CN1065661A - The preparation method of heterogeneous ring compound - Google Patents

The preparation method of heterogeneous ring compound Download PDF

Info

Publication number
CN1065661A
CN1065661A CN91102395A CN91102395A CN1065661A CN 1065661 A CN1065661 A CN 1065661A CN 91102395 A CN91102395 A CN 91102395A CN 91102395 A CN91102395 A CN 91102395A CN 1065661 A CN1065661 A CN 1065661A
Authority
CN
China
Prior art keywords
formula
methyl
dihydro
interior
rudimentary
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.)
Granted
Application number
CN91102395A
Other languages
Chinese (zh)
Other versions
CN1040756C (en
Inventor
T·J·沃德
J·C·怀特
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
John Wyeth and Brother Ltd
Original Assignee
John Wyeth and Brother Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to GB898923209A priority Critical patent/GB8923209D0/en
Priority to HU9201270A priority patent/HU217427B/en
Priority to ZA912466A priority patent/ZA912466B/en
Application filed by John Wyeth and Brother Ltd filed Critical John Wyeth and Brother Ltd
Priority to CN91102395A priority patent/CN1040756C/en
Publication of CN1065661A publication Critical patent/CN1065661A/en
Application granted granted Critical
Publication of CN1040756C publication Critical patent/CN1040756C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Landscapes

  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The preparation method of following formula: compound and their acid salt.R in the formula 1Be the substituting group of hydrogen or one or several regulation, X is-O-or-NR 2-, R wherein 2Be the replacement low alkyl group or the R of low alkyl group, low-grade alkenyl, low-grade alkynyl, aryl or regulation 2Represent group-Z-, this base is linked 8 of aromatic ring and is gone up to form 5 to 7 element heterocycles, and Y is O or NR 3, R wherein 3Be hydrogen or low alkyl group, B is saturated azabicyclo (as tropane base or the peaceful cyclic group of quinoline) or its N-oxide compound.These compounds are 5-HT 3Antagonist can be used for treating spirit-sacred disease.

