 MES 100 9 0.97 PTZ 100 100 MES 300 1.28 300 MES 300 100 11 2.56 PTZ 300 WOo 97/09314 PCT/EP96/03295 Comparison substance Test 3 Dose 4 Action 5 MES 100 100 Carbamazepine PTZ 100 0 MES 100 0 Valproate PTZ 100 Notes for Table 1: 1) For numbering of examples the compounds see working 2) Octanol/water partition coefficient 3) MES maximum pentetrazole electroshock, PTZ s.c.
4) in mg/kg in of the protected animals The preparation of the novel compounds of the general formula 1 will be illustrated in greater detail with the aid of working examples.
Working Examples General procedure for the preparation of the compounds of the formula 1 according to Table 1, Examples 1-11.
Variant A 0.05 mol of 1-arylimidazolin-2,4-dione of the general formula 2 [lacuna] 200 mg of 4-toluenesulfonic acid [lacuna] added to 100 ml of an appropriate secondary amine. The mixture is then heated under reflux in a Soxhlet extractor, the extraction thimble previously being filled with about 25 g of a water- WO 97/09314 7 PCT/EP96/03295 binding solid (calc. sodium sulfate, magnesium sulfate, NaOH, KOH, zeolites are suitable). After a reaction time of 8 to 30 hours, the solution is filtered hot and distilled to approximately half the volume in a rotary evaporator. The clear solution is cooled in an ice bath and the crystal magma obtained is separated off from the amine. Starting substance contained in the crude product is extracted with 50 ml of hot acetone. The product is recrystallized from n-propanol.
About 0.02 mol of unreacted l-arylimidazolin-2,4-dione can be recovered from the separated amine.
Variant B 0.05 mol of l-aralkylimidazolin-2,4-dione of the general formula 2 is reacted with a sec. amine as described under A. After a reaction time of 8 to hours, the solution is filtered hot and then concentrated to dryness in a rotary evaporator. 50 ml of methylene chloride and 50 ml of 2N HC1 are added to the residue. The organic phase is separated off and the aqueous phase is extracted a further two times with methylene chloride. The aqueous phase isolated is rendered alkaline with 50 ml of 10% strength NaOH and the l-4-amino-l-aralkylimidazolin-2-one [sic] is extracted with 100 ml of methylene chloride. The ether extracts are dried over sodium sulfate. After distilling off the methylene chloride, the crude product is recrystallized from ethanol or acetone.
Variant C 0.05 mol of 1-ar(alk)ylimidazolin-2,4-dione of the general formula 2 is reacted with 100 ml of dimethylammonium dimethylcarbamate as described under A and B. After a reaction time of 40 hours, the mixture is worked up according to variant A or B.
i: i N
I*
WO 97/09314 PCT/EP96/03295 H Table 2 1) recovered starting material was taken into account when calculating the yield
Claims (8)
1. Novel compounds of the general formula 1 -(CH 2 H H N H n=0, 1 m 0, 1, 2, 3,4, in which X hydrogen, CI-C 4 -alkyl, CI-C 4 -alkoxy, trifluoromethyl or halogen RI and R 2 CI-C 4 -alkyl, cycloalkyl or heteroalkyl where the alkyl group in each case contains 5-7 carbon atoms or RI and R 2 together are an alkylene group having 2-6 carbon atoms in which a -CH 2 group can be replaced by oxygen, nitrogen or sulfur.
2. Compounds according to claim 1, 1 -phenyl-4-morpholinoimidazolin-2-one 1 -(4-methoxy)-4-piperidinoimidazolin-2-one 1 -(4-chlorophenyl)-4-inorpholinoimidazolin-2-one 1 -(4-chlorophenyl)-4-piperidinoimidazolin-2-one 1 -(4-chlorophenyl)-4-dimethylaminoimidazolin-2-one -(4-bromophenyl)-4-morpholinoimidazolin-2-one 1 -chlorophenyl)-4-morpholinoimidazolin-2-one 1 -(4-chlorophenyl)-4-hexamethyleneiminoimidazolin-2-one V900. 20 1 -(4-chlorophenyl)-4-(4-methylpiperazino)imidazolin-2-one 1 -(4-methylphenyl)-4-morpholinoimidazolin-2-one 1 -(4-chlorophenyl)-4-(cyclohexylmethylamino)imidazolin-2-one *1 -(4-fluorophenyl)-4-morpholinoimidazolin-2-one 1 -benzyl-4-morpholinoimidazolin-2-one
3. A 4-amino-i -(phenyl or phenalkyl)-1 ,5-dihydroimidazol-2-one derivative, substantially as hereinbefore described with reference to any one of the Examples.
