CN1069969A - Synthetic aryl polyamines as exicitatory/amino acid neurotransmitter antagonists - Google Patents
Synthetic aryl polyamines as exicitatory/amino acid neurotransmitter antagonists Download PDFInfo
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- CN1069969A CN1069969A CN92109681A CN92109681A CN1069969A CN 1069969 A CN1069969 A CN 1069969A CN 92109681 A CN92109681 A CN 92109681A CN 92109681 A CN92109681 A CN 92109681A CN 1069969 A CN1069969 A CN 1069969A
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- OCDGBSUVYYVKQZ-UHFFFAOYSA-N gramine Chemical compound C1=CC=C2C(CN(C)C)=CNC2=C1 OCDGBSUVYYVKQZ-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical class NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- AOTWFFIHNOVINQ-UHFFFAOYSA-N n-[3-[3-[4-(3-aminopropylamino)butylamino]propylamino]propyl]-2-(1h-indol-3-yl)acetamide Chemical compound C1=CC=C2C(CC(=O)NCCCNCCCNCCCCNCCCN)=CNC2=C1 AOTWFFIHNOVINQ-UHFFFAOYSA-N 0.000 description 1
- QROKOTBWFZITJZ-UHFFFAOYSA-N n-pyridin-2-ylacetamide Chemical compound CC(=O)NC1=CC=CC=N1 QROKOTBWFZITJZ-UHFFFAOYSA-N 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229950010883 phencyclidine Drugs 0.000 description 1
- 238000005375 photometry Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002385 psychotomimetic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical class NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
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- Engineering & Computer Science (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The acid salt that has the compound of following formula and pharmaceutically be suitable for is effective exicitatory/amino acid neurotransmitter antagonists,
R-(CH
2)
m-CO-R′
Above-claimed cpd can be used as the Mammals psychotherapeutic drugs, can be used as the effective constituent in the medicinal compositions and is used for the treatment of mammalian diseases, the insect pest of control invertebrates of being transmitted by exicitatory/amino acid neurotransmitter.
Description
The salt that the present invention relates to a class aryl polyamines and pharmaceutically be suitable for, they are antagonists of exicitatory/amino acid neurotransmitter.Described neurotransmitter influences the various organisms neuronal cell of (comprising invertebrates and vertebrates).Polyamines of the present invention is the synthetic analogues that is present in some polyamines in the Agelenopsis aperta spider poisonous substance.The present invention also relates to the application aspect the antagonism exicitatory/amino acid neurotransmitter of described polyamines and salt thereof.Described neurotransmitter influences cell (if any the cell of organism nervous system).The invention still further relates to the application aspect the disease of treatment Mammals exicitatory/amino acid neurotransmitter transmission of described polyamines and salt thereof, and the application aspect the insect pest of control invertebrates, the invention still further relates to the composition that contains described polyamines and salt thereof.The present invention also relates to prepare the method for described polyamines.
Jackson, people such as H. report, Agelenopsis aperta spider poisonous substance contains at least two kinds of toxin (Soc.Neu.Sci.Abstr.12:1078(1987) that influence calcium current).As if Jackson, people such as H. disclose its molecular weight of a kind of toxin (being called AG2) less than 1,000 dalton, and this toxin has the effect that suppresses calcium current in the tissue of broad range.In addition, Jackson, people such as H. have also reported another toxin (Soc.Neu.Sci.Abstr.12:730(1986) that molecular weight is about 6,000 dalton's compositions that contains that obtains from Agelenopsis aperta).It is reported that this toxin can be blocked the transmission of pre-synapse, and think this toxin calcium channel relevant capable of blocking with neurotransmitter.
Be present in some polyamines in the Agelenopsis aperta spider poisonous substance at United States Patent (USP) 5,037, April 28 1989 846(date of application, and transfer transferee in this article) in open.Described polyamines and the open blocker of the salt that pharmaceutically is suitable for thereof, and a kind of described polyamines (B as excitatory amino acid receptor in the cell
1) also open blocker as calcium channel.
The exicitatory/amino acid neurotransmitter antagonists compounds serves many purposes.Exicitatory/amino acid neurotransmitter antagonists can be used for treatment as apoplexy, cerebral hemorrhage, deterioration of neurons sufferer (as alzheimer's disease with the Dian Epilepsy), and especially can be used as psychotherapeutic drug.See Excitatory Amino Acids In Health and Disease, D.Lodge, E., John Wiley and Sons Ltd., New York, NY 1988, and content is wherein incorporated into own forces in this application as a reference.In addition, described compound can be used for the Physiologic Studies and the insect pest of control invertebrates of cell (as neuronal cell).
L-glutamic acid is excitatory neurotransmitter main in the mammal brain.Because the pharmacological development of glutamate receptor, therefore obtained significant cheering progress in this respect in the many decades in the past, and thought and to be divided into several branches.The glutamate receptor branch that belongs to exogenesis stimulant N-methyl-D-aspartate (NMDA) selectively acting is popular research topic, because described acceptor works in multiple neuropathy pathology (comprising apoplexy, Dian Epilepsy and neurodegenerative disease, as alzheimer's disease).Current have a main nmda receptor antagonist of two classes, and they are just actively promoting the research of clinical application medicine.The first kind comprises interference L-glutamic acid and its acceptor site bonded competitive antagonist.This compounds is characterised in that it is strong polar compound, as phosphonate ester compound AP7 and AP5.The strong band charge structure of competitive antagonist makes them can not see through blood/brain barrier, has therefore limited the application in their treatments.Second class is included in the noncompetitive antaganist that stops the nmda receptor effect on the ionic channel relevant with nmda receptor complex.Described compound comprises MK-801 and phencyclidine (PCP).By above-mentioned mechanism, the effective psychotomimetic drugs effect of this compounds is the tangible unfavourable condition of known drug.
According to by the new glutamate antagonist of finding in the spider poisonous substance, recently, the 3rd class antagonist is studied in great detail.U.S. Patent Application Serial 554,17 days July nineteen ninety date of application of 311() and United States Patent (USP) 5,037,31 days July nineteen ninety date of application of 846() the isolated arylamines type of structured compound that the Mammals nmda receptor is had effective and specific antagonistic action from Agelenopsis aperta poisonous substance is disclosed.Isolated above-mentioned arylamines is the composite structure that is linked together by amido linkage by aromatic acid and polyamines segment from Agelenopsis aperta poisonous substance.In described structure, some amine is functionalized with N-oxyamine or quaternary ammonium form in the polyamines segment.The chemical structure of arylamines is different from aforementioned general competitive drug AP5 or AP7 and noncompetitive compound MK-801.For example, in aforesaid U.S. Patent 5,037, disclose polyamines AGEL416 in 846 and had following structure:
Described aryl amine also is different from aforementioned competitive compound MK-801/PCP compounds to the mechanism of NMDA antagonistic action.Therefore, the arylamines in the spider poisonous substance provides a class the new compound that nmda receptor is had antagonistic action.
Announcement about the benefit of naturally occurring compound is, the method that can use now except that separation/purification (from whole poisonous substances of Agelenopsis aperta) obtains above-claimed cpd, therefore can synthesize non-natural similar compound that exist, same type.
The application relates to a class following formula synthetic aryl polyamines:
Wherein R is five～seven-element carbon ring system or eight～undeca carbon ring system, perhaps is by being independently selected from F, Cl, Br, OH, C more than 1 or 1
1～C
4Alkyl, C
1～C
4Alkoxyl group, CF
3, phenyl, amino, C
1～C
4Alkylamino and two (C
1～C
4) the above-mentioned either carbon loop systems that replaces of alkylamino substituting group,
M is zero or 1
R ' is-[NH(CH
2)
n]
XNH
2; Each n is 2～5 independently; X is 1～6.