Description

The preparation method of heterogeneous ring compound
The present invention relates to heterogeneous ring compound and preparation method thereof.The pharmaceutical composition that particularly relates to new amides and ester compound, its method for making, its application and comprise them.New compound of the present invention is applicable to the antagonist as specific serotonine (5-HT) acceptor class as described below.
Many prior art patent specifications all disclose the 5-HT of various structures 3Antagonist, as EP-A-0200444, GB-A-2153821, GB-A-2125398 and EP-A-323077.
New compound of the present invention is compound and its pharmaceutically-acceptable acid addition of logical formula I.
Figure 91102395X_IMG10
In the formula
R 1Represent H or one or several following substituting group: low alkyl group, hydroxyl, lower alkoxy, fontanel element, methylene radical dioxy base, fontanel generation (rudimentary) alkyl, nitro, amino, (rudimentary) alkylamino and two (rudimentary) alkylamino.
X representative-O-or-NR 2-, wherein
R 2Represent low alkyl group, low-grade alkenyl, low-grade alkynyl, ring (rudimentary) alkyl, ring (rudimentary) alkyl-low alkyl group, aryl, aryl (rudimentary) alkyl, formula-(CH 2) r-Y-R 8Base (wherein r is the integer of 1-4, and Y is O, S or NR 5, R wherein 5Be hydrogen or low alkyl group, R 8Be hydrogen, low alkyl group or ring low alkyl group) or the base of formula-Z-, Z connects 8 of this aromatic ring, so form 5-7 person's heterocycle, wherein the part by the ring of Z representative is one or several methylene radical (also can be replaced by one or several low alkyl group), or is selected from O, S, SO 2Or NR 5, R wherein 5Be H or low alkyl group.
Y represents O or NR 3, R wherein 3Be H or low alkyl group,
B represents saturated azabicyclo or its nitrogen oxide of following formula II to one of formula (V),
M is 2,3 or 4 in the formula, R 4Be H or (rudimentary) alkyl,
Figure 91102395X_IMG12
P is 1,2 or 3 in the formula IV, R 4Implication the same,
Figure 91102395X_IMG13
Q is 0,1 or 2 in the formula (V).
The implication of " rudimentary " described here is meant and contains the group that can reach 6 carbon atoms at most.This group preferably contains nearly 4 carbon atoms.For example, low alkyl group can be straight chain or side chain, can be methyl, ethyl, propyl group or butyl.An example of preferred low-grade alkenyl is an allyl group.The example of lower alkoxy is methoxyl group, oxyethyl group, propoxy-or butoxy.The example of ring (rudimentary) alkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Preferred aryl groups is phenyl or substituted-phenyl, and substituting group can be one or several above-mentioned R 1Those bases of representative.Work as R 1When representing one or several fontanel element substituting group, these substituting groups are chlorine or fluorine preferably.Preferred fontanel element (rudimentary) alkyl substituent is a trifluoromethyl.The example of preferred ring (rudimentary) alkyl-low alkyl group is the cyclopropyl methyl.Preferred aryl groups (rudimentary) alkyl is that benzyl or substituting group are R 1Those basic substituted benzyls of representative.
As X representative-NR 2-, R wherein 2During representative-Z-, these compounds have following general formula:
Figure 91102395X_IMG14
In this general formula, the preferred example of Z comprises-(CH 2) n-, wherein n is 2 or 3, two of alkyl replacement-or three-methene chain, as-CH 2The CH(low alkyl group)-,-CH 2C(is rudimentary) alkyl) 2-or comprise an alkylidene group (with or without low-grade alkyl substituent) and a heteroatomic chain, as-OCH 2-,-the OC(low alkyl group) 2-,-SCH 2CH 2-and-CH 2OCH 2-.
In the group of logical formula II, preferably m is 2, R 4Be low alkyl group, preferable methyl.Wherein m be 2, R 4The group that is methyl is known as tropane-3-base, is 8-methyl-8-azabicyclo [3.2.1] oct-3-yl again.
The group of logical formula III is known as the peaceful cyclic group of quinoline, or 1-azabicyclo [2.2.2] oct-3-yl.
In the group of logical formula IV, preferred p is 2, preferred R 4Be 1-4 carbon alkyl, especially methyl.
In the base of general formula (V), it is 1 that q preferably is worth.
Compound of the present invention can contain 1 or several unsymmetrical carbon, and compound can be existed with different stereoisomer forms.For example, these compounds can racemic form or the existence of optical activity form.Its optical activity form can obtain by taking its racemoid apart, or use has the raw material of optical activity form and obtains in following method.And then the configuration existence that logical formula II and those groups in (IV) can be different exists as the interior type in the tropine or as the external form in the pseudotropine.Preferred configuration is interior type.
Compound of the present invention can be by method as known in the art from known feedstock production or from being prepared by the raw material that ordinary method makes.Y is-NR in preparation 3A kind of method of acid amides of formula I in, use formula (VII) (R in the formula 1With the definition of X with aforementioned) acid or its acylated derivatives to R 3With the definition of B with aforesaid formula VI NHR 3A kind of amine shown in the B carries out acidylate.
Figure 91102395X_IMG15
The example of this acylated derivatives comprises acyl fontanel (as acyl chlorides), acylazide thing, acid anhydrides, acyl imidazoles thing (as obtaining from carbonyl dimidazoles), activatory ester class or from a kind of carbodiimide such as dialkyl group carbodiimide, the O-acylurea that special dicyclohexyl carbodiimide obtains.The acidylate of preferred amine is at a kind of coupling agent, as dicyclohexyl carbodiimide, 1,1 '-existence of carbonyl dimidazoles, isobutyl chloroformate or diphenyl phosphine chlorine carries out with sour down.
