CN1827621A - Novel derivatives and analogues of galanthamin - Google Patents
Novel derivatives and analogues of galanthamin Download PDFInfo
- Publication number
- CN1827621A CN1827621A CN 200610054791 CN200610054791A CN1827621A CN 1827621 A CN1827621 A CN 1827621A CN 200610054791 CN200610054791 CN 200610054791 CN 200610054791 A CN200610054791 A CN 200610054791A CN 1827621 A CN1827621 A CN 1827621A
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- Prior art keywords
- alkyl
- hydrogen
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- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- -1 2-methoxy-propyl Chemical group 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 26
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
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- 125000002636 imidazolinyl group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
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- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical class O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 26
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- AIXQQSTVOSFSMO-RBOXIYTFSA-N Norgalanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CNCC[C@]23[C@@H]1C[C@@H](O)C=C2 AIXQQSTVOSFSMO-RBOXIYTFSA-N 0.000 description 12
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- AIXQQSTVOSFSMO-UHFFFAOYSA-N N-norgalanthamine Natural products O1C(=C23)C(OC)=CC=C2CNCCC23C1CC(O)C=C2 AIXQQSTVOSFSMO-UHFFFAOYSA-N 0.000 description 11
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
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- 230000001684 chronic effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BLCTWBJQROOONQ-UHFFFAOYSA-N ethenyl prop-2-enoate Chemical compound C=COC(=O)C=C BLCTWBJQROOONQ-UHFFFAOYSA-N 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 238000002444 silanisation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Abstract
The invention relates to novel compounds of general formula (IV).
Description
The application is to be 01801342.2 divide an application in the application number that on January 21st, 2002 submitted to Patent Office of the People's Republic of China, therefore is clear that for those skilled in the art, can be with reference to the content of quoting in above-mentioned female case application for the understanding of this case application content.
The present invention relates to the benzofuran derivative of new replacement, its preparation method and salt with and following purposes:
A) treatment alzheimer's disease,
B) treatment Parkinson disease,
C) treatment Heng Tingdunshi disease (huntington's chorea),
D) treatment multiple sclerosis,
E) treatment amyotrophic lateral sclerosis,
F) treatment epilepsy,
G) treatment apoplexy sequela,
H) treatment craniocerebral trauma sequela,
I) sequela of diffusion oxygen and nutraceutical shortage in treatment and the prevention of brain, for example in anoxic, anoxia, suffocate, after asystolia and the poisoning and the complication when the baby has difficult labour or observed in the anesthesia situation,
J) also can prophylactically treat the vertical sex change of taking off in the neurone especially, particularly by the local radiotherapy of cerebral tumor or chemotherapy infringement,
K) treatment bacterial meningitis,
L) treat and take off the constituent element diseases associated of hanging down, the consequence of the cytopathy that amyloid is relevant in particular,
M) treatment diabetes are if this disease is accompanied by the islet cells amyloidosis especially.
Lycoremine derivative that the present invention is new and analogue can improve alzheimer's disease patient's muscular strength and endurance.
New compound of the present invention is the compound of general formula I V
Wherein substituting group has the implication of explained later:
Aa) R
1Be hydrogen or Br;
Ab) R
2Be hydrogen;
B) R
3Expression OCH
3,
D) R
4And R
5Be
Da) two is hydrogen, perhaps
Db) R
4And R
5One of be hydrogen, alkyl, aralkyl, alkenyl, aralkenyl, alkynyl or sweet-smelling alkynyl, R
4And R
5In another be:
Dbi) OR
6, R wherein
6Expression hydrogen, rudimentary C
1-C
10, straight or branched alkyl or cycloalkyl, C
3-C
10The silyl that replaces, C
2-C
10-alpha-alkoxy base alkyl, 2-methoxy-propyl, ethoxyethyl group, THP trtrahydropyranyl, tetrahydrofuran base, phenoxymethyl or 1-phenoxy group ethyl;
Dbii) O-CS-NHR
6, R wherein
6Have above-mentioned Dbi) in the implication that provides;
Dbiii) O-CO-NHR '
7, R ' wherein
7Have following meanings:
Dbiv) O-CO-R
6, R wherein
6Have above-mentioned Dbi) in the implication that provides,
Dbv) NR
7R
7, two substituent R wherein
7Be identical or different, and represent hydrogen, rudimentary C
1-C
4, straight or branched alkyl or cycloalkyl, perhaps substituent R
7Expression-(CH together
2)
n-, wherein n is 3 to 5;
Dbvi) NH-COR
6, R wherein
6Have above-mentioned Dbi) in the implication that provides;
Dbvii) S-R
6, R wherein
6Have above-mentioned Dbi) in the implication that provides;
Dbviii) SO
nR
8, wherein n is 0,1 or 2, wherein R
8Be C
1-C
10, straight or branched or cyclisation, replacement or unsubstituted alkyl or aralkyl;
Dbix) R
4Be hydrogen, R
5Be OH, CN, CO
2-alkyl, CONR
aR
b, R wherein
aBe hydrogen, rudimentary C
1-C
6, straight or branched or cyclisation, replacement or unsubstituted alkyl, R
bBe hydrogen, rudimentary C
1-C
6, straight or branched, replacement or unsubstituted alkyl, perhaps R
a+ R
bBe together-(CH
2)
n-, wherein n is 2 to 6, perhaps-and (CH
2)
nE (CH
2)
n-, wherein E is that NH, N-alkyl, O or S and n are 0 to 5, aryl, and 6-π heterocyclic radical, imidazolinyl, thiazolinyl Huo oxazolinyl,
Dbx) R
4And R
5Be together=O ,=N-NH-R
9,=N-NR
9R
10Perhaps=N-OR
10, R wherein
9Be hydrogen, rudimentary C
1-C
6, straight or branched or cyclisation, replacement or unsubstituted alkyl, aralkyl or alkyl-carbonyl, aromatic alkyl carbonyl, alkyl-carbonyl oxygen base, aromatic alkyl carbonyl oxygen base or sulfonic group, and R
10Be hydrogen, rudimentary C
1-C
6, straight or branched or cyclisation, replacement or unsubstituted alkyl, aralkyl or alkyl-carbonyl, aromatic alkyl carbonyl, sulfonic group;
Dbxi) R
4And R
5Represent following type substituting group together
Y wherein
1And Y
2Be identical or different, and expression O, S, NH or N-R
9, wherein free valency under any circumstance all is a hydrogen, R
8Have above-mentioned Dbiii) in the implication mentioned, and R
9Have above-mentioned Dbx) in the implication mentioned;
E) G
1:-(CH
2)
x-, wherein x is 1 or 2;
F) G
2:-(CH
2)
y-, wherein y is 0 to 2; With
R wherein
18And R
19Expression hydrogen, alkyl, aryl or aralkyl, and wherein carry substituent R
18And R
19The C atom interconnect through singly-bound or two key, W represents CH or N.
Preferably substituting group W is nitrogen and/or substituting group G in the general formula I V compound
1Be-(CH
2)
x-, wherein x is 1 or 2 and G
2Expression-(CH
2)
y-, wherein y is 0 to 2, and precondition is that x+y is 2 at least, and maximum is 4.
At above-mentioned Dbi) in R
6Represent triethylsilyl, trimethyl silyl, tert-butyl dimetylsilyl or 3,5-dimethylphenyl silyl further, methoxymethyl, ethoxyl methyl, 2-methoxy-propyl, ethoxyethyl group.
And above-mentioned 6-π heterocyclic radical can be imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazyl, oxadiazole base, thiadiazolyl group, pyridazinyl, pyrimidyl, pyrazinyl and substituted these groups, and the substituting group under the wherein replacement situation has above-mentioned D) described in implication.
In addition advantageously, above-mentioned R
5The outer implication of expression dehydrogenation, R
4Expression OH.
