CN1297439A - 4-amino-(ethylamino)-oxindole dopamine autoreceptor agonists - Google Patents
4-amino-(ethylamino)-oxindole dopamine autoreceptor agonists Download PDFInfo
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- CN1297439A CN1297439A CN99805030A CN99805030A CN1297439A CN 1297439 A CN1297439 A CN 1297439A CN 99805030 A CN99805030 A CN 99805030A CN 99805030 A CN99805030 A CN 99805030A CN 1297439 A CN1297439 A CN 1297439A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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Abstract
Compounds having dopaminegic activity are provided or pharmaceutically acceptable salts thereof, having formula (I) wherein R<1> and R<2> are each, independently, hydrogen, C1-10 alkyl, or (CH2)mR<4>, wherein R<4> is phenyl or naphthyl which may be substituted by one or two substituents selected from the group consisting of C1-6 alkyl, halogen, C1-6 alkoxide and trifluoromethyl and m is 1 to 5; and R<3> is hydrogen or C1-6 alkyl.
Description
Invention field
The present invention relates to a series of 4-amino-(ethylamino)-oxindoles with dopaminergic character.The compound of this invention is used for the treatment of the various diseases that influenced by dopamine agonist, such as Parkinson's disease, Tu Leiteshi syndrome, schizophrenia and alcohol and medicine habituation.
Background of invention
Produce to suppress psychoactive effort with Dopamine HCL autoreceptor agonist induction and obtained success (such as seeing people such as Dorsini, Adv.Biochem.Psychopharmacol., 16:645-648 (1977); People such as Tamminga, Science.200:567-568 (1975); With people such as Tamminga, Psychiatry 398-402 (1986)).People such as nearest Lahti at Mol.Pharm., have reported a kind of at dopamine D among the 42:432-438 (1993)
2Measure the method for intrinsic activity on the acceptor.With the low-affinity agonist state of acceptor (just, LowAg) and high-affinity agonist state (just, ratio HighAg), the intrinsic activity of LowAg/HighAg prediction just.The agonist of these ratios and given compound, partial agonist is relevant with antagonistic activity.These activity have represented that compound brings out the mentalistic feature of inhibition.
WO 9109849 extensively discloses a series of indoles ammoniates, and such as following compd A and B, they are disclosed the reverse transcriptase inhibitors as the treatment AIDS.
Yet, in this piece document, do not have to disclose or advise that these compounds have D
2Receptor agonist activity or the other diseases symptom that plays alleviation Parkinson's disease, schizophrenia or influenced by Dopamine HCL.
Summary of the invention
Compound of the present invention is pharmaceutically acceptable salt of the amino of 4-shown in the formula I-(ethylamino)-oxindole or its:
R wherein
1And R
2Independent respectively is hydrogen, C
1-10Alkyl, or (CH
2)
mR
4, R in the formula
4Be phenyl or naphthyl, they can be selected from C by one or two
1-6Alkyl, halogen, C
1-6Group in alkoxide and the trifluoromethyl replaces and m is 1 to 5; R
3Be hydrogen or C
1-6Alkyl.
Compound of the present invention is to have the dopamine agonist of inherent dopaminergic activity in various degree.In these compounds some are autoreceptor agonists optionally, (just only activate autoreceptor rather than postsynaptic D
2The partial agonist of Dopamine Receptors).Like this, these compounds provide the function Accommodation of brain dopamine system and can not cause the excessive blocking-up of postsynaptic Dopamine Receptors.The observed generation severe side effect of attending the meeting of excessive blocking-up like this, this side effect is usually seen for the clinical effective known agent of treatment schizophrenia.And compound of the present invention has very high intrinsic activity, and therefore, they can be used as natural neurotransmitter, just as full agonist.Like this, they are used for the treatment of the disease that is caused by abnormal dopamine concentration, for example Parkinson's disease.Detailed Description Of The Invention
The compound that compound preferred formula of the present invention is an I or its be acceptable salt pharmaceutically, wherein:
R
1And R
2Independent respectively is C
1-10Alkyl, or (CH
2)
mR
4, R in the formula
4Be that phenyl and m are 1; R
3Be hydrogen or C
1-6Alkyl.