Y of the present invention is-ester of O-can be the B-OH(VIII by the acid and the general formula of general formula (VII)) the esterification preparation of alcohol.The implication of B is with aforementioned in the formula (VIII).Esterification can be carried out with method as known in the art.For example, this alcohol can react with a kind of acyl fontanel in the presence of a kind of acid acceptor.
The acid of formula (VII) is known or can be made by currently known methods.For example X is-NR 2-acid can be by the preparation of following reaction scheme:
Figure 91102395X_IMG16
(wherein Y is-NR to prepare acid amides of the present invention 3-) other method comprise the compound of cyclisation formula (IX),
Figure 91102395X_IMG17
R in the formula (IX) 1, R 2, R 3With the implication of B with aforementioned, R 6Be (rudimentary) alkyl, as ethyl.This cyclization can carry out in the presence of a kind of cyclodehydration agent such as Tripyrophosphoric acid.The raw material of formula (IX) can be by formula (X) (R wherein 1And R 2Implication with aforementioned) amine and the reaction of the unsaturated compound of a kind of formula (XI) make R in the formula (XI) 3, R 6The same with the implication of B, R 7Be (rudimentary) alkyl, preferred ethyl.This reaction can be heated by independent reacting by heating thing or in suitable solvent and be carried out.
Prepare compound of the present invention, wherein X is-NR 2-, R 2Be low alkyl group, ring (rudimentary) alkyl, ring (rudimentary) alkyl-low alkyl group, aryl, aryl (rudimentary) alkyl or-(CH 2) r-Y-R 8Other method comprise compound cyclisation with formula (XII),
Figure 91102395X_IMG20
R in the formula 1, R 2, Y and B implication the same, R 9Be a leavings group, as fontanel element (as fluorine or chlorine) or alkyl-or aryl-sulfonyloxy.This cyclisation can be handled with a highly basic (as sodium hydride) and finish.The raw material of formula (XII) can be by the currently known methods preparation that is used to make similar compound.
X of the present invention is-NR 2-compound can be by X-the alkylation preparation of the respective compound of NH-.-NR 2-middle R 2Be low alkyl group, low-grade alkenyl, low-grade alkynyl, ring (rudimentary) alkyl, ring (rudimentary) alkyl-low alkyl group, aryl, aryl (rudimentary) alkyl or-(CH 2) r-Y-R 8This alkylated reaction can be in the presence of alkali, by (rudimentary) alkyl, low-grade alkenyl, low-grade alkynyl, ring (rudimentary) alkyl, ring (rudimentary) alkyl-low alkyl group, aryl, aryl (rudimentary) alkyl or-(CH 2) r-Y-R 8Fontanelle compound reaction carry out.X is-initial compounds of NH-can be by producing from the compound (VII) of suitable replacement with the aforesaid method similar methods.
On behalf of formula II to the compound of N-oxide compound of (V) base, B of the present invention can represent formula II to the compound of (V) base to make with for example hydrogen peroxide or a kind of mistake acid oxidase by B.
If in above-mentioned arbitrary method, a reagent contains the group that influenced by used reaction conditions, and then this group can be protected by protected base, this protecting group is removed again.
If in aforesaid method, The compounds of this invention makes with the acid salt form, and its free alkali form can be alkalized by the solution with this acid salt and get.On the contrary, if the product of method is a kind of free alkali, then a kind of acid salt, particularly a kind of pharmaceutically-acceptable acid addition can be by the conventional steps from basic cpd relieving haperacidity additive salt, by free alkali is dissolved in appropriate organic solvent, make with this solution of a kind of acid treatment again.
The example of acid salt is those salt that form from mineral acid and organic acid, as sulfuric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, tartrate, fumaric acid, toxilic acid, citric acid, acetate, formic acid, methylsulfonic acid, right-toluenesulphonic acids, oxalic acid and succsinic acid.
Compound of the present invention has pharmaceutical active.The activity of their antagonism warm-blooded animal specificity serotonine (5-HT) acceptor aspects particularly.Specifically, these compounds have 5-HT 3Antagonistic activity is therefore at needs antagonism 5-HT 3Be valuable under the situation of acceptor.5-HT 3Antagonist is also referred to as the antagonist and the serotonin M-receptor antagonist of " neurone " 5-hydroxytryptamine receptor.
The following step is used to test The compounds of this invention to the vagal 5-HT of mouse 3Antagonistic activity:
This test method(s) is similar in appearance to Ireland and Tyers, Br.J.Pharmac., and 1987,90, the method for delivering on the 229-238, and depend on 5-HT to the unpolarized ability of external vagus nerve.
It is indoor that the vagus nerve segment of fetching on one's body from the Sprague-Dawley mouse is placed into a synthetic glass, fills the solution with Krebs.The electrode that is contained in neural segment both sides is used to be recorded in the potential difference that produces when neural segment one end adds various concentration 5-HT.Can get before neural segment and the balance of Krebs solution that contains substances in this way and afterwards, to concentration-response curve of 5-HT.These results are carried out Schild analyze, can obtain measuring of antagonism potentiality, be expressed as pA 2Value.When with the test of this step, the pA of a representative compounds of the present invention (interior-the N-[8-azepine-8-methyl bicycle [3.2.1] oct-3-yl]-1-toluquinoline-4-ketone-3-methane amide) 2Value is 8.4.
The present invention further provides a kind of compound or its pharmaceutically-acceptable acid addition of formula I, to be used for the intravital 5-HT of antagonism Mammals 3Acceptor.
5-HT 3Antagonist can be used for treating nerve-mental disorder, as anxiety disorder psychosis (as schizophrenia), to the dependence syndrome of Drug abuse or other material, the illness of understanding aspect; Can be used for treating gastrointestinal illness, as vomiting, nauseating; And treatment migraine.Therefore, the invention provides the application of The compounds of this invention in above-mentioned one or more treatments.The present invention also provides one or more above-mentioned treatment of diseases methods, and it comprises the compound of the present invention of using significant quantity to the warm-blooded animal of needs.