In addition, Y
1Be NH and Y
2Be N-R
9, and R
4And R
5By-(CH
2)
n-connection, wherein n=2,3 or 4.
From racemize Norgalanthamine separating optical isomers:
In addition, the present invention includes chiral separation (6R)-3-methoxyl group-5,6,9,10,11,12-six hydrogen-4aH[1] the cumarone method of [3a, 3,2-ef] [2] benzo-aza-6-alcohol (Norgalanthamine) (4) also
(+) and separating by fractional crystallization of (-) isomer carry out in the following manner:
* with mixture of optical isomers in
* in the solvent of 3 to 50 times of amounts, the mixture of water, methyl alcohol, ethanol, propyl alcohol, Virahol, acetone or solvent for example, solution in the particular methanol or suspension
* mix with equimolar amount or excessive chiral acid (O-two-right-toluyl tartrate, it is dissolved in one of above-mentioned solvent for unsubstituted, that single or multiple replaces (+) or (-) tartrate, citric acid, lactic acid, preferred (+)-O)
* this solution is used by natural (-) lycoremine derivative and chiral organic acid, for example (+)-O, O-two-right-toluyl tartrate, the crystal inoculation of preparation,
* and-40 to+20 spend, preferred 0 degree was placed 2-24 hour or longer down,
* filter the crystal that forms, and dry,
* then, with excessive N H
4OH mixes, and, isolate (-) Norgalanthamine accordingly by solvent distillation with for example chloroform, methylene dichloride, ethyl acetate, butylacetate, diethyl ether, t-butyl methyl ether, dibutyl ether, sherwood oil, dimethylbenzene, benzene, toluene or similar solvent extraction of organic solvent.
In the method, the evaporation concentration mother liquor absorbs excessive N H
4Among the OH, extraction (same as above) is with an organic solvent also evaporated other cut of Norgalanthamine, thus in the same manner described above, and by chiral organic acid (-)-O for example, O-two-toluoyl base tartrate preparation (+) Norgalanthamine.
The product that obtains according to the present invention can be by the method that is fit to, and for example distillation, fractional crystallization or chromatography are carried out purifying.
In compound of the present invention, consider the compound of mentioning below especially:
In the table look-up below, " AchE " represents acetylcholinesterase, and " BchE " represents butyrylcholine esterase, " hr " expression people recombinant chou, and the pre-cultivation of the enzyme of inhibitor is adopted in " mE " expression, and " IC
50" the concentration when 50% inhibition takes place in expression.
In scope of the present invention, especially especially should consider compound (6R)-3-methoxyl group-5,6,9,10,11,12-six hydrogen-4a[H1] cumarone [3a also, 3,2-ef] [2] benzo-aza-6-alcohol (Norgalanthamine), particularly racemize Norgalanthamine, (-) Norgalanthamine and (+) Norgalanthamine.Racemize Norgalanthamine and (+) thereof-and (-)-isomer itself or with other active ingredient make up be used for the treatment of as activeconstituents above-mentioned a) to m) under in the pharmaceutical composition of the disease mentioned.
Compound of the present invention can synthesize by correctly adopting the method and the process form that prepare lycoremine and lycoremine derivative described among WO 96/12692 and the WO 97/40049.
Except that above-mentioned synthetic method, compounds more of the present invention can also adopt (or similarly) synthetic technology of combination to prepare.In this synthetic method, interested basic framework (or core element) is fixed on the solid phase (for example granulated glass sphere, polymeric beads or other inert support), this solid is easy to isolate remaining reactive component mutually from improved basic framework.Employed in each case solid depends on supporting capacity, employed reagent and reaction solvent mutually.Especially, should consider polymeric beads, for example Merriefield resin, Wang resin or TentaGel (Rapp) resin.
The fixing of basic framework can be realized by the functional group that regains in the synthetic final step under the reaction conditions that is fit to.Described final step is by the required product of the middle mutually separation of solid.The selection that basic molecule is coupled to the connector element of solid phase is depended on reagent and is obtained maximum yield and/or the combination and/or the result of the reaction conditions that purity is required.In addition, adopt different contacts (Linker), can be under different conditions isolate product mutually from identical solid.This technology allows the synthetic fast automatically synthetic compound of the present invention that comprises.
About chemical combination and/or similar synthetic,, ordinary method has been described in these documents referring to following reference:
1) Abelson, J.N., " combinatorial chemistry " (Combinatorial Chemistry), academic press (Academic Press), San Diego (1996).
2) Epton, R., " innovation that solid is combined to and prospect " (Innovation andPerspectives in Solid Phase Synthesis and CombinatorialLibraries), Mayflower Scientific Limited, Birmingham (1996).
3) Wilson, S.R.and Czarnik, A.W., " combinatorial chemistry " are (CombinatorialChemistry). " synthetic and application " (Synthesis and Applications) .JohnWiley; Sons, Inc., New York (1997).
4) Gordon, E.M.and Kerwin, J.F.J., " synthetic chemistry in the drug discovery and molecular diversity " (Combinatorial Chemistry and Molecular Diversityin Drug Discovery) .John Wiley and Sons, Inc., New York (1998).
5)Thompson，L.A.，Ellman，J.A.Chem.Rev.96，555(1996).
6) " particular problem in the combinatorial chemistry " (Special Issue on CombinatorialChemistry), referring to Acc.Chem.Res., 29,111 (1996).
7) Fruchtel, J.S.; Jung, G. " applied chemistry " is Int.Ed.Engl.35 (Angew.Chem.), and 17 (1996).
8) Cheng, S.; Comer, D.D.; Williams, J.P.; Myers, P.L.; Boger, D.L. " Journal of the American Chemical Society " (J.Am.Chem.Soc.), 118,2567 (1996).
9) out of Memory in the field of relevant this fast development referring to:
Http:// www.5z.comThe dynamic data of reference in the molecular diversity (A Dynamic Database of References inMolecular Diversity).
10)Bayer，E.；Angew Chem.Int.Ed.，30，113-129(1991).
11)Mayer，J.P.；Zhang，J.；Bjergarde，K.；Lentz，D.M.；Gaudino，J.J.；Tetrahedron Letters，37，8081(1996).
12)Bayer，E.；Angew.Chem.Int.Ed.，30，113-129(1991).
13)DE 19745628 A1.
At Norgalanthamine structure (G
1=G
2=G
3=methylene radical; W=NH) or " high lycoremine (G
1=G
2=G
3=methylene radical; W=CH-NH
2) example in, molecule is alternate with solid can (((N-connection) or oxygen center (O-connection) comes bonding for (C-is connected), nitrogen center through carbon center.Bonding point depends on the improved type of desired structure.In the reaction synoptic diagram of the illustrative of mentioning below, the various variation that is bonded in the basic framework that different solids go up mutually by contact is described.
Contact=-X (CH
2)
nCO (X=CH
2, CO, O, S, NH) ,-X (CH
2)
nOCO (X=CH
2, CO, O, S, NH),
-XC
6H
4CH
2-(X＝CH
2，CO，O，S，NH)，THP，-X(CH
2)
nSi(alkyl)
2-，
The variation of the O-contact of the skeleton of Norgalanthamine class and " high lycoremine " class
Contact=X (CH
2)
nCO (X=CH
2, O, NH, SO
0-2), X (CH
2)
nCS (X=CH
2, O, NH, SO
0-2),
X(CH
2)
nJCO(X＝CH
2，O，NH，SO
0-2；J＝NH，O，S)，XC
6H
4CH
2(X＝CH
2，O，S)，
The variation of the N-contact of Norgalanthamine quasi-molecule skeleton
E=H, halogen, acyl group, alkoxy carbonyl, contact=-(CH
2)
nSi (alkyl)
2-,-C
6H
4Si (alkyl)
2-,
NO
2-(CH
2)
nSn (alkyl)
2-,-C
6H
4Sn (alkyl)
2-,
-(CH
2)
nS，-C
6H
4S
The variation of the C-contact of Norgalanthamine class skeleton
Contact=-(CH
2)
nSi (alkyl)
2-,-C
6H
4Si (alkyl)
2-,
-(CH
2)
RSn (alkyl)
2-,-C
6H
4Sn (alkyl)
2-,
-(CH
2)
nS，-C
6H
4S
The variation of the C-contact of " high lycoremine skeleton "
The activeconstituents that compound of the present invention and pharmaceutically acceptable acid additive salt thereof can be used as in the pharmaceutical composition for example is used for the treatment of disease with taking off the group nothing (apoptotischer Komponente) of hanging down.