The invention still further relates to following formula: compound or its acid salt that pharmaceutically is suitable for,
R-（CH
2）
m-CO-R′
Wherein R is five～seven-element carbon ring system or eight～undeca carbon ring system, perhaps is by being independently selected from F, Cl, Br, OH, C more than 1 or 1
1～C
4Alkyl, C
1～C
4Alkoxyl group, CF
3, phenyl, amino, C
1～C
4Alkylamino and two (C
1～C
4) the above-mentioned either carbon loop systems that replaces of alkylamino substituting group,
M is zero or 1,
Each n is 2～5 independently; X is zero～4; Y and Z are 1～5 independently of one another; And the bigger summation among X and Y and the Z is 1～5.
In addition, the application also relates to following formula: compound or its acid salt that pharmaceutically is suitable for,
Wherein R is five～seven-element carbon ring system or eight～undeca carbon ring system, perhaps is by being independently selected from F, Cl, Br, OH, C more than 1 or 1
1～C
4Alkyl, C
1～C
4Alkoxyl group, CF
3, phenyl, amino, C
1～C
4Alkylamino and two (C
1～C
4) the above-mentioned either carbon loop systems that replaces of alkylamino substituting group,
M is zero or 1,
Here each a is identical, and is 2～5; Each b is identical, and is 2～5; Each n is 2～5 independently; X is zero～3; Each Y is identical, and is zero or 1; Z is zero～3; And X+Y+Z is zero～4.
Carbon-loop system of the present invention can be saturated, undersaturated or aromatic, and the aromatic series system is preferably.About single-loop system, phenyl is preferably.Bicyclic system can be to condense or bridged ring, and nine～ten yuan the system of condensing is preferably, for example naphthyl or indenes.In above-mentioned dicyclo, naphthyl is good especially.
R ' group is that wherein X is 4 or 5 preferably, and each n is 3 or 4 independently.Good especially R ' group is
Polyamines of the present invention and the salt that pharmaceutically is suitable for thereof are the antagonists of exicitatory/amino acid neurotransmitter.Therefore, such polyamines itself can be used for the described exicitatory/amino acid neurotransmitter of antagonism.Polyamines of the present invention also can be used for controlling invertebrates insect pest and treatment by mammalian diseases and illness that exicitatory/amino acid neurotransmitter transmitted.Such polyamines also can be used as the Mammals psychotherapeutic drugs.
The invention still further relates to the medicinal compositions that contains above-mentioned polyamines, the method for taking the method for above-mentioned polyamines and preparing such polyamines.
The synthetic method of preparation following formula polyamines is seen following reaction formula A～C.
Reaction formula A
According to reaction formula A, polyamine intermediate compound compound formula IV is begun to make by series of steps by diaminobutane.Its proper reaction conditions of midbody compound formula VIII of preparation feedback route A is seen example 5, step 1-7.Reaction scheme B has listed the method for preparing midbody compound formula IX.Prepare this intermediate proper reaction conditions and see example 5, step 8.The method for preparing polyamine compounds formula XII of the present invention is seen reaction scheme C.Coupling midbody compound formula VIII and IX proper reaction conditions and the suitable reaction conditions of following step preparation formula XII compound are seen example 5, step 1～11.
Polyamines of the present invention is the antagonism exicitatory/amino acid neurotransmitter reversibly, and this neurotransmitter can influence cell, as the multiple organism nervous system cell of (comprising invertebrates and vertebrates).The term vertebrates that the application uses means and comprises Mammals.The term invertebrates that the application uses means and comprises for example insect, epizoon and endoparasite.
The ability of polyamine compounds antagonism exicitatory/amino acid neurotransmitter of the present invention represents that by the ability that the cGMP that is caused by N-methyl D aspartic acid (NMDA) in their blocking-up neonate rat cerebellums raises its method is described below.Excise the Wistar rat cerebellum of 10 orders on the 8th～14 fast, place 4 ℃ of Krebs/ sodium bicarbonate buffer liquid (PH7.4), use Mcllwain histotome (The Nickle Laboratory Engineering CO.Gomshall then, Surrey England) is cut into 0.5 * 0.5 millimeter thin slice.It is in 37 ℃ the 100ml Krebs/ sodium bicarbonate buffer liquid that the cerebellar slice of gained moves to temperature, and this damping fluid was with 95: 5 O
2/ CO
2Continuous balance in addition.With cerebellar slice's incubation 90 minutes, change damping fluid therebetween 3 times by this way.Pour out damping fluid then, tissue is carried out centrifugal (3200 rev/mins, 1 minute), tissue is resuspended in the 20ml Krebs/ sodium bicarbonate buffer liquid.Therefrom take out 250 μ l aliquots containigs (being equivalent to 2 milligrams of tissues approximately), placing capacity is the centrifuge tube of 1.5ml.From stock solution sucking-off test-compound 10 μ l, be added in these centrifuge tubes.The adding 10 μ l 2.5mM NMDA solution that continue are to start reaction.The NMDA final concentration is 100 μ M.Control tube does not add NMDA.Place 37 ℃ to shake water-soluble incubation 1 minute centrifuge tube, add 750 μ l 50mM Tris-HCl then, 5mM EDTA solution is with termination reaction.Immediately with in the centrifuge tube dislocation boiling water bath 5 minutes.Fix on 3 grades probe ultrasonic sound appratus then with power level, each centrifuge tube content was made supersound process 15 seconds.Take out 10 μ l, measure protein concn with Lowry method (Anal.Biochem 100:201～220,1979).Then with each pipe centrifugal (10,000g, 5 minutes), take out supernatant liquor 100 μ l, adopt New England Nuclear company (Boston, Massachusetts) the cGMP RIA detection kit of Sheng Chaning are measured ring-type GMP(cGMP by the method for producer) level.The result reaches with the cGMP pmol numerical table that every milligram of albumen was produced.
In addition, the ability of polyamine compounds antagonism exicitatory/amino acid neurotransmitter of the present invention is by free [Ca in the cytosol that is caused by the NMDA/ glycine in their blocking-up dissociative cerebellar granule cells
2+] the concentration increase represents that its method is described below.Made rat cerebellum prepare cerebellar granule cell (Wilkin, people such as G.P. with 8 days; Brain Res:115:181-199,1976).Square (1cm
2) Aclar(Proplastics Inc., 5033 Industrial Ave., Wall, N.J., 07719) use the poly-l-lysine dressing, and immigration contains in 12 porose discs of 1 milliliter of Eagles Basal medium.Cell is dissociated out, will contain 6.25 * 10
6The aliquots containig of individual cell is added in each hole of containing square Aclar.Be coated with back 24 hours, and added cytosine(Cyt)-β-D-arbinofuranose glycosides (final concentration is 10 μ M).Cultivated the back 6,7 and 8 days, respectively Fura 2 content of analysis of cells.The cell immigration that adheres on the square Aclar is contained 1 milliliter of 2 μ M fura 2/AM(Molecular probes Inc., Eugene, OR 97402) the HEPES damping fluid (contain 0.1% bovine serum albumin, 0.1% glucose, PH7.4, no magnesium ion) in 12 porose disc.Cell was cultivated 40 minutes at 37 ℃; Remove the damping fluid that contains fura 2/AM, put into 1 milliliter of same buffer that does not contain fura 2/AM again.The damping fluid that in quartz cuvette, adds 37 ℃ of 2 milliliters of pre-temperature.To move in the cuvette at the cell on the square Aclar, cuvette inserts in the colorimetric glass stand that disposes magnetic stirring apparatus of constant temperature (37 ℃), measure fluorescence intensity with fluorescence classification of photometry meter (Biomedical Instrument Group, University of Pennsylvania).About 2 minutes of steady time of fluorescent signal.
Adding the cytosol free calcium concentration increase that produces behind 50 μ M NMDA and the 1mM glycine, increase expression with fluorescence.In cuvette, add then and be dissolved in phosphate buffered saline (PBS, PH7.4) the test-compound stock solution 5-20 μ l of the proper concn in.Adopt Grynkiewiez, the method that people such as G. (J.Biol.Chem.260:3440,1985) set up is carried out the correction and the fura 2/AM spill down correction of fluorescent signal.During each off-test, add and measure maximum fluorescence value (Fmax) behind the 35 μ M ionomycins, continue adding EGTA(12mM) behind the chelating calcium, measure minimum fluorescent value (Fmin).Adopt aforementioned operation,, can prove the ability of purpose compound antagonism exicitatory/amino acid neurotransmitter with the index that is reduced to of fluorescence behind the adding purpose compound.