For more above-mentioned illnesss, know that very these compounds can be used for prevention and alleviate acute symptom.Here the saying of " treatment " or similar wording is understood to include prophylactic treatment and to the treatment of acute disease.
The compounds of this invention has anti-emetic performance, particularly advantageous aspect the treatment nausea and vomiting relevant with cancer chemotherapeutic agent and radiotherapy.Therefore, The compounds of this invention has therapeutic action in use chemotherapeutics (cytotoxic agent or the agent of inhibition cell are as Platinol, adriamycin and cyclophosphamide) and radiotherapy in the treatment cancer.Thereby the present invention also provides a kind of product that contains cancer chemotherapeutic agent and a kind of compound of the present invention, as compound formulation simultaneously, and independent or follow-up use.
Another aspect of the present invention provides a kind of pharmaceutical composition that contains compound of the present invention and pharmaceutically acceptable carrier.Any suitable carrier as known in the art all can be used for preparing this pharmaceutical composition.In this based composition, carrier is solid or liquid or solidliquid mixture normally.
The solid form composition comprises powder, particle, tablet, capsule (as hard and soft gelatine capsule), suppository, medicated vaginal suppository.Solid carrier for example can be one or more materials that following effect can be arranged: flavouring agent, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, binding agent or tablet disintegrant; It is capsule material also.Carrier in powder agent is and levigated activeconstituents blended levigated solid.In tablet, activeconstituents mixes with certain proportion with the constrictive carrier with necessity, and is pressed into shape and the size that needs.These pulvis and tablet preferably contain up to 99%, as 0.03 to 99%, and the activeconstituents of 1-80% especially.Suitable solid carrier for example comprises calcium phosphate, Magnesium Stearate, talcum powder, sucrose, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone, low melt point paraffin and ion exchange resin.
Term " composition " is intended to comprise that a kind of activeconstituents and the capsule material of making carrier form capsular prescription, and wherein activeconstituents (containing or do not contain other carrier) is surrounded by carrier, therefore prescription and carrier related system.In similar cachet also is included in.
The composition of liquid form comprises as solution, suspension, emulsion, syrup, elixir and pressurized compositions.Activeconstituents for example can be dissolved in or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, the mixture of the two, pharmaceutically acceptable oil or fat.This liquid vehicle also can contain other suitable medicated premix such as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, flavouring agent, suspension agent, thickening material, pigment, consistency modifiers, stablizer or Osmolyte regulator.The suitable example of the liquid vehicle that oral and parenteral road is taken comprises that water (especially contains above-mentioned additive; During as derivatived cellulose, preferably carboxymethyl cellulose sodium), alcohols (comprising monohydroxy-alcohol and polyvalent alcohol, for example glycerine and glycol) and their derivative, and oils (as fractionated Oleum Cocois and peanut oil).For the parenteral canal drug administration, carrier also can be an oily ester, as ethyl oleate and Isopropyl myristate.When sterile liquid form composition is used for the parenteral canal drug administration, use sterile liquid carrier.
The composition of liquid medicine of sterile solution or form of suspension is muscle, intraperitoneal or subcutaneous injection for example.Sterile solution also can the administration of intravenously mode.When compound had Orally active, mode that can the liquid or solid composition forms was oral.
Compound of the present invention also can the nasal feeding method administration.When being made into the nasal feeding administering mode, composition is included in the compound of the present invention in the liquid vehicle; These compositions can be for example with spraying or drops form administration.Liquid vehicle can be water (it can contain other component that required isotonicity and viscosity are provided to composition).Said composition also can comprise additional vehicle, as sanitas, tensio-active agent etc.Said composition also can be placed in the medicator, makes the composition can be with drops or spray pattern administration.During for the administration of usefulness aerosol container, also should comprise a kind of aerosol matrix in the composition.
Be used for the treatment of and/or prevent the pharmaceutical composition of nausea and vomiting, except that compound of the present invention, can contain a kind of cyclooxygenase-2 inhibitors.The example of cyclooxygenase-2 inhibitors comprises NSAID series medicine, as INDOMETHACIN, pyrrole sieve happiness health.
Preferred pharmaceutical composition is a presented in unit dosage form, as tablet or capsule.During with this kind form, composition is divided into the dosage unit that contains the proper amt active ingredient; This presented in unit dosage form can be a packaged composition, for example packed powder, bottle, ampoule, pre-filled syringe or contain the sachet of liquid.Unit dosage can for example be capsule or tablet itself, or the packed form composition of fair amount.
In the composition unitary dose quantity of active ingredient also can from 0.5mg or with down to 750mg or above between change or regulate, this activity on concrete needs and activeconstituents is decided.
