CN1148340A - Method for treating 5HT2B receptor related conditions - Google Patents

Method for treating 5HT2B receptor related conditions Download PDF

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Publication number
CN1148340A
CN1148340A CN95193029A CN95193029A CN1148340A CN 1148340 A CN1148340 A CN 1148340A CN 95193029 A CN95193029 A CN 95193029A CN 95193029 A CN95193029 A CN 95193029A CN 1148340 A CN1148340 A CN 1148340A
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alkyl
chemical compound
indole
hydrogen
cycloalkyl
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J·E·奥迪亚
M·L·科恩
J·S·吉达
D·L·G·纳尔逊
S·R·贝克
J·艾茨奎拉-卡勒拉
C·拉马斯-佩泰拉
C·佩德里加-特塞罗
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Eli Lilly and Co
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Eli Lilly and Co
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Priority claimed from US08/380,565 external-priority patent/US5663178A/en
Priority claimed from US08/380,566 external-priority patent/US5688807A/en
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of CN1148340A publication Critical patent/CN1148340A/en
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Abstract

The present invention provides methods for binding a 5-HT2B receptor in mammals using both known and novel compounds. Further, the invention provides a method for treating or preventing 5-HT2B related conditions. Finally, the invention provides an article of manufacture.

Description

Treatment and 5HT 2BThe method of receptor related conditions
Invention field
The present invention relates to treatment and 5HT 2BThe method of receptor related conditions, and the application discloses the new chemical compound of formula XI and XII hereinafter.
Background of invention
The present invention relates to suffer from or easily suffer from and 5-HT 2BReceptor is regulated the mammiferous Therapeutic Method that related disorders is arranged.
The blocking-up serotonin receptor shows that it can produce many favourable pharmacological effects, comprises from the recovery of morbid state such as morbid state such as hypertension, depression, anxiety; See US5,141,944.People such as Nelson, people such as the psychopharmacology of nerve conduction receptor and biochemistry (Psychopharm.andBiochem.of Neurotr.Rec.) eds.H.I.Yamamura, Elsevier/NorthHolland Inc., p325 has also confirmed multiple serotonin recognition site.The total class of serotonin receptor is called the 5-HT receptor.Concrete 5-HT acceptor site comprises 5-HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 2A, 5-HT 2B, 5-HT 2C, 5-HT 3, and 5-HT 4The position.Each all transmits certain physiological action in these receptors.See Leonard, B.E., international clinical psychopharmacology (Intern.Clin.Psychopharm.) 7:13-31 (1992).
The invention provides and be used in 5-HT 2BActivated compounds for treating or prevention and 5-HT 2BRelevant disease.In addition, the present invention also provides and selectively blocks 5-HT 2BThe method of receptor.In addition, the present invention also provides blocking-up human 5-HT 2BThe method of receptor.5-HT 2BAcceptor active compound provides and makes 5-HT 2BThe useful tool of receptor characterization.
The invention provides one group of 5-HT 2BReceptor agonist compounds.The applicant finds that these chemical compounds are competitive inhibitor that the colon that brings out of serotonin shrinks.Therefore, the invention provides the chemical compound that can make gastrointestinal motility normalization, and this chemical compound is useful for the treatment intestinal dysfunction.
The applicant also finds, 5-HT 2BAt the bottom of receptor is positioned at the lung, stomach of Mus, uterus, bladder and colon.5-HT 2BReceptor is positioned at the interesting position of human body and includes but are not limited to brain and blood vessel.Therefore, can enough adjusting 5-HT 2BThe disease of the compounds for treating of receptor comprises, for example, and psychosis, depression, anxiety neurosis, hysteropathy such as endometriosis, fibrosis of uterus and other abnormal uterine contraction, panic attack, migraine, eating disorder, seasonal disease, tuberculosis, cardiovascular diseases such as thrombosis, hypertension, angina pectoris, vasospasm and other vessel sealing disease, incontinence, vesical dysfunction, breathing/airway disorders such as asthma etc.
Summary of the present invention
The invention provides and suffer from or easily trouble and dysfunction or not normal 5-HT 2BReceptor for stimulating has the mammiferous Therapeutic Method of related disorders, comprises the chemical compound of using effective dose, and this chemical compound is as analeptic or local stimulant or antagonist and 5-HT 2BAcceptor interaction, and be selected from chemical compound or its pharmaceutically acceptable salt or the solvate of formula I-X.
Formula I chemical compound:
Figure A9519302900221
Wherein:
Q is hydrogen or (CHR 2) R 4
R 1Be hydrogen or C 1-C 3Alkyl;
R 2Be hydrogen or C 1-C 3Alkyl;
R 3Be hydrogen or C 1-C 3Alkyl;
R 4Be C 5-C 8Cycloalkyl, the C of replacement 5-C 8Cycloalkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, the dicyclo of dicyclo or replacement;
A is selected from following groups:
Figure A9519302900222
Wherein:
R 6And R 7Be respectively hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5
M is 1 or 2;
R 5Be hydrogen or C independently 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 8Be independently selected from R 6, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl; Or
R 6And R 7Carbon atom with the A group forms 5-8 unit carbocyclic ring;
Formula II chemical compound:
Figure A9519302900232
Wherein:
R 8Be selected from hydrogen, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, halogen, halo (C 2-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, OR 5, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, and C 7-C 20Aralkyl;
R 5Be hydrogen or C independently 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 9And R 10Be selected from hydrogen respectively, C 1-C 6Alkyl, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl;
R 11Be selected from C 1-C 4Alkyl, OR 5 ', fluorine, bromine, iodine, and chlorine;
R 12 'Be selected from hydrogen and C 1-C 4Alkyl;
The formula III chemical compound:
Wherein:
R 12Be C 1-C 4Alkyl and pi-allyl;
R 13Be-O-or-N (R 15)-;
R 15Be hydrogen or C 1-C 4Alkyl;
R 14Be C 1-C 4Alkyl, hydroxyl C 1-C 4Alkyl, C 3-C 7Cycloalkyl and the C that is replaced by hydroxyl or methoxyl group 3-C 7Cycloalkyl;
Formula IV chemical compound: Wherein: R 15' be C 1-C 4Alkyl; R 16Be pi-allyl or C 1-C 4Straight chained alkyl; R 17Be hydrogen or C 1-C 4Straight chained alkyl; R 18Be hydrogen, C 1-C 4Alkyl, hydroxyl, or C 1-C 4Alkoxyl; M ' is 0,1,2 or 3; Formula V chemical compound:
Figure A9519302900252
Wherein: R 19Be C 1-C 4Alkyl; R 20Be pi-allyl or C 1-C 4Straight chained alkyl; R 21Be hydrogen or C 1-C 4Straight chained alkyl; R 22Be pyridine radicals or imidazole radicals; Alk is from straight or branched C 1-C 5The deutero-divalent organic base of alkane; Formula VI chemical compound: Wherein: R 23Be C 1-C 3Alkyl or pi-allyl; R 24Be C 1-C 3Hydroxy alkyl or C 1-C 3The dihydroxy alkyl; R 25Be hydrogen or CH 3Formula VII chemical compound:
Figure A9519302900262
Formula VIII chemical compound: Wherein: R 25 'Be hydrogen or methoxyl group; Formula IX chemical compound:
Figure A9519302900272
Wherein:
Y bForm the replacement that is selected from following groups or do not replace aromatics 5-unit heterocycle with the carbon atom that it connected, R 26Be hydrogen, C 1-C 3Alkyl, pi-allyl or
Figure A9519302900281
R 27Be hydrogen, C 1-C 3Alkyl, pi-allyl,
Or (CH 2) N '-X ";
N ' is 1 to 5;
X " be the phenyl that replaces arbitrarily, C 1-C 3Alkoxyl, or C 1-C 3Alkylthio group;
R 28And R 29Be respectively hydrogen, C 1-C 3Alkyl, C 1-C 3Alkoxyl, hydroxyl, C 1-C 3Alkylthio group, halogen, CN, phenyl; Or formation-(CH together 2) P "-;
P " be 3 to 6;
Y aBe-CH 2-,-O-,-S (O) M "-;
M " be 0,1, or 2; And
Formula X chemical compound:
Figure A9519302900283
The invention provides treatment suffers from or easily trouble and dysfunction or not normal 5-HT 2BReceptor for stimulating has the mammiferous method of related disorders, comprises the chemical compound of using effective dose, and this chemical compound is as analeptic or local stimulant or antagonist and 5-HT 2BAcceptor interaction, and be selected from formula XI chemical compound
Or its pharmaceutically acceptable salt;
Wherein:
Q ' is selected from hydrogen, R 34(CHR 2) R 4
R 34Be selected from the spiral shell dicyclo, the spiral shell dicyclo of replacement, the dicyclo of dicyclo or replacement;
R 1Be hydrogen or C 1-C 3Alkyl;
R 2Be hydrogen or C 1-C 6Alkyl;
R 3Be hydrogen or C 1-C 3Alkyl;
R 4Be C 5-C 8Cycloalkyl, the C of replacement 5-C 8Cycloalkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, the dicyclo of dicyclo or replacement;
A is selected from following groups:
Wherein:
R 6And R 7Be respectively hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5
M is 1 or 2;
R 5Be hydrogen or C 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 8Be independently selected from R 6, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl; Or
R 6And R 7Carbon atom with the A group forms 5-8 unit carbocyclic ring;
R 30And R 31Form 3-8 unit carbocyclic ring together; Or
R 30And R 31Be selected from C respectively 1-C 6Alkyl and C 2-C 6Alkenyl;
The invention provides treatment suffers from or easily trouble and dysfunction or not normal 5-HT 2BReceptor for stimulating has the mammiferous method of related disorders, comprises the chemical compound of using effective dose, and this chemical compound is as analeptic or local stimulant or antagonist and 5-HT 2BAcceptor interaction, and be selected from formula XII chemical compound Or its drug acceptable salt, A is selected from following groups:
Figure A9519302900302
Figure A9519302900311
Wherein:
R 6And R 7Be respectively hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5
M is 1 or 2;
R 8Be selected from hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 2-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, and C 7-C 20Aralkyl;
R 5Be hydrogen or C independently 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 6And R 7Carbon atom with the A group forms 5-8 unit carbocyclic ring;
R 9And R 10Be selected from hydrogen respectively, C 1-C 6Alkyl, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl;
R 11Be selected from C 1-C 4Alkyl, OR 5 ', fluorine, bromine, iodine, and chlorine;
R 30And R 31Form 3-8 unit carbocyclic ring together; Or
R 30And R 31Be selected from C respectively 1-C 6Alkyl and C 2-C 6Alkenyl;
Secondly, the invention provides and in mammalian body, block 5-HT 2BThe method of receptor comprises using occupying 5-HT 2BThe above-mentioned formula I of receptor dosage, II, III, IV, V, VI, VII, VIII, IX and X chemical compound or its pharmaceutically acceptable salt or solvate.
The invention provides and in mammalian body, block 5-HT 2BThe method of receptor comprises using occupying 5-HT 2BThe above-mentioned formula XI of receptor dosage and XII chemical compound or its pharmaceutically acceptable salt or solvate.
The 3rd, the invention provides selectively with mammalian body in 5-HT 2BThe method of acceptor interaction comprises to administration being selected from above-mentioned formula I, II, III, IV, V, VI, VII, VIII, the 5-HT of IX and X chemical compound or its pharmaceutically acceptable salt or solvate 2BAlternative cpd.
The invention provides selectively with mammalian body in 5-HT 2BThe method of acceptor interaction comprises the 5-HT that is selected from above-mentioned formula XI and XII chemical compound or its pharmaceutically acceptable salt or solvate to administration 2BAlternative cpd.
The invention provides formula XI chemical compound
Figure A9519302900321
Or its drug acceptable salt or solvate;
Wherein:
Q ' is selected from hydrogen, R 34(CHR 2) R 4
R 34Be selected from the spiral shell dicyclo, the spiral shell dicyclo of replacement, the dicyclo of dicyclo or replacement;
R 1Be hydrogen or C 1-C 3Alkyl;
R 2Be hydrogen or C 1-C 6Alkyl;
R 3Be hydrogen or C 1-C 3Alkyl;
R 4Be C 5-C 8Cycloalkyl, the C of replacement 5-C 8Cycloalkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, the dicyclo of dicyclo or replacement;
A is selected from following groups:
Wherein:
R 6And R 7Be respectively hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5
M is 1 or 2;
R 5Be hydrogen or C 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 8Be independently selected from R 6, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl; Or
R 6And R 7Carbon atom with the A group forms 5-8 unit carbocyclic ring;
R 30And R 31Form 3-8 unit carbocyclic ring together; Or
R 30And R 31Be selected from C respectively 1-C 6Alkyl and C 2-C 6Alkenyl;
The invention provides formula XII chemical compound Or its pharmaceutically acceptable salt or solvate;
A is selected from following groups:
Wherein:
R 6And R 7Be respectively hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5
M is 1 or 2;
R 8Be selected from hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 2-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, and C 7-C 20Aralkyl;
R 5Be hydrogen or C independently 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 6And R 7Carbon atom with the A group forms 5-8 unit carbocyclic ring;
R 9And R 10Be selected from hydrogen respectively, C 1-C 6Alkyl, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl;
R 11Be selected from C 1-C 4Alkyl, OR 5 ', fluorine, bromine, iodine, and chlorine;
R 30And R 31Form 3-8 unit carbocyclic ring together; Or
R 30And R 31Be selected from C respectively 1-C 6Alkyl and C 2-C 6Alkenyl.