Compound of the present invention most preferably from:
4-(2-benzyl ammonia-ethylamino)-1,3-dihydro-indol-2-one dihydrochloride; With 4-[(2-benzyl-methylamino)-ethylamino]-1,3-dihydro-indol-2-one dihydrochloride.
Here the term of usefulness " alkyl " and " alkoxyl group " refer to straight or branched alkyl and alkoxy base respectively.Term " halogen " refers to chlorine, bromine, fluorine and iodine.
Compound of the present invention can be with its pharmaceutically form use of acceptable acid salt, and these salt have the effect of free alkali.These salt can be by the known method preparation of the people who knows this area, and they are to form salt with inorganic or organic acid, such as, fumaric acid, toxilic acid, phenylformic acid, xitix, pamoic, succsinic acid, dimethylene Whitfield's ointment, methylsulfonic acid, ethionic acid, acetate, oxalic acid, propionic acid, tartrate, Whitfield's ointment, citric acid, glyconic acid, lactic acid, oxysuccinic acid, amygdalic acid, styracin, citraconic acid, aspartic acid, stearic acid, L-glutamic acid, Phenylsulfonic acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, cyclohexyl thionamic acid, phosphoric acid, nitric acid.
Compound of the present invention is a Dopamine HCL autoreceptor agonist, and it is regulated the synthetic of neurotransmitter dopamine and discharges.Like this, they are used for the treatment of dopaminergic system disorder; Such as being used for schizophrenia, Parkinson's disease, Tu Leiteshi syndrome.These compounds also are the partial agonists of postsynaptic D2 Dopamine Receptors, so also are used for the treatment of other illnesss that influenced by these agonists, such as alcohol and drug habit.
These compounds can be by the known any suitable traditional method preparation of the people who knows this area.Yet these compounds are preferably prepared by the whole process that scheme I and II are described.
The invention provides pharmaceutically preparation method of acceptable salt of the compound of formula I or its, wherein
(a) compound of handling general formula C is removed removable blocking group, X
4-NX
3-CH
2-CH
2-NX
2-X
1(C) X wherein
1Be removable blocking group or R
1X
2Be removable blocking group or R
2X
3Be removable blocking group or R
3And X
1, X
2And X
3In at least one is removable blocking group; X
4Be 2-oxo-1,3-dihydro-indoles-4-base; Or
(b) handle the compound of general formula D with X
5Change into 2-oxo-1,3-dihydro-indoles-4-base; X
5-NX
3-CH
2-CH
2-NX
2-X
1(D) X wherein
1Be removable blocking group or R
1X
2Be removable blocking group or R
2X
3Be removable blocking group or R
3And X
5Be 2-oxo-1, the precursor of 3-dihydro-indoles-4-base; Work as X
1, X
2And X
3In at least one when being removable blocking group, the processing reaction product is removed removable blocking group; Or
(c) compound of the compound of general formula E and general formula F reaction X
4-NR
3X in-H (E) general formula (E)
4And R
3By above definition, X
6-CH
2-CH
2-NX
2-X
1(F) X in the general formula (F)
1Be removable blocking group or R
1X
2Be removable blocking group or R
2And X
6It is leavings group; Work as X
1And X
2In at least one when being removable blocking group, the processing reaction product is removed removable blocking group; Or
(d) compound of formula I forms pharmaceutically acceptable acid salt with acid treatment.
In method (a), preferred trifluoroacetyl group is as removable blocking group.It can with suitable alkaline condition such as, remove with the sodium hydroxide in the methyl alcohol.The compound of general formula C can be prepared by several different methods, such as, as step (b) or primary reaction product (c).Step (b) can be with 3-chloro-1H-indoles-4-base as X
5Step (c) can be carried out with the standard method of preparation amine.X
6Such as being chlorine, bromine, alkylsulfonyloxy, aryl-sulfonyl oxygen.
The present invention makes an explanation by the non-restrictive example of following mask body.