Polyamines of the present invention itself can be used for the antagonism exicitatory/amino acid neurotransmitter.Therefore, polyamines of the present invention also can be used for controlling the invertebrates insect pest, disease and the illness that mammiferous exicitatory/amino acid neurotransmitter transmits treated in smelting, as apoplexy, cerebral ischemia, deterioration of neurons sufferer (as alzheimer's disease with the Dian Epilepsy).Such polyamines can also be used as mammiferous psychotherapeutic drugs.In addition, polyamines of the present invention also can be used for studying cell (including but not limited to nervous system cell) physiology.
The salt that pharmaceutically is suitable for of polyamines of the present invention also within the scope of the invention.The method of knowing with present technique field professional can obtain described salt.The acid salt that for example, can prepare polyamines of the present invention according to general method.The acid salt of polyamines of the present invention, example hydrochloric acid salt and trifluoroacetate are preferably.The hydrochloride of polyamines of the present invention is good especially.
When the salt that pharmaceutically is suitable for of polyamines of the present invention was taken to Mammals, it can be taken individually, perhaps according to general medicinal preparations compound method it and the carrier or the mixing diluents that pharmaceutically are suitable for was taken with the form of medicinal compositions.The salt that polyamines of the present invention or its pharmaceutically are suitable for can orally or non-be taken through gi tract.Non-taking through gi tract comprises intravenous injection, intramuscular injection, peritoneal injection, subcutaneous injection and topical.
For oral polyamines of the present invention or its salt that pharmaceutically is suitable for, can be with the form administration of compound, perhaps with aqueous pharmaceutical or suspendible liquor form administration with for example tablet or capsule.For oral tablet, application carrier comprises lactose and W-Gum usually, and adds lubricant such as Magnesium Stearate usually.For oral capsule, thinner commonly used has the W-Gum of lactose and drying.For the suspendible liquor of oral application, be that effective constituent is mixed with emulsifying agent and suspensoid.If desired, can add some sweet taste and/or perfume compound.
For intramuscularly, peritoneal injection, subcutaneous injection and intravenous injection, prepare the sterile solution of effective constituent usually, and the pH value of this solution suitably should be regulated and cushioned.For intravenous injection, should control the total concn of solute, be isoosmotic so that make said preparation.
When polyamines of the present invention or its salt are used for man-hour, the dosage of every day is determined by the doctor that prescription power is arranged usually.But the suitable dose of polyamines of the present invention is about 1-30 milligram/kg/day.In addition, the dosage of polyamines of the present invention can change with the effect of the severity of patient's age, body weight, each reaction and patient's illness and the particular compound of taking.Therefore, it is possible that dosage surpasses above given dosage range, and this also belongs to scope of the present invention.
When polyamines of the present invention or its salt are used to control the invertebrates insect pest, described compound can be directly used in this invertebrates, perhaps provide it to the environment at this invertebrates place.For example The compounds of this invention is sprayed on this invertebrates with solution.Controlling the required dosage of this invertebrates insect pest can change with invertebrates and envrionment conditions, and can be determined by the personnel that use this compound.
When polyamines of the present invention or its salt are used for stechiology research, can this compound be used for cell according to the method that present technique field professional knows.For example, this compound can be used for cell with suitable physiological buffer form.The suitable concn that is used for the The compounds of this invention of this research is 100 μ M.But can be higher than 100 μ M or be lower than 100 μ M in compound concentrations described in this research.Administered compound dosage can be determined according to the professional of the method for knowing by the present technique field.
Example
The type of experimental technique
(A) with two-tertiary butyl pyrocarbonate protection secondary amine
(B) cyanoethlation of primary amine
(C) the nitrile catalytic hydrogenation is a primary amine
(D) form the amido linkage reaction
(D
1) dimethylamino-propyl, ethyl carbodiimide/hydroxybenzotriazole
(D
2) dicyclohexylcarbodiimide/hydroxybenzotriazole
(D
3) dimethylamino-propyl, ethyl carbodiimide/hydroxybenzotriazole/triethylamine
(D
4) dicyclohexylcarbodiimide/N-Hydroxysuccinimide
(the protecting group of sloughing the N-Boc Substrate with HCl in the) Zai diox E
(F) use the TFA(trifluoroacetic acid) protecting group of sloughing the N-Boc Substrate
(G) carry out the alkylation of amine with N-Boc-3-bromine propylamine
Example 1 preparation H
2N[(CH
2)
3NH]
XThe polyamines side chain
Step 1-method B
Under agitation restrain 1,3-diaminopropanes sample and 45 milliliters of MeOH chemical combination with 103 in 4 ℃.In 90 minutes, vinyl cyanide (100ml, 81 grams, 1.1 equivalents) is added drop-wise in the solution through the pressure equilibrium feed hopper.After 3 hours, take out 500 milligrams and usefulness
13C NMR measures; Do not observe 1, the 3-diaminopropanes.The crude product that contains product amino-nitrile 8 under reduced pressure distills, and collects the fraction of 3 parts of 100-125 ℃ of temperature ranges; Whole purity is enough to and the di-t-butyl carbonate reaction, subsequently by the silica gel column chromatography purifying.
1H NMR（250 MHz，CDCl
3）δ2.67（t，2H，J＝6.6Hz），2.54-2.43（m，4H），2.28（t，2H，J＝6.6Hz），1.37（m，2H，J＝6.7Hz），1.05（s，3H）;
13C NMR（63.1 MHz，CDCl
3）δ118.8，46.9，44.9，40.2，33.4，18.5.
Step 2-method A
In 0 ℃ to amino-nitrile 8(23 gram, 0.18 mole) the 500ml dichloromethane solution in add di-t-butyl pyrocarbonate (di-tert-butyl dicarbonate, 80 grams, 0.36 mole, 2 equivalents).Reaction mixture stirred under room temperature 16 hours, and handled with other di-t-butyl pyrocarbonate (8 grams, 0.036 mole).Behind other 4 hours of the restir, reaction solution is with 1N KOH(2 * 60ml) washing, through K
2CO
3Drying, filtration and vacuum concentration.Product is through flash chromatography (SiO
2, 20 → 100% ethyl acetate isohexane solution) and purifying, obtain product N-Boc-nitrile 9, be clarifying oily matter (14 grams, productive rate is 24%).
1H NMR（250 MHz，CDCl
3）δ3.40（t，2H，J＝6.7Hz），3.28（t，2H，J＝6.6Hz），3.05（bs，2H），2.63-2.46（m，2H），1.70-1.56（m，2H），1.42（s，9H），1.38（s，9H）;
13C NMR（63.1 MHz，CDCl
3）δ155.8，155.1，118.5，80.7，78.9，45.7，44.4，43.4，32.4，28.3，28.2.
Step 3-method C
With N-Boc nitrile 9(49 gram, 0.4 mole), 1000ml acetate and 20 gram Pd(OH)
2/ C(20%Pd(OH)
2, the weight meter) and place 2.6L Pa Er jolting bottle.The jolting bottle charges into hydrogen to 50 pound/inch
2And jolting 4 hours.Reaction solution is with 0.47 μ filter paper filtering, and vacuum concentration.Resistates is dissolved in 1.5L CH
2Cl
2In, with IN KOH(2 * 200ml) washing.Alkali layer CH
2Cl
2(400ml) extraction merges CH
2Cl
2Layer is through K
2CO
3Drying is filtered and vacuum concentration, obtains N-Boc amine 11, is clarifying colorless oil (43 grams, productive rate 86%).
1H NMR（250 MHz，CDCl
3）δ3.28-3.12（m，2H），3.11-3.00（m，4H），2.64（t，2H，J＝7Hz），1.65-1.50（m，4H），1.42（s，9H），1.38（s，9H）;
13C NMR（63.1 MHz，CDCl
3）δ155.8，79.3，78.5，44.0，43.4，39.2，32.3，31.6，28.5，28.2.