4. Process for the preparation of the compounds of the general formula 1, characterised in that a compound of the general formula 2 [n:\libc]03345:MEF n 0, 1 m=0, 1,2,3,4,5 in which X hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, trifluoromethyl or halogen is reacted with a secondary amine HNR 1 R 2 at temperatures between 50 0 C and 160 0 C, R 1 and R 2 having the meaning indicated.
A process for the preparation of a 4-amino-l-(phenyl or dihydroimidazol-2-one derivative, substantially as hereinbefore described with reference to any one of the Examples.
6. A 4-amino-l-(phenyl or phenalkyl)-l,5-dihydroimidazol-2-one derivative prepared by the process of claim 4 or claim
7. A pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 3 or 6 together with a pharmaceutically acceptable carrier, diluent or adjuvant therefor.
8. A method for the treatment or prophylaxis of epileptic disorders in a mammal requiring said treatment or prophylaxis, which method comprises administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 3 or 6 or of a composition according to claim 7. Dated 3 April, 1998 20 Arzneimittelwerk Dresden GmbH Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [n:\libc]03345:MEF
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19532668A DE19532668A1 (en) | 1995-09-05 | 1995-09-05 | Novel, anticonvulsant 1-ar (alk) yl-imidazolin-2-ones which contain a disubstituted amine radical in the 4-position, and process for their preparation |
| DE19532668 | 1995-09-05 | ||
| PCT/EP1996/003295 WO1997009314A1 (en) | 1995-09-05 | 1996-07-26 | Novel 1-ar(alk)yl-imidazolin-2-ones containing a disubstituted amine radical in the 4th position, having an anti-convulsive effect, and process for their production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6737596A AU6737596A (en) | 1997-03-27 |
| AU700602B2 true AU700602B2 (en) | 1999-01-07 |
Family
ID=7771261
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU67375/96A Expired AU700602B2 (en) | 1995-09-05 | 1996-07-26 | Novel 1-ar(alk)yl-imidazolin-2-ones containing a disubstituted amine radical in the 4th position, having an anti-convulsive effect, and process for their production |
Country Status (31)
| Country | Link |
|---|---|
| EP (1) | EP0863880B1 (en) |
| JP (1) | JP4030578B2 (en) |
| CN (1) | CN1103762C (en) |
| AR (1) | AR003502A1 (en) |
| AT (1) | ATE254606T1 (en) |
| AU (1) | AU700602B2 (en) |
| BG (1) | BG63917B1 (en) |
| BR (1) | BR9610359A (en) |
| CA (1) | CA2184871C (en) |
| CZ (1) | CZ291839B6 (en) |
| DE (2) | DE19532668A1 (en) |
| DK (1) | DK0863880T3 (en) |
| EA (1) | EA000535B1 (en) |
| EE (1) | EE03562B1 (en) |
| ES (1) | ES2208758T3 (en) |
| FR (1) | FR13C0049I2 (en) |
| GE (1) | GEP20022652B (en) |
| HU (1) | HU225956B1 (en) |
| IL (1) | IL123333A (en) |
| LT (1) | LT4482B (en) |
| LU (1) | LU92263I2 (en) |
| NO (1) | NO313829B1 (en) |
| NZ (1) | NZ315624A (en) |
| PL (1) | PL188287B1 (en) |
| PT (1) | PT863880E (en) |
| SK (1) | SK284868B6 (en) |
| TR (1) | TR199800476T1 (en) |
| TW (1) | TW422838B (en) |
| UA (1) | UA46790C2 (en) |
| WO (1) | WO1997009314A1 (en) |
| ZA (1) | ZA967014B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19721580A1 (en) * | 1997-05-23 | 1998-11-26 | Dresden Arzneimittel | Use of 1-ar (alk) yl-imidazolin-2-one for the treatment of anxiety and tension |
| US20050070537A1 (en) * | 2002-10-10 | 2005-03-31 | Chris Rundfeldt | Use of dihydroimidazolones for the treatment of dogs |
| RU2354377C2 (en) * | 2003-07-11 | 2009-05-10 | Берингер Ингельхайм Ветмедика Гмбх | Method of treatment or prevention of central nervous system diseases by means of compounds possessing selectivity with respect to alpha-3-subunit of benzodiazepine receptor |