Intermediate 1
2-hydrogen-N-(1H-indoles-4-yl)-ethanamide
(1.0 grams, 7.57mmol), (1.07ml 7.57mmol) places the 50ml methylene dichloride to form suspended substance to triethylamine to the 4-amino indole, keeps 0 ℃, and (0.615ml 7.57mmol) is dissolved in the solution that the 5ml methylene dichloride forms to be added dropwise to chloroacetyl chloride.After 30 minutes, solution is by (2 * 100ml) washings; With anhydrous magnesium sulfate drying.By silica gel chromatography (60 gram, 40% ethyl acetate-hexane) purifying and from hexane-ethyl acetate crystallization obtain title compound, be white solid (1.17 grams, 74.1%), mp114-116 ℃; MS EI m/e 208/210 (M
+).
C
10H
9CIN
2The ultimate analysis of O
Calculated value: C, 57.54; H, 4.39; N, 13.31
Measured value: C, 57.32; H, 4.19; N13.19
Intermediate 2a
2-benzyl amino-N-(1H-indoles-4-yl)-ethanamide
(3.0 grams, 14.4mmol), (4.76 grams 43.1mmol) place 60mlDMSO to form solution to benzylamine to 2-chloro-N-(1H-indoles-4-yl)-ethanamide, stir at ambient temperature 16 hours.In the mixture impouring 700m water, the crude product crystallization goes out solid.After leaching, solid is dissolved in ethyl acetate (600ml), and with 200ml water and the water washing of 200ml salt, anhydrous magnesium sulfate drying filters.Ethyl acetate concentrates and obtains title compound, is white solid, (3.36 grams, 83.6%) mp158-161 ℃; MS EI m/e 279 (M
+).
C
17H
17N
3The ultimate analysis of O
Calculated value: C, 73.10; H, 6.13; N, 15.04
Measured value: C, 73.19; H, 6.17; N, 14.68
Intermediate 2b
2-(benzyl-methyl-amino)-N-(1H-indoles-4-yl)-ethanamide
Repeat to prepare the method that intermediate 2a describes with N-benzyl methylamine.Title compound is yellowish green oil (98.0%); MS EI m/e 293 (M
+).
C
18H
19N
3The ultimate analysis of O
Calculated value: C, 73.69; H, 6.53; N, 14.32
Measured value: C, 73.47; H, 6.31; N, 13.97
Intermediate 3a
N-benzyl-N '-(1H-indoles-4-yl)-ethane-1,2-diamines 0.25 water
(3.03 grams 10.8mmol) are dissolved in the 300ml tetrahydrofuran (THF) 2-benzyl amino-N-(1H-indoles-4-yl)-ethanamide, and nitrogen slowly adds the Lithium Aluminium Hydride tetrahydrofuran solution (54ml) of 1.0M down.Mixture refluxed 5 hours, cooling, and with the rapid stopped reaction of tetrahydrofuran aqueous solution, (1.0M 100ml), tells organic layer to add sodium hydroxide.Water layer is with ethyl acetate (2 * 200ml) washings.(2 * 200ml), salt solution (200ml) washing is with anhydrous magnesium sulfate drying with water for the organic layer that merges.Filter, solvent concentrates and obtains title compound is brown oil (2.80 grams, 99.0%); MS EI m/e 265 (M
+).
C
17H
19N
30.25H
2The ultimate analysis of O
Calculated value: C, 75.66; H, 7.28; N, 15.57
Measured value: C, 75.40; H, 7.23; N, 15.31
Intermediate 3b
N-benzyl-N '-(1H-indoles-4-yl)-N-methyl-ethyl-1, the 2-diamines
Repeat to prepare the method that intermediate 3a sets forth with 2-(benzyl methylamino)-N-(1H-indoles-4-yl)-ethanamide.Title compound is linen solid (63.9%), mp73-74 ℃; MS EI m/e 279 (M
+).