Step 4-method B
With 38 gram N-Boc amine 11(0.114 moles) sample restrains the 60ml methanol solution chemical combination of vinyl cyanide (0.126 mole, 1.1 equivalents) with 6.7, and stirred 11 hours.Remove and desolvate, obtain 43 gram (productive rate 100%) nitriles 12, be clarifying colorless oil, need not further pure can the application.
1H NMR（250 MHz，CDCl
3）δ3.18（bs，4H），3.03（m，2H），2.85（t，2H，J＝6.6Hz），2.57（t，2H，J＝6.7Hz），2.45（t，2H，J＝6.7Hz），1.72-1.53（m，4H），1.41（s，9H），1.38（s，9H）;
13C NMR（63.1 MHz，CDCl
3）δ155.9，118.6，79.6，78.9，46.3，45.0，43.9，37.4，28.8，28.3，18.6.
Step 5-method A
In 0 ℃ with 43 grams above the nitrile 12(0.114 mole for preparing) sample and di-t-butyl pyrocarbonate (25.6 restrain, 0.120 mole, 1.05 equivalents) and 350ml CH
2Cl
2Chemical combination, and stirred 9 hours.Thin-layer chromatography (TLC) (EtOAc, KMnO
4) showing that no starting raw material is residual, reactant is pressed the identical method purifying of N-Boc-nitrile 9, obtains N-Boc-nitrile 13, is clarifying colorless oil (34 restrain productive rate 63%).
1H NMR（250 MHz，CDCl
3）δ3.45（t，2H，J＝6.6Hz），3.39-2.97（m，8H），2.68-2.46（2，2H），1.82-1.56（m，4H），1.44（s，18H），1.87（s，9H）;
13C NMR（75.7MHz，CDCl
3）δ155.9，80.5，79.7，78.9，46.5，44.5，43.9，37.6，28.4，28.3，16.9.
Step 6-method C
Press N-Boc-nitrile 9 and prepare the method for N-Boc-amine 11, by N-Boc-nitrile 13 preparation N-Boc-amine 14, productive rate is the 99%(30 gram).
1H NMR（300 MHz，CDCl
3）δ3.32-2.94（m，10H），2.62（t，2H，J＝6.7Hz），1.76-1.52（m，6H），1.39（s，18H），1.37（s，9H），1.25（s，2H）;
13C NMR（63.1 MHz，CDCl
3）δ155.5，79.5，79.3，45.5-43.7，39.1，37.3，32.3，28.3.
Step 7-method B
Press N-Boc-amine 11 and prepare the method for nitrile 12, by N-Boc-amine 14 preparation nitriles 15, productive rate is 90%.
1H NMR(300 MHz, CDCl
3) δ 3.29-3.02(m, 14H), 2.86(t, 2H, J=6.7Hz), and 2.57(t, 2H, J=6.6Hz), and 2.46(t, 2H, J=6.6Hz), 1.72-1.57(m, 6H), 1.41(s, 9H), 1.40(s, 9H), 1.39(s, 9H);
13C NMR(75.7 MHz, CDCl
3) δ 155.5,155.0,118.7,79.6,79.5,46.7-46.0,45.2-43.3,38.0-36.9,28.4,18.7. nitrile 15 and nitrile 12
13C NMR composes (300 MHz, CDCl
3) the feature unanimity.
Step 8-method A
Pressing nitrile 12 and prepare the method for N-Boc-nitrile 13, by nitrile 15 preparation N-Boc-nitriles 16, is clarifying colorless oil (30 grams, productive rate 87%).
1H NMR（300 MHz，CDCl
3）δ3.36（t，2H，J＝6Hz），3.18-2.90（m，14H），2.57-2.42（m，2H），1.72-1.48（m，6H），1.40-1.28（m，27H）.
Step 9-method C
Press N-Boc-nitrile 9 and prepare the method for N-Boc-amine 11, by N-Boc-nitrile 16 preparation N-Boc-amine 17, productive rate is the 74%(2.61 gram).
1H NMR（250 MHz，CDCl
3）δ3.39-2.97（m，14H），2.63（t，2H，J＝6.6Hz），1.80-1.53（m，8H），1.39（s，27H），1.38（s，9H），1.23 9（s，2H）.
Step 10-method B
Press method that N-Boc-amine 11 prepares nitrile 12 by N-Boc-amine 17 preparation nitriles 18, productive rate is the 91%(19 gram), and need not to be further purified and can use.
1H NMR（300 MHz，CDCl
3）δ3.24-2.94（m，14H），2.87（t，2H，J≈6Hz），2.57（t，2H，J≈6Hz），2.47（t，2H，J≈6Hz），1.74-1.54（m，8H），1.45-1.36（m，36H）.
Step 11-method A
Press nitrile 12 and prepare the method for N-Boc-nitrile 13, by nitrile 18 preparation N-Boc-nitrile 19(16 grams, productive rate 74%).
1H NMR（250 MHz，CDCl
3）δ3.43（t，2H，J＝6.6Hz），3.28-3.02（m，16H），2.62-2.50（m，2H），1.80-1.56（m，8H），1.43（s，9H），1.42（s，9H），1.41（s，18H），1.39（s，9H）.
Step 12-method C
Press N-Boc-nitrile 9 and prepare the method for N-Boc-amine 11, by N-Boc-nitrile 19 preparation N-Boc-amine 20(17 grams, productive rate 99%).
1H NMR（300 MHz，CDCl
3）δ3.24-2.95（m，18H），2.6（t，2H，J≈6H），1.72-1.52（m，10H），1.42-1.32（m，45H）.
Step 13-method B
Press N-Boc-amine 11 and prepare the method for nitrile 12, by N-Boc-amine 20 preparation nitriles 21, productive rate is 99%.
1H NMR（250 MHz，CDCl
3）δ3.32-3.03（m，16H），2.91（t，2H，J＝6.7Hz），2.61（t，2H，J≈6Hz），2.51（t，2H，J＝6.6Hz），1.82-1.57（m，10H），1.44（s，36H），1.43（s，9H）.
Step 14-method A
Press nitrile 12 and prepare the method for N-Boc-nitrile 13, by nitrile 21 preparation N-Boc-nitriles 22, productive rate is 99%.
3.45ppm（t，2H，J＝6.6Hz），3.26-3.02（m，18H），2.65-2.53（m，2H），1.79-1.55（m，10H），1.43（s，9H），1.42（s，9H），1.41（s，18H），1.40（s，9H）;
13C NMR｛
1H｝（250 MHz，CDCl
3）δ155.2，79.3，44.7，28.3，28.3，28.2.
Step 15-method C
Press N-Boc-nitrile 9 and prepare the method for N-Boc-amine 11, by N-Boc-nitrile 22 preparation N-Boc-amine 23(8 grams, productive rate 99%).
1H NMR（300 MHz，CDCl
3）δ3.32-2.98（m，22H），2.65（t，2H，J＝6.6Hz），1.78-1.53（m，12H），1.41（s，54H），1.40（s，9H）.
Step 16-method B
Press N-Boc-amine 11 and prepare the method for nitrile 12, by N-Boc-amine 23 preparation nitriles 24, productive rate is 99%.
1H NMR（250 MHz，CDCl
3）δ3.32-3.04（m，22H），2.90（t，2H，J＝6.7Hz），2.61（t，2H，J≈6Hz），2.53（t，2H，J＝6.7Hz），1.82-1.57（m，12H），1.44（s，45H），1.43（s，9H）.
Step 17-method A
Press nitrile 12 and prepare the method for N-Boc-nitrile 13, by nitrile 24 preparation N-Boc-nitrile 25(5.5 grams, productive rate 74%).
1H NMR（250 MHz，CDCl
3）δ3.45（t，2H，J≈6.7Hz），3.40-2.97（m，24H），2.66-2.51（m，2H），1.80-1.55（m，12H），1.54-1.30（s，63H）.