Human nervous system's neurodegenerative disease comprises these syndromess, promptly now to its no methods of treatment or ill-founded methods of treatment only is provided.The disease that this class chronic neuropathic is learned is at first answered following being interpreted as:
--abiotrophic degeneration's dementia (mainly being the alzheimer's disease),
--brain and backbone paralysis (amyotrophic lateral sclerosis, multiple sclerosis),
--the former obstacle of central inducedmotion (Parkinson disease and Heng Tingdunshi disease) and
--epilepsy class disease.
Yet neurodegeneration works in the direct result of nervosa acute disease equally, wherein mainly mentions following:
--ischemic stroke (destroying the artery of supply brain),
--hemorrhagic stroke (ICH),
--skull-big cerebral trauma, and
--the brain injury (anoxic/anoxia) after heart failure or the breath stopped.
The active ingredient that acceptable acid additive salt can be used as in the medicine on compound of the present invention and the pharmacology thereof is used for the treatment of neurodegenerative process, and its purpose is not mainly to improve acute symptom, but delays and alleviate relevant therewith process.
In type ii diabetes, the effect of amyloid fragment in the cytopathy of the islet cells that produces Regular Insulin is more and more significant.This cytopathy can go into to increase the weight of by uncontrolled calcium current.
1，2，3
Acceptable acid additive salt can be used as the active ingredient in the medicine on compound of the present invention and the pharmacology thereof, for example, is used for the treatment of the degenerative disease (type ii diabetes) of islet cells.
Compound of the present invention can be used as the active ingredient in the medicine, and its purposes is as follows
A) treatment alzheimer's disease,
B) treatment Parkinson disease,
C) treatment Heng Tingdunshi disease (huntington's chorea),
D) treatment multiple sclerosis,
E) treatment amyotrophic lateral sclerosis,
F) treatment epilepsy,
G) treatment apoplexy sequela
H) treatment craniocerebral trauma sequela
I) sequela of diffusion oxygen and nutraceutical shortage in treatment and the prevention of brain, for example in anoxic, anoxia, suffocate, after asystolia and the poisoning and the complication when the baby has difficult labour or observed in the anesthesia situation.
J) also can prophylactically treat the vertical sex change of taking off in the neurone especially, particularly by the local radiotherapy of cerebral tumor or chemotherapy infringement.
K) treatment bacterial meningitis,
L) treat and take off the constituent element diseases associated of hanging down, the consequence of the cytopathy that amyloid is relevant in particular,
M) treatment diabetes are if this disease is accompanied by the islet cells amyloidosis especially.
Acceptable acid additive salt on compound of the present invention or its pharmacology, for example, (seeing table) such as hydrobromide, hydrochloride, methyl-sulfate, methiodide, tartrate, fumarate, oxalate can oral, rectal administration, perhaps by subcutaneous, intramuscular, vein or sheath inner injecting medicine-feeding, perhaps diffusion or big Intraventricular administration are for example used and are implanted container.
When taking these activeconstituentss, general dosage depends on the characteristic of compound used therefor, and when intravenously administrable, according to patient's body situation and other medicining condition, application dosage is 2.0 milligrams of every day and every kg body weight 0.01 to.
Can use the following customization agent of giving:
Contain 0.5 to 50 milligram tablet or capsule
The solution that contains 0.1 to 30 milligram of activeconstituents/milliliter through administered parenterally
Concentration is the liquid preparation of the oral administration of 0.1 to 15 mg/ml
Concentration is the liquid preparation of the big Intraventricular administration of 1 to 5 milligram of activeconstituents/milliliter.
Compound of the present invention also can be that burst size is the formulation of the percutaneous dosing of 0.1 to 10 mg/day.
The formulation of percutaneous dosing is formed as the storage layer of the active substance of free alkali or salt together with tenderizer (for example Isopropyl myristate) with infiltration accelerator (for example dimethyl sulfoxide (DMSO)), carboxylic acid (for example sad) and subcutaneous polyacrylic ester (for example vinylformic acid polyhexamethylene/vinyl acrylate/acrylic copolymer) in case of necessity by comprising 0.1 to 30 milligram.Can be used as tectal is that thickness for example is 0.35 millimeter the impermeable skin of activeconstituents, polyethylene surgical adhesive for example washing, silanization.In order to prepare adhesive layer, for example can be used in the first dimethylaminomethyl acrylate/Sipacril 2739OF in the organic solvent.
The invention still further relates to pharmaceutical composition, it comprises the compound that at least a the present invention of significant quantity proposes in the treatment in acceptable assistant on pharmacology.
The present invention also extends to these compounds and is used for the purposes of pharmaceutical compositions and the method for these compounds of preparation.
Especially, compound of the present invention shows the effect that suppresses Pseudocholinesterase in many cases, is suitable for the activeconstituents that treats and/or prevents as senile dementia, alzheimer's disease etc.The compound that the present invention proposes be a kind of new tetra-atomic ring, condensed, heterogeneous ring compound.
Except that having the performance for the treatment of and/or preventing, compound of the present invention and composition can also be used to diagnose the state of an illness of the above-mentioned type disease.
Document:
1) Kawahara, M.; Kuroda, Y.; Arispe, N.; Rojas, E.; " according to the general mechanism Alzheimer amyloid-beta in hypothalamus BnRH neuronal cell system; free ca rising (PrionProtein Fragment Evoke Intracellular Free Calcium Elevations bya Common Mechanism in a Hypothalamic BnRH Neuronal Cell Line) " " journal of biological chemistry " (J Biol Chem) 2000 in the born of the same parents that human cell island amylopectin and prion protein fragment cause, 5,12; 275 (19): 14077-83
2) Ma, Z.:Westermark, P.; Westermark, GT; " amyloid in the human pancreas islet: the immune evidence (Amyloid in Human Islets of Langerhans:Immunologic Evidencethat Islet Amyloid Polypeptide is Modified in Amyloidogenesis) that islet amyloid sample protein polypeptide is modified in amyloid generates " Pancreas 2000,8; 21 (2): 212-8
3) Rhoades, E.; Agarwal, J.; Gafni, A.; " amyloid of human cell island amyloid polypeptide generates segmental congregation (Aggregation of anAmyloidogenic Fragment of Human Islet Amyloid Polypeptide) " Biotin Biophys Acta 2000 February 9; 1476 (2): 230-8
Below, the working rule and the embodiment that prepare compound of the present invention are described.
In a word bright
" concentrate " and refer under reduced pressure remove desolvate by means of rotary gasifier.
" MPLC " is illustrated in the chromatogram purification on silica gel 20-60 μ m under the condition of using Buech chromatographic column, Shimadzu LC-8A pump and Shimadzu 6AVUV detector.
Embodiment 1:
Step 1:4-bromo-2-methoxyl group-5-(2-nitroethylene base)-phenol
C
8H
7BrO
3[231.05] C
9H
8BrNO
4[274.07]
Under refluxing, 40.0g (173mmol) 2-bromo-5-hydroxyl-4-methoxybenzaldehyde and 13.3g (173mmol) ammonium acetate were heated 15 minutes in 400 milliliters of Nitromethane 99Min.s.This reaction mixture is evaporated to drying, with resistates boiling in about 70 ml methanol, suction subsequently.In order to obtain second fraction of this product, the methanol solution evaporation concentration to about 30 milliliters, is poured in 500 ml waters then.Go out precipitated solid by suction filtration, with about 100 ml waters washing, and dry under 50 ℃/50 millibars with first fraction, therefore obtain 43.6g (92% theoretical value) yellow crystals shape 4-bromo-2-methoxyl group-5-(2-nitroethylene base)-phenol altogether, its fusing point is 152-154 ℃.