The present invention also comprises the compound that exists with unit dosage form when not containing carrier.
Following example is used to illustrate the present invention:
Example 1
(interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-1,4-dihydro-1-methyl-4-oxygen quinoline-3-methane amide.
With 1,4-dihydro-1-methyl-4-oxygen quinoline-3-carboxylic acid (1.02g, 5mmol) and carbonyl dimidazoles (0.85g, 5mmol) suspension in dimethyl formamide (15ml) obtains settled solution 80 ℃ of heated and stirred 0.5 hour.(1.06g 5mmol), adds triethylamine (1.3g) again, continues to stir to make to be reflected at 80 ℃ and to carry out 2 hours again to add (interior)-3-Aminotropane dihydrochloride then.Cooling mixture, water (25ml) dilution, collecting precipitation product (1.2g), water (150 milliliters) recrystallize obtains 0.7g title alkali.This alkali is dissolved in ethanol (7ml),, makes title compound be precipitated as hydrochloride (0.55g), m.p.＞300 ℃ with adding the ether hcl acidifying.
Example 2
(interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl) 1,4-dihydro-1-butyl-4-oxygen quinoline-3-methane amide
With 1-butyl-1,4-dihydro-4-oxygen quinoline-3-carboxylic acid (0.98g, 4mmol), carbonyl dimidazoles (0.7g, 4.4mmol) and the mixture of dimethyl formamide (12ml) stirred 1.5 hours at 80 ℃.(0.56g 4mmol), continues to stir 1.5 hours under uniform temp to add (interior)-3-Aminotropane then.Remove and desolvate, with frozen water (15g) dilution residue.The solid of collecting precipitation is with icy water washing and dry air.In the hot mixt with this alkali water-soluble (5ml) and ethanol (3ml), use ice-cooledly again, add strong aqua and regulate pH to 11 and make the crystallized product precipitation, collecting precipitation is with rare cold ammonia scrubbing.The alkali (0.82g) of purifying is dissolved in ethanol (8ml),, uses ether (3ml) dilution again with adding ethanol-HCl acidifying.Ice-cooled, provide m.p.267-268 ℃ of product hydrochloride (0.49g).
Example 3
(interior)-N-(8-methyl-azabicyclo (3.2.1) oct-3-yl)-and 1-benzyl-1,4-dihydro-4-oxygen quinoline-3-methane amide
(1.14g 7.04mmol) at room temperature handles 1-benzyl-1, and the solution in the 4-dihydro-4-oxygen quinoline-3-carboxylic acid (1.96g is 7.03mmol) in dry DMF(20ml) is again 80 ℃ of heated mixt 3 hours with carbonyl dimidazoles.(0.99g 7.07mmol), continues heated overnight (19 hours), obtains a suspension to add (interior)-3-Aminotropane.Water (40ml) diluted mixture thing, enriching wet chemical with pH regulator to 9-10.Collect solid, the water thorough washing, drying, recrystallize from ethanol (20ml) and water (20ml) obtains product free alkali (1.72g).This product is dissolved in the ethanol that boils (15ml), uses alcohol hydrochloric acid the solution acidifying.The precipitation that collection obtains is used washing with alcohol, 80 ℃ of vacuum-dryings, obtains hydrochloride, hydrate and 1/3rd ethylates (1.91g) of title compound, m.p.296-297 ℃.
Example 4
(interior)-N-(8-azepine-8-methyl bicycle (3.2.1) oct-3-yl) chromone-3-methane amide
(a) with the mixture reflux of chromone-3-carboxylic acid (1.25g) and thionyl chloride (6ml) 5 minutes.Reaction mixture is used hexanaphthene (15ml) dilution and ice-cooled then.Filtration method is collected crystalline deposit, and with the hexanaphthene washing, vacuum-drying provides chromone-3-carbonyl chloride (1.2g).
(b) in 5 minutes with chromone-3-carbonyl chloride (1.04g, 5mmol) solution in methylene dichloride (20 milliliters) dropwise add ice-cooled and the mixture of (the interior)-3-Aminotropane that stirring (0.7g, 5mmol), anhydrous K CO(3g) and methylene dichloride (20ml) in.Add the back and continue to stir 0.5 hour, and dilute this mixture with 50ml water.Organic phase is separated, used dried over sodium sulfate, revaporization to get a solid (1.7g).This alkali is dissolved in ethanol (15ml), uses the alcohol hcl acidifying with precipitation crude salt hydrochlorate (0.9g).Recrystallize is three times from ethanol, obtains the pure hydrochloric acid salt (0.3g) of title compound, m.p.＞300 ℃.
Example 5
(interior)-N-(9-methyl-9-azabicyclo (3.3.1) ninth of the ten Heavenly Stems-3-yl)-1,4-dihydro-1-methyl-4-oxygen quinoline-3-methane amide
With 1, (1.02g 5mmol) and the suspension in the carbonyl dimidazoles (0.85g is 5mmol) at DMF(15ml), 85 ℃ of stirring heating 3 hours, obtains a settled solution to 4-dihydro-1-methyl-4-oxygen quinoline-3-carboxylic acid.Add (interior)-3-amino rises the tropane dihydrochloride (1.13g, 5mmol) and diisopropylethylamine (1.29g, 10mmol), continuation heated overnight (19 hours).Solution is cooled to room temperature, with the dilution of 25ml water.Add a small amount of potassium hydroxide aqueous solution pH is transferred to 10-11.The solid of collecting precipitation washes with water, and drying obtains title alkali 1.25g again, wherein with this alkali recrystallize three times from water/alcohol mixeding liquid.Alkali is dissolved in the hot ethanol (12ml), uses the alcohol hydrochloric acid acidifying, obtain containing the hydrochloride (0.92g) of the title compound of 1.25 crystal water, m.p.278-81 ℃ (decomposition).
Example 6
(interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-1,8-ethano--1,4-dihydro-4-oxygen quinoline-3-methane amide
With 1,8-ethano--1,4-dihydro-4-oxygen quinoline-3-carboxylic acid (1.08g, 5mmol) and carbonyl dimidazoles (0.89g, 5.5mmol) suspension in dimethyl formamide (15ml) obtains a settled solution 80 ℃ of stirring heating 1.25 hours.(0.7g 5mmol), continues 80 ℃ of heated and stirred reactions 2 hours once to add (interior)-3-Aminotropane.Use ice-cooled reaction, with the dilution of 25ml water, the product of collecting precipitation, recrystallize twice from 2: 1 ethanol/water solution, obtains 0.7g title alkali.This alkali is dissolved in the hot ethanol (15ml), uses the alcohol hydrochloric acid acidifying, obtain the hydrochloride (0.55g) of title compound, m.p.＞300 ℃.
Example 7
(interior)-N-(8-azepine-8-methyl bicycle (3.2.1) oct-3-yl)-1,4-dihydro-1,8-bridge propylidene quinoline-4-ketone-3-methane amide