Step 18-method C
Press N-Boc-nitrile 9 and prepare the method for N-Boc-amine 11, by N-Boc-nitrile 25 preparation N-Boc-amine 26(5.01 grams, productive rate 91%).
1H NMR（250 MHz，CDCl
3）δ3.30-2.97（m，26H），2.60（t，2H，J＝6Hz），1.81 1.57（m，14H），1.53-1.28（m，63H）.
13C NMR（250 MHz，CDCl
3）δ155.2，79.3，44.7，28.7，28.4，27.5.
Example 2
Step 1, the formation-method D1 of amido linkage
Stirring and exsiccant N
2Under the air-flow, with 0.19 gram ferrocenecarboxylic acid (0.82 mmole, 1.1 equivalents), 0.12 gram hydroxybenzotriazole (0.89 mmole, 1.2 equivalents), 0.17 gram 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (hydrochloride, 0.90 mmole, 1.2 equivalents) and 10ml CH
2Cl
2Place the single neck RBF of 50ml to carry out chemical combination.After 30 minutes, add 0.61 gram N-Boc-amine 27(0.75 mmole in solution, 1.0 equivalents are seen the preparation of example 5a).TLC(2 * MeOH after 2 hours, I
2) show that N-Boc-amine runs out of.Reaction solution is diluted to 400ml with EtOAc, and use successively PH4 damping fluid (2 * 25ml), 25ml H
2O, IN KOH(2 * 25ml), 25ml H
2O and the water washing of 50ml salt.The EtOAc layer is through Na
2SO
4Drying is filtered, is also removed and desolvate, and obtains 712 milligrams of (93%) products, is orange.
1H NMR（250 MHz，CDCl
3）δ4.78（s，2H），4.32（t，2H，J＝1.8Hz），4.19（s，5H），3.45-3.04（m，20H），1.83-1.59（m，12H），1.50（s，9H），1.45（s，18H）.1.44（s，9H），1.43（s，9H）.
Step 2, polyamines are sloughed protection-method F
In the single neck RBF of 100ml, use exsiccant N in 0 ℃
2Bubbling air-flow (passing through polyfluortetraethylene pipe) outgases trifluoroacetic acid (30ml).The ferrocene ammonia four acyl group polyamines (712 milligrams, 0.69 mmole) of top step 1 are dissolved in 2ml CH
2Cl
2In, and be added among the TFA of stirring, with 3 * 2ml CH
2Cl
2Rinsing.After 30 minutes, remove ice bath; After other 30 minutes, under reduced pressure remove and desolvate again, concentrate by high vacuum then.Remaining light red brown oil thing and Et
2O(3 * 30ml) grind together generates yellow solid, and is collected under nitrogen pressure on porous " B " sintered plate.The solid ether rinse, remaining ether is driven away with nitrogen pressure, obtains 690 milligrams of solid products (productive rate 93%).
1H NMR(DMSO) δ 4.71(t, 2H, J=1.73Hz), and 4.38(t, 2H, J=2Hz), 4.15(s, 5H), 3.28-3.21(m, 2H), 3.03-2.81(m, 18H), 2.04-1.72(m, 8H), 1.61-1.50(m, 4H);
13C NMR(250 MHz, D
2O) 177.3,78.5,76.1,74.3,49.7,48.1,47.3., 47.2,47.1,39.3,38.8,28.5,26.5,25.5,25.4.HPLC purity (being not less than) 96.08%; Novapak C
18Post was used 5-40%CH in 60 minutes
3CN/2%TH
2The O wash-out detects elution time: 23.2 minutes in the 230nm place.
HRMS（FAB）：（M+H），C
27H
48N
6O，
Calculated value: 529.3328845
Measured value: 529.33172
Example 3
Step 1, the formation-method D3 of amido linkage
With 2-pyridyl acetic acid hydrochloride (0.105 gram, 0.60 mmole, 1.0 equivalents) and 0.16ml TEA(1.15 mmole, 2 equivalents) and 4 milliliters of CH
2Cl
2Chemical combination.After 10 minutes, add the DEC(0.12 gram, 0.62 mmole, 1.0 equivalents) and 0.09 gram HOBt(0.66 mmole, 1.1 equivalents), and with mixture stirring 2 hours.Add N-Boc-amine 27(0.44 gram, 0.54 mmole, 0.9 equivalent), reaction solution restir 10 hours.TLC(2 * MeOH, I
2) show that N-Boc-amine runs out of.Reaction solution is diluted to 400ml with EtOAc, uses IN KOH(40ml successively), salt solution (50ml) washing, and through MgSO
4Drying is filtered EtOAc solution, removes and desolvates, and obtains the clarifying green oily matter of 0.4 gram.Crude product is eluent through 10 gram silica gel (with EtOAc furnishing pulpous state) chromatography with EtOAc.Merge suitable cut, remove and desolvate, obtain 0.20 gram (productive rate 40%) clarifying light green oily matter.
1H NMR（250 MHz，CDCl
3）δ8.59-8.52（m，
1H），7.76-7.68）（m，1H），7.62-7.49（m，
1H），7.37（d，
1H，J＝8Hz），3.78（s，2H），3.31-3.02（m，20H），1.80-1.56（m，12H），1.56-1.34（m，45H）.
Step 2, polyamines are sloughed protection-method F
In the single neck RBF of 100ml, use exsiccant N in room temperature
2Bubbling air-flow (passing through polyfluortetraethylene pipe) is with trifluoroacetic acid (30ml) continuous degassing.The 2-pyridyl ethanamide (180 milligrams) of top step 1 is dissolved in 2ml CH
2Cl
2In, and be added in the trifluoroacetic acid (TFA) of stirring.After 1 hour, under reduced pressure remove and desolvate, resistates places under the high vacuum and concentrates.(3 * 30ml) grind resistates, form white solid, and are collected under nitrogen pressure on porous " B " sintered plate, remove residual ether with nitrogen pressure with ether; Obtain 169 milligrams of (productive rate 91%) separated products.
1H NMR（250 MHz，D
2O）δ8.48（d，
1H，J＝15Hz），7.98（t，1H，J＝6Hz），7.51-7.47（m，2H），3.86（s，2H），3.32（t，2H，J≈9Hz），3.17-2.96（m，18H），2.17-1.98（m，6H），1.98-1.81（m，2H），1.81-1.69（m，4H）.
Example 4
Step 1, the formation-method D4 of amido linkage
With 4-biphenyl acetic acid (53 milligrams, 0.25 mmole, 1.2 equivalents) and 5ml CH
2Cl
2, 84 μ l triethylamine (0.6 mmoles, 3 equivalents), 70 milligrams of dicyclohexylcarbodiimide (0.34 mmoles, 1.6 equivalent), 11 milligrams of N-Hydroxysuccinimide (0.09 mmole, 45 moles of %) and 175 milligrams of N-Boc-amine 27(0.21 mmoles, chemical combination 1.0 equivalents).TLC(2 * MeOH after 16 hours, KMnO
4) show that N-BOC-amine runs out of.Instead with regard to liquid CH
2Cl
2Be diluted to 100ml, use 20% NH
4(2 * 100ml) washings of the OH aqueous solution.Alkali layer CH
2Cl
2(3 * 50ml) extractions; With whole CH
2Cl
2Extraction liquid merges, and uses salt solution (50ml) washing then, through K
2CO
3Drying is filtered, and removes and desolvates, and obtains 281 milligrams of (productive rate＞100%) crude products.Through flash chromatography on silica gel (12 gram silica gel CH
2Cl
2The furnishing pulpous state is used 0-10%MeOH/CH
2Cl
2Carry out gradient elution), separate obtaining pure products, be white waxy solid (190 milligrams, productive rate 88%).
1H NMR（250 MHz，CDCl
3）δ7.56-7.50（m，4H），7.43-7.28（m，5H），3.56（s，2H），3.26-2.98（m，20H），1.78-1.52（m，12H），1.48-1.36（m，45H）.