C
18H
21N
3Ultimate analysis
Calculated value: C, 77.38; H, 7.58; N, 15.04
Measured value: C, 77.24; H, 7.64; N, 15.07
Intermediate 4a
N-[2-(benzyl-trifluoroacetyl group amino) ethyl]-2,2,2-three fluoro-N-(1H-
Indoles-4-yl)-ethanamide
N-benzyl-N '-(1H-indoles-4-yl)-ethane-1, and the 2-diamines (1.22 grams, 4.60mmol), triethylamine (2.56ml, 18.4mmol) and methylene dichloride (40ml) be mixed into solution, keep 0 ℃, (1.56ml 11.0mmol) is dissolved in the solution that the 5ml methylene dichloride forms to splash into trifluoroacetic anhydride.After 1 hour, solution, filters with anhydrous magnesium sulfate drying with water (2 * 100) washing.By silica gel chromatography (60 gram, 40% ethyl acetate-hexane) purifying and from hexane recrystallization obtain title compound, be white solid (1.79 grams, 85.7%), mp174-177 ℃; MS EI m/e 459 (M
+).
C
21H
17F
6N
3O
2Ultimate analysis
Calculated value: C, 55.15; H, 3.75; N, 9.19
Measured value: C, 55.19; H, 3.62; N, 9.15
Intermediate 4b
N-[2-(benzyl-methyl-amino)-ethyl]-2,2,2-three fluoro-N-(the 1H-indoles-
The 4-yl)-ethanamide
With N-benzyl-N '-(1H-indoles-4-yl)-N-methyl-ethyl-1, the 2-diamines repeats to prepare the step that intermediate 4a sets forth.Title compound is pale solid (91.2%), mp105-108 ℃; MS EI m/e 375 (M
+).
C
20H
20F
3N
3The ultimate analysis of O
Calculated value: C, 63.99; H, 5.37; N, 11.19
Measured value: C, 64.06; H, 5.32; N, 11.22
Intermediate 5a
N-[2-(benzyl-trifluoroacetyl group amino) ethyl]-2,2,2-three fluoro-N-(3-chlorine
-1H-indoles-4-yl)-ethanamide
N-[2-(benzyl-trifluoroacetyl group amino) ethyl]-2,2,2-three fluoro-N-(3-chloro-1H-indoles-4-yl)-ethanamide
(5.9 the gram, 12.9mmol), N-chloro-succinimide (1.76 the gram, 12.9mmol) and the solution of acetonitrile (40ml) stirred at ambient temperature 16 hours.Mixture concentrates, and resistates is dissolved in the 50ml ethyl acetate.(2 * 100ml), salt solution (100ml) washs organic layer, and anhydrous magnesium sulfate drying filters with water.Solvent concentrates, and crystallization obtains title compound from hexane, is white solid (6.0 grams, 95.4%), mp139-142 ℃; MS EI m/e 491/493 (M
+).
C
21H
16CIF
6N
3O
2Ultimate analysis
Calculated value: C, 51.29; H, 3.28; N, 8.54
Measured value: C, 51.17; H, 3.05; N, 8.43
Intermediate 5b
N-[2-(benzyl-methyl-amino) ethyl]-N-(3-chloro-1H-indoles-4-yl)-2,
2, the 2-trifluoroacetamide
With N-[2-(benzyl-methyl-amino) ethyl]-2,2,2-three fluoro-N-(1H-indoles-4-yl)-ethanamide repeats to prepare the step of intermediate 5a.Title compound is pale solid (72.6%), mp150-153 ℃; MS EI m/e 409/411 (M
+).