Step by example 6 prepares this title compound, just with 1, and 8-bridge propylidene-1,4-dihydro-4-oxygen quinoline-3-carboxylic acid replaces 1,8-ethano--1,4-dihydro-4-oxygen quinoline-3-carboxylic acid.The product that obtains is the hydrochloride of title compound, m.p.＞300 ℃.
Example 8
(interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-1,4-dihydro-4-oxygen-1-n-propyl quinoline-3-methane amide
Under argon atmospher with 1,4-dihydro-4-oxygen-1-n-propyl quinoline-3-carboxylic acid (1.58g, 6.82mmol) and triethylamine (0.7g 7mmol) is dissolved in the methylene dichloride (20ml).Under agitation (1.6g 6.76mmol) all adds wherein immediately with diphenyl phosphinyl chloride.Solution was kept 6 hours, add again (interior)-3-Aminotropane (1.0g, 7.14mmol) and triethylamine (0.7g, 7mmol).Solution was kept 3 days revaporization.Residue is water-soluble, use the concentrated hydrochloric acid acidifying.Remove by filter precipitation, wash with water and precipitation is discarded.Filtrate is alkalized with yellow soda ash, and evaporation.Residue grinds twice with ethyl acetate, boils off ethyl acetate, and water (6ml) and strong aqua (1ml) grind again, obtain a kind of white solid (1.34g).Get this material (3.68mmol) and be dissolved in hot ethanol (15ml), to wherein add oxalic acid dihydrate (0.47g, 3.73mmol).With gained solution freeze overnight.Collecting precipitation is used washing with alcohol, and drying obtains the oxalate that contains 0.5 crystal water (1.24g) of title compound, m.p.227-231 ℃.
Example 9-14
According to the step of example 1, but replace 1 with following reagent, 4-dihydro-1-methyl-4-oxygen quinoline-3-carboxylic acid obtains following product:
Example 9
Reagent: 1,4-dihydro-1-ethyl-4-oxygen quinoline-3-carboxylic acid.
Product: (interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-1,4-dihydro-1-ethyl-4-oxygen quinoline-3-methane amide, the semihydrate of hydrochloride, m.p.298-302 ℃.
Example 10
Reagent: 1,4-dihydro-1-(2-methoxy ethyl)-4-oxygen quinoline-3-carboxylic acid
Product: (interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-1,4-dihydro-1-(2-methoxy ethyl)-4-oxygen quinoline-3-methane amide, 1: 1 fumarate, m.p.243-245 ℃.
Example 11
Reagent: 9-fluoro-6,7-dihydro-5-methyl isophthalic acid-oxygen-1H, 5H-benzo (ij) quinaldic acid
Product: (interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-9-fluoro-6,7-dihydro-5-methyl isophthalic acid-oxygen-1H, 5H-benzo (ij) quinolizine-2-methane amide contains the hydrochloride of 0.25 crystal water, m.p.＞320 ℃.
Example 12
1-cyclohexyl-1,4-dihydro-4-oxygen quinoline-3-carboxylic acid
(interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-1-cyclohexyl-1 product:, 4-dihydro-4-oxygen quinoline-3-methane amide contains 1: 1 oxalate of 1.5 crystal water, m.p.217 ℃.
Example 13
Reagent: 1-(cyclopropyl methyl)-1,4-dihydro-4-oxygen quinoline-3-carboxylic acid
(interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-1-cyclopropyl methyl isophthalic acid product:, 4-dihydro-4-oxygen quinoline-3-methane amide contains the hydrochloride of 0.75 crystal water, m.p.164-166 ℃ (decomposition).
Example 14
Reagent: the 1-(4-fluorophenyl)-1,4-dihydro-4-oxygen quinoline-3-carboxylic acid
Product: (interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-the 1-(4-fluorophenyl)-1,4-dihydro-4-oxygen quinoline-3-methane amide, hydrochloride, m.p.240 ℃ (decomposition).
Example 15
According to the step of example 1, but replace (interior)-3-Aminotropane with 1-azabicyclo (2.2.2) suffering-3-amine (3-amino quinine ring).The product that obtains is N-(1-azabicyclo (2.2.2) oct-3-yl)-1,4-dihydro-1-methyl-4-oxygen quinoline-3-methane amide, hydrochloride hydrate, m.p.179-181 ℃.
Example 16
(interior)-N-(9-methyl-9-azabicyclo (3.3.1) ninth of the ten Heavenly Stems-3-yl)-1,4-dihydro-1-ethyl-4-oxygen quinoline-3-methane amide
With 1,4-dihydro-1-ethyl-4-oxygen quinoline-3-carboxylic acid (1.52g, 7mmol) and triethylamine (0.7g, 7mmol) at the suspension of methylene dichloride (20ml) in argon atmospher, at room temperature stirred 1 hour.(0.96g 7.03mmol), stirred the mixture 1 hour to add isobutyl chloroformate.Add again triethylamine (1.4g, 14mmol) and (interior)-3-amino-9-methyl-9-azabicyclo (3.3.1) nonane dihydrochloride (1.58g, 6.96mmol).After reaction is carried out three days, add methyl alcohol reaction is stopped, boiling off solvent.Water (10ml) and strong aqua (2ml) grind residue, collect solid, and be with the strong aqua washing, dry again.With this material IPA/ methyl alcohol (2: 1, be converted into its fumarate of 1: 1 in 15ml), obtain the semihydrate (73.1%) of fumarate of 1: 1 title compound, m.p.184-185 ℃.
Example 17
(interior)-N-(9-methyl-9-azabicyclo (3.3.1) ninth of the ten Heavenly Stems-3-yl)-and 1-butyl-1,4-dihydro-4-oxygen-quinoline-3-methane amide
Press the step of example 16, make 1,4-dihydro-1-butyl-4-oxygen quinoline-3-formic acid reacts with (interior)-3-amino-9-methyl-9-azabicyclo (3.3.1) nonane, obtains the maleate of 1: 1 title compound, m.p.203-205 ℃.
Example 18
(interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-and 1-ethyl-6-fluoro-1,4-dihydro-4-oxygen quinoline-3-methane amide
Step by example 16 makes 1, and 4-dihydro-1-ethyl-6-fluoro-4-oxygen quinoline-3-carboxylic acid reacts with (interior)-3-Aminotropane, obtains 0.75 hydrate of the hydrochloride of title compound, m.p.315-317 ℃.
Example 19
According to above-mentioned steps, adopt suitable reagent, obtain:
(interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-1,4-dihydro-1-cyclopropyl-4-oxygen quinoline-3-methane amide, and corresponding 1-cyclobutyl, 1-cyclopentyl, the 1-tertiary butyl and 1-(fourth-3-thiazolinyl) analogue;
(interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-1,4-dihydro-1-ethyl-6,7-methylene radical dioxy-4-oxygen quinoline-3-methane amide;
(interior)-N-(8-methyl-8-azabicyclo (3.2.1) oct-3-yl)-1,4-dihydro-1-ethyl-7-fluoro-4-oxygen quinoline-3-methane amide, and by the 7-trifluoromethyl; The 8-fluorine; 6, the 7-difluoro; Analogue with 6-fluoro-8-methyl replacement 7-fluoro substituents.