At last, the invention provides in human body and people 5-HT 2BThe method of receptor acting comprises to the people and uses blocking-up 5-HT 2BThe above-mentioned formula I of receptor dosage, II, III, IV, V, VI, VII, VIII, IX and X chemical compound or its pharmaceutically acceptable salt or solvate.
The invention provides in human body and people 5-HT 2BThe method of receptor acting comprises to the people and uses blocking-up 5-HT 2BThe above-mentioned formula XI of receptor dosage and XII chemical compound or its pharmaceutically acceptable salt or solvate.
The further instantiation of the present invention is made in order to the explanation medicine, comprises packaging material and one or more medicaments that are included in the said packaging material, and this medicament is conquered 5-HT to needs 2BThe treatment of conditions of receptor is effectively, and this medicament contains above-mentioned formula I, II, III, IV, V, VI, VII, VIII, IX and X chemical compound or its pharmaceutically acceptable salt or solvate; Said packaging material have label, indicate said medicament and can be used in and need 5-HT 2BThe treatment of conditions that receptor is regulated.
Another instantiation of the present invention is still made in order to the explanation medicine, comprises packaging material and one or more medicaments that are included in the said packaging material, and this medicament is conquered 5-HT to needs 2BThe treatment of conditions of receptor is effectively, and this medicament contains above-mentioned formula XI and XII chemical compound or its pharmaceutically acceptable salt or solvate; Said packaging material have label, indicate said medicament and can be used in and need 5-HT 2BThe treatment of conditions that receptor is regulated.
The present invention describes in detail
Terminology used here " treatment " comprises the prevention of disease so-called health and/or spirit or has suffered from and the improvement or the elimination of developed health and/or spiritual disease.
Terminology used here " C 1-C nAlkyl ", n=2-10, representative has a branched-chain or straight-chain alkyl to the specific quantity carbon number.Typical C 1-C 6Alkyl comprises methyl, ethyl, n-pro-pyl, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl or the like.
Terminology used here " R 30And R 31Form 3-8 unit carbocyclic ring together " mean R 30And R 31Most preferably be selected from C respectively 1-C 6Alkyl and C 2-C 6Alkenyl.The carbocyclic ring of Xing Chenging can be saturated or undersaturated like this.Here these used rings can be expressed as: N wherein 30Be whole carbon numbers of such ring that forms.This carbocyclic ring can be replaced by 1-4 substituent group, and this substituent group can be selected from hydrogen, C respectively 1-C 6Alkyl, NO 2, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, C 2-C 6Alkenyl, CO 2R 5, (C 1-C 6Alkyl) mAmino ,-SR 5, and OR 5Preferred examples is R 30And R 31Form C together 3-C 6Unit's saturated carbon ring.Another preferred examples is R 30And R 31Form C together 3-C 5Unit's saturated carbon ring.
If R 30And R 31Can not form a carbocyclic ring together, then preferred embodiment is R 30And R 31Be selected from C respectively 1-C 3Alkyl.
Terminology used here " C 2-C nAlkenyl ", n=3-10, representative has the unsaturated side chain or the straight-chain alkenyl of 2-10 carbon atom and at least one two key.These examples of groups comprise the 1-acrylic, 2-acrylic (CH 2-CH=CH 2), 1,3-butadiene base (CH=CHCH=CH 2), 1-butylene base (CH=CHCH 2CH 3), hexenyl, pentenyl or the like.
Term " halogenide ", " halogen " and " halogen " comprises fluorine, chlorine, bromine and iodine.Preferred halogen is a chlorine.
Term " halo (C 1-C 6) alkyl " and " halo (C 2-C 6) alkenyl " referring to have the alkyl or alkenyl substituent group of one or more halogen atoms, this halogen atom is linked respectively on one or more effective carbon atoms.Said term comprises chloromethyl, bromoethyl, trifluoroethyl, trifluoromethyl, trifluoro vinyl, the 3-bromopropyl, 3-bromo-1-acrylic, 2-bromopropyl, 2-bromo-1-acrylic, 3-chlorobutyl, 3-chloro-crotyl, 2,3-two chlorobutyls, chlorovinyl, 5-fluoro-3-pentenyl, 3-chloro-2-bromo-5-hexenyl, 3-chloro-2-bromo-butyl, trichloromethyl, Dichloroethyl, 1,4-two chlorobutyls, 3-bromine amyl group, 1,3-two chlorobutyls, 1,1-two chloropropyls or the like.Preferred halo (C 1-C 6) alkyl is trichloromethyl, three chloroethyls and trifluoromethyl.Most preferred halo (C 1-C 6) alkyl is trifluoromethyl.
Term " C 1-C 10Alkanoyl " representative formula such as C (O) (C 1-C 9) alkyl.Concrete C 1-C 10Alkanoyl comprises acetyl group, propiono, bytyry or the like.
Term " (C 1-C 6Alkyl) mAmino ", m=1-2 wherein, refer to one-or dialkyl amido, alkyl wherein can be a straight or branched.This examples of groups has methylamino, dimethylamino, ethylamino, lignocaine, 2-third amino, 1-third amino, two (n-pro-pyl) amino, two (isopropyl) amino, methyl-n-propylamine base, uncle's fourth amino or the like.
Term " C 3-C nCycloalkyl ", wherein n=4-8 represents cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring octyl group.
The term " (C of replacement 5-C n) cycloalkyl " referring to can be by the above-mentioned cycloalkyl of 1-4 substituent group replacement, this substituent group is respectively hydrogen, C 1-C 6Alkyl, NO 2, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, C 2-C 6Alkenyl, CO 2R 5, (C 1-C 6Alkyl) mAmino ,-SR 5, and OR 5
Term " C 3-C 8Cycloalkyl-(C 1-C 3) alkyl " represent endways carbon atom by C 3-C 8The straight chained alkyl of cycloalkyl substituted.Typical cycloalkyl-alkyl comprises the cyclohexyl ethyl, cyclohexyl methyl, 3-cyclopenta propyl group or the like.
Term " C 5-C 8Cycloalkenyl group " represent the unsaturated ring of olefinic that 5-8 carbon atom arranged, for example, phenyl, cyclohexadienyl, cyclohexenyl group, cyclopentenyl, cycloheptenyl, cyclo-octene base, cyclopentadienyl group, cyclo-octatriene base or the like.
The term " (C of replacement 5-C 8) cycloalkenyl group " referring to that wherein cycloalkenyl group can be by the above-mentioned cycloalkenyl group of 1-4 substituent group replacement, this substituent group is respectively hydrogen, C 1-C 6Alkyl, NO 2, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, C 2-C 6Alkenyl, COR 5, C 1-C 10Alkanoyl, C 7-C 20Aralkyl, CO 2R 5, (C 1-C 6Alkyl) mAmino ,-SR 5, and OR 5
Term " C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl " represent endways carbon atom by C 5-C 8The straight chain C that cycloalkenyl group replaces 1-C 3Alkyl.
Phenyl or naphthyl represented in term " aryl ".This aryl can unsubstitutedly maybe can have one or two substituent group that is respectively following groups: C 1-C 6Alkyl, C 3-C 8Cycloalkyl, the C of replacement 3-C 8Cycloalkyl, C 2-C 6Alkenyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, phenyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, COR 5, C 1-C 10Alkanoyl, OR 5, C 7-C 16Aralkyl.Substituent group can be on any significance bit of aromatic ring.
Term " C 7-C 20Aralkyl " represent aryl-(C 1-C 10) alkyl substituent, wherein alkyl is a straight chain, for example, and benzyl, phenethyl, 3-phenyl propyl, or side chain, for example phenyl-tert-butyl group.
Unsaturated or saturated stable 7-12 unit's bridge of term " dicyclo " representative or thick bicyclic carbocyclic.This dicyclo can have been linked on any carbon atom of rock-steady structure effect.This term comprises (but being not limited only to) naphthyl, dicyclohexyl, two cyclohexenyl groups or the like.
Term " unsaturated dicyclo " representative has the stable dicyclo of 7-12 carbon atom.This unsaturated dicyclo can have been linked on any carbon atom of rock-steady structure effect.This unsaturated dicyclo can be replaced by 1-4 " dicyclo of replacement " substituent group that defines below.
General terms " dicyclo of replacement " refers to 4 substituent bicyclic systems of as many as, and these substituent groups are connected in the position of any requirement on this bicyclic system.The dicyclo substituent group can be selected from hydrogen, C respectively 1-C 6Alkyl, NO 2, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, C 2-C 6Alkenyl, COR 5, C 1-C 10Alkanoyl, C 7-C 20Aralkyl, CO 2R 5, (C 1-C 6Alkyl) mAmino ,-SR 5, and OR 5R wherein 5As above definition.This dicyclo substituent group that shows replacement can be linked CHR by any effective carbon atom key in the bicyclic system 2On the base.This term comprises (but being not limited only to) 2-methyl bicyclic hexyl, 3-hydroxyl dicyclohexyl, benzo cyclohexyl, benzo cyclohexenyl group, 2-methoxyl group benzo cyclohexyl, 6-chlorobenzene and cyclohexenyl group, 8-vinyl benzo cyclohexyl or the like.
Term " spiral shell-dicyclo " and " spiral shell-dicyclo of replacement " refer to that the dicyclo (as above definition) of dicyclo or replacement directly links on the carbon atom of female ring in substituent group Q ' position.For being illustrated, the connection of spiral shell-dicyclo is as shown below:
Term " naphthyl " refers to the naphthalene ring system substituent group, as be generally used for vitochemical.This naphthyl substituted base can be linked CHR by any effective carbon atom key in the naphthyl ring system 2On the base.Term " naphthyl of replacement " refers to have 4 substituent naphthalene ring systems at the most, and these substituent groups are linked on the desired any position of this naphthalene ring system.The naphthyl substituted base can be selected from above-mentioned " dicyclo of replacement " respectively.
Here used term " phenyl " refers to that unsubstituted phenyl ring is.Term " phenyl of replacement " refers to have 1-3 substituent phenyl ring, and this substituent group is selected from above-mentioned dicyclo substituent group respectively; R 5Definition as above.
Term " C 1-C 4Alkoxyl " representative has the straight or branched oxyalkyl chain of 1-4 carbon atom.C 1-C 4Alkoxyl comprises methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy or the like.
M ' is that the ring of linking on the amide nitrogen atom is a cyclopenta in 0 the formula IV chemical compound therein; When m ' was 1, ring was a cyclohexyl; M ' is 2 o'clock, and ring is a suberyl; M ' is 3 o'clock, and ring is the ring octyl group.If cycloalkyl is substituted, then substituent group can be on any position of share of this ring.
Term " pyridine radicals " refers to 2-, 3-, or 4-pyridine radicals.Term " imidazole radicals " refers to 1-, 2-, or 4-imidazole radicals.
Term " alk " refers to from straight or branched C 1-C 5The deutero-divalent organic group of alkane.These groups comprise (but being not limited only to)-CH 2-,-CH (CH 3)-,-C (CH 3) 2-,-CH (C 2H 5)-,-CH 2CH 2-,-CH 2CH (CH 3)-,-CH 2C (CH 3) 2-,-CH 2CH (CH 3) CH 2-,-CH (CH 3) CH (CH 3)-,-CH (CH 3) CH 2CH (CH 3)-or the like.
Term " phenyl that replaces arbitrarily " refers to contain 1 or 2 substituent phenyl ring, and substituent group is selected from C 1-C 3Alkyl, C 1-C 3Alkoxyl, C 1-C 3Alkylthio group, halogen, NO 2, and CN.
Term is " selectively with 5-HT 2BAcceptor interaction " refer to compare 5-HT 2AReceptor or 5-HT 2CReceptor to a greater degree with 5-HT 2BThe method of acceptor interaction.
Term " Bronsted acid " refers to have the acid of acidic hydrogen.Preferred Bronsted acid comprises hydrochloric acid, and formic acid is crossed chloric acid, sulphuric acid and phosphate aqueous solution.Most preferred Bronsted acid is hydrochloric acid, sulphuric acid and formic acid.
Term " organic solvent " comprises and contains carbon solvent, as halogenated hydrocarbon, and ether, toluene, dimethylbenzene, benzene, and oxolane.
Term " stirring " comprises stirring, and is centrifugal, hybrid technology and other similar approach.
The polar solvent of electric constant of equal value during term " aprotic solvent " refers to (not containing acidic hydrogen).The example of aprotic solvent commonly used has: dimethyl sulfoxide (DMSO), and dimethyl formamide, tetramethylene sulfone, oxolane, ether, methyl-uncle's butyl ether, or 1, the 2-dimethoxy-ethane.
Term " proton solvent " refers to hydrogeneous solvent, and hydrogen is connected in oxygen, and therefore acidity arranged.Proton solvent commonly used comprises as water, methanol, ethanol, 2-propanol and 1-butanols.
Term " inert atmosphere " refers to that mixture is by the reaction condition of noble gas such as nitrogen or argon gas blanketing covering.
Except as otherwise noted, used here abbreviation all has its suitable implication, and for example, " Me " and " Et " be fingernail base and ethyl respectively, and " t-Bu " refers to the tert-butyl group.Abbreviation " RT " room temperature or environmental condition, except as otherwise noted.
Term " ligand " refers to the chemical compound with the designated receptor bonding.Can be used for optionally occupying the special receptor position or play selective excitement agent effect in the special receptor position as the chemical compound of selective coordination body.