Step 2, polyamines are sloughed protection-method F
Use successive N in 0 ℃
2Bubbling air-flow (passing through polyfluortetraethylene pipe) outgases trifluoroacetic acid (30ml).The xenyl ethanamide that top step 1 is dry powdered (150 milligrams, 0.15 mmole) is added among the TFA of stirring.Remove ice bath after 40 minutes; After 20 minutes, under reduced pressure remove again and desolvate, concentrate through high vacuum then.After 2 hours, with brown oil and the Et that generates
2O(3 * 30ml) grind together; Form white solid, under nitrogen pressure, be collected on porous " C " sintered plate.Solid is soluble in water, via the sintered plate washing, and lyophilize, obtain 136 milligrams of (productive rate 99%) products, be white solid.
1H NMR（300 MHz，D
2O）δ7.62-7.56（m，5H），7.4（t，2H，J＝7.5Hz），7.38-7.31（m，2H），3.45（s，2H），3.13（t，2H，J＝6.7Hz），3.02-2.80（m，18H），2.00-1.54（m，12H）.
Example 5 1H-indole-3-acetamide-N-(16-amino-4,8,13-three nitrogen n-Hexadecane-1-base
Step 1
Press Yamamoto, Hisashi(J.Am.Chem.Soc.103:6133-6136(1981)) method delivered, with diaminobutane and vinyl cyanide preparation formula 1 compound
Step 2
Under nitrogen gas stream to N-cyanoethyl-1,4-diaminobutane (6.44 grams, 0.0457 add KF/ diatomite (11 gram) in acetonitrile (200ml) solution mole), in 7 hours, drip the N-(tert-butoxycarbonyl subsequently)-3-bromine propylamine (10.87 grams, 0.0457 mole).Reaction solution stirred under room temperature 16 hours, was heated to 70 ℃ then, kept 24 hours.With reaction solution cooling, filtration and vacuum concentration.Resistates is dissolved in CH
2Cl
2(200ml), use 1N NaOH(100ml) washing, dry and vacuum concentration, obtain crude product, this crude product through silica gel column chromatography (with 9: 1 CH
2Cl
2/ MeOH), obtain 3.32 donaxine III.
1H NMR(CDCl
3) δ 1.19-1.59(m, 17H), 2.42(t, J=6.6Hz, 2H), 2.44-2.58(m, 6H), and 2.82(t, J=6.6Hz, 2H), 3.08(m, 2H), 5.22(br s, 1H);
13C NMR(CDCl
3) δ 18.68,27.70,27.74,28.42,29.94,39.16,45.03,47.68,48.99,49.65,78.78,118.75,156.11; Real side value (M+H) m/z=299.2434 of HR FABMS, C
15H
31N
4O
2(calculated value 299.2447).
Step 3
Under nitrogen gas stream, will be dissolved in the 150ml methylene dichloride by described 4.7 gram (15.8 mmole) the formula III compounds that make of above step 2.Add 7.56 gram (34.7 mmole) di-t-butyl pyrocarbonates then, reaction mixture stirs under room temperature and spends the night.Then with the mixture vacuum concentration, and through 400 gram silica gel column chromatographies, with 50: 50 ethyl acetate/hexane solvent elutions.Cut is by TLC monitoring (50: 50 ethyl acetate/hexane).The reaction solution that will contain formula IV product merges, and vacuum concentration, obtains 7.9 gram products, is oily matter.
1H NMR(CDCl
3) δ 1.20-1.59(m, 33H), 2.55(m, 2H), 3.01-3.37(m, 8H), and 3.39(t, J=6.6Hz, 2H), 5.25(br s, 1H);
13C NMR δ 17.21,25.73,25.94,28.22,28.24,28.27,37.91,43.78,44.24,46.60,47.95,78.96,79.57,80.44,155.01,155.75,155.98; Real side value (M+H) m/z=499.3501 of HR FABMS, C
25H
47N
4O
6(calculated value 499.3496).
Step 4
Under nitrogen gas stream, in 125ml acetate, add) by described 7.85 gram (15.8 mmole) formula IV compounds that make of above step 3 and 6.5 gram Pd(OH
2/ carbon.Mixture is in 50 pounds/inch
2Hydrogenation is 2 hours under the pressure.Filtration catalizer, filter cake washs with acetate.Concentrated filtrate, and be dissolved in the 250ml methylene dichloride, with 100 milliliters of 1N NaOH washings 2 times, and through K
2CO
3Dry.Solution is filtered, and vacuum concentrated filtrate, 7.8 gram formula V compounds obtained.
1H NMR(CDCl
3) δ 1.24-1.59(m, 35H), 2.14(s, 2H), and 2.61(t, J=6.7Hz, 2H), 2.98-3.14(m, 10H), 5.22(br s, 1H);
13C NMR(CDCl
3) δ 25.89,28.42,31.38,32.36,37.55,38.95,43.95,46.65,79.34,79.48,155.65,156.03; Real side value (M+H) m/z=503.3804 of HR FABMS, C
25H
51N
4O
6(calculated value m/z=503.3809).
Step 5
Under nitrogen gas stream, will be dissolved in the 150ml methyl alcohol by described 7.15 gram (14.2 mmole) the formula V compounds that make of above step 4.Add the 1.03ml(15.6 mmole then) vinyl cyanide, reaction solution stirred under room temperature 72 hours.Reaction mixture is concentrated, from methylene dichloride, concentrate 3 times again and under vacuum, remove and desolvate, obtain 7.65 gram formula V products, be oily matter.
1H NMR(CDCl
3) δ 1.26-1.73(m, 36H), 2.44(t, J=6.7Hz, 2H), and 2.54(t, J=6.7Hz, 2H), and 2.83(t, J=6.7Hz, 2H), 3.00-3.16(m, 10H), 5.24(br s, 1H);
13C NMR(CDCl
3) δ 18.64,25.84,28.09,28.43,28.74,37.84,44.18,44.68,45.14,46.29,46.73,46.85,49.70,78.90,79.29,79.46,118.52,155.84,155.98; Real side value (M+H) m/z=556.4064 of HR FABMS, C
28H
54N
5O
6(calculated value m/z=556.4074).
Step 6
Under nitrogen gas stream, will be dissolved in the 125ml methylene dichloride by described 6.45 gram (11.6 mmole) the formula VI compounds that make of above step 5.Add 2.6 gram (12 mmole) di-t-butyl pyrocarbonates in this solution, reaction mixture stirs under room temperature and spends the night.Subsequently with the mixture vacuum concentration, and through 400 gram silica gel column chromatographies, with 50: 50 ethyl acetate/hexane wash-outs.Merge the cut that contains product and also concentrate, obtain 6.6 gram formula VIII products, be oily matter.
1H NMR(CDCl
3) δ 1.26-1.73(m, 44H), 3.03-3.24(m, 14H), and 3.42(t, J=6.6Hz, 2H), 5.25(br s; 1H);
13C NMR(CDCl
3) δ 17.20,25.88,27.83,28.12,28.35,28.45,28.77,37.87,43.91,44.20,44.77,46.27,46.88,78.94,79.42,79.50,80.54,117.91,154.96,155.44,155.74,155.99; Real side value (M+H) m/z=656.4579 of HR FABMS, C
33H
62N
5O
8(calculated value m/z=656.4598).
Step 7
In nitrogen gas stream, in 150ml acetate, add) by described 6.6 gram (10.1 mmole) formula VII compounds that make of above step 6 and 6 gram Pd(OH
2/ carbon.Mixture is in 50 pounds/inch
2Hydrogenation is 2 hours under the pressure.Filtration catalizer, filter cake acetate thorough washing.Concentrated filtrate, and be dissolved in the 200ml methylene dichloride, with 100ml 1N NaOH washing 2 times, and through K
2CO
3Dry.Solution is filtered, and vacuum concentrated filtrate, 6.5 gram formula VIII compounds obtained.