C
20H
19CIF
3N
3The ultimate analysis of O
Calculated value: C, 58.61; H, 4.67; N, 10.25
Measured value: C, 58.64; H, 4.73; N, 10.19
Intermediate 6a
N-[2-(benzyl-trifluoroacetyl group amino)-ethyl]-2,2,2-three fluoro-N-(2-oxo-2,3-dihydro-1H-indoles-4-yl)-ethanamide
N-[2-(benzyl-trifluoroacetyl group amino) ethyl]-2,2, (1.4 grams 2.85mmol) are dissolved in the 18ml acetate 2-three fluoro-N-(3-chloro-1H-indoles-4-yl)-ethanamide, add the phosphoric acid of 10ml 85% and the mixture of 3ml water.React on 75-80 ℃ 16 heating hour.Mixture is to going in the 100ml water, and the crude product crystallization goes out solid.After the filtration, solid is dissolved in the 100ml ethyl acetate, with 50ml water, and 50ml saturated sodium bicarbonate solution and the water washing of 20ml salt, anhydrous magnesium sulfate drying filters.By silica gel chromatography (40% hexane-ethyl acetate) purifying and from ether-sherwood oil crystallization obtain title compound, be white solid (0.31 gram, 23.0%), mp108-111 ℃; MS EI m/e 473 (M
+).
C
21H
17F
6N
3O
3Ultimate analysis
Calculated value: C, 53.28; H, 3.62; N, 8.88
Measured value: C, 53.01; H, 3.37; N, 8.92
Embodiment 1
4-(2-benzylamino-ethylamino)-1,3-dihydro-indol-2-one two hydrochloric acid
Salt 0.1 water
N-[2-(benzyl-trifluoroacetyl group amino) ethyl]-2,2,2-three fluoro-N-(2-oxos-2; 3-dihydro-1H-indoles-4-yl)-ethanamide (1.0 grams; 2.1mmol) being dissolved in the 40ml tetrahydrofuran (THF), under the room temperature, the sodium hydroxide (1.0ml) of adding 50% is dissolved in the solution that 10ml methyl alcohol forms.After 15 minutes, mixture concentrates, and resistates is dissolved in the 50ml ethyl acetate.Organic layer is with 2 * 50ml water, the water washing of 50ml salt, and anhydrous magnesium sulfate drying filters.By silica gel chromatography purifying (7%2N ammonia methyl alcohol-ethyl acetate), crystallization obtains free alkali from ethyl acetate, is light green solid (0.7 gram, 87.5%), mp120-124 ℃; MS EI m/e 281 (M
+).
C
17H
19N
3O0.25H
2The ultimate analysis of O
Calculated value: C, 71.43; H, 6.88; N, 14.70
Measured value: C, 71.81; H, 6.71; N, 14.73
4-(2-benzylamino-ethylamino)-1, (0.45 restrains the 3-dihydro-indol-2-one, 1.6mmol) is dissolved in 25ml tetrahydrofuran (THF) and the 20ml methyl alcohol forming solution, adds hydrogenchloride ether (4.0ml) solution of 1M.Solvent concentrates, title compound crystallization, mp184-195 ℃ of gray solid (0.52 gram, 91.2%); MS EI m/e 281 (M
+).
C
17H
19N
3O2HCI0.1H
2The ultimate analysis of O
Calculated value: C, 57.34; H, 6.00; N, 11.94
Measured value: C, 57.00; H, 5.90; N, 11.72
Embodiment 2
4-[2-(benzyl-methyl-amino)-ethylamino]-1,3-dihydro-indol-2-one two
Hydrochloride 0.8 water
N-[2-(benzyl-methyl-amino) ethyl]-N-(3-chloro-1H-indoles-4-yl)-2,2, (5b, 1.75 restrain the 2-trifluoroacetamide, 4.27mmol) are dissolved in the 27ml acetate forming solution, add 70% phosphoric acid (20ml).Reacting on 75-80 ℃ of heating 16 hours. mixture is poured in the 100ml water, and the crude product crystallization goes out solid.After the filtration, solid is dissolved in 100ml ethyl acetate *, with 50ml water, and 50ml saturated sodium bicarbonate solution and the water washing of 20ml salt, anhydrous magnesium sulfate drying filters.Ethyl acetate concentrates, and obtains crude product intermediate 6b, is deep green resistates (1.5 gram).Without further purification, this material is dissolved in the 40ml tetrahydrofuran (THF), under the room temperature, adds 1.0ml 50% sodium hydroxide and is dissolved in the mixture that 10ml methyl alcohol forms.After 15 minutes, mixture concentrates, and resistates is dissolved in the 50ml ethyl acetate.Organic layer is with 2 * 50ml water, the water washing of 50ml salt, and anhydrous magnesium sulfate drying filters.By silica gel chromatography purifying (7%2N ammonia methyl alcohol-ethyl acetate), crystallization obtains free alkali from ethyl acetate, is pale solid (0.48 gram, 40.4%), mp122-124 ℃; MS EI m/e 295 (M
+).