Term " pure substantially " means required enantiomer or stereoisomer and compares shared percentage ratio with other possible configuration and be at least about 90 molar percentages, more preferably at least about 95 molar percentages, most preferably at least about 98 molar percentages.
Other is attempted in order to regulate 5-HT 2BThe chemical compound of receptor comprises (but being not limited only to):
7-bromo-8-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-isopropyl-8-methoxyl group-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
5-chloro-8-ethyoxyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-chloro-7-methyl-8-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
5-dimethylamino-8-hydroxyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-nitro-8-butyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
7-cyclohexyl-8-hydroxyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-[3-methyl-cyclohexyl base]-the 8-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-benzyl-8-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
5-cyclohexyl methyl-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-carboxyl-8-bromo-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-ethyoxyl-8-isopropyl-3-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6,8-two chloro-4-menaphthyls-1,2,3,4-tetrahydrochysene-9H-pyrido [3, b]-indole,
6,8-dimethyl-3,4-dimethyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
7,8-two fluoro-2 (N)-methyl isophthalic acids, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6,8-dibutyl-2 (N)-cyclopropyl methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6,8-two bromo-2 (N)-cyclohexenyl group methyl isophthalic acids, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
8-chloro-2 (N)-benzyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
8-fluoro-4-methyl-2 (N)-cyclohexyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-methylamine-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-chloromethyl-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
7-methoxyl group-1-naphthylpiperazine,
The 1-naphthylpiperazine,
7-bromo-1H-indole-3-ethamine,
7-fluoro-1H-indole-3-ethamine,
7-methoxyl group-1H-indole-3-ethamine,
7-chloro-1H-indole-3-ethamine,
5-methyl-7-chloro-1H-indole-3-ethamine,
1-H-benzo (G) indole-3-ethamine,
6-methyl-7-chloro-1H-indole-3-ethamine,
6-bromo-7-Methyl-1H-indole-3-ethamine,
6-Methyl-1H-indole-3-ethamine,
5-methyl-7-bromo-1H-indole-3-ethamine,
6,7-dimethyl-1H-indole-3-ethamine,
6-methyl-7-bromo-1H-indole-3-ethamine,
(8 β)-N-cyclohexyl-1-isopropyl-6-normal-butyl-ergoline-8-Methanamide,
(8 β)-N-cyclohexyl-N-ethyl-1-isopropyl-6-methyl ergoline-8-Methanamide,
U.S. patent 4,931,447 described other (8 β)-1-alkyl-6-(replacement) ergolines, U.S. patent 4,981, the cycloalkyl amide of 859 described (8 β)-1-alkyl-6-(replacement) ergolines, U.S. patent 4,563,461 described chemical compounds, U.S. patent 4,902,691 described chemical compounds, above-mentioned 4 United States Patent (USP)s are incorporated herein by reference
1,2-dimethyl-3-ethyl-5-(dimethylamino)-indole,
2-(two n-propylamine bases)-8-(isothiazole-3-yl)-1,2,3, the 4-naphthane,
2-ethylamino-8-(isoxazole-3-base)-1,2,3, the 4-naphthane,
2-(N-methyl-N-benzyl amino)-8-(5-n-pro-pyl-1,2,3-oxadiazole-4-yl)-1,2,3, the 4-naphthane,
2-diallyl amino-8-(pyrazole-3-yl)-1,2,3, the 4-naphthane,
2-lignocaine-8-(1,3,4-oxadiazole-2-yl)-1,2,3, the 4-naphthane,
2-(two n-propylamine bases)-8-(3-Methoxy Pyridine-2-yl)-1,2,3, the 4-naphthane,
2-benzyl methylamino-8-(3-Methoxy Pyridine-2-yl)-1,2,3, the 4-naphthane,
2-benzyl methylamino-8-(benzofuran-2-yl)-1,2,3, the 4-naphthane,
2-dimethylamino-8-(1,3,5-triazines-2-yl)-1,2,3, the 4-naphthane,
2-(two-cyclopropyl methylamino)-8-(oxazole-4-yl)-1,2,3, the 4-naphthane,
2-ethylamino-8-(1,2,3-oxadiazole-4-yl)-sulfo--1,2,3, the 4-naphthane,
2-n-butyl amine base-8-(5-methoxy pyrimidine-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(5-Lv oxazole-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(pyrimidine-2-base)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(2-aminopyrimidine-4-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(3-phenyl-1,2,4-oxadiazole-5-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(pyrazine-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-6-(bromo-pyrazine-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(benzothiazole-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(benzoxazole-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(indol-3-yl)-1,2,3, the 4-naphthane,
3-(two-n-propylamine base)-5-(isoxazole-2-yl)-1,2,3, the 4-naphthane,
3-(two-n-propylamine base)-5-(isoxazole-2-yl)-benzodihydropyran,
5-(isoxazole-5-base)-3-(dipropyl amino) benzodihydropyran,
5-(3-methyl-isoxazole-5-yl)-3-(dipropyl amino) benzodihydropyran,
5-(4-methyl-isoxazole-5-yl)-3-(dipropyl amino) benzodihydropyran,
5-(3,4-dimethyl isoxazole-5-yl)-3-(dipropyl amino) benzodihydropyran,
5-(3-methyl-isoxazole-5-yl)-3-(dipropyl amino) sulfo-benzodihydropyran,
5-(4-methyl-isoxazole-5-yl)-3-(dipropyl amino) sulfo-benzodihydropyran,
5-(3,4-dimethyl isoxazole-5-yl)-3-(dipropyl amino) sulfo-benzodihydropyran,
8-(4,5,6, the 7-tetrahydro benzo [c] isoxazole-1-yl)-2-(dimethylamino) naphthane, or the like.
Be used to regulate 5-HT 2BThe special preferred compound of receptor comprises:
7-bromo-8-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-isopropyl-8-methoxyl group-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
5-chloro-8-ethyoxyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-chloro-7-methyl-8-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
5-dimethylamino-8-hydroxyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-nitro-8-butyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
7-cyclohexyl-8-hydroxyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-[3-methyl-cyclohexyl base]-the 8-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-benzyl-8-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
5-cyclohexyl methyl-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-carboxyl-8-bromo-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-ethyoxyl-8-isopropyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6,8-two chloro-4-menaphthyls-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6,8-dimethyl-3,4-dimethyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
7,8-two fluoro-2 (N)-methyl isophthalic acids, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6,8-dibutyl-2 (N)-cyclopropyl methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6,8-two bromo-2 (N)-cyclohexenyl group methyl isophthalic acids, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
8-chloro-2 (N)-benzyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
8-fluoro-4-methyl-2 (N)-cyclohexyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-methylamine-8-chloro-3-isopropyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
6-chloromethyl-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole,
7-methoxyl group-1-naphthylpiperazine,
The 1-naphthylpiperazine,
7-bromo-1H-indole-3-ethamine,
7-fluoro-1H-indole-3-ethamine,
7-methoxyl group-1H-indole-3-ethamine,
7-chloro-1H-indole-3-ethamine,
5-methyl-7-chloro-1H-indole-3-ethamine,
1-H-benzo (G) indole-3-ethamine,
6-methyl-7-chloro-1H-indole-3-ethamine,
6-bromo-7-Methyl-1H-indole-3-ethamine,
6-Methyl-1H-indole-3-ethamine,
5-methyl-7-bromo-1H-indole-3-ethamine,
6,7-dimethyl-1H-indole-3-ethamine,
6-methyl-7-bromo-1H-indole-3-ethamine,
1,2-dimethyl-3-ethyl-5-(dimethylamino)-indole,
2-(two-n-propylamine base)-8-(isothiazole-3-yl)-1,2,3, the 4-naphthane,
2-ethylamino-8-(isoxazole-3-base)-1,2,3, the 4-naphthane,
2-(N-methyl-N-benzyl amino)-8-(5-n-pro-pyl-1,2,3-oxadiazole-4-yl)-1,2,3, the 4-naphthane,
2-diallyl amino-8-(pyrazole-3-yl)-1,2,3, the 4-naphthane,
2-lignocaine-8-(1,3,4-oxadiazole-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(3-Methoxy Pyridine-2-yl)-1,2,3, the 4-naphthane,
2-benzyl methylamino-8-(3-Methoxy Pyridine-2-yl)-1,2,3, the 4-naphthane,
2-benzyl methylamino-8-(benzofuran-2-yl)-1,2,3, the 4-naphthane,
2-dimethylamino-8-(1,3,5-triazines-2-yl)-1,2,3, the 4-naphthane,
2-(two-cyclopropyl methylamino)-8-(oxazole-4-yl)-1,2,3, the 4-naphthane,
2-ethylamino-8-(1,2,3-oxadiazole-4-yl)-sulfo--1,2,3, the 4-naphthane,
2-n-butyl amine base-8-(5-methoxy pyrimidine-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(5-Lv oxazole-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(pyrimidine-2-base)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(2-aminopyrimidine-4-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(3-phenyl-1,2,4-oxadiazole-5-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(pyrazine-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-6-(bromo-pyrazine-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(benzothiazole-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(benzoxazole-2-yl)-1,2,3, the 4-naphthane,
2-(two-n-propylamine base)-8-(indol-3-yl)-1,2,3, the 4-naphthane,
5-(isoxazole-5-base)-3-(dipropyl amino) benzodihydropyran,
5-(3-methyl-isoxazole-5-yl)-3-(dipropyl amino) benzodihydropyran,
5-(4-methyl-isoxazole-5-yl)-3-(dipropyl amino) benzodihydropyran,
5-(3,4-dimethyl isoxazole-5-yl)-3-(dipropyl amino) benzodihydropyran,
5-(3-methyl-isoxazole-5-yl)-3-(dipropyl amino) sulfo-benzodihydropyran,
5-(4-methyl-isoxazole-5-yl)-3-(dipropyl amino) sulfo-benzodihydropyran,
5-(3,4-dimethyl isoxazole-5-yl)-3-(dipropyl amino) sulfo-benzodihydropyran,
8-(4,5,6, the 7-tetrahydro benzo [c] isoxazole-1-yl)-2-(dimethylamino) naphthane, and
3-(two-n-propylamine base)-5-(isoxazole-2-yl)-1,2,3, the 4-naphthane.
Formula IX preferred compound has following array structure: R wherein 26, R 27, R 28, R 29And Y aDefinition as above.
When Q was hydrogen, preferred formula I chemical compound had following structure:
Figure A9519302900482
R wherein 6Be selected from C 1-C 4Alkyl, OR 5 ', fluorine, bromine and chlorine;
R 5 'Be C 1-C 4Alkyl; With
R 1, R 7And R 8Definition as above.
5-HT 2BReceptor rat each the tissue and organ in identified 5-HT 2BReceptor residing main region in rat is a lung, the uterus, and bladder, the harmonization of the stomach colon, and, 5-HT 2BReceptor human body each the tissue and organ in also identified.5-HT in the human body 2BThe residing main region of receptor is (but being not limited to) brain and blood vessel.
According to the position of receptor, by 5-HT 2BPhysiology's disease that receptor is regulated comprises incontinence, bladder function obstacle, functional intestinal disease, gastric emptying disorder, respiratory disorder comprises asthma, uterine dysfunction comprises endometriosis, fibre modification and functional disease are as (but being not limited to) induced labor, and sleep disorder, eating disorder comprise voracity and obesity, pulmonary tuberculosis, the thermoregulation disease, sexual disorders, superfunction, over-drastic aggressive behavior, alcoholism, anxiety, anancastic disease, depressed, psychosis, schizophrenia and schizoid disease, panic and Gilles de laTourette syndrome, Alzheimer ' s disease, with cardiovascular disease such as thrombosis, hypertension, vasospasm (periphery and/or maincenter) is as apoplexy, angina pectoris, and other vessel sealing disease.In addition, migraine also can be with stimulating 5-HT 2B5-HT is used in the The compounds of this invention treatment of receptor 2BThe preferred embodiment of the disease of receptor treatment comprises cardiovascular disease, uterine dysfunction, sleep disorder, illusory activity, psychosis, anxiety, depression, thermoregulation disease, eating disorder, and hypertension.See Leonard, B.E., international clinical psychopharmacology (InternationalClinical Psvchopharmacologv), 7,13-21 (1992).Use 5-HT 2BThe antagonist for treating intestinal dysfunction is particularly preferred.