TLC：CH
2Cl
2∶MeOH＝9∶1
1H-NMR(CDCl
3；δ(ppm)：3.85(s，3H，OCH
3)；7.30(s，1H，H-6)；7.38(s，1H，H-3)；8.03(d，
3J
HH＝13.41Hz，1H，ArCH＝)；8.16(d，
3J
HH＝13.41Hz，1H，＝CHNO
2)
13C-NMR(CDCl
3；δ(ppm)：56.3(q，OCH
3)；114.7(d，C-6)；116.1(d，C-3)；116.6(s，C-2)；121.4(s，C-1)；136.8(d，ArCH＝)；137.6(d，＝CHNO
2)；146.5(s，C-5)；152.2(s，C-4)
Step 2:4-bromo-2-methoxyl group-5-(2-amino-ethyl)-phenol
C
9H
8BrNO
4[274.07] C
9H
12BrNO
2[246.11]
Method A:
Under 0 ℃, under nitrogen atmosphere, 7.2g (74mmol) vitriol oil is added drop-wise in 168ml (148mmol) the 0.88N solutions of lithium aluminium hydride in diethyl ether.10.0g (36.5mmol) 4-bromo-2-methoxyl group-5-(2-nitroethylene base)-phenol is dissolved in 1 liter of anhydrous diethyl ether under the boiling temperature by part, then, at room temperature, supernatant liquor is added in the aluminum hydride solution by means of liquid-transfering needle pipe and exsiccant nitrogen.After adding fully, come the diethyl ether of reaction mixture in receiving flask, to distill undissolved 4-bromo-2-methoxyl group-5-(2-nitroethylene base)-phenol 700ml.Prepare a kind of saturated solution by being heated to reflux, and it is added in the above-mentioned reaction mixture.Repeat this process (3 to 4 times) until adding 4-bromo-2-methoxyl group-5-(2-nitroethylene base)-phenol fully.Then, 0 ℃ of following water hydrolysis.And ether used the 4N hcl as extraction agent 2 times mutually, 300 milliliters of each consumptions.This acid solution is mixed with 22.2g (148mmol) L-(+)-tartrate, be adjusted to alkalescence with dense ammoniacal liquor, and with chloroform extraction to the greatest extent.The organic phase that merges is washed dry (Na with saturated sodium-chloride water solution
2SO
4), filter and evaporation concentration, therefore obtain 2.20g (24% theoretical value) clear crystal shape 4-bromo-2-methoxyl group-5-(2-amino-ethyl)-phenol, its fusing point is 170-172 ℃.
Method B:
Under nitrogen, 18.0g (65.7mmol) 4-bromo-2-methoxyl group-5-(2-nitroethylene base)-phenol was added drop-wise to 15.0g (394.2mmol) lithium aluminum hydride of reflux in the solution of 1 liter of anhydrous tetrahydro furan in the solution of 200ml anhydrous tetrahydro furan in 2 hours.Then, with ice-cooled down, reaction mixture with about 20 ml water hydrolysis, and is evaporated to drying regime.In residual collection to 500 milliliter 2N hydrochloric acid, and with the washing of 500 milliliters of ethyl acetate.To wash with 200 milliliters of 2N hydrochloric acid and rock repeatedly, and add 70g (467mmol) L-(+)-tartrate, and be adjusted to alkalescence, and with chloroform extraction 3 times, consumption is 800 milliliters at every turn with dense ammoniacal liquor at the aqueous phase that contains that merges.The organic phase that merges through dried over sodium sulfate, is filtered and evaporation concentration, therefore obtain 9.92g (61% theoretical value) clear crystal shape 4-bromo-2-methoxyl group-5-(2-amino-ethyl)-phenol, its fusing point is 170-172 ℃.
Step 3:4-bromo-5-{N-[(4-hydroxy phenyl) methyl]-the 2-amino-ethyl }-the 2-methoxyphenol
C
9H
12BrNO
2[246.11] C
7H
6O
2[122.12] C
16H
18BrNO
3[352.23]
With 6.4g (26.0mmol) 4-bromo-2-methoxyl group-5-(2-amino-ethyl)-phenol and 3.2g (26.0mmol) right-hydroxyl-phenyl aldehyde reflux 2 hours in 150 milliliters of dehydrated alcohols.Then, down add 5.0g (132.0mmol) sodium borohydride, and reheat refluxes half an hour, destroy remaining sodium borohydride by adding about 1 milliliter of Glacial acetic acid and 50 ml waters down ice-cooled, and this solution evaporation is concentrated ice-cooled.With resistates 2N hcl acidifying, and with the washing of 50 milliliters of chloroforms.During hydrolysis, may form a large amount of solid fragments, because they comprise a large amount of products, so before extraction, must grind.To wash with 30 milliliters of 2N hydrochloric acid and rock repeatedly, and the water that contains that will merge is adjusted to alkalescence with dense ammoniacal liquor, and with ethyl acetate extraction 3 times, 80 milliliters of each consumptions.Organic phase is merged,, filters and evaporation concentration, therefore obtain 8.9g (97% theoretical value) clear crystal shape 4-bromo-5-{N-[(4-hydroxy phenyl through dried over sodium sulfate) methyl]-the 2-amino-ethyl }-the 2-methoxyphenol, its fusing point is 69-72 ℃.
TLC：CHCl
3∶MeOH＝9∶1+2％NH
3
1H-NMR(DMSO；δ(ppm))：2.55-2.78(m，4H，ArCH
2CH
2NH)；3.58(s，2H，NHCH
2Ph)；3.73(s，3H，OCH
3)；6.60-6.76，7.02-7.14(2
*m，6H，2
*Ph)
13C-NMR(DMSO；δ(ppm))：35.2(t，ArCH
2)；48.7(t，CH
2CH
2NH)；52.2(t，NHCH
2Ph)；55.9(q，OCH
3)；111.3(s，C-4)；114.8(d，C-3′)；115.9(d，C-6)；117.3(d，C-3)；129.1(d，C-2′)；130.7(s，C-5)；131.4(s，C-1′)；146.0(s，C-2)；146.8(s，C-1)；156.0(s，C-4′)
Step 4:N-[2-(2-bromo-5-hydroxyl-4-p-methoxy-phenyl) ethyl]-the N-[(4-hydroxy phenyl) methyl] methane amide:
C
16H
18BrNO
3[352.23] C
17H
18BrNO
4[380.24]
With 8.5g (24.1mmol) 4-bromo-5-{N-[(4-hydroxy phenyl) methyl]-the 2-amino-ethyl }-2-methoxyphenol and 10ml (123.8mmol) ethyl formate and 2.5ml formic acid, 10ml N, a dinethylformamide and full spatula point dimethyl aminopyridine reflux 24 hours in 150 milliliters of anhydrous dioxane.When reaction finished soon, it is clear that initially white suspension becomes, and this mixture is mixed with 50 ml waters.Steam and remove dioxane, go out the white precipitate of generation by suction filtration, and wash with water, therefore obtain first fraction.With ethyl acetate extraction 3 times, 50 milliliters of each consumptions through dried over sodium sulfate, filter the organic phase that merges and evaporation concentration with filtrate.By column chromatography (50g silica gel, moving phase: CHCl subsequently
3: MeOH=97: 3) obtain another fraction.These two kinds of fractions are dry under 50 ℃/50 millibars, until constant weight, therefore obtain to amount to 6.6g (72% theoretical value) clear crystal shape N-[2-(2-bromo-5-hydroxyl-4-p-methoxy-phenyl) ethyl]-the N-[(4-hydroxy phenyl) methyl] methane amide, its fusing point is 104-106 ℃.