C
18H
21N
3O 0.25H
2The ultimate analysis of O
Calculated value: C, 72.09; H, 7.23; N, 14.01
Measured value: C, 72.11; H, 7.16; N, 14.05
Title compound obtains brown solid, MS EI m/e 295 (M from the preparation of HCI-tetrahydrofuran (THF)
+).
C
18H
21N
3OHCI0.8H
2The ultimate analysis of O
Calculated value: C, 62.56; H, 6.99; N, 11.79
Measured value: C, 62.49; H, 6.79; N, 11.63
To the avidity of Dopamine HCL autoreceptor by Seemen and Schaus at EuropeanJournal of Pharmacology, 203:105-109 (1991). the standard test trace routine of middle record is determined.According to this program, the mouse striatum cerebral tissue of homogenizing is cultivated with the detection compound of suitable concn, filters, and washs and counts with the Betaplate scintillometer.
To the high-affinity of dopamine D-2 acceptor by people such as Fields. people such as Brain Res.136:578 (1977) and Yamamura at Neurotransmitter ReceptorBinding, the standard test trace routine of record is determined among the Raven Press, N.Y. (1978).The edge cerebral tissue of homogenizing with
3The detection compound of H-Spiropitan (Spiper.) and suitable concn is cultivated together, filter, washing jolts with Hydrofluor scintillationcocktail (obtaining from National Diagnostics), counts with Packard 460 CD scintillometer.
The detected result of representation compound of the present invention is described below:
The embodiment numbering | IC 50(nM) D 2Quin. | IC 50(nM) D 2?Spiper | Ratio |
????1 | ?13.2 | ?892 | ?67.7 |
Therefore, as can be seen, compound of the present invention has been realized the synthetic of neurotransmitter dopamine, and thereby is Dopamine HCL autoreceptor agonist.These compounds are used for the treatment of the dopaminergic disorder such as schizophrenia, Parkinson's disease, Tu Leiteshi syndrome, alcohol addiction, cocaine habituation and similar drug habit.
The compounds of this invention can be to take separately or with the oral or non-enteron aisle mode of the carrier-bound form of conventional medicament.The solid carrier that can use can comprise one or more materials, and they are also as seasonings, lubricant, solubilizing agent, suspension agent, weighting agent, glidant, compression auxiliary, tamanori, tablet disintegrant, or capsule material.When adopting powder-form, carrier is to pulverize good solid, and this solid mixes with pulverizing good active ingredient.When adopting tablet form, active ingredient is pressed into desired shapes and size with having essential compressible carrier with suitable mixed.Pulvis and tablet preferably comprise the active ingredient up to 99%.The people who is familiar with this area knows that any solid carrier all can be used for making preparation with The compounds of this invention.Specially suitable solid carrier comprises such as calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone, low-melting wax and ion exchange resin.
Liquid vehicle can be used to prepare the solution of The compounds of this invention, suspension agent, emulsion, syrup, and elixir.Compound of the present invention can be dissolved in or be suspended in pharmaceutically the acceptable liquid vehicle such as water, organic solvent, both mixtures or acceptable oil ﹠ fat pharmaceutically.Liquid vehicle can comprise other suitable medicinal additives such as solubilizing agent, emulsion, damping fluid, sanitas, sweetener, seasonings, suspension agent, thickening material, tinting material, viscosity-controlling agent, stablizer or Osmolyte regulator.Oral and parenterai administration is taken suitable liquid vehicle and is comprised that water is (particularly including top additive such as derivatived cellulose, the preferably carboxymethyl cellulose sodium solution), alcohol (comprising that single hydroxyl alcohol and polyhydroxy-alcohol are such as ethylene glycol) their derivative and oil (such as Oleum Cocois after the fractionation and peanut oil).For non-enteral administration, carrier also can be grease such as ethyl oleate, the Semen Myristicae isopropyl ester.For parenterai administration, sterile liquid carrier is used as sterile liquid carrier form component.