Use 5-HT of the present invention 2BThe disease of CNS more specifically of regulating compounds for treating includes, but are not limited to: (numeral in the bracket is the DSM-III-R sorting code number) attention-deficient superfunction disease (314.01), conductive impairment (312.20,312.00,312.90), senile outbreak Alzheimer type primary degenerative dementia (290.30,290.20,290.21,290.00), presenile outbreak Alzheimer type primary degenerative dementia (290.11,290.12,290.13,290.10), alcohol withdrawal delirium (291.00), ethanol hallucinosis (291.30), the ethanol dementia (291.20) relevant with alcoholism, Fructus Cannabis vain hope disease (292.11), cocaine poisoning (305.60), hallucinogen mood disorders (292.84), narcotic withdrawal disease (292.00), the aromatic ring hexylamine poisoning (305.90) of phencyclidine or similar effect, other is to the work poisoning (305.90) of material of spirit, delirium (293.00), dull-witted (294.10), organic vain hope (293.81), organic hallucination (293.82), organic mood disorder (293.83), organic anxiety (294.80), organic personality disorder (310.10), organic mental disorders (294.80), catatonic schizophrenia (295.21,295.22,295.23,295.24,295.25,295.20), disorganized schizophrenia (295.11,295.12,295.13,295.14,295.15,295.00), paranoid schizophrenia (295.31,295.32,295.33,295.34,295.35,295.00), mixed type schizophrenia (295.91,295.92,295.93,295.94,295.95,295.00) and remaining type schizophrenia (295.61,295.62,295.63,295.64,295.65,295.60), vain hope (the vain hope sample) sick (297.10), schizoid obstacle (295.40), emotionality Split disease (295.70), the psychosis of bringing out (297.30), the existing manic outbreak of mixed type has the affective psychosis (296.61,296.62,296.63 of paralepsy again, 296.64,296.65,296.66,296.60), manic existing manic outbreak has the affective psychosis (296.41 of paralepsy again, 296.42,296.43,296.44,296.45,296.46,296.40), the existing manic outbreak of depressive type has the affective psychosis (296.51 of paralepsy again, 296.52,296.53,296.54,296.55,296.56,296.50), the major depression (296.21,296.22 of simple outbreak, 296.23,296.24,296.25,296.26,296.20), the major depression (296.31,296.32,296.33 of recurrence, 296.34,296.35,296.36,296.30), anancastic obstacle (300.30), post-traumatic nervous obstacle (309.89), the anxiety neurosis of diffusion (300.02), hypochondriasis (300.07), somatization disease (300.81), male erectile disorder (302.72), outburst disease (312.34) intermittently, impulsion control disease (312.39), class paranoea (301.00), schizophrenia (301.20), class schizophrenia (301.22), antisocial disease (301.70) and unknown cause disease (301.83).Psychotic diagnostic ﹠ statistical manual (Diagnostic andStatistical Manualof Mental Disorders), 3rd.Ed, Revised (1980), name of credit union of the sick student's federation of Americanism and statistics ad hoc working group.
Therefore, the present invention also provides the method for the treatment of and preventing the disease of above-mentioned title.
Those skilled in the art can think that the disease of psychosis or psychosis sample is with hallucination, vain hope, or dystropy is feature, the patient has obvious impairment when checking.Therefore the medicine that has antipsychotic activity can be used in the various important psychosiss of treatment.
Term used herein " intestinal dysfunction " is meant functional gastrointestinal disease, show as (1) stomachache and/or (2) and upset the defecation syndrome (promptly, ooze out incomplete excretory sensation, the feces shape [denseness] of change and the times of defecation/time that changes) and/or (3) swelling (expansion).Term " intestinal dysfunction " includes, but is not limited to irritable colon syndrome, and gastrointestinal motility is excessive, and the low level esophagus that ichlasia, height ooze expands about flesh, and the gastric antrum electrical activity is hyperfunction, constipation, and the gastrointestinal motility relevant with irritable colon syndrome is excessive.
The feature of intestinal dysfunction is abnormal gastrointestinal function, but discovers less than organizing deformity, and abnormal gastrointestinal function comprises diarrhoea, constipation, no mycete gastroenteropathy, pain or discomfort in the sigmoid colon process.This disease is subjected to the influence of psychology factor and nervous animation.
Intestinal dysfunction, irritable colon syndrome (IBS) is a kind of modal gastrointestinal disease, the clinical gastrointestinal disease patient of 20-50% suffers from IBS, other has 14% to suffer from the IBS syndrome in healthy population apparently approximately, the IBS syndrome is a kind of disease of complexity, partly cause is because it is not a disease, but it is a kind of syndrome by the disease combination of many similar performances.
The present Therapeutic Method of intestinal dysfunction is limited to treatment fraction patient's medicine, for example, anticholinergic agent can reduce spasticity, therefore can alleviate some stomachache, histamine H2 receptor antagonist can be secreted by gastric acid inhibitory, can alleviate some dyspepsia syndrome, also not have to alleviate at present the medicine of most of functional bowel syndrome.
Term " intestinal dysfunction " comprises that the low level esophagus that irritable colon syndrome, ichlasia, height ooze expands about flesh, and the gastric antrum electrical activity is hyperfunction, the excessive and constipation of the gastrointestinal motility relevant with irritable colon syndrome.
Chemical compound energy described herein and various mineral acid and organic acid form acid-addition salts.Operable typical acid comprises sulphuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, hypophosphoric acid, hydroiodic acid, sulfamic acid, citric acid, acetic acid, maleic acid, malic acid, succinic acid, tartaric acid, cinnamic acid, benzoic acid, ascorbic acid, mandelic acid, p-methyl benzenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, hippuric acid etc.Pharmaceutically-acceptable acid addition is for treatment and 5-HT 2BReceptor related disease is particularly preferred.
Some chemical compound is preferred for treatment and regulates 5-HT 2BReceptor related disease.Following embodiment of the present invention and can be independently in conjunction with producing many preferred chemical compounds and embodiment of the present invention with the listed chemical compound characteristic of form.Below listed embodiment of the present invention limit the scope of the invention never by any way.
A) R 1Be hydrogen;
B) R 2Be hydrogen or methyl;
C) R 3Be hydrogen or methyl;
D) R 4Be C 5-C 8The C of cycloalkenyl group or replacement 5-C 8Cycloalkenyl group, the bicyclic group of dicyclo or replacement, substituent group wherein is selected from hydrogen, C 1-C 6Alkyl, NO 2, halogen, halo (C 1-C 6Alkyl), C 2-C 6Alkenyl, COR 5, (C 1-C 6Alkyl) mAmino ,-SR 5, and OR 5
E) A is the group of formula III;
F) A is the group of formula IV, wherein R 6And R 7Be C 1-C 6Alkyl or halogen, R 8Be hydrogen, C 1-C 5Alkyl, halogen, C 5-C 8Cycloalkyl, the phenyl of phenyl or replacement;
G) and 5-HT 2BThe chemical compound of receptor acting is 5-HT 2BReceptor antagonist;
H) and 5-HT 2BThe chemical compound of receptor acting is 5-HT 2BThe receptor local stimulant;
I) R 4Be the C that replaces 5-C 8Cycloalkenyl group; Substituent group wherein is selected from hydrogen, NO 2, halogen, (C 1-C 6Alkyl) mAmino and OR 5
J) A is the group of formula IV, wherein R 6Be hydrogen, R 7And R 8Be independently selected from halogen and C 1-C 4Alkyl;
K) R 4Be the naphthyl of naphthyl or replacement, naphthyl substituted base wherein is selected from (C 1-C 6Alkyl) mAmino and OR 5
L) Y aBe CH 2, R 26And R 27Each is C 2-C 3Alkyl; R 28And R 29Each is a hydrogen;
M) formula I, II, III, IV and V chemical compound;
N) formula II, III and VIII chemical compound;
O) formula VI, VIII, IX, XI and XII chemical compound;
P) formula X chemical compound;
Q) R wherein 6Be methyl, R 2Be methyl and R 4Be the chemical compound of the thiazolinyl of replacement, wherein alkenyl is phenyl and has two to be the substituent group of methoxyl group;
R) 5-HT 2BThe disease of regulating is an intestinal dysfunction;
S) intestinal dysfunction is an irritable colon syndrome;
T) 5-HT 2BThe disease of regulating is a psychosis;
U) 5-HT 2BAlternative cpd is to 5-HT 2BReceptor comparison 5-HT 2AReceptor has bigger affinity;
V) 5-HT 2BAlternative cpd is to 5-HT 2BReceptor comparison 5-HT 2CReceptor has bigger affinity;
W) 5-HT 2BThe disease of regulating is selected from urinary incontinence, bladder function obstacle, uterine dysfunction, cardiovascular disease and respiratory disorder;
X) chemical compound is with the unit dosage form administration;
Y) should illustrate on the label of the medicine of Zhi Zaoing that chemical compound is used for the treatment of urinary incontinence, bladder function obstacle, uterine dysfunction, cardiovascular disease and respiratory disorder and intestinal dysfunction;
Z) pharmaceutical preparation contains one or more pharmaceutically acceptable excipient and 5-HT 2BReceptor is regulated chemical compound;
Z1) R wherein 4It is the chemical compound of aryl;
Z2) R wherein 4It is the chemical compound of fragrant dicyclo;
Z3) formula VII chemical compound;
Some chemical compound of formula II is used to regulate 5-HT 2BReceptor.Some formula 1I chemical compound in the scope of the invention is preferred for this purposes.Following embodiment of the present invention and with the listed chemical compound characteristic of the form many preferred chemical compounds of combination results and embodiment of the present invention respectively.Below listed embodiment of the present invention be intended to anything but limit the scope of the invention.
A) R 9And R 10Each is a hydrogen;
B) R 11Be C 1-C 3Alkyl;
C) R 11Be chlorine, fluorine or bromine;
D) R 11Be-OCH 3
E) R 6Be C 1-C 4Alkyl;
F) R 6It is methyl;
G) with one or more formula I and/or II chemical compound in conjunction with 5-HT 2BThe method of receptor;
H) with the method for one or more formula I and/or II compounds for treating intestinal dysfunction;
I) stimulate 5-HT with one or more formula I and/or II chemical compound 2BReceptor treatment urinary incontinence, bladder function obstacle, uterine dysfunction, the method for cardiovascular disease and respiratory disorder;
J) with the method for one or more formula I and/or II compounds for treating irritable colon syndrome;
K) contain the pharmaceutical preparation of formula I and/or II chemical compound and one or more pharmaceutically acceptable excipient;
Chemical compound of the present invention is used for regulating or blocking-up 5-HT 2BReceptor.Some formula XI and XII chemical compound are preferred for this purposes.Following embodiment of the present invention and can select respectively or be used in combination to obtain many preferred chemical compounds of the present invention and embodiment with the listed chemical compound characteristic of form.Below listed embodiment of the present invention never mean by any way and limit the scope of the invention.
A) R 1Be hydrogen;
B) R 2Be hydrogen or methyl;
C) R 3Be hydrogen or methyl;
D) R 4Be C 5-C 8The C of cycloalkenyl group or replacement 5-C 8Cycloalkenyl group, substituent group wherein is selected from hydrogen, C 1-C 6Alkyl, NO 2, halogen, halo (C 1-C 6Alkyl), C 2-C 6Alkenyl, COR 5, (C 1-C 6Alkyl) mAmino ,-SR 5, and OR 5
E) A is the group of formula III;
F) A is the group of formula IV, wherein R 6And R 7Be C 1-C 6Alkyl or halogen; R 8Be hydrogen, C 1-C 5Alkyl, halogen, C 5-C 8Cycloalkyl, the phenyl of phenyl or replacement;
G) R 2Be hydrogen;
H) R 3Be hydrogen or methyl;
I) R 4Be the C that replaces 5-C 8Cycloalkenyl group, substituent group wherein is selected from hydrogen, NO 2, halogen, (C 1-C 6Alkyl) mAmino, or OR 5
J) A is the group of formula IV, wherein R 6Be hydrogen, R 7And R 8Be independently selected from halogen and C 1-C 4Alkyl;
K) Q ' is (CHR 2) R 4
L) R 30And R 31In conjunction with forming 3-6 unit carbocyclic ring;
M) R 30And R 31In conjunction with forming 3-5 unit carbocyclic ring;
N) R 30And R 31Each is a methyl
O) R 4It is naphthyl;
P) R 4Be the dicyclo hydrocarbon system that replaces arbitrarily, 7-12 carbon atom and 0,1,2 or 5 two keys are arranged;
Q) R 4It is the unsubstituted bicyclic ring system of 6-10 carbon atom;
R) Q ' is the dicyclo of dicyclo or replacement;
S) R 34Be
Figure A9519302900541
T) R 34It is the dicyclo substituent group that replaces arbitrarily;
U) R 9And R 10Respectively be hydrogen;
V) R 9Be selected from C 1-C 6Alkyl, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl;
W) R 4It is aryl;
X) R 34It is the spiral shell dicyclo of spiral shell dicyclo or replacement;
Y) Q ' is a hydrogen;
The all kinds of of following feature are more preferably arranged:
A-C, E or F, I, L, N, P, R and W;
The all kinds of of following feature are most preferably arranged:
A, G-J, M and Q;
Be used for selectivity 5-HT 2BThe preferred compound of ligand is all kinds of that following feature is arranged:
A-D, E or J, M and O;
Be used for selectivity 5-HT 2BThe most preferred compound of ligand is all kinds of that following feature is arranged:
A, G-J, M and O;
Formula XI and XII chemical compound are used in particular for regulating 5-HT 2BReceptor.The present invention's some chemical compound in this scope is preferred for this purposes.Following embodiment of the present invention and can select respectively or be used in combination to obtain many preferred chemical compounds of the present invention and embodiment with the listed chemical compound characteristic of form.Below listed embodiment of the present invention never mean by any way and limit the scope of the invention.
A) R 9And R 10Each is a hydrogen;
B) R 11Be C 1-C 3Alkyl;
C) R 11Be chlorine, fluorine or bromine
D) R 11Be-OCH 3
E) R 30And R 31In conjunction with forming 3-8 unit carbocyclic ring;
F) R 30And R 31In conjunction with forming 3-6 unit carbocyclic ring;
G) chemical compound of above-mentioned preferred property such as above-mentioned;
H) with one or more formula XI and/or XII chemical compound in conjunction with 5-HT 2BThe method of receptor;
I) with the method for one or more formula XI and/or XII compounds for treating intestinal dysfunction;
I) regulate 5-HT with one or more formula XI and/or XII chemical compound 2BReceptor is with the method for treatment intestinal dysfunction;
J) with the method for one or more formula XI and/or XII compounds for treating irritable colon syndrome;
K) contain the pharmaceutical preparation of XI and/or XII chemical compound and one or more pharmaceutically acceptable excipient.