TLC：CHCl
3∶MeOH＝9∶1
1H-NMR(DMSO；δ(ppm))：2.56-2.78(m，2H，ArCH
2)；3.43-3.53(m，2H，CH
2N)；3.72(s，3H，OCH
3)；4.14(dd，2H，NCH
2Ph)；6.67-6.80，7.00-7.11(2
*m，6H，Ar，Ph)；9.30，9.48(2
*s，1H，CHO)
13C-NMR(DMSO；δ(ppm))：32.6，34.2(2
*t，ArCH
2)；41.5，44.3(2
*t，CH
2N)；46.1，50.4(2
*t，NCH
2Ph)；56.1(q，OCH
3)；111.4，111.6(2
*s，C-4)；115.1，115.2(2
*d，C-6)；115.6，115.7(2
*d，C-3′)；117.7，118.0(2
*d，C-3)；126.8，127.0(2
*s，C-5)；129.4(d，C-2′)；130.0(s，C-1′)；146.5，146.6(2
*s，C-2)；147.5，147.6(2
*s，C-1)；157.1，157.5(2
*s，C-4′)；162.7，163.0(2
*d，CHO)
Step 5:(4a α, 8a α)-4a, 5,9,10,11-six hydrogen-1-bromo-3-methoxyl group-6-oxygen-6H-cumarone is [3a, 3,2-ef]-[3] benzo-aza -10-formaldehyde also
C
17H
18BrNO
4[380.24] C
17H
16BrNO
4[378.23]
The sour potassium of 13g (39.5mmol) six cyanogen high ferros (III), 300ml chloroform and 50ml 10% wet chemical are heated to 60 ℃, under vigorous stirring, with 3g (7.9mmol) N-[2-(2-bromo-5-hydroxyl-4-p-methoxy-phenyl) ethyl]-the N-[(4-hydroxy phenyl) methyl] methane amide mixes, and then mechanical stirring 10 minutes tempestuously.Filter out the brown solid of generation then through Hyflo, use chloroform repetitive scrubbing 3 times, 30 milliliters of each consumptions, and firmly extruding.Then, filtrate is washed with about 150 ml waters, will wash with 150 milliliters of chloroforms and rock repeatedly, the organic phase that merges through dried over mgso, is filtered and evaporation concentration.By column chromatography (15g silica gel, moving phase: CHCl
3: MeOH=97: 3) purifying, obtain 580mg (19% theoretical value) clear crystal, its fusing point is 218-220 ℃.
TLC：CHCl
3∶MeOH＝9∶1
1H-NMR(CDCl
3；δ(ppm))：2.58-4.27(m，8H，H-5/5′/9/9′/11/11′/12/12′)；3.80(s，3H，OCH
3)；4.85(dd，1H，H-4a)；6.09(dd，1H，H-8)；6.53(dd，1H，H-7)；7.01(s，1H，H-2)；8.10，8.30(2
*s，1H，CHO
Conf，A/B)
13C-NMR(CDCl
3；δ(ppm))：33.4，35.3(2
*t，C-9
Conf，A/B)；37.2，37.4(2
*t，C-5
Conf，A/B)；43.7(t，C-11)；48.7，49.0(2
*t，C-12
Conf，A/B)；50.9，51.4(2
*s，C-8a
Conf，A/B)；56.2(q，OCH
3)；83.8，84.3(2
*s，C-4a
Conf，A/B)；115.3，115.7(2
*s，C-1
Conf，A/B)；116.8，117.0(2
*d，C-8
Conf，A/B)；127.6，128.9(2
*s，C-12a
Conf，A/B)；128.0，128.8(2
*d，C-7
Conf，A/B)；129.8，130.8(2
*s，C-12b
Conf，A/B)；141.5，141.7(2
*d，C-2
Conf，A/B)；143.8，144.0(2
*s，C-3a
Conf，A/B)；146.8(s，C-3)；161.7，162.3(2
*d，CHO)；193.0，193.4(2
*s，C-6)
C
17H
16BrNO
4 (JOS 1526) 378.23g/mol
Calculated value: C 53.99 H 4.26 N 3.70
Measured value: C 53.70 H 4.47 N 3.41
Step 6:(4a α, 8a α)-4a, 5,9,10,11-six hydrogen-1-bromo-3-methoxyl group-6H-cumarone is [3a, 3,2-ef]-[3] benzo-aza -6-alcohol also
C
17H
16BrNO
4[378.23] C
16H
18BrNO
3[352.23]
Under-12 ℃, under nitrogen, 4ml (4.00mmol) 1N L-selectride drips of solution is added to 500mg (1.32mmol) (4a α, 8a α)-4a, 5,9,10,11-six hydrogen-1-bromo-3-methoxyl group-6-oxygen-6H-cumarone is [3a, 3 also, 2-ef]-[3] benzo-aza -10-formaldehyde in the solution of 12 milliliters of anhydrous tetrahydro furans, subsequently reaction mixture was stirred 1 hour down at-10 ℃.Then,, this solution evaporation to dry, is collected in 50 milliliters of 2N hydrochloric acid with 3 ml methanol hydrolysis, and vigorous stirring 1 hour again.Aqueous solution is washed with 50 milliliters of ethyl acetate, will wash with 20 milliliters of 2N hydrochloric acid and rock repeatedly, the water that contains that merges is adjusted to alkalescence with strong aqua, and with ethyl acetate extraction 3 times, consumption is 50 milliliters at every turn.With the organic phase that merges through dried over mgso, filter, and evaporation concentration, 380mg (82% theoretical value) pale yellow crystals shape (4a α therefore obtained, 8a α)-4a, 5,9,10,11-six hydrogen-1-bromo-3-methoxyl group-6H-cumarone is [3a also, 3,2-ef]-[3] benzo-aza -6-alcohol, its fusing point is 132-136 ℃.
TLC：CHCl
3∶MeOH＝9∶1
1H-NMR(CDCl
3；δ(ppm))：1.87(ddd，1H，H-5)；2.62(ddd，1H，H-5′)；2.68(ddd，1H，H-11)；2.78(d，1H，H-9，
2J
9/9′＝12.6Hz)；2.85(ddd，1H，H-11′)；2.98(d，1H，H-9′，
2J
9/9′＝12.6Hz)；3.30(ddd，1H，H-12)；3.37(ddd，1H，H-12′)；3.80(s，3H，OCH
3)；4.08(ddd，1H，H-6)；4.50(dd，1H，H-4a)；6.08(dd，1H，H-8，
3J
7/8＝10.2Hz)；6.15(d，1H，H-7，
3J
7/8＝10.2Hz)；6.96(s，1H，H-2)
13C-NMR(CDCl
3；δ(ppm))：30.2(t，C-5)；36.7(t，C-9)；49.7(t，C-11)；51.6(s，C-8a)；56.0(q，OCH
3)；57.3(t，C-12)；62.0(d，C-6)；85.5(d，C-4a)；114.9(s，C-1)；115.7(d，C-8)；127.3(d，C-2)；127.7(d，C-7)；130.5(s，C-12a)；134.2(s，C-12b)；143.5(s，C-3a)；145.4(s，C-3)
Step 7:(4a α, 8a α)-4a, 5,9,10,11-six hydrogen-1-bromo-3-methoxyl group-10-methyl-6H-cumarone is [3a, 3,2-ef]-[3] benzo-aza -6-alcohol also
C
16H
18BrNO
3[352.23] C
17H
20BrNO
3[366.26]
Under vigorous stirring, successively 165mg (2.63mmol) the cyano group sodium borohydride with 1ml 35% formalin and branch composition adds 370mg (1.05mmol) (4a α, 8a α)-4a, 5,9,10,11-six hydrogen-1-bromo-3-methoxyl group-6H-cumarone is [3a also, 3,2-ef] [3] benzo-aza -6-alcohol is in the solution of 12 milliliters of acetonitriles, and at room temperature with this reaction mixture vigorous stirring 1 hour.Then, make this solution acidifying with the hydrochloric acid of 2N, with 15 milliliters of washed with dichloromethane.To wash with 15 milliliters of 2N hydrochloric acid and rock repeatedly.The water that contains that merges is adjusted to alkalescence with dense aqueous ammonia, and with dichloromethane extraction 3 times, consumption is 30 milliliters at every turn.With the organic phase that merges through dried over mgso, filter and evaporation concentration, therefore obtain 355mg (92% theoretical value) yellow crystals shape (4a α, 8a α)-4a, 5,9,10,11-six hydrogen-1-bromo-3-methoxyl group-10-methyl-6H-cumarone is [3a, 3 also, 2-ef]-[3] benzo-aza -6-alcohol, its fusing point is 158-161 ℃.