The liquid pharmaceutical compositions of sterile solution or form of suspension can carry out for example intramuscular, intraperitoneal, or subcutaneous injection.Sterile solution also can carry out intravenous injection.Oral composition can be the liquid or solid composition forms.
The pharmaceutical compositions that contains The compounds of this invention preferably uses such as tablet or capsule with the form of unitary dose.In this form, composition can be subdivided into the suitable unitary dose that contains these compounds again.The form of unitary dose can be the composition after the packing, such as, the powder after the packing, bottle, ampoule, the syringe and the pouch that contains liquid that give filling.In addition, unit dosage form may be the composition such as capsule or tablet itself or any suitable quantity that exists with packaged form.
Take the treatment significant quantity of The compounds of this invention and take mode, comprise patient's body weight according to several factors, the age, sex and medical conditions, the severity of disease, approach of taking and frequency, used particular compound etc. alters a great deal.Yet, think that the typical range that pharmaceutical compositions can comprise The compounds of this invention is about 0.1 to about 2000 milligrams, be preferably about 0.5 to about 500 milligrams, be more preferably between about 1 to 100 milligram.The supposition daily dosage portion of active compound is about 0.01 to 100 milligram an of per kilogram of body weight, and daily dosage portion is 2 to 4 administrations every day easily.
The present invention can be embodied in the various forms under not deviating from its spirit and essential characteristic prerequisite, so reference should add to be not only in the claims and invests in the specification sheets that the front illustrates the scope of the invention.
Claims (8)
1. general formula is pharmaceutically acceptable salt of the compound of following formula or its:
R wherein
1And R
2Independent respectively is hydrogen, C
1-10Alkyl, or (CH
2)
mR
4, R in the formula
4Be phenyl or naphthyl, they can be selected from C by one or two
1-6Alkyl, halogen, C
1-6Group in alkoxide and the trifluoromethyl replaces and m is 1 to 5; And R
3Be hydrogen or C
1-6Alkyl.
2. the compound of claim 1 or its acceptable salt pharmaceutically, wherein
R
1And R
2Be respectively C
1-10Alkyl, or (CH
2)
mR
4, R in the formula
4Be that phenyl and m are 1; And R
3Be hydrogen or C
1-6Alkyl.
3. the compound of claim 1, it is 4-(2-benzyl amino-ethyl amino)-1,3-dihydro-indol-2-one or its be the acid additive salt of acceptable pharmaceutically.
4. the compound of claim 1, it is a 4-[(2-benzyl methylamino)-ethylamino]-1,3-dihydro-indol-2-one or its be the acid additive salt of acceptable pharmaceutically.
5. contain pharmaceutically pharmaceutical composition of acceptable salt of following general formula compound or its:
R wherein
1And R
2Independent respectively is hydrogen, C
1-10Alkyl, or (CH
2)
mR
4, R in the formula
4Be phenyl or naphthyl, they can be selected from C by one or two
1-6Alkyl, halogen, C
1-6Group in alkoxide and the trifluoromethyl replaces and m is 1 to 5; And R
3Be hydrogen or C
1-6Alkyl.
6. the abnormal dopaminergic of treatment transmits the method for relative disease, comprises to patient using pharmaceutically acceptable salt of the following compound of general formula of significant quantity or its:
R wherein
1And R
2Independent respectively is hydrogen, C
1-10Alkyl, or (CH
2)
mR
4, R in the formula
4Be phenyl or naphthyl, they can be selected from C by one or two
1-6Alkyl, halogen, C
1-6Group in alkoxide and the trifluoromethyl replaces and m is 1 to 5; And R
3Be hydrogen or C
1-6Alkyl.