Formula XI examples for compounds includes but not limited to:
10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
8-chloro-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
6-(2, the 4-dimethoxy-benzyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
7-fluoro-6-(2, the 4-dimethoxy-benzyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
8-methoxyl group-6-(2, the 4-dimethoxy-benzyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
7-nitro-6-(3, the 4-dimethoxy-benzyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
5-(2, the 4-dimethoxy-benzyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
7-bromo-5-(2, the 4-dimethoxy-benzyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
6-ethyoxyl-5-(3, the 4-dimethoxy-benzyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
7-nitro-6-(3, the 4-dimethoxy-benzyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
7-(3, the 4-dimethoxy-benzyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also
7-nitro-6-(3,4-diethoxy benzyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
6-methyl-8-bromo-1-[(3, the 4-dimethoxy phenyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-C] quinoline also,
7-(1, the 1-dimethyl ethyl)-5-(1-naphthyl-1-ethyl)-1,2,3,4,4a, 5,6,7,10c-octahydro-pyrido [3,4-b] indole hydrochloride thing,
7-methoxyl group-1-(2-methylamino naphthyl)-1-ethyl)-1,2,3,4,4a, 5,6,7,1 0c-octahydro-cyclopenta [a] pyrido [3,4-b] indole,
(Z) 2-butylene two acid esters,
6-(1, the 1-dimethyl ethyl)-1-(1-(3-lignocaine naphthyl)-1-ethyl)-1,2,3,4,4a, 5,6,7,10c-octahydro-cyclopenta [a] pyrido [3,4-b] indole hydrochloride thing and,
6-methyl-5-[(4-methylamino naphthyl) methyl]-1,2,3,4,4a, 5,6,7,10c-octahydro-cyclopenta [a] pyrido [3,4-b] indole hydrochloride thing.
Formula XII examples for compounds includes but not limited to:
3-(2-amino-cyclopenta)-6, the 7-dimethyl indole,
3-(2-amino-cyclopenta)-5-methyl-7-bromo indole,
3-(2-amino-cyclopenta)-6-methyl-7-chloro-indole,
3-(2-amino-cyclopenta)-6-bromo-7-methylindole,
3-(2-amino-cyclopenta)-benzo (G) indole,
3-(2-amino-cyclohexyl)-5-methyl-7-chloro-indole,
3-(2-amino-cyclohexyl)-7-chloro-indole,
3-(2-amino-cyclopropyl)-7-methoxyl group indole,
3-(2-amino-suberyl)-7-fluoro indole,
3-(2-amino-cyclohexyl)-7-bromo indole,
3-(2-amino-cyclopropyl)-6-methyl-7-bromo indole,
3-(2-amino-cyclopenta)-5-fluoro-7-methoxyl group indole,
3-(2-amino-cyclopenta)-5-nitro-7-chloro-indole,
3-(2-amino-ring octyl group)-2-ethyl-7-fluoro indole and
3-(2-amino-suberyl)-2-methyl-7-fluoro indole.
Be used to block 5-HT 2BThe chemical compound of receptor comprises that racemic mixture and pure basically formula I arrive the stereoisomer of formula XII.Normally used the same in term used herein " enantiomer " and the organic chemistry, being meant can the planar chemical compound of rotatory polarization, and therefore, " enantiomer " to anticlockwise, is called the levo-compound of formula I-XII with the plane of polarization.The known disassemble technique of one routine can with+and-Chiral Separation.The useful especially handbook of describing this method is people such as Jacques, enantiomer, racemic modification and method for splitting (John Wiley and Sons1981), suitable method for splitting comprises direct recrystallization, separate and with optics active solvent recrystallization (Heterocvcles, Chrisey, L.A., 267,30,1990).Preferred method for splitting is synthetic with optics active acid recrystallization or chirality, as method (A.I.Meyers.Loewe, M.F.et al, the Tetrahedron Letters that uses among the embodiment 46,3291,26,1985:Meyers, A.I.et al., JACS, 4778,110,1988).Preferred optical activity acid comprises camphorsulfonic acid and tartaric acid derivatives.
The present invention includes " R " and " S " two kinds of configurations, term used herein " R " and " S " are meant the particular configuration of chiral centre as normally used in the organic chemistry, see R.t.Morrison and R.N.Boyd, organic chemistry, pp138-139 (4th Ed.Allvn﹠amp; Bacon, Inc., Boston) and Orchin, et al. organic chemistry compilation (The Voeabularvof Organic Chemistry), p.126, (John Wiley and Sons, Inc.).
For example, the present invention includes but be not limited to the purposes of following chemical compound:
(-)-(S)-7-methyl-8-bromo-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole;
(-)-(S)-5,7-dimethyl-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-9H-pyrido [3,4-b] indole;
(-)-(S)-5-fluoro-6-methyl isophthalic acid-[(2-chloro-3,4-Dimethoxyphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole; With
(-)-(S)--6-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-[(3,4-3,5-dimethylphenyl) methyl]-9H-pyrido [3,4-b] indole; The present invention also includes, but are not limited to the purposes of following chemical compound:
(+)-(S)-7-methyl-8-bromo-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole;
(+)-(S)-5,7-dimethyl-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-9H-pyrido [3,4-b] indole;
(+)-(S)-5-fluoro-6-methyl isophthalic acid-[(2-chloro-3,4-Dimethoxyphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole;
(-)-(R)-7-methyl-8-bromo-1-[(3, the 4-3,5-dimethylphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole;
(-)-(R)-5,7-dimethyl-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-9H-pyrido [3,4-b] indole;
(-)-(R)-5-fluoro-6-methyl isophthalic acid-[(2-chloro-3,4-Dimethoxyphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole;
(-)-(R)-6-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-[(3,4-3,5-dimethylphenyl) methyl]--9H-pyrido [3,4-b] indole;
(+)-(R)-7-methyl-8-bromo-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole;
(+)-(R)-5,7-dimethyl-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-9H-pyrido [3,4-b] indole;
(+)-(R)-5-fluoro-6-methyl isophthalic acid-[(2-chloro-3,4-Dimethoxyphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole; With
(-)-(S)-6-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-[(3,4-3,5-dimethylphenyl) methyl]--9H-pyrido [3,4-b] indole.
Be used for and 5-HT 2BThe chemical compound of receptor acting is that known energy and appropriate solvent form hydrate and solvate, the preferred solvent of preparation solvate comprises water, alcohol, oxolane, DMF and DMSO, preferred alcohol is methanol and ethanol, other appropriate solvent can be selected according to the size of solvent molecule, little solvent molecule is preferred for forming the corresponding solvent thing, solvate or hydrate generally are to form at recrystallization process or in the salifiable process of shape, about one of solvate useful handbook is Sykes, Peter, organic chemistry mechanism guide (A Guidebook to Mechanism in Organic Chemitry), 6,56, (1986, John Wiley﹠amp; Sons, New York).Term used herein " solvate " comprises hydrate such as monohydrate and dihydrate.
Be used for and 5-HT 2BSome chemical compound of receptor acting is that prior art is known or obtain easily by conventional synthetic method.For example, the formula III chemical compound can use Semonsky et al in U.K.No.81 6,273 (July 8,1959), and U.S.P.No 2,736, the method for instruction preparation in 728 and 2,774,763, and these United States Patent (USP)s are in this article as a reference.Formula IV chemical compound can be used U.S.P.No 4,981,859 and 4,931, the method preparation described in 447, and this paper is as a reference.The preparation method of formula V chemical compound is recorded in U.S.P.No4, and in 902,691, this paper as a reference.The preparation method of formula VI chemical compound is recorded in U.S.P.No 4,563, and in 461, this paper as a reference.The preparation method of formula VII chemical compound is recorded in J.Med.Chem., 36:1104-1107 (Forbes, I.T., 1993).Formula VIII chemical compound is that prior art is known and can buy, and perhaps can prepare according to known method.The technical staff can obtain the method for preparation formula IX chemical compound in disclosed european patent application, this European Patent Publication No is that (August 12,1992 for 0498590 A1; Bulliten 92/33), and the American technology personnel can obtain English text rapidly.Formula X chemical compound is known and available known method preparation.
Chemical compound of the present invention can still prepare the method that the most preferred method of formula I chemical compound of the present invention is to use following reaction process V with this professional accessible chemical method preparation in the prior art; The most preferred method of preparation formula II chemical compound is to use the conventional method described in the following reaction process II, wherein R 9, R 12And/or R 10The formula II chemical compound that is not hydrogen is to use acceptable chemical method as corresponding tryptamines reductive alkylation or direct alkylation are prepared.
Wherein Q is that the formula I chemical compound of hydrogen can make the acetaldehyde compound of formula (i) and the amine prepared in reaction of formula (h), the reaction of this Pictet-Spengler type is generally used, the productive rate ideal can obtain stable intermediate, and the form that product generally can required salt is directly separated.
Formula (a) chemical compound as the The compounds of this invention raw material can have been bought from limit-line store, perhaps uses known chemical method preparation; Formula (b) chemical compound as the The compounds of this invention raw material can be according to reaction process I preparation, R 4Group definition as above.
The preparation method of The compounds of this invention is discussed in more detail below.
Reaction process I
Figure A9519302900591
According to required product, chemical compound among the reaction process I (a) can be that replace or unsubstituted, can buy for necessary most numerical expression (a) raw materials of compound of preparation azalide, the formula of other replacement (a) chemical compound can prepare with common chemical method, see Furniss, B.S.etal., (John Wiley New York N.Y.1989) sees the 989-993 page or leaf to Wo Geer organic chemistry textbook (Vogel ' s Textbook of Practical OrganicChemistry) especially.
Usually reaction process I is by preparation chemical compound (a); acetyl-glycine; the solution of acetic anhydride of sodium acetate begins; reaction is usually in about 90 ℃-Yue 110 ℃ of heating 2-15 hour; reactant mixture is chilled to about room temperature; in inert atmosphere stir about 0-10 hour, the response time can change according to replacement degree and the reacting finisheding degree of R4.
After reaction is finished mixture is poured in the ice under stirring, azalide (b) can be separated as filtering by the isolation technics of standard, and is dry down in decompression.
Chemical compound among the reaction process II (d) is as the raw material of preparation I compound, and these chemical compounds can have been bought, and perhaps can use the known Fischer indole synthesis preparation that is applicable to tryptamines, Fischer synthetic method such as reaction process II, and " A " defines as above.
Reaction process II
Figure A9519302900601
The chloro butyraldehyde chemical compound that uses among the reaction process II can prepare by the hydrogenation of chlorobutyroyl chloride, and hydrogenation reaction can be used catalyst such as Pd/C, and other halo butyraldehyde chemical compound also can be used for reaction process II.Starting compound among the reaction process II (c) can have been bought or prepare with known method, as March, and J., senior organic chemical reactions, mechanism and structure (AdvancedOrganic Chemistry Reactions, Mechanisms, andStructure) 3rd (JohnWiley﹠amp; Sons, New York, 1985) described, see 1163 pages especially.
Fischer is synthetic usually from suitable saturated alkali such as sodium carbonate being added to the organic solvent such as the chloroform suspension of the hydrazonium salt that is stirring, the hydrochlorate of hydrazine is particularly preferred hydrazonium salt, required hydrazine separates the alkali organic extractant phase, grease is put into alcohol and water solution also handle with suitable alkali such as sodium acetate.Add the halo butyraldehyde, test tube noble gas such as nitrogen wash, the gained mixture is put in the oil bath that is heated to about 90-110 ℃, the about 17-19 of heating blends hour, mixture is chilled to room temperature, concentrates down in decompression, residue is distributing between as chloroform/methanol and aqueous sodium carbonate between suitable organic facies and the alkali liquor, concentrate organic facies, obtain chemical compound (d) and purify with standard method such as flash chromatography.When using chromatography, the fraction that will contain product merges and concentrates.Grease is dissolved in appropriate solvent as containing in the about 1% alcoholic acid ether, and preferred alcohols is a methanol.Chemical compound with exsiccant sour gas such as the gas disposal of dry hydrogen chloric acid, is obtained the corresponding acid-addition salts of required compound (d).
A method of preparation I compound is that shown in reaction process III, substituent group defines as above with the Pictet-Spengler reaction.
Reaction process III
Figure A9519302900611
Usually, reaction process III carries out the aldehyde of chemical compound (e) and selection in appropriate solvent such as ethanol or methanol, according to required product reaction about 1-50 hour, can reflux in case of necessity.The product that is settled out is collected as filtering by common separation method, and purifies with recrystallization.If need obtain R 1Substituent chemical compound carries out reductive alkylation reaction again, and reductive alkylation is shown in reaction process IV.
Reaction process IV
Figure A9519302900612
Bronsted acid and aldehyde solution join in chemical compound (f) water-soluble usually, and most preferred Bronsted acid is a formic acid, and most preferred aldehyde is formaldehyde.The technical staff can easily select other suitable reagent so that reductive alkylation reaction carries out smoothly, and gained solution was refluxed about 4-80 hour, and the back of refluxing is made alkalescence with suitable alkali such as potassium carbonate with solution.Required product, concentrates the product drying with suitable organic facies such as chloroform extraction, purifies with known method such as flash chromatography.
Prepare wherein R 2The method for optimizing that is the formula I chemical compound of hydrogen is that shown in reaction process V, substituent group defines as above with aforesaid improved Pictet-Spengler reaction.