Claims (12)

1, the method for the compound of a kind of preparation general formula (I) and its pharmaceutically-acceptable acid addition:
Figure 91102395X_IMG2
In the formula
R 1Represent H or one or several following substituting group: low alkyl group, hydroxyl, lower alkoxy, fontanel element, methylene radical dioxy base, fontanel generation (rudimentary) alkyl, nitro, amino, (rudimentary) alkylamino and two (rudimentary) alkylamino;
X representative-0-or-NR 2-, wherein
R 2Represent low alkyl group, low-grade alkenyl, low-grade alkynyl, ring (rudimentary) alkyl, ring (rudimentary) alkyl-low alkyl group, aryl, aryl (rudimentary) alkyl, formula-(CH 2) r-Y-R 8Base (wherein r is the integer of 1-4, and Y is O, S or NR 5, R wherein 5Be hydrogen or low alkyl group, R 8Be hydrogen, low alkyl group or ring low alkyl group) or the base of formula-Z-, Z connects 8 of this aromatic ring, so form 5-7 person's heterocycle, wherein the part by the ring of Z representative is one or several methylene radical (also can be replaced by one or several low alkyl group), or is selected from O, S, SO 2Or NR 5Contain heteroatom group, wherein R 5Be H or low alkyl group;
Y represents 0 or NR 3, R wherein 3Be H or low alkyl group,
B represents saturated azabicyclo or its nitrogen oxide of following formula (II) to one of formula V,
Figure 91102395X_IMG3
M is 2,3 or 4 in the formula, R 4Be H or (rudimentary) alkyl,
Figure 91102395X_IMG4
P is 1,2 or 3 in the formula (IV), R 4Implication the same,
Figure 91102395X_IMG5
Q is 0,1 or 2 in the formula V.
This method comprises
(a) with the acid of formula (VII) or the amine of its acylated derivatives acidylate formula VI
(R in the formula VI 3The same with the implication of B),
Figure 91102395X_IMG6
(R in the formula (VII) 1The same with the implication of X),
Or
(b) acid of the above-mentioned formula of pure esterification (VII) of usefulness formula (VIII)
(implication of B is the same in the formula (VIII)),
Or
(c) compound of cyclisation formula (IX)
Figure 91102395X_IMG7
R in (IX) in the formula 1, R 2, R 3The same with the implication of B, R 6Be (rudimentary) alkyl, obtain Y and be-NR 3-formula (I) compound,
Or
(d) compound of cyclisation formula (XII)
Figure 91102395X_IMG8
R in the formula (XII) 1, Y and B implication the same, R 2Be low alkyl group, ring (rudimentary) alkyl-low alkyl group, aryl, aryl (rudimentary) alkyl or-(CH 2) r-Y-R 8, R 9Be a leavings group, obtain X and be-NR 2-(R wherein 2Implication with down described definition of this segmentation (XII)) the formula I compound, or
(e) be-the formula I alkylation of NH-to obtain X and be-NR X 2-, R wherein 2The following formula I compound of implication, R 2Be low alkyl group, low-grade alkenyl, low-grade alkynyl, ring (rudimentary) alkyl, ring (rudimentary) alkyl-low alkyl group, aryl, aryl (rudimentary) alkyl or ((CH 2) r-Y-R 8, or
(f) oxidation B represents the formula I compound of formula II to one of the base of (V), obtains its corresponding N-oxide compound,
Or
(g) alkali of conversion formula I is its pharmacy acceptable salt,
Or
(h) salt of the compound of conversion formula I is a kind of free alkali.
2, method according to claim 1, wherein product is compound or its pharmaceutically-acceptable acid addition of following formula,
Figure 91102395X_IMG9
R in the formula 1, B and Y implication with described in the claim 1, Z is-(CH 2) n-, wherein n is 2 or 3, two of alkyl replacement-or trimethylene chain ,-OCH 2-,-the OC(low alkyl group) 2-,-S-CH 2CH 2Or-CH 2OCH 2-.
3, method according to claim 2, wherein Z is-CH 2CH 2-or-CH 2CH 2CH 2-.
4, method according to claim 1, wherein in product X be-O-or-NR 2-, R wherein 2It is low alkyl group or ring (rudimentary) alkyl-low alkyl group.
5, method according to claim 1, wherein X is-NR in product 2-, R wherein 2It is aryl (rudimentary) alkyl.
6, according to arbitrary method of claim 1-5, wherein B represents formula II in product, wherein m be 2, R 4It is methyl.
7, method according to claim 1, product wherein are (interior)-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yls)-1,4-dihydro-1-methyl-4-oxygen quinoline-3-methane amide or its pharmaceutically-acceptable acid addition.
8, according to the product that the process of claim 1 wherein be
(interior-the N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-1,4-dihydro-1-butyl-4-oxygen quinoline-3-methane amide or
(interior)-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-1-benzyl-1,4-dihydro-4-oxygen quinoline-3-methane amide or
(interior)-N-(8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) chromone-3-methane amide or
(interior)-N-(9-methyl-9-azabicyclo [3.2.1] ninth of the ten Heavenly Stems-3-yl)-1,4-dihydro-1-methyl-4-oxygen quinoline-3-methane amide or
(interior)-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-1,8-ethano--1,4-dihydro-4-oxygen quinoline-3-methane amide or
(interior)-N-(8-azepine-8-methyl bicycle [3.2.1] oct-3-yl)-1,4-dihydro-1,8-bridge propylidene quinoline-4-ketone-3-methane amide or its pharmaceutically-acceptable acid addition.
9, method according to claim 1, product wherein is
(interior)-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-1,4-dihydro-4-oxygen-1-n-propyl quinoline-3-methane amide or
(interior)-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-1,4-dihydro-1-ethyl-4-oxygen quinoline-3-methane amide or
(interior)-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-1,4-dihydro-1-(2-methoxy ethyl)-4-oxygen quinoline-3-methane amide or
(interior)-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-9-fluoro-6,7-dihydro-5-methyl isophthalic acid-oxygen-1H, 5H-benzo (ij) quinolizine-2-methane amide or
(interior)-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl-1-cyclopropyl methyl isophthalic acid, 4-dihydro-4-oxygen quinoline-3-methane amide or
(interior)-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-the 1-(4-fluorophenyl)-1,4-dihydro-4-oxygen quinoline-3-methane amide or
(interior)-3-Aminotropane or N-(1-azabicyclo [2.2.2] oct-3-yl)-1,4-dihydro-1-methyl-4-oxygen quinoline-3-methane amide
Or its pharmaceutically-acceptable acid addition.
10, method according to claim 1, wherein product is (interior)-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-1-cyclohexyl-1,4-dihydro-4-oxygen quinoline-3-methane amide or its pharmaceutically-acceptable acid addition.
11, a kind of method of pharmaceutical compositions is comprising the compound of the formula I of claim 1 definition or its a kind of pharmaceutically-acceptable acid addition and a kind of pharmaceutically acceptable carrier are combined.
12, the described method of claim 11, activeconstituents wherein is by the described method preparation of claim 1.
CN91102395A 1989-10-14 1991-04-09 heterocyclic compounds Expired - Fee Related CN1040756C (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB898923209A GB8923209D0 (en) 1989-10-14 1989-10-14 Heterocyclic compounds
HU9201270A HU217427B (en) 1989-10-14 1990-10-10 Heterocyclic compounds and pharmaceutical compositions containing them as active components and process for producing
ZA912466A ZA912466B (en) 1989-10-14 1991-04-03 Heterocyclic compounds
CN91102395A CN1040756C (en) 1989-10-14 1991-04-09 heterocyclic compounds