7. treat the method for suffering from the sick patient of Parkinson's disease for one kind, comprise to this patient and use pharmaceutically acceptable salt of the following compound of the general formula of significant quantity or its:
R wherein
1And R
2Independent respectively is hydrogen, C
1-10Alkyl, or (CH
2)
mR
4, R in the formula
4Be phenyl or naphthyl, they can be selected from C by one or two
1-6Alkyl, halogen, C
1-6Group in alkoxide and the trifluoromethyl replaces and m is 1 to 5; R
3Be hydrogen or C
1-6Alkyl.
8. the sick patient's of the trouble schizophrenia of a treatment method comprises to this patient and uses pharmaceutically acceptable salt of the following compound of general formula of antipsychotic significant quantity or its:
R wherein
1And R
2Independent respectively is hydrogen, C
1-10Alkyl, or (CH
2)
mR
4, R in the formula
4Be phenyl or naphthyl, they can be selected from C by one or two
1-6Alkyl, halogen, C
1-6Group in alkoxide and the trifluoromethyl replaces and m is 1 to 5; And R
3Be hydrogen or C
1-6Alkyl.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5883498A | 1998-04-13 | 1998-04-13 | |
US09/058,834 | 1998-04-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1297439A true CN1297439A (en) | 2001-05-30 |
Family
ID=22019205
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN99805030A Pending CN1297439A (en) | 1998-04-13 | 1999-04-12 | 4-amino-(ethylamino)-oxindole dopamine autoreceptor agonists |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP1073636A1 (en) |
JP (1) | JP2002511450A (en) |
CN (1) | CN1297439A (en) |
AR (1) | AR014847A1 (en) |
AU (1) | AU3555099A (en) |
CA (1) | CA2327477A1 (en) |
WO (1) | WO1999052870A1 (en) |
ZA (1) | ZA992670B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7053092B2 (en) | 2001-01-29 | 2006-05-30 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1a receptor subtype agonist |
AR032641A1 (en) * | 2001-01-29 | 2003-11-19 | Otsuka Pharma Co Ltd | RECEIVER SUBTIPE AGONIST 5-HT 1A. |
US8703772B2 (en) | 2001-09-25 | 2014-04-22 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
AR033485A1 (en) | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | MEDICINAL SUBSTANCE OF ARIPIPRAZOL OF LOW HYGROSCOPICITY AND PROCESS FOR THE PREPARATION OF THE SAME |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4452808A (en) * | 1982-12-07 | 1984-06-05 | Smithkline Beckman Corporation | 4-Aminoalkyl-2(3H)-indolones |
GB8712073D0 (en) * | 1987-05-21 | 1987-06-24 | Smith Kline French Lab | Medicament |
JPH07506823A (en) * | 1992-05-18 | 1995-07-27 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Use of indolone derivatives for the treatment of memory disorders, sexual dysfunction and Parkinson's disease |
KR20000035818A (en) * | 1996-08-27 | 2000-06-26 | 이곤 이 버그 | 4-aminoethoxy indolone derivatives |
-
1999
- 1999-04-12 CN CN99805030A patent/CN1297439A/en active Pending
- 1999-04-12 CA CA002327477A patent/CA2327477A1/en not_active Abandoned
- 1999-04-12 JP JP2000543433A patent/JP2002511450A/en active Pending
- 1999-04-12 AR ARP990101678A patent/AR014847A1/en unknown
- 1999-04-12 EP EP99917423A patent/EP1073636A1/en not_active Withdrawn
- 1999-04-12 AU AU35550/99A patent/AU3555099A/en not_active Abandoned
- 1999-04-12 WO PCT/US1999/007967 patent/WO1999052870A1/en not_active Application Discontinuation
- 1999-04-12 ZA ZA9902670A patent/ZA992670B/en unknown
Also Published As
Publication number | Publication date |
---|---|
ZA992670B (en) | 2000-10-12 |
WO1999052870A1 (en) | 1999-10-21 |
CA2327477A1 (en) | 1999-10-21 |
EP1073636A1 (en) | 2001-02-07 |
AU3555099A (en) | 1999-11-01 |
AR014847A1 (en) | 2001-03-28 |
JP2002511450A (en) | 2002-04-16 |
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