Reaction process V
Figure A9519302900621
Chemical compound (h) contacts in suitable protonic acid aqueous solution with chemical compound (i), when being the chemical compound of hydrogen on needing the 1-position, can replace with glyoxylic acid (i), and this step reaction can be finished under inert conditions.Chemical compound (h) and chemical compound (i) can reflux under atmosphere or inert atmosphere about 20-30 hour, and preferred Bronsted acid comprises sulphuric acid and hydrochloric acid, and most preferred acid solution is 1NHCl.If can not direct effectively isolating words, reactant mixture can be neutralized with suitable alkali such as potassium carbonate, use organic facies such as chloroform extraction subsequently, remove the back of desolvating by chromatographic isolation such as silica gel chromatography or other post isolation technics products of separated.Generally be that isolated in form with acid-addition salts goes out product, suitable salt form as mentioned above.
As above-mentioned, chemical compound of the present invention can exist with detachable enantiomer, and single (-) enantiomer can be by the chemical resolution method preparation of the A.I.Meyers shown in following reaction process VI.(+) enantiomer uses known disassemble technique preparation, and all substituent group definition as above.
Reaction process VI
Figure A9519302900631
In reaction process VI, CSA represents camphorsulfonic acid, and butylformadine (1) is prepared by valine with known method, also available other Formadine chemical compound.In step 1, the solution of chemical compound (k) and butylformadine (1) refluxed about 70-80 hour, and the back flow reaction product is purified as flash chromatography with standard isolation methods, and isolated grease need not further be purified and can be used.
The chemical compound (m) of step 1 preparation is joined in oxolane (THF) suspension of hydrofining (KH), in solution, add tetramethylethylenediamine (TMEDA) and chloromethyl methyl ether (MOMCl) again, shown in step 2.Stirred the mixture about 1 hour, the mixture water treatment distributes between suitable organic solvent such as ether and water, uses organic extractant phase, the potassium carbonate drying, and concentrate, gained grease need not further be purified and be can be used for next step reaction.
In step 3, positive fourth lithium slowly is added drop-wise in the anhydrous THF solution of refrigerative (-76 to-80 ℃ approximately) formadine that is stirring, stir about 1 hour, add the chlorine-containing compound among the anhydrous THF, in lowering the temperature down again with the about 4-5 of solution stirring hour, mixture is chilled to the about 4-14 of room temperature hour, add wet THF, concentrated solution, residue are dissolved in the suitable organic solvent such as chloroform, wash with water, organic facies is with suitable desiccant such as sodium carbonate drying, carry out the purification of required product after concentrating, product separates with flash chromatography and concentrates, and gained grease need not further be purified and be can be used for next step reaction.
The beginning (about 0 ℃) under the temperature that reduces of the deprotection reaction of step 4 expression; water; acetic acid and hydrazine hydrate are added in the chemical compound (o); reaction temperature be reduced to approximately-10 to-20 ℃ about 60-120 hour; mixture is warmed to room temperature and concentrated; product is dissolved in the suitable organic solvent such as chloroform; wash organic facies with water; with suitable desiccant such as sodium carbonate drying; be condensed into heavy-gravity grease, it is dissolved in appropriate solvent such as the ether, with appropriate organic or mineral acid treatment; obtain required acid-addition salts, isolate this salt and also purify with common chemical method.
If required product is at R 3Alkyl is arranged, the reaction that available use reaction process VII represents on the position.
Reaction process VII
Figure A9519302900641
In flow process VII, suitable saturated aqueous slkali such as sodium carbonate join in the chemical compound (q), the salt of required compound (q) can prepare with the method for above-mentioned flow process II, mixture about 1 hour in stirring at room, water layer is with suitable organic solvent such as chloroform extraction after the layering, organic facies is with suitable desiccant such as dried over sodium sulfate, concentrate, residue is dissolved in appropriate solvent such as the toluene, handle with phthalic anhydride,, solution is cooled off the solution 12-20 hour azeotropic drying simultaneously that reflux, concentrate, recrystallization obtains chemical compound (r).
In next step, chemical compound (r) and THF mix, suitable alkali such as hydrofining refrigerative (about 0 ℃) suspension in anhydrous THF is slowly joined in the solution of chemical compound (r), add after the alkali mixture stir about 1 hour, add tetramethylethylenediamine (TMEDA), add alkyl halide such as methyl iodide again, (MeI), add water retention after 1 hour and end reaction,, also concentrate with suitable desiccant such as dried over mgso organic facies with appropriate organic solvent such as extracted with diethyl ether.
The solution of spissated chemical compound (s) can be directly used in next step reaction, it is contacted with appropriate solvent such as methanol, handle with hydrazine, mixture was refluxed about 2 hours, be cooled to room temperature, handle with concentrated acid such as HCl, mixture reuse alcohol is handled and backflow 12-20 hour, preferred alcohol comprises methanol, ethanol, butanols, after being cooled to room temperature, mixture distributes between suitable organic facies and water, and a kind of suitable cooperation is chloroform and dense sodium carbonate liquor, further aqueous phase extracted, merge organic facies, drying concentrates, and product is purified with flash chromatography, concentrate, change into required salt, gained chemical compound (t) can be used for flow process III or V, to produce required formula I chemical compound.
Formula XI and formula XII chemical compound can be used method for preparing, but the reaction process VIII explanation of the method for optimizing of preparation chemical compound formula XI and XII.
Reaction process VIII R wherein 32Be independently selected from C 1-C 6Alkyl, A and Q ' definition are as above.In addition, the chemical compound of embodiment 108 can prepare shown in following flow process: The chemical compound of same embodiment 109 can prepare shown in following flow process:
Figure A9519302900662
Following examples further specify some formula I, II, and the preparation of XI and XII chemical compound, embodiment only is used for explanation, is not the restriction for the scope of the invention.
Column chromatography is used standard flash chromatography technology, and the known reference of flash chromatography technology is Still W.C.Kahn and Mitra, J.Org Chem.1978, and 43,2932. level part common vapourisation under reduced pressure that contain product obtain product.
Polariscopy uses methanol, and pyridine or other solvent obtain.
The hydrochlorate of individual compound contains alcohol as preparing in the ether of methanol or in other appropriate solvent mixture by its separation alkali is joined, stir the solution of this ether on one side,, become acidity up to solution Yi Bian drip the HCl solution in the ether, in addition, ethereal solution also can be used the HCl gas disposal of doing.
The maleate of individual compound filters the precipitation that forms by separating alkali and put into ethyl acetate or other appropriate solvent and handling with maleic acid, and drying obtains separating the corresponding hydrochlorate or the maleate of alkali.
Formula I-VI chemical compound and formula VIII-XII chemical compound are for the 5-HT that treats mammiferous and abnormal or malfunction 2BThe receptor for stimulating diseases related is preferred.In addition, formula I-VI chemical compound and formula VIII-XII chemical compound are for blocking in the mammalian body or external 5-HT 2BReceptor
Be preferred.Simultaneously, to be used to prepare medicine be preferred for formula I-VI chemical compound and formula VIII-XII chemical compound.
Figure A9519302900671
4.HClaX″＝5-Me??????aX″＝5-Me?????n 30＝3(90)?aX″＝5-Me??????n 30＝4?R，R′＝H(95)??bX″＝7-Cl??????bX″＝7-Cl?????n 30＝3(91)?bX″＝7-Cl??????n 30＝4?R，R′＝H(96)cX″＝5，7-diMe?cX″＝5，7-Me 2n 30＝3?????cX″＝5-Me??????n 30＝3?R＝3，4-(OMe) 2Bn，R′＝H(97)
dX″＝5-Me?????n 30＝4(92)?dX″＝7-Cl??????n 30＝3?R＝3，4-(OMe) 2Bn，R′＝H(98)
eX″＝7-Cl?????n 30＝4(93)?eX″＝5，7-Me 2?n 30＝3?R＝3，4-(OMe) 2Bn，R′＝H(99)
fX″＝5，7-Me 2n 30＝4(94)?fX″＝5-Me??????n 30＝4?R＝3，4-(OMe) 2Bn，R′＝H(100)
gX″＝5-Me?????n 30＝5?????gX″＝7-Cl??????n 30＝4?R＝3，4-(OMe) 2Bn，R′＝H(101)
hX″＝5，7-Me 2?n 30＝4?R＝3，4-(OMe) 2Bn，R′＝H(102)
iX″＝5-Me??????n 30＝5?R＝3，4-(OMe) 2Bn，R′＝H(103)
JX "=5-Me n 30=3 R=1-naphthyls, R '=H (104)
KX "=5-Me n 30=4 R=1 naphthyls, R '=H (105)
LX "=5,7-Me 2n 30=4 R=1-naphthyls, R '=H (106)
mX″＝5-Me??????n 30＝4?R，R′＝H??(107)
Figure A9519302900672
Ether in the time of suitably among the embodiment 90-109 steams from the benzophenone sodium ketyl that uses in advance, and all direct draughts that are reflected at argon carry out, 1-NMR and 13C-NMR data BrukerAC-200P (200MHz) record, ir data obtains with Nicolet510 P-FT (film and KBr), fusing point is measured with Buchi fusing point instrument, not calibrated, analyze the TLC use and be coated with F254 silica gel 60 (UV, 254nm and iodine) Merck TLC glass plate operation, used in chromatograph 230-400 order silica gel (Merck), N-BOC-aziridines (2a-d) prepares according to standard method from corresponding alkene.
Preparation example 1
The preparation of 4-chlorobutyraldehyde
Figure A9519302900681
4-chlorobutanoylchloride (300g, 2.13mol) be dissolved among the anhydrous THF (3L), in this solution, add 2,6-lutidines (252ml), add 5%Pd/C (30g) subsequently, mixture is put into the Parr hydrogenator and was vibrated 6 hours down in the 60psi hydrogen pressure, and the mixture nitrogen wash filters, with THF (500ml) washing catalyst, the room temperature decompression concentrates down, obtains 4-chlorobutyraldehyde (148.3g) after the distillation, is colourless liquid.
Embodiment 1
8-methyl isophthalic acid-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
3; 4-dimethoxy benzaldehyde (24.5g; 0.15mol), the N-acetyl-glycine (17.4g, 0.15mol) and sodium acetate (12.1g; 0.15mol) solution in acetic anhydride (135ml) be heated to 100 ℃ 12 hours; reactant mixture is chilled to room temperature, pours in the ice (300ml) the isolated by filtration product under stirring; water (3 * 50ml) and ether (3 * 50ml) washings, decompression down dry product (16.3g)
Azalide (the 1.35g of above-mentioned preparation, 5.46mmol) and 7-methyltryptamine hydrochloride (1.15g, 5.46mmol) suspension in 1N HCl (50ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, neutralize with the unsaturated carbonate aqueous solutions of potassium, use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is purified (ethyl acetate/0.2% ammonium hydroxide eluting) with silica gel chromatography, merges the fraction that contains product, concentrating under reduced pressure, residue is dissolved in the ethyl acetate that contains 1% methanol, handles filtration product with maleic acid, separate (mp=168 ℃ is decomposed) with maleate (730mg).
Elementary analysis value of calculation measured value
C???????66.36??????66，15
H????????6.24???????6.28
N????????6.19???????5.79
Embodiment 2
8-bromo-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Toward the 2 bromo phenyl hydrazine hydrochlorate (25.8g that is stirring, 115mmol) add saturated sodium carbonate solution (500ml) in the suspension in chloroform (500ml), mixture stirred 30 minutes, with chloroform (2 * 200ml) extractions, concentrate the organic facies that merges, the hydrazine that obtains yellow oily separates alkali, and this grease is dissolved in the methanol (100ml), (12.3g 115mmol) handles slowly to use the 4-chlorobutyraldehyde.Mixture is put into tube sealing, with nitrogen wash 10 minutes, seal test tube and in oil bath, be preheated to 95 ℃, continue heating 18 hours, the dark-coloured solution of gained is chilled to room temperature, and concentrating under reduced pressure, residue distributes between chloroform/methanol (75/25 volume ratio) and aqueous sodium carbonate, concentrate organic facies, with the thick indole ethanolamine of flash chromatography on silica gel purification, (solution of 0-25% methanol in chloroform is made gradient elution), merge the fraction that contains product and also concentrate, grease is dissolved in the ether (300ml) that contains 1% methanol, with dry HCl gas disposal, filter to isolate hydrochlorate, with 2-propanol (50ml) and ether (100ml) washing, obtain light solid 7-bromine tryptamines hydrochloride (3.6g) after the drying, need not further purify and to use.
Azalide is (as embodiment 1 preparation, 1.16g, 4.7mmol) and 7-bromine tryptamines hydrochloride (1.0g, 3.6mmol) suspension in 1N HCl (100ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, the isolated by filtration crude product, brown solid develops (3 * 50ml) with isopropyl alcohol, (3 * 50ml) washings, recrystallization obtains the hydrochlorate (mp=279-281 ℃ is decomposed) of required product from ethanol with ether.