TLC：CHCl
3∶MeOH＝9∶1
1H-NMR(CDCl
3；δ(ppm))：1.91-2.04(m，1H，H-5)；2.27-2.48(m，2H，H-5′/11)；2.41(s，3H，NCH
3)；2.60-2.81(m，2H，H-9/11′)；2.92-3.16(m，2H，9′/12)；3.34(dd，
3J
11/12′＝6.37Hz，
2J
12/12′＝16.48Hz，1H，H-12′)；4.13-4.25(m，1H，H-6)；4.58(b，1H，H-4a)；6.02(dd，
3J
7/8＝10.17Hz，
4J
6/8＝5.08Hz，1H，H-8)；6.18(d，
3J
7/8＝10.17Hz，1H，H-7)；6.92(s，1H，H-2)
Step 8:(4a α, 8a α)-4a, 5,9,10,11-six hydrogen-3-methoxyl group-10-methyl-6H-cumarone is [3a, 3,2-ef]-[3] benzo-aza -6-alcohol also
C
17H
20BrNO
3[366.26] C
17H
21NO
3[287.36]
Will be by 340mg (0.93mmol) (4a α, 8a α)-4a, 5,9,10,11-six hydrogen-1-bromo-3-methoxyl group-10-methyl-6H-cumarone is [3a also, 3,2-ef]-active zinc powder that solution that [3] benzo-aza -6-alcohol, 722mg (6.51mmol) calcium chloride and 40ml 50% ethanol are formed is new with 1.4g (22.32mmol) (zinc powder (Fa.Aldrich) and 2N mixed in hydrochloric acid, thoroughly mixing filters out, earlier be washed till neutrality with distilled water, thoroughly wash with methyl alcohol again), mix, and refluxed 5 hours.Then, filter out zinc, use methanol wash, and the evaporation concentration residual solution.In residual collection to 50 milliliter 1N hydrochloric acid,, and will wash with 20 milliliters of hydrochloric acid and rock repeatedly with 30 milliliters of ethyl acetate washings.The water that contains that merges is adjusted to alkalescence with strong aqua, and with ethyl acetate extraction 3 times, consumption is 50 milliliters at every turn.With the organic phase that merges through dried over mgso, filter and evaporation concentration, therefore obtain 230mg (86% theoretical value) yellow crystals shape (4a α, 8a α)-4a, 5,9,10,11-six hydrogen-3-methoxyl group-10-methyl-6H-cumarone is [3a, 3 also, 2-ef]-[3] benzo-aza -6-alcohol, its fusing point is 152-155 ℃.
TLC:EE: EtOH=9: 1 (can be observed) by the oxidizing reaction in the iodine chamber
1H-NMR(CDCl
3；δ(ppm))：1.90-2.04(m，1H，H-5)；2.26-2.46(m，2H，H-11/11′)；2.42(s，3H，NCH
3)；2.62-2.80(m，3H，H-5′/9/9′)；3.01-3.12(m，1H，H-12)；3.12-3.29(m，1H，H-12′)；3.83(s，3H，OCH
3)；4.12-4.22(m，1H，H-6)；4.57(b，1H，H-4a)；6.01(ddd，
3J
7/8＝10.16Hz，
4J
6/8＝5.18Hz，
5J
5/8＝0.95Hz；1H，H-8)；6.22(dd，
3J
7/8＝10.16Hz，
4J
5/7＝1.09Hz，1H，H-7)；6.61(d，
3J
1/2＝8.21Hz，1H，H-2)；6.66(d，
3J
1/2＝8.21Hz，1H，H-1)
13C-NMR(CDCl
3；δ(ppm))：30.0(t，C-5)；34.5(t，C-9)；48.9(s，C-8a)；49.3(q，NCH
3)；55.6(q，OCH
3)；59.1(t，C-11)；62.0(d，C-6)；66.3(t，C-12)；85.6(d，C-4a)；111.1(d，C-1)；121.5(d，C-8)；126.5(d，C-2)；128.3(d，C-7)；130.9(s，C-12a)；132.7(s，C-12b)；142.9(s，C-3a)；145.3(s，C-3b)
Embodiment 2 (embodiment 119 of female case)
[4aS-(4a α, 6 β, 8aR
*)]-4a, 5,9,10-tetrahydrochysene-3-methoxyl group-6H-cumarone is [3a, 3,2-ef] [2] benzo-aza -6-alcohol also, 11-oxide compound (MH-142)
4.25g (15.55mmol) demethylation lycoremine (27)
85mg (0.77mmol)=5% tin anhydride
70ml 10% moisture H
2O
2Solution (35%) (oxidizing solution) in acetone
The demethylation lycoremine is dissolved in the oxidizing solution under no moisture, and is cooled to 0 ℃.Then, add SeO
2, and stirred 20 minutes down at 0 ℃ earlier, at room temperature stirred then 4 hours, wherein separate out white precipitate, with its suction, use washing with acetone, and dry.Filtrate is mixed with water, under vacuum, distills out acetone, and will keep contain the water dichloromethane extraction.The organic phase that merges is washed with saturated common salt solution,, filter, and extract solvent out through dried over sodium sulfate.The oily residual collection in acetone, is separated out white precipitate, and it can be used as second fraction and obtains.By carrying out evaporation concentration filtrate repeatedly and being collected in the acetone, obtain other fraction.
Productive rate: 3.53g (12.29mmol=79% theoretical value) white powder
C
16H
17NO
4[287.31]
DC:R
f=0.42 (CHCl
3: the dense NH of MeOH=9: 1+1%
4OH)
Fusing point: 232-233 ℃ (CHCl
3); Discharge liquid from 215 ℃
C
16H
17NO
4x0.2H
2O[290.91]
| ％C | ％H | ％N | |
| The calculated value measured value | 66.06 66.11 | 6.03 6.05 | 4.81 4.73 |
1H-NMR(200MHz，DMSO-d
6)：δ7.82(s，1H)，6.90(s，2H)，5.81(dd，J＝10.1，4.4Hz，1H)，5.54(d，J＝10.1Hz，1H)，4.64(bs，1H)，4.36(d，J＝5.5Hz，1H)，4.14-4.02(m，2H)，3.79(s，3H)，2.39-1.99(m，4H)；
13C-NMR(50MHz，DMSO-d
6)：δ146.1(s)，144.6(s)，134.6(d)，131.8(s)，128.3(d)，127.6(d)，122.4(d)，118.3(s)，112.6(d)，86.7(d)，61.8(d)，59.1(t)，55.7(q)，45.3(s)，34.2(t)，29.7(t)
Embodiment 3 (second embodiment 119 of female case)
[4aS-(4a α, 6 β, 8aR
*)]-4a, 5,9,10,13,14a-six hydrogen-6-hydroxyl-3-methoxyl group-6H, 14H-cumarone also [3a, 3,2-ef] isoxazole is [3,2-a] [2] benzo-aza -13 (or 14)-carboxylic acid also, methyl esters (MH-143)
175mg (0.61mmol) lycoremine nitrone (LXXXIV)
0.05ml (0.61mmol) methyl acrylate
The 6ml dry toluene
Under argon gas atmosphere, reagent was heated 48 hours under refluxing, then, extract solvent out.With resistates through column chromatography (CHCl
3: the dense NH of MeOH=9: 1+1%
4OH) purifying.