1H NMR(CDCl
3) 1.28-1.71(m, 46H), 2.16(br s, 2H), and 2.65(t, J=6.7Hz, 2H), 3.01-3.18(m, 14H), 5.24(br s, 1H);
13C NMR(CDCl
3) δ 25.85,27.66,28.45,28.76,39.10,44.21,44.91,46.80,79.27,79.46,155.41,155.67,155.99; Real side value (M+H) m/z=660.4914 of HR FABMS, C
33N
66N
5O
8(calculated value 660.4911).
Under nitrogen gas stream, 1.75 gram (10 mmole) indolylacetic acids, 1.15 gram (10 mmole) N-hydroxy-succinamides and 2.06 gram (10 mmole) dicyclohexylcarbodiimide are added in the 75ml tetrahydrofuran (THF).Reaction mixture stirs under room temperature, forms precipitation after about 5 minutes.About 1.5 hours after-filtration precipitations, filter cake obtains 1.84 grams with 75ml tetrahydrofuran (THF) washing, filter cake through dry air.The filtrate that merges is concentrated, and be dissolved in the ethyl acetate, filter, and wash with ethyl acetate.Concentrated filtrate obtains foam.This foam grinds with the 75ml ether, obtains hard jelly.Add about 30ml ethyl acetate and ether then in succession.Filter to isolate solid, dry under nitrogen with the ether washing, obtain 1.74 gram formula IX products.Find that simultaneously mother liquor is handled with sherwood oil can obtain 0.47 other gram product.
Step 9
In nitrogen gas stream with under stirring, will be dissolved in the 10ml methylene dichloride by described 0.33 gram (5 mmole) the formula VIII compound that makes of above step 7, add then by described 0.136 gram (5 mmole) the formula IX compound that makes of above step 8.Reaction solution stirs under room temperature and spends the night.With methylene dichloride reaction mixture is diluted to 35ml then, with 10ml 0.5N NaOH washing, through K
2CO
3Dry and concentrated.Concentrated solution is through silica gel column chromatography, with 4: 1 ethyl acetate/hexane wash-outs.The cut that will contain product concentrates, and obtains the white foam shape thing that 0.37 gram contains formula X product and has some ethyl acetate.
Step 10
Under nitrogen gas stream, will be dissolved in the 10ml methylene dichloride by described 0.37 gram (0.45 mmole) the formula X compound that makes of above step 9.Add 0.218 gram (1 mmole) di-t-butyl pyrocarbonate and 12ml(0.1 mmole then in succession) 4-(N, the N-dimethylamino) pyridine.Reaction solution is in stirring at room 1 hour, standing over night then.Reaction mixture with 4: 1 ethyl acetate/hexane wash-outs, concentrates the cut that contains product through silica gel column chromatography, obtains 0.32 gram formula XI product, is white foam shape thing.
Step 11
Under nitrogen gas stream, will be added in the 15ml trifluoroacetic acid by described 0.32 gram (0.35 mmole) the formula XI compound that makes of above step 10, and stir 15 minutes.Grind then with the reaction mixture vacuum concentration, and with ether, obtain 0.30 gram product, be the white powder thing.
Prepare N-Boc-amine 27 with following structure by similar method.
According to above step 1-7, the N-Boc-amine of production VIII.
Step 8a
(example 5, step 5) prepare the method for nitrile VI, prepare nitrile X III with N-Boc-amine VIII, obtain 1.00 gram products (productive rate 93%) to press N-Boc-amine V.
1H NMR(CDCl
3) δ 1.26-1.66(m, 47H), 2.45(t, J=6.6Hz, 2H), and 2.56(t, J=6.7Hz, 2H), and 2.85(t, J=6.6Hz, 2H), 3.01-3.30(m, 14H), 5.25(br s, 1H);
13C NMR(CDCl
3) δ 18.68,25.92,28.46,28.48,37.49,44.19,44.88,45.16,46.73,78.93,79.32,79.44,118.70,155.46,155.61,156.04; Real side value (M+H) m/z=713.5191 of HR FABMS, C
36H
69N
6O
8(calculated value m/z=713.5177).
Step 9a
Application method A prepares N-Boc-nitrile X I V with nitrile X III by the amine provide protection.
Step 10a
Prepare the method for N-Boc-amine VIII (this case step 7) according to N-Boc-nitrile VII, the hydrogenation by N-Boc-nitrile X I V prepares N-Boc-amine 27.
Example 6 and 7
With polyamines 20 and suitable R-acetate (m=1) or carboxylic acid (m=0) is starting raw material, has R(CH by method D1 and method F preparation
2)
mCO[NH(CH
2)
3]
5NH
2The compound of 5TFA structure.
Example m R
60 ferrocene
71 3-indoles
Example 8-29
With polyamines 27 and suitable R-acetate or carboxylic acid is starting raw material, by the following method the compound of preparation with following structure.
R(CH
2)
mCO[NH(CH
2)
3]
3NH(CH
2)
4NH(CH
2)
3NH
25HCl(method E) or
R(CH
2)
mCO[NH(CH
2)
3]
3NH(CH
2)
4NH(CH
2)
3NH
25TFA(method F)
Example m R method
Use F behind the 80 ferrocene D1,
Use F behind the 90 2-pyridine D3,
Use F behind the 10 0 3-pyridine D3,
Use F behind the 11 0 4-pyridine D3,
Use F behind the 12 1 2-pyridine D3,
Use F behind the 13 1 3-pyridine D3,
Use F behind the 14 1 4-pyridine D3,
Use F behind the 15 0 2-quinoline D1,
Use F behind the 16 0 3-quinoline D2,
Use E behind the 17 1 3-indoles D1,
Use F behind 18 1 3-(5-oxyindole) D2,
Use E behind 19 1 3-(4-oxyindole) D2,
Use F behind 20 1 3-(5-bromo indole) D2,
Use F behind 21 1 3-(4-fluoro indole) D2,
Use F behind 22 0 2-(5-fluoro indole) D2,
Use F behind 23 1 2-(5-fluoro indole) D2,
Use F behind 24 1 3-(the 5-methoxyl group indoles) D2,
Use F behind the 25 0 2-quinoxaline D2,
Use F behind the 26 0 quinhydrones D2,
Use F behind the 27 0 4-resorcinol D2,
Use F behind 28 1 couples of biphenyl D4,
Use F behind the 29 1 2-naphthalene D2,
Example 30 and 31
With polyamines 17 and suitable R-acetate or carboxylic acid is starting raw material, has R(CH by method D1 and F preparation
2)
mCO[NH(CH
2)
3]
4NH
2The compound of 4TFA structure.
Example m R
30 0 ferrocene
31 1 3-indoles
Example 32 and 33
With polyamines 14 and suitable R-acetate or carboxylic acid is starting raw material, has R(CH with method F preparation then by method D1
2)
mCO[NH(CH
2)
3]
3NH
2The compound of 3TFA structure.
Example m R
32 0 ferrocene
33 1 3-indoles
Example 34 and 35
With polyamines 11 and suitable R-acetate or carboxylic acid is starting raw material, has R(CH with method F preparation then by method D1
2)
mCO[NH(CH
2)
3]
2NH
2The compound of 2TFA structure.Example m R
34 0 ferrocene
35 1 3-indoles
Example 36 and 37
With polyamines 7 and suitable R-acetate or carboxylic acid is starting raw material, has R(CH by method D1 and F preparation
2)
mCONH(CH
2)
3NH
2The compound of TFA structure.
Example m R
36 0 ferrocene
37 1 3-indoles
Example 38 and 39
With polyamines 23 and suitable R-acetate or carboxylic acid is starting raw material, has R(CH by method D1 and F preparation
2)
mCO[NH(CH
2)
3]
6NH
2The compound of 6TFA structure.
Example m R
38 0 ferrocene
39 1 3-indoles
Example 40 and 41
With polyamines 26 and suitable R-acetate or carboxylic acid is starting raw material, has R(CH by method D1 and F preparation
2)
mCO[NH(CH
2)
3]
7NH
2The compound of 7TFA structure.