Elementary analysis value of calculation measured value
C???????54.87??????54.75
H????????5.07???????5.20
N????????6.40???????6.23
Embodiment 3
6,8-two bromo-1-[(3,4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
Toward refrigerative (5 ℃) 2 that stirring, 4-dibromo aniline (50.0g, 0.2mol) concentrated hydrochloric acid solution (110ml) in drip sodium nitrite (13.8g in water-soluble (110ml), 0,2mmol), rate of addition answers holding temperature to be lower than 5 ℃, being added dropwise to complete the back continued to stir the mixture 30 minutes in 5 ℃, drip stannic chloride monohydrate (135.4g, 0.6mol) concentrated hydrochloric acid (cumulative volume 170ml) solution and holding temperature be lower than 5 ℃, continued to stir the mixture 30 minutes after being added dropwise to complete and in 5 ℃, mixture is put into refrigerator overnight, the light brown solid that isolated by filtration is settled out, wash with cool brine, use petroleum ether/ethyl ether (2/1 subsequently, volume ratio) washing, this solid is slowly joined in 50% ice-cooled sodium hydroxide solution/ethyl acetate mixture, the mixture ethyl acetate extraction, the organic facies dried over mgso, after the filtration with solution concentration to cumulative volume 400ml, with ether (1.5L) dilution, handle with exsiccant HCl, product 2,4-dibromo phenyl hydrazonium salt acidulants (45.9g) is separated with white solid, need not further purify.
Toward stirring 2,4-dibromobenzene hydrazonium salt acidulants (22.0g, 83mmol) drip saturated sodium carbonate solution (500ml) in the suspension in chloroform (500ml), mixture stirred 30 minutes, and (2 * 200ml) extractions concentrate the organic facies that merges with chloroform, the hydrazine that obtains yellow oily separates alkali, this grease is dissolved in the methanol (163ml), and (8.8g 83mmol) slowly handles with the 4-chlorobutyraldehyde.Mixture is put into tube sealing, with nitrogen wash 10 minutes, seal tube sealing and in oil bath, be preheated to 95 ℃, continue heating 18 hours, the dark-coloured solution of gained is chilled to room temperature, and concentrating under reduced pressure, residue distributes between chloroform/methanol (75/25 volume ratio) and aqueous sodium carbonate, concentrate organic facies, with the thick indole ethanolamine of flash chromatography on silica gel purification, (solution of 0-25% methanol in chloroform is made gradient elution), merge the fraction that contains product and also concentrate, grease is dissolved in the ether (300ml) that contains 1% methanol, with exsiccant HCl gas disposal, filter to isolate hydrochloride, with 2-propanol (50ml) and ether (100ml) washing, obtain light solid 7-bromine tryptamines hydrochloride (1.5g) after the drying, need not further purify and to use.
Azalide is (as embodiment 1 preparation, 0.45g, 1.82mmol) and 5,7-dibromo tryptamines hydrochloride (0.58g, 1.64mmol) suspension in 1N HCl (65ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, with unsaturated carbonate aqueous solutions of potassium neutralization and use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is purified (ethyl acetate/0.2% ammonium hydroxide eluting) with silica gel chromatography, merges the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handle isolated by filtration product maleate (340mg) (mp=177-179 ℃ is decomposed) with maleic acid.
Elementary analysis value of calculation measured value
C???????48.34?????48.61
H????????4.06??????4.17
N????????4.70??????4.69
Embodiment 4
6-methyl-8-bromo-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Toward refrigerative (5 ℃) the 2-bromo-4-monomethylaniline. (50.54g that is stirring, 0.272mol) concentrated hydrochloric acid solution (200ml) in drip sodium nitrite (18.9g in water-soluble (200ml), 0,274mmol), rate of addition answers holding temperature to be lower than 5 ℃, continued to stir the mixture 30 minutes after being added dropwise to complete and in 5 ℃, drip stannic chloride monohydrate (185.4g, 0.822mol) concentrated hydrochloric acid (cumulative volume 400ml) solution and holding temperature be lower than 5 ℃, being added dropwise to complete the back continued to stir the mixture 30 minutes in 5 ℃, mixture is put into refrigerator overnight, the light brown solid that isolated by filtration is settled out, wash with cool brine, use petroleum ether/ethyl ether (2/1 subsequently, volume ratio) washing, this solid is slowly joined in 50% ice-cooled sodium hydroxide solution/ethyl acetate mixture, the mixture ethyl acetate extraction, the organic facies dried over mgso, after the filtration with solution concentration to cumulative volume 400ml, dilute with ether (1.5L), handle with exsiccant HCl, product 2-bromo-4-methylphenylhydrazine hydrochloride (52.4g) is separated with white solid, need not further purify.
Except that using 2-bromo-4-procarbazine hydrochloride (21g) to do the raw material, according to embodiment 3 described preparation 5-methyl-7-bromine tryptamines hydrochlorides (4.95g).
Azalide is (by embodiment 5 preparations, 1.44g, 6.07mmol) and 5-methyl-7-bromine tryptamines hydrochloride (1.12g, 3.87mmol) reflux 24 hours under blanket of nitrogen of the suspension in 1N HCl (80ml), reactant mixture is chilled to room temperature, the isolated by filtration crude product, (3 * 50ml) development brown solids are with ether (3 * 50ml) washings with isopropyl alcohol, recrystallization from ethanol, obtain the required product of 1.06g, be light solid (mp=251-253 ℃ is decomposed).
Elementary analysis value of calculation measured value
C?????????55.83?????56.08
H??????????5.35??????5.32
N??????????6.20??????6.33
Embodiment 5
8-methoxyl group-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
2-methoxybenzene hydrazonium salt acidulants (14.44g toward the cooling (0 ℃) of stirring, add 4-chlorobutyraldehyde (9.0g in the suspension among THF 83mmol) (600ml), 84mmol), drip the triethylamine (8.6g among the THF (20ml) subsequently, 85mmol), remove cryostat after being added dropwise to complete, agitating solution 1 hour, filter reaction mixture, filter cake washs with THF (100ml), the filtrate that merges is condensed into orange, it is dissolved in methanol (150ml) and the water (5ml), solution is put into tube sealing, with nitrogen wash 10 minutes, seal tube sealing and in oil bath, be preheated to 95 ℃, heat after 14 hours, reactant mixture is chilled to room temperature, and concentrating under reduced pressure, residue is at the chloroform of unsaturated carbonate aqueous solutions of potassium and 3: 1: distribute between the 2-propanol, organic facies is with dried over sodium sulfate and concentrate, residue is with the flash chromatography on silica gel (eluent: 15% methanol of purifying, the solution of 0.2% ammonium hydroxide in chloroform), merge the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in methanol and handles with exsiccant HCl, concentrate and obtain stable foam 7-methoxytryptamine hydrochloride (4.04g), need not further purify and to use.
Azalide is (as embodiment 1 preparation, 1.20g, 4.85mmol) and 7-methoxytryptamine hydrochloride (1.0g, 4.4mmol) suspension in 1N HCl (120ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, neutralize with the unsaturated carbonate aqueous solutions of potassium, use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is with silica gel chromatography purify (ethyl acetate/0.2% ammonium hydroxide eluting), merge the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid, filters, product is with maleate (770mg) separated (mp=219-220 ℃ is decomposed).
Elementary analysis value of calculation measured value
C????????64.09??????64.04
H?????????6.04???????6.18
N?????????5.98???????5.93
Embodiment 6
6,8-two fluoro-1-[(3,4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
Toward stirring 2,4-difluorophenyl hydrazine hydrochloride (18.5g, 128mmol) add saturated sodium carbonate solution (500ml) in the suspension in chloroform (500ml), mixture stirred 30 minutes, with chloroform (2 * 200ml) extractions, concentrate the organic facies that merges, the hydrazine that obtains yellow oily separates alkali, this grease is dissolved in methanol (163ml), in the solution of water (36ml) and sodium acetate (10.57g), (13.7g 128mmol) handles slowly to use the 4-chlorobutyraldehyde.Mixture is put into tube sealing, with nitrogen wash 10 minutes, seal tube sealing, in oil bath, be preheated to 95 ℃, continue heating 15 hours, the dark-coloured solution of gained is chilled to room temperature and concentrating under reduced pressure, residue distributes between chloroform/methanol (75/25 volume ratio) and aqueous sodium carbonate, concentrate organic facies, with the thick indole ethanolamine of flash chromatography on silica gel purification, (solution of 0-25% methanol in chloroform is made gradient elution), merge the fraction that contains product and also concentrate, grease is dissolved in the ether (300ml) that contains 1% methanol, with exsiccant HCl gas disposal, isolated by filtration hydrochloride, with 2-propanol (50ml) and ether (100ml) washing, obtain light solid 7-bromine tryptamines hydrochloride (6.3g) after the drying, need not further purify and to use.
Azalide is (as embodiment 1 preparation, 1.07g, 4.33mmol) and 5,7-difluoro tryptamines hydrochloride (1.0g, 4.3mmol) suspension in 1N HCl (70ml) reflux 65 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, with unsaturated carbonate aqueous solutions of potassium neutralization and use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residual with silica gel chromatography purification (ethyl acetate/0.2% ammonium hydroxide eluting), merge the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handle isolated by filtration product maleate (450mg) (mp=164-166 ℃ is decomposed) with maleic acid.
Elementary analysis value of calculation measured value
C?????????60.76?????60.63
H??????????5.10??????5.14
N??????????5.90??????5.82
Embodiment 7
7-methyl-8-bromo-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Except that using 2-bromo-3-monomethylaniline. to do the raw material, prepare 2-bromo-3-procarbazine hydrochloride (23g) according to the method for the embodiment 4 described 2-of preparation bromo-4-methyl-phenyl hydrazine hydrochloride things.
Except that using 2-bromo-3-procarbazine hydrochloride to do the raw material, prepare 6-methyl-7-bromine tryptamines hydrochloride (2.42g) according to the method for the embodiment 4 described 5-of preparation methyl-7-bromine tryptamines hydrochloride.
Azalide is (by embodiment 5 preparations, 3.63g, 14,7mmol) with 6-methyl-7-bromine tryptamines hydrochloride (4.25g, 4.21mmol) suspension in 1N HCL (150ml) reflux 18 hours under blanket of nitrogen, reactant mixture is chilled to room temperature,, uses chloroform extraction with the neutralization of unsaturated carbonate potassium solution, the organic facies that concentrating under reduced pressure merges, residue is purified (ethyl acetate/0.2% ammonium hydroxide eluting) with silica gel chromatography, merges the fraction that contains product, and concentrating under reduced pressure, residue is dissolved in the ethyl acetate that contains 1% methanol, handle with exsiccant HCL, filter, product is separated with hydrochlorate (3.11g).m/e＝414
Elementary analysis value of calculation measured value
C?????????55.83?????56.13
H??????????5.18??????5.29
N??????????6.20??????6.31
Embodiment 8
6-(1, the 1-dimethyl ethyl)-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Remove to use 4-(1, the 1-dimethyl ethyl) phenyl hydrazine hydrochloride thing (6.00g) to do outside the raw material, prepare 5-(1, the 1-dimethyl ethyl) tryptamines hydrochloride (2.95g) according to the method for the embodiment 4 described 5-of preparation methyl-7-bromine tryptamines hydrochloride.
Azalide is (as embodiment 1 preparation, 1.25g, 5.26mmol) and 5-(1, the 1-dimethyl ethyl) tryptamines hydrochloride (1.33g, 5.26mmol) reflux 24 hours under blanket of nitrogen of the suspension in 1NHCL (50ml), reactant mixture is chilled to room temperature, the isolated by filtration crude product, (3 * 50ml) development brown solids are with ether washing (3 * 50ml) with isopropyl alcohol, recrystallization obtains the required product of 0.74g from ethanol, is light solid.
Elementary analysis value of calculation measured value
C?????????69.47?????69.66
H??????????7.53??????7.50
N??????????6.75??????6.71
Embodiment 9
5-fluoro-6-methyl isophthalic acid-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
Except that using 3-fluoro-4-monomethylaniline. to do the raw material, prepare 3-fluoro-4-procarbazine hydrochloride (21.4g) according to the method for the embodiment 4 described 2-of preparation bromo-4-procarbazine hydrochlorides.
Except that using 3-fluoro-4-procarbazine hydrochloride (6.00g) to do the raw material, prepare 4-fluoro-5-methyltryptamine hydrochloride (2.20g) according to the method for the embodiment 4 described 5-of preparation methyl-7-bromine tryptamines hydrochloride.
Azalide is (as embodiment 1 preparation, 0.76g, 3.06mmol) and 4-fluoro-5-methyltryptamine hydrochloride (0.70g, 3.06mmol) suspension in 1N HCl (40ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, neutralize with the unsaturated carbonate potassium solution, use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is purified (ethyl acetate/0.2% ammonium hydroxide eluting) with silica gel chromatography, merges the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handle with maleic acid, filter, with maleate (60mg) separated product.mp.191-194℃
Elementary analysis value of calculation measured value
C?????????63.82?????63.60
H??????????5.78??????5.65
N??????????5.95??????5.92
Embodiment 10
7,8,9,10-tetrahydrochysene-10-[(3,4-Dimethoxyphenyl) methyl]-preparation of 11H-benzo [g] pyrido [3,4-b] indole
Except that using 1-naphthyl hydrazonium salt acidulants (6.00g) to do the raw material, according to the embodiment 4 described method preparations 6 that prepare 5-methyl-7-bromine tryptamines hydrochloride, 7-benzo tryptamines hydrochloride (2.85g).
Azalide is (as embodiment 1 preparation, 1.51g, 6.11mmol) and 6,7-benzo tryptamines hydrochloride (1.50g, 6.11mmol) suspension in 1N HCl (40ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, with the neutralization of unsaturated carbonate potassium solution, use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is with silica gel chromatography purify (ethyl acetate/0.2% ammonium hydroxide eluting), merge the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid, filter, with maleate (240mg) separated product.M/e=373, mp.187 ℃ (decomposition).