The glassy oil that solidifies of productive rate: 225mg (0.60mmol=99% theoretical value) light brown
C
20H
23NO
6[373.40]
DC:R
f=0.74 (CHCl
3: the dense NH of MeOH=9: 1+1%
4OH)
C20H23NO6x0.5H
2O[382.40]
| ％C | ％H | ％N | |
| The calculated value measured value | 62.82 62.88 | 6.33 6.17 | 3.66 3.65 |
The mixture of forming by steric isomer and positional isomers.The more accurate processing of collection of illustrative plates is at table 2.2, in the structure explanation.
Embodiment 4 (embodiment 120 of female case)
[4aS-(4a α, 6 β, 8aR
*, 14aS
*)]-4a, 5,9,10-tetrahydrochysene-6-hydroxyl-3-methoxyl group-6H, 14aH-cumarone also [3a, 3,2-ef] isoxazole is [3,2-a] [2] benzo-aza -14-carboxylic acid also, methyl esters (MH-145)
200mg (0.70mmol) lycoremine nitrone (LXXXIV)
0.06ml (0.70mmol) acetylenecarboxylic acid methyl esters (propynoic acid methyl esters)
The 5ml dry toluene
Under argon gas atmosphere, with reagent heating 10 minutes under refluxing, wherein during heating solution orange, extract solvent then out.Resistates is passed through column chromatography (CHCl
3: MeOH=9: 1) purifying.Oily resistates recrystallize from ethanol is gone out, therefore obtain yellow spicule.
The light yellow spicule of productive rate: 261mg (0.70mmol=100% theoretical value)
C
20H
21NO
6[371.39]
DC：R
f＝0.73(CHCl
3∶MeOH＝9∶1)
Fusing point: 151-154 ℃
| ％C | ％H | ％N | |
| The calculated value measured value | 64.68 64.59 | 5.70 5.89 | 3.77 3.67 |
1H-NMR(200MHz，CDCl
3)：δ7.54(s，1H)，6.96(d，J＝8.4Hz，1H)，6.74(d，J＝8.4Hz，1H)，5.96-5.77(m，2H)，5.67(s，1H)，4.55(bs，1H)，4.10(bs，1H)，3.85(s，3H)，3.68(s，3H)，3.59(ddd，J＝14.3，6.8，3.8Hz，1H)，3.30(ddd，J＝12.9，9.3，3.4Hz，1H)，2.64(dd，J＝15.7，3.7Hz，1H)，2.15(td，J＝7.7，3.4Hz，1H)，2.01(ddd，J＝15.6，5.3，1.9Hz，1H)，1.54(ddd，J＝15.6，6.7，3.5Hz，2H)；
13C-NMR(50MHz，CDCl
3)：δ163.9(s)，154.6(d)，146.8(s)，145.1(s)，133.3(s)，130.3(d)，126.9(d)，125.3(s)，123.3(d)，111.3(d)，109.9(s)，89.1(d)，68.7(d)，61.4(d)，55.8(q)，52.4(t)，51.4(q)，47.2(s)，29.2(t)，28.0(t)
Embodiment 5 (embodiment 121 of female case)
[4aS-(4a α, 6 β, 8aR
*)]-4a, 5,9,10,13,14a-six hydrogen-6-hydroxyl-3-methoxyl group-6H, 14H-cumarone also [3a, 3,2-ef] isoxazole is [3,2-a] [2] benzo-aza -13 (or 14)-formonitrile HCN (MH-146) also
200mg (0.70mmol) lycoremine nitrone (LXXXIV)
0.05ml (0.70mmol) vinyl cyanide
The 5ml dry toluene
Under argon gas atmosphere, reagent was heated 2 hours under refluxing, extract solvent then out.Resistates is passed through column chromatography (CHCl
3: MeOH=9: 1) purifying.
Productive rate: 230mg (0.68mmol=97% theoretical value) light yellow oil
C
19H
20N
2O
4[340.38]
DC：R
f＝0.74(CHCl
3∶MeOH＝9∶1)
C
19H
20N
2O
4x0.2H
2O[343.98]
| ％C | ％H | ％N | |
| The calculated value measured value | 66.34 66.22 | 5.98 6.03 | 8.14 7.86 |
The mixture of forming by 4 steric isomers and positional isomers.The more accurate processing of collection of illustrative plates is at table 2.2, in the structure explanation.
Embodiment 6 (embodiment 122 of female case)
[4aS-(4a α, 6 β, 8aR
*, 14aS
*)]-4a, 5,9,10,13,14a-six hydrogen-6-hydroxyl-3-methoxyl group-6H, 14aH-cumarone also [3a, 3,2-ef] isoxazole is [3,2-a] [2] benzo-aza -6 also, 13-glycol, 13-acetic ester (MH-153)
200mg (0.70mmol) lycoremine nitrone (LXXXIV)
0.24ml (2.10mmol)=4 equivalent acetic ester vinyl
The 5ml dry toluene
Under nitrogen atmosphere, reagent was heated 4 days under refluxing, wherein add 1 equivalent acetic ester vinyl every day.Extract solvent then out, and resistates is passed through column chromatography (CHCl
3: MeOH=9: 1) purifying.Oil recrystallize from methyl alcohol of purifying is gone out.
Productive rate: 256mg (0.69mmol=98% theoretical value) true qualities crystal
C
20H
23NO
6[373.41]
DC：R
f＝0.70(CHCl
3∶MeOH＝9∶1)
Fusing point: 132-134 ℃
C
20H
23NO
6x0.6H
2O[384.21]
| ％C | ％H | ％N | |
| The calculated value measured value | 62.52 62.59 | 6.35 6.12 | 3.65 3.61 |
1H-NMR is (by the mixture that two kinds of isomer are formed, 200MHz, CDCl
3): δ 6.76 and 6.73 (d, J=8.3Hz, 1H), 6.68 and 6.60 (d, J=7.7Hz, 1H), 6.36 (d, J=4.1Hz, 1H), 6.30 (d, J=10.6Hz, 1H), 6.08-5.91 (m, 1H), 4.60 and 4.50 (b s, 1H), 4.32 (dd, J=11.3,5.6Hz, 1H), 4.13 (bs, 1H), 3.84 (s, 3H), 3.80 (dd, J=19.1,9.8Hz, 1H), 3.22 (ddd, J=10.0,6.8,2.8Hz, 1H), 2.92 (dd, J=12.3,5.8Hz, 1H), and 2.78-2.57 (m, 2H), 2.09 (s, 3H), 2.07-1.79 (m, 2H);
13C-NMR is (by the mixture that two kinds of isomer are formed, 50MHz, CDCl
3): δ 169.6 (s), 145.8 (s), 143.8 (s), 134.1 (s), 129.8 (d), 128.0 and 127.7 (d), 127.0 (s), 118.7 with 118.5 (d), 111.4 and 110.9 (d), 95.3 and 94.5 (d), 88.7 with 88.2 (d), 61.4 (d+d), 55.7 and 55.5 (q), 54.5 (t), 47.3 (s), 41.7 (t), 29.7 (t), 29.3 (t), 21.0 and 20.9 (q)
Embodiment 7 (embodiment 123 of female case)
[4aS-(4a α, 6 β, 8aR
*, 14aS
*)]-4a, 5,9,10-tetrahydrochysene-6-hydroxyl-3-methoxyl group-6H, 14aH-cumarone also [3a, 3,2-ef] isoxazole is [3,2-a] [2] benzo-aza -14-formonitrile HCN (MH-159) also
500mg (1.74mmol) lycoremine nitrone (LXXXIV)
90mg (1.74mmol) ethynyl nitrile
The 10ml dry toluene
At room temperature, reagent was stirred 7 days under argon gas atmosphere, wherein solution yellow, extracts solvent then out.Resistates crystallization from methyl alcohol is gone out, suction, and use methanol wash.With the filtrate evaporation concentration, and by column chromatography (CHCl
3: MeOH=9: 1) from this resistates, obtain the second product fraction.