Example m R
40 0 ferrocene
41 1 3-indoles
Preparation method A
Under nitrogen gas stream, with the 600ml N of 34.5 gram (157.6 mmole) 3-bromine propylamine HBr, dinethylformamide solution stirring.In this solution, add 34.4 gram (157.6 mmole) di-t-butyl pyrocarbonate and 32.3ml(236 mmoles in succession) triethylamine.Form precipitation immediately.The reactant stirring is spent the night.Reaction mixture is diluted to 1.5L with ethyl acetate then, with 500 1N HCl washing 1 time, and with 500ml water washing 3 times, with salt water washing 1 time, and through Na
2SO
4Dry.After concentrating, product is through 800 gram silica gel column chromatographies, and with 4: 1 hexane/ethyl acetate wash-outs, cut was by TLC(hexane/ethyl acetate, KMnO
4/ I
2) monitoring.The cut that will contain product merges, and concentrates under vacuum, uses 50ml washed with dichloromethane 2 times, and concentrated and purified by high vacuum, obtains the product of 25.8 these one step preparation methods of gram.
Claims (6)
1, the method for preparing following formula: compound,
Wherein R be five to seven-element carbon ring system or eight to the undeca carbon ring system, perhaps for by being independently selected from F, Cl, Br, OH, C more than 1 or 1
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, phenyl, amino, C
1-C
4Alkylamino and two (C
1-C
4Alkyl) the arbitrary above-mentioned carbon-loop system of amino substituting group replacement,
M is zero or 1,
R ' is-[NH (CH
2)
n]
xNH
2,
Each n is 2-5 independently,
X is 1-6,
This method comprises
(a) based on the reagent of carbodiimide and form in the presence of the catalyzer of amido linkage,, make formula R compound and formula Boc-NH (CH in reaction is in the inert solvent
2)
n[N (Boc) (CH
2)
n]
X-1The reaction of N (Boc) H compound, wherein Boc represents tert-butoxycarbonyl, and the definition of R, n and x is the same,
(b) use the organic or inorganic acid treatment, slough tert-butoxycarbonyl.
2, in accordance with the method for claim 1, wherein the reagent system based on described carbodiimide is selected from dimethylamino-propyl, ethyl carbodiimide and dicyclohexylcarbodiimide, and the catalyzer system of described formation amido linkage is selected from hydroxybenzotriazole and N-Hydroxysuccinimide.
3, according to claim 1 or 2 described methods, wherein the solvent that reaction is inert is a methylene dichloride, and described organic or inorganic acid system is selected from trifluoroacetic acid and hydrochloric acid.
4, according to any one described method among the claim 1-3, wherein x is 5, and each n is 3 or 4 independently.
5, according to any one described method among the claim 1-4, wherein R is a phenyl or by the mono-substituted phenyl of F, Cl, Br, OH or MeOH, and m is 1.
6, according to any one described method among the claim 1-5, wherein R is-[NH(CH
2)
3]
3-NH(CH
2)
4-NH(CH
2)
3-NH
2
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US74901491A | 1991-08-23 | 1991-08-23 | |
| US749,014 | 1991-08-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1069969A true CN1069969A (en) | 1993-03-17 |
Family
ID=25011863
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92109681A Pending CN1069969A (en) | 1991-08-23 | 1992-08-22 | Synthetic aryl polyamines as exicitatory/amino acid neurotransmitter antagonists |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0641312A1 (en) |
| JP (1) | JPH06505996A (en) |
| CN (1) | CN1069969A (en) |
| AU (1) | AU2426392A (en) |
| BR (1) | BR9206403A (en) |
| CA (1) | CA2114798A1 (en) |
| CZ (1) | CZ39994A3 (en) |
| FI (1) | FI940833A0 (en) |
| HU (1) | HU9400503D0 (en) |
| IL (1) | IL102835A0 (en) |
| MX (1) | MX9204866A (en) |
| PT (1) | PT100801A (en) |
| WO (1) | WO1993004036A1 (en) |
| ZA (1) | ZA926314B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6071970A (en) * | 1993-02-08 | 2000-06-06 | Nps Pharmaceuticals, Inc. | Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases |
| US6750244B2 (en) | 1993-02-08 | 2004-06-15 | Nps Pharmaceuticals, Inc. | Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases |
| US7087765B2 (en) | 1995-06-07 | 2006-08-08 | Nps Pharmaceuticals, Inc. | Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases |
| US6211245B1 (en) | 1993-02-08 | 2001-04-03 | Nps Pharmaceuticals, Inc. | Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases |
| US6017965A (en) * | 1993-02-08 | 2000-01-25 | Nps Pharmaceuticals, Inc. | Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases |
| AU710575B2 (en) | 1994-02-08 | 1999-09-23 | Nps Pharmaceuticals, Inc. | Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases |
| US6261996B1 (en) * | 1995-06-08 | 2001-07-17 | Rhone-Poulenc Inc. | Pregerminated rice seed |
| US7087648B1 (en) | 1997-10-27 | 2006-08-08 | The Regents Of The University Of California | Methods for modulating macrophage proliferation using polyamine analogs |
| US8198334B2 (en) | 1997-10-27 | 2012-06-12 | Pathologica Llc | Methods for modulating macrophage proliferation in ocular disease using polyamine analogs |
| AU2003231670B2 (en) * | 1997-10-27 | 2006-06-08 | Slil Biomedical Corporation | Methods for modulating macrophage proliferation using polyamine analogs |
| JP2005506354A (en) | 2001-10-16 | 2005-03-03 | スリル バイオメディカル コーポレイション | Oligoamine compounds and their derivatives for cancer treatment |
| JP2007505044A (en) * | 2003-09-09 | 2007-03-08 | ユニバーシティ オブ フロリダ リサーチ ファウンデイション、インコーポレイテッド | Polyamine-metal chelator assembly |
| CN103073448B (en) * | 2012-12-29 | 2015-11-18 | 河南大学 | Containing the polyamine derivative and its preparation method and application of aromatic ring structure |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5037846A (en) * | 1990-01-02 | 1991-08-06 | Pfizer Inc. | Indolyl-3 polyamines and their use as antagonists of excitatory amino acid neurotransmitters |
-
1992
- 1992-08-10 AU AU24263/92A patent/AU2426392A/en not_active Abandoned
- 1992-08-10 HU HU9400503A patent/HU9400503D0/en unknown
- 1992-08-10 CA CA002114798A patent/CA2114798A1/en not_active Abandoned
- 1992-08-10 JP JP5504331A patent/JPH06505996A/en active Pending
- 1992-08-10 BR BR9206403A patent/BR9206403A/en not_active Application Discontinuation
- 1992-08-10 WO PCT/US1992/006482 patent/WO1993004036A1/en not_active Application Discontinuation
- 1992-08-10 EP EP92916921A patent/EP0641312A1/en not_active Withdrawn
- 1992-08-10 CZ CS94399A patent/CZ39994A3/en unknown
- 1992-08-17 IL IL102835A patent/IL102835A0/en unknown
- 1992-08-21 ZA ZA926314A patent/ZA926314B/en unknown
- 1992-08-21 MX MX9204866A patent/MX9204866A/en unknown
- 1992-08-21 PT PT100801A patent/PT100801A/en not_active Application Discontinuation
- 1992-08-22 CN CN92109681A patent/CN1069969A/en active Pending
-
1994
- 1994-02-22 FI FI940833A patent/FI940833A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| MX9204866A (en) | 1993-04-01 |
| FI940833A (en) | 1994-02-22 |
| BR9206403A (en) | 1994-12-27 |
| AU2426392A (en) | 1993-03-16 |
| ZA926314B (en) | 1994-02-21 |
| WO1993004036A1 (en) | 1993-03-04 |
| CZ39994A3 (en) | 1994-11-16 |
| CA2114798A1 (en) | 1993-03-04 |
| EP0641312A1 (en) | 1995-03-08 |
| IL102835A0 (en) | 1993-01-31 |
| JPH06505996A (en) | 1994-07-07 |
| FI940833A0 (en) | 1994-02-22 |
| PT100801A (en) | 1993-09-30 |
| HU9400503D0 (en) | 1994-05-30 |
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