Elementary analysis value of calculation measured value
C????????68.84?????68.63
H?????????5.78??????5.91
N?????????5.73??????5.67
Embodiment 11
6-cyclohexyl-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Except that using 4-cyclohexyl aniline to do the raw material, prepare 4-cyclohexyl benzene hydrazonium salt acidulants (35.6g) according to the method for the embodiment 4 described 2-of preparation bromo-4-procarbazine hydrochlorides.
Except that using 4-cyclohexyl benzene hydrazonium salt acidulants to do the raw material, prepare 5-cyclohexyl tryptamines hydrochloride (1.29g) according to the method for the embodiment 4 described 5-of preparation methyl-7-bromine tryptamines hydrochloride.
Azalide is (as embodiment 1 preparation, 0.54g, 2.18mmol) and 5-cyclohexyl tryptamines hydrochloride (0.6g, 2.18mmol) suspension in 1N HCl (30ml) reflux 14 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, neutralize with the unsaturated carbonate potassium solution, use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is purified (ethyl acetate/0.2% ammonium hydroxide eluting) with silica gel chromatography, merges the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handle with maleic acid, filter, with maleate (140mg) separated product.m/e＝404
Elementary analysis value of calculation measured value
C?????????69.21?????69.17
H??????????6.97??????7.01
N??????????5.38??????5.53
Embodiment 12
5,8-dimethyl-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-preparation of 9H-pyrido [3,4-b] indole hydrochloride thing
Remove and use 2,5-3,5-dimethylphenyl hydrazonium salt acidulants (16.8g) is done outside the raw material, according to the embodiment 4 described method preparations 4 that prepare 5-methyl-7-tryptamines hydrochloride, 7-dimethyltryptamine hydrochloride (0.94g).
Azalide is (as embodiment 1 preparation, 1.04g, 4.21mmol) and 4,7-dimethyltryptamine hydrochloride (0.94g, 4.21mmol) suspension in 1N HCL (40ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, with the neutralization of unsaturated carbonate potassium solution, use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is with silica gel chromatography purify (ethyl acetate/0.2% ammonium hydroxide eluting), merge the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handles with exsiccant HCl, filter, with hydrochlorate (370mg) separated product.m/e＝349
Elementary analysis value of calculation measured value
C????????68.29?????68.59
H?????????7.03??????6.92
N?????????7.24??????7.04
Embodiment 13
6-(1-Methylethyl)-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
Toward the 4-cumene hydrazonium salt acidulants monohydrate (15.3g that is stirring, 91.95mmol) add saturated sodium carbonate solution (250ml) in the suspension in chloroform (250ml), mixture stirred 30 minutes, (2 * 200ml) extractions concentrate the organic facies that merges, and the hydrazine that obtains yellow oily separates alkali with chloroform, this grease is dissolved in methanol (200ml) and the water (5ml), (6.72g, 82mmol) (8.7g 82mmol) handles with the 4-chlorobutyraldehyde with sodium acetate.Mixture is put into tube sealing, with nitrogen wash 10 minutes, seal tube sealing, in oil bath, be preheated to 100 ℃, continue heating 18 hours, the dark-coloured solution of gained is chilled to room temperature and concentrating under reduced pressure, residue distributes between chloroform/methanol (75/25 volume ratio) and aqueous sodium carbonate, concentrate organic facies, with the thick indole ethanolamine of flash chromatography on silica gel purification, (solution of 0-25% methanol in chloroform is made gradient elution), merge the fraction that contains product and also concentrate, grease is dissolved in the ether (300ml) that contains 1% methanol, with exsiccant HCl gas disposal, isolated by filtration hydrochloride, with 2-propanol (50ml) and ether (100ml) washing, obtain light solid 5-isopropyl tryptamines hydrochloride (9.8g) after the drying, need not further purify and to use.
Azalide is (as embodiment 1 preparation, 1.55g, 6.31mmol) and 5-isopropyl tryptamines hydrochloride (1.76g, 7.37mmol) suspension in 1N HCl (40ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, with unsaturated carbonate aqueous solutions of potassium neutralization and use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is purified (ethyl acetate/0.2% ammonium hydroxide eluting) with silica gel chromatography, merges the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handle isolated by filtration product maleate (310mg), m/e=365 with maleic acid, mp.196-200 ℃
Elementary analysis value of calculation measured value
C?????????67.48?????67.74
H??????????6.71??????6.75
N??????????5.83??????5.92
Embodiment 14
6,8-dimethyl-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-preparation of 9H-pyrido [3,4-b] indole hydrochloride thing
Remove and use 2,4-dimethyl hydrazinobenzene hydrochloride (15.0g) is done outside the raw material, according to the embodiment 4 described method preparations 5 that prepare 5-methyl-7-bromine tryptamines hydrochloride, 7-dimethyltryptamine hydrochloride (2.86g).
Azalide is (as embodiment 1 preparation, 1.65g, 6.67mmol) and 5,7-dimethyltryptamine hydrochloride (1.50g, 6.67mmol) reflux 24 hours under blanket of nitrogen of the suspension in 1N HCl (70ml), reactant mixture is chilled to room temperature, the isolated by filtration crude product, (3 * 50ml) developments are with hexane wash (3 * 50ml) with ethanol/hexane for solid, isolated by filtration product (820mg), m/e=350.
Elementary analysis value of calculation measured value
C?????????68.29????68.07
H??????????7.03?????7.12
N??????????7.24?????7.23
Embodiment 15
5,7-dimethyl-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-preparation of 9H-pyrido [3,4-b] indole hydrochloride thing
Remove and use 3,5-dimethyl hydrazinobenzene hydrochloride (7.65g) is done outside the raw material, according to the embodiment 4 described method preparations 4 that prepare 5-methyl-7-bromine tryptamines hydrochloride, 6-dimethyltryptamine hydrochloride (1.06g).
Azalide is (as embodiment 1 preparation, 1.16g, 4.69mmol) and 4,6-dimethyltryptamine hydrochloride (1.05g, 4.67mmol) reflux 24 hours under blanket of nitrogen of the suspension in 1N HCl (60ml), reactant mixture is chilled to room temperature, the isolated by filtration crude product, (3 * 50ml) developments are with hexane (3 * 50ml) washings with ethanol/hexane for solid, isolated by filtration product (770mg), m/e=350.
Elementary analysis value of calculation measured value
C?????????68.29????68.09
H??????????7.03?????7.12
N??????????7.24?????7.02
Embodiment 16
6,7-dimethyl-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-preparation of 9H-pyrido [3,4-b] indole
Toward 5 of the cooling (0 ℃) of stirring, 6-dimethyl indole (3.69g, 25.4mmol) absolute ether (75ml) solution in dripped oxalyl chloride (3.8ml in about 2 minutes, 43.0mmol), behind the restir 30 minutes, filter to isolate flaxen acyl chlorides (5.99g), wash with absolute ether, above-mentioned acyl chlorides portioning is joined in the rapid ammonium hydroxide aqueous solution that is stirring (30%, 100ml), after adding, mixture is continued to stir 30 minutes in room temperature, filter to isolate crude product, recrystallization from the THF/ ether obtains the solid product (3.05g) of brown.
Toward what stirring, amide (the 3.05g of the above-mentioned preparation that refluxes, 14.1mmol) THF solution in dripped lithium aluminium hydride reduction (3.07g in about 1 hour, 81.3mmol) the THF suspension, after adding, mixture was continued reflux 14 hours, reactant mixture is chilled to 0 ℃, water (3.1ml) successively, 15% sodium hydroxide solution (3.1ml) and water (9.3ml) handled, remove by filter salt, concentrating under reduced pressure filtrate, residue are dissolved in the ether (80ml) that contains 5% ethyl acetate, handle with exsiccant HCl, isolated by filtration hydrochlorate (2.65g) washs with absolute ether.
Azalide is (as embodiment 1 preparation, 1.10g, 4.45mmol) and 5,6-dimethyltryptamine hydrochloride (1.00g, 4.45mmol) suspension in 1N HCl (60ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium, use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is purified (ethyl acetate/0.2% ammonium hydroxide eluting) with silica gel chromatography, merges the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handle with maleic acid, filter, product is separated with maleate (450mg), mp=197-200 ℃
Elementary analysis value of calculation measured value
C?????????66.94????67.01
H??????????6.48?????6.56
N??????????6.00?????5.98
Embodiment 17
6-ethyl-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-preparation of 9H-pyrido [3,4-b] indole
5-ethylindole (4.0g toward the cooling (0 ℃) of stirring, 27.5mmol) absolute ether (250ml) solution in dripped oxalyl chloride (4.8ml in about 2 minutes, 55.1mmol), restir 30 minutes, the flaxen acyl chlorides of isolated by filtration, wash with absolute ether, above-mentioned acyl chlorides portioning is joined in the rapid ammonium hydroxide aqueous solution that is stirring (30%, 200ml), after adding mixture is continued to stir 30 minutes in room temperature, isolated by filtration crude product (4.7g) is the solid of brown.
Toward what stirring, amide (the 4.7g of the above-mentioned preparation that refluxes, 21.7mmol) THF solution in dripped lithium aluminium hydride reduction (4.7g in about 1 hour, THF suspension 121mmol), after adding mixture was continued reflux 14 hours, reactant mixture is chilled to 0 ℃, water (4.7ml) successively, 15% sodium hydroxide solution (4.7ml) and water (14.1ml) handled remove by filter salt, concentrating under reduced pressure filtrate, residue is dissolved in the ether (80ml) that contains 5% ethyl acetate, handle with exsiccant HCl, isolated by filtration hydrochlorate (4.02g) washs with absolute ether.
Azalide is (as embodiment 1 preparation, 1.10g, 4.45mmol) and 5,6-dimethyltryptamine hydrochloride (1.00g, 4.45mmol) suspension in 1N HCl (60ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium, use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is purified (ethyl acetate/0.2% ammonium hydroxide eluting) with silica gel chromatography, merges the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handle with maleic acid, filter, product is separated with maleate (520mg), mp=185 ℃ (decomposition)
Elementary analysis value of calculation measured value
C????????66.94?????66.95
H?????????6.48??????6.55
N?????????6.01??????5.99
Embodiment 18
6-bromo-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-preparation of 9H-pyrido [3,4-b] indole
Azalide is (as embodiment 1 preparation, 0.91g, 3.7mmol) and 5-bromine tryptamines hydrochloride (1.01g, 3.7mmol) suspension in 1N HCl (60ml) reflux 18 hours under blanket of nitrogen, reactant mixture is chilled to room temperature,, uses chloroform extraction with the neutralization of unsaturated carbonate aqueous solutions of potassium, the organic facies that concentrating under reduced pressure merges, residue is purified (ethyl acetate/0.2% ammonium hydroxide eluting) with silica gel chromatography, merges the fraction and the concentrating under reduced pressure that contain product, and residue is dissolved in the ethyl acetate that contains 1% methanol, handle with maleic acid, filter, product is separated with maleate (800mg), mp=184-188 ℃ (decomposition), m/e=403
Elementary analysis value of calculation measured value
C?????????55.72????55.51
H??????????4.87?????5.09
N??????????5.41?????5.36
Embodiment 19
7,8-dimethyl-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-preparation of 9H-pyrido [3,4-b] indole hydrochloride thing
Remove and use 2,2-procarbazine hydrochloride (15.0g) is done outside the raw material, according to the embodiment 4 described method preparations 6 that prepare 5-methyl-7-bromine tryptamines hydrochloride, 7-dimethyltryptamine hydrochloride (2.26g).
Azalide is (as embodiment 1 preparation, 1.39g, 5.62mmol) and 6,7-dimethyltryptamine hydrochloride (1.26g, 5.61mmol) suspension in 1N HCl (70ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium, use chloroform extraction, the organic facies that concentrating under reduced pressure merges, residue is purified (ethyl acetate/0.2% ammonium hydroxide eluting) with silica gel chromatography, merges the fraction and the concentrating under reduced pressure that contain product, residue is dissolved in the ethyl acetate that contains 1% methanol, handle with exsiccant HCl, filter, product is separated with hydrochlorate (290mg), m/e=350
Elementary analysis value of calculation measured value
C????????68.29?????68.51
H?????????7.03??????6.87
N?????????7.24??????7.22
Embodiment 20
6-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-preparation of 9H-pyrido [3,4-b] indole hydrochloride thing
Azalide is (as embodiment 1 preparation, 3.4g, 12.4mmol) and 5-methyltryptamine hydrochloride (2.0g, 9.9mmol) suspension in 1N HCl (100ml) reflux 24 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, the isolated by filtration crude product, wash with ethanol development solid and with ether, filter, product is with hydrochlorate separated (3.2g), mp.245-246 ℃ (decomposition).
Elementary analysis value of calculation measured value
C?????????67.64????67.42
H??????????6.67?????6.66
N??????????7.51?????7.25
Embodiment 21
6-methyl isophthalic acid-[(3,4, the 5-trimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
3; 4; the 5-TMB (20.0g, 0.10mol), N-acetyl-glycine (11.9g; 0.10mol) and sodium acetate (8.4g; 0.10mol) solution in acetic anhydride (100ml) was in 100 ℃ of heating 2 hours, reactant mixture is chilled to room temperature, pours in the ice (300ml) under stirring; water (3 * 50ml) and ether (3 * 50ml) washing, drying under reduced pressure (5.6g).
Azalide is (as above-mentioned preparation, 2.0g, 7.2mmol) and 5-methyltryptamine hydrochloride (