Productive rate: 570mg (1.68mmol=97% theoretical value) clear crystal
C
19H
18N
2O
4[338.37]
DC：R
f＝0.60(CHCl
3∶MeOH＝9∶1)
Fusing point: 137-139 ℃
| ％C | ％H | ％N | |
| The calculated value measured value | 67.45 67.17 | 5.36 5.41 | 8.28 8.19 |
1H-NMR(200MHz，CDCl
3)：δ7.09(d，J＝8.6Hz，1H)，6.76(d，J＝8.6Hz，1H)，5.98(s，2H)，5.54(s，1H)，4.52(bs，1H)，4.11(bs，1H)，3.83(s，3H)，3.75-3.59(m，1H)，3.42-3.25(m，1H)，2.64(dd，J＝15.9，3.2Hz，1H)，2.44(d，J＝11.5Hz，1H)，2.11-1.94(m，2H)，1.71-1.52(m，1H)；
13C-NMR(50MHz，CDCl
3)：δ156.5(d)，147.1(s)，145.5(s)，132.7(s)，129.6(d)，127.9(d)，123.8(s)，120.8(d)，114.0(s)，111.7(d)，88.9(d)，88.6(s)，68.4(d)，61.3(d)，55.9(q)，52.5(t)，47.2(s)，29.3(t)，28.3(t)。
Claims (5)
1. the new compound of general formula I V
Wherein substituting group has the implication of explained later:
Aa) R
1Be hydrogen or Br;
Ab) R
2Be hydrogen;
B) R
3Expression OCH
3,
D) R
4And R
5Be
Da) two is hydrogen, perhaps
Db) R
4And R
5One of be hydrogen, alkyl, aralkyl, alkenyl, aralkenyl, alkynyl or sweet-smelling alkynyl, R
4And R
5In another be:
Dbi) OR
6, R wherein
6Expression hydrogen, rudimentary C
1-C
10, straight or branched alkyl or cycloalkyl, C
3-C
10The silyl that replaces, C
2-C
10-alpha-alkoxy base alkyl, 2-methoxy-propyl, ethoxyethyl group, THP trtrahydropyranyl, tetrahydrofuran base, phenoxymethyl or 1-phenoxy group ethyl;
Dbii) O-CS-NHR
6, R wherein
6Have above-mentioned Dbi) in the implication that provides;
Dbiii) O-CO-NHR '
7, R ' wherein
7Have following meanings:
Dbiv) O-CO-R
6, R wherein
6Have above-mentioned Dbi) in the implication that provides,
Dbv) NR
7R
7, two substituent R wherein
7Be identical or different, and represent hydrogen, rudimentary C
1-C
4, straight or branched alkyl or cycloalkyl, perhaps substituent R
7Expression-(CH together
2)
n-, wherein n is 3 to 5;
Dbvi) NH-COR
6, R wherein
6Have above-mentioned Dbi) in the implication that provides;
Dbvii) S-R
6, R wherein
6Have above-mentioned Dbi) in the implication that provides;
Dbviii) SO
nR
8, wherein n is 0,1 or 2, wherein R
8Be C
1-C
10, straight or branched or cyclisation, replacement or unsubstituted alkyl or aralkyl;
Dbix) R
4Be hydrogen, R
5Be OH, CN, CO
2-alkyl, CONR
aR
b, R wherein
aBe hydrogen, rudimentary C
1-C
6, straight or branched or cyclisation, replacement or unsubstituted alkyl, R
bBe hydrogen, rudimentary C
1-C
6, straight or branched, replacement or unsubstituted alkyl, perhaps R
a+ R
bBe together-(CH
2)
n-, wherein n is 2 to 6, perhaps-and (CH
2)
nE (CH
2)
n-, wherein E is that NH, N-alkyl, O or S and n are 0 to 5, aryl, and 6-π heterocyclic radical, imidazolinyl, thiazolinyl Huo Evil azoles quinoline base,
Dbx) R
4And R
5Be together=O ,=N-NH-R
9,=N-NR
9R
10Perhaps=N-OR
10, R wherein
9Be hydrogen, rudimentary C
1-C
6, straight or branched or cyclisation, replacement or unsubstituted alkyl, aralkyl or alkyl-carbonyl, aromatic alkyl carbonyl, alkyl-carbonyl oxygen base, aromatic alkyl carbonyl oxygen base or sulfonic group, and R
10Be hydrogen, rudimentary C
1-C
6, straight or branched or cyclisation, replacement or unsubstituted alkyl, aralkyl or alkyl-carbonyl, aromatic alkyl carbonyl, sulfonic group;
Dbxi) R
4And R
5Represent following type substituting group together
Y wherein
1And Y
2Be identical or different, and expression O, S, NH or N-R
9, wherein free valency under any circumstance all is a hydrogen, R
8Have above-mentioned Dbiii) in the implication mentioned, and R
9Have above-mentioned Dbx) in the implication mentioned;
E) G
1:-(CH
2)
x-, wherein x is 1 or 2;
F) G
2:-(CH
2)
y-, wherein y is 0 to 2; With
R wherein
18And R
19Expression hydrogen, alkyl, aryl or aralkyl, and wherein carry substituent R
18And R
19The C atom interconnect through singly-bound or two key, W represents CH or N.
2. the compound of claim 1 is wherein at Dbi) in R
6Expression triethylsilyl, trimethyl silyl, tert-butyl dimetylsilyl or 3,5-dimethylphenyl silyl, methoxymethyl, ethoxyl methyl, 2-methoxy-propyl, ethoxyethyl group.
3. the compound of claim 1, wherein 6-π heterocyclic radical is imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazyl, oxadiazole base, thiadiazolyl group, pyridazinyl, pyrimidyl, pyrazinyl and substituted these groups, the D that the substituting group under the wherein replacement situation has claim 1) described in implication.
4. the compound of one of claim 1 to 3, wherein R
5The outer implication of expression dehydrogenation, R
4Expression OH.
5. the compound of claim 1, wherein Y
1Be NH and Y
2Be N-R
9, and R
4And R
5By-(CH
2)
n-connection, wherein n=2,3 or 4.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT5462000 | 2000-03-31 | ||
| ATA546/2000 | 2000-03-31 | ||
| ATA238/2001 | 2001-02-15 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01801342A Division CN1380883A (en) | 2000-03-31 | 2001-03-22 | Novel derivatives and analogues of galanthamin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1827621A true CN1827621A (en) | 2006-09-06 |
Family
ID=36946195
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200610054791 Pending CN1827621A (en) | 2000-03-31 | 2001-03-22 | Novel derivatives and analogues of galanthamin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1827621A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860955A (en) * | 2015-04-22 | 2015-08-26 | 华东理工大学 | Galantamine analogue and application thereof |
| CN110183461A (en) * | 2013-12-24 | 2019-08-30 | 哈佛学院院长等 | Cortex chalone analog and its synthesis and purposes |
-
2001
- 2001-03-22 CN CN 200610054791 patent/CN1827621A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110183461A (en) * | 2013-12-24 | 2019-08-30 | 哈佛学院院长等 | Cortex chalone analog and its synthesis and purposes |
| CN104860955A (en) * | 2015-04-22 | 2015-08-26 | 华东理工大学 | Galantamine analogue and application thereof |
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