| EP2093218A1 (en) * | 2008-02-22 | 2009-08-26 | Ruggero Fariello | Arylalkyl substituted imidazolidinones |
| WO2013024036A1 (en) | 2011-08-12 | 2013-02-21 | Boehringer Ingelheim Vetmedica Gmbh | Funny current (if) inhibitors for use in a method of treating and preventing heart failure in feline |
| US9820988B2 (en) | 2014-03-24 | 2017-11-21 | Boehringer Ingelheim Vetmedica Gmbh | Treatment of epileptic disorders in feline animals |
| IT202100000782A1 (en) | 2021-01-18 | 2022-07-18 | Procos Spa | PROCESS FOR THE SYNTHESIS OF IMEPITOIN |
| EP4553066A1 (en) | 2023-11-10 | 2025-05-14 | Justesa Imagen S.A.U. | Improved process for the synthesis of imepitoin |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE790380A (en) | 1971-10-21 | 1973-04-20 | American Cyanamid Co | NEW (P-CHLORO) PHENYL-1 METHYL-3 IMIDAZOLIDINES, 2,4-DISUBSTITUTIONS USEFUL IN PARTICULAR AS ANTIALDOSTERONE DIURETIC AGENTS AND THEIR PREPARATION PROCESS |
| US4044021A (en) * | 1971-10-21 | 1977-08-23 | American Cyanamid Company | Tetrasubstituted imidazolidine diuretics useful in the treatment of hyperaldosteronism |
| US3932452A (en) * | 1975-02-07 | 1976-01-13 | Morton-Norwich Products, Inc. | 1-Arylmethyl-2-imidazolidinones |
-
1995
- 1995-09-05 DE DE19532668A patent/DE19532668A1/en not_active Ceased
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1996
- 1996-07-26 ES ES96927607T patent/ES2208758T3/en not_active Expired - Lifetime
- 1996-07-26 CZ CZ1998661A patent/CZ291839B6/en not_active IP Right Cessation
- 1996-07-26 BR BR9610359A patent/BR9610359A/en active IP Right Grant
- 1996-07-26 AU AU67375/96A patent/AU700602B2/en not_active Expired
- 1996-07-26 EE EE9800063A patent/EE03562B1/en unknown
- 1996-07-26 TR TR1998/00476T patent/TR199800476T1/en unknown
- 1996-07-26 WO PCT/EP1996/003295 patent/WO1997009314A1/en not_active Ceased
- 1996-07-26 EA EA199800271A patent/EA000535B1/en not_active IP Right Cessation
- 1996-07-26 PL PL96325413A patent/PL188287B1/en unknown
- 1996-07-26 PT PT96927607T patent/PT863880E/en unknown
- 1996-07-26 HU HU9802941A patent/HU225956B1/en unknown
- 1996-07-26 SK SK216-98A patent/SK284868B6/en not_active IP Right Cessation
- 1996-07-26 JP JP51080097A patent/JP4030578B2/en not_active Expired - Lifetime
- 1996-07-26 IL IL12333396A patent/IL123333A/en not_active IP Right Cessation
- 1996-07-26 EP EP96927607A patent/EP0863880B1/en not_active Expired - Lifetime
- 1996-07-26 CN CN96197801A patent/CN1103762C/en not_active Expired - Lifetime
- 1996-07-26 UA UA98041717A patent/UA46790C2/en unknown
- 1996-07-26 AT AT96927607T patent/ATE254606T1/en active
- 1996-07-26 DK DK96927607T patent/DK0863880T3/en active
- 1996-07-26 GE GEAP19964221A patent/GEP20022652B/en unknown
- 1996-07-26 NZ NZ315624A patent/NZ315624A/en not_active IP Right Cessation
- 1996-07-26 DE DE59610827T patent/DE59610827D1/en not_active Expired - Lifetime
- 1996-08-19 ZA ZA967014A patent/ZA967014B/en unknown
- 1996-09-03 TW TW085110749A patent/TW422838B/en not_active IP Right Cessation
- 1996-09-04 AR ARP960104226A patent/AR003502A1/en active IP Right Grant
- 1996-09-05 CA CA002184871A patent/CA2184871C/en not_active Expired - Lifetime
-
1998
- 1998-02-27 BG BG102287A patent/BG63917B1/en unknown
- 1998-03-02 NO NO19980906A patent/NO313829B1/en not_active IP Right Cessation
- 1998-04-03 LT LT98-047A patent/LT4482B/en not_active IP Right Cessation
-
2013
- 2013-08-07 LU LU92263C patent/LU92263I2/en unknown
- 2013-08-13 FR FR13C0049C patent/FR13C0049I2/en active Active
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