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB898923209A GB8923209D0 (en) 1989-10-14 1989-10-14 Heterocyclic compounds
ZA912466A ZA912466B (en) 1989-10-14 1991-04-03 Heterocyclic compounds
CN91102395A CN1040756C (en) 1989-10-14 1991-04-09 heterocyclic compounds

Publications (2)

Publication Number Publication Date
CN1065661A true CN1065661A (en) 1992-10-28
CN1040756C CN1040756C (en) 1998-11-18

Family

ID=36778144

Family Applications (1)

Application Number Title Priority Date Filing Date
CN91102395A Expired - Fee Related CN1040756C (en) 1989-10-14 1991-04-09 heterocyclic compounds

Country Status (4)

Country Link
CN (1) CN1040756C (en)
GB (1) GB8923209D0 (en)
HU (1) HU217427B (en)
ZA (1) ZA912466B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100427484C (en) * 2003-07-31 2008-10-22 神经研究公司 2-methoxymethyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane tartrate salts
CN101405287B (en) * 2006-02-17 2011-05-18 神经研究公司 Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
CN114466654A (en) * 2019-06-12 2022-05-10 普拉西斯生物技术有限责任公司 Integrated stress response pathway modulators

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0135545A1 (en) * 1983-02-19 1985-04-03 Beecham Group Plc Azabicycloalkyl benzamide and anilide derivatives
DE3650772T2 (en) * 1985-04-27 2003-04-03 F. Hoffmann-La Roche Ag, Basel Derivatives of indazole-3-carboxamide and -3-carboxylic acid

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100427484C (en) * 2003-07-31 2008-10-22 神经研究公司 2-methoxymethyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane tartrate salts
CN101405287B (en) * 2006-02-17 2011-05-18 神经研究公司 Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
CN114466654A (en) * 2019-06-12 2022-05-10 普拉西斯生物技术有限责任公司 Integrated stress response pathway modulators

Also Published As

Publication number Publication date
HUT61020A (en) 1992-11-30
ZA912466B (en) 1992-12-30
HU217427B (en) 2000-01-28
GB8923209D0 (en) 1989-11-29
CN1040756C (en) 1998-11-18

Similar Documents

Publication Publication Date Title
CN1083448C (en) 1-phenyl-4-benzylpiperazines: dopamine receptor subtype specific ligands (D4)
CN1022566C (en) Process for preparation of substituted 1-piperidylalkylene-pyridopyrimidone or thiazolpyrimidone
CN1149873A (en) Piperazine derivatives as 5HT1A antagonists
CN1227542A (en) N-substituted indol-3-glyoxylamid with antiasthmatic, antiallergic and immunosuppressive/immunomodulating effect
CN1042537A (en) Carbostyril derivative
CN1761644A (en) Synthesis of 4-(amino)-2-butenoyl chlorides and their use in the preparation of 3-cyano quinolines
CN1044909C (en) Indole derivatives
CN1283637C (en) Substd. N-Benzyl-indol-3-yl glyoxylic acid derivs. having anti-tumoral effect
CN1080289A (en) 3-(1H-tetrazolium-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one contains the pharmaceutical composition and the preparation thereof of this compound
CN1126472A (en) 5-HT4 receptor antagonists
CN86102683A (en) The preparation method of antimicrobial drug
CN87100298A (en) Improving one's methods of preparation quinoline-3-carboxylic acid antiseptic-germicide
CN86106372A (en) Quinoline
CN1040194A (en) Psycholeptic 3-piperazinyl indole derivatives
CN1053605A (en) Preparation method with new replacement 4-phenyl-4-piperidyl urea of toponarcosis and analgesic effect
CN1237179A (en) 1,2,3,4-tetrahydro-benzofuro [3,2-c] pyridine derivatives
CN1043574C (en) Heterocyclic amines having central nervous system activity
CN1040756C (en) heterocyclic compounds
CN1054123C (en) Carbamic acid derivatives and method for preparing same
CN87105791A (en) Quinazoline diones and Pyridopyrimidine diketone and preparation method thereof
CN1629156A (en) Pyrudyl and pyrimidylpiperazine derivatives, preparation method thereof and pharmaceutical composition containing the derivatives
CN1077890C (en) 4-aminoethyoxy-indolone derivatives as dopamine D2 agonists
CN1297439A (en) 4-amino-(ethylamino)-oxindole dopamine autoreceptor agonists
CN1195344A (en) Polycyclic alcaloid-derivatives as NMDA-receptor antagonists
CN1050875A (en) Aroyl-urres

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C15 Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993)
OR01 Other related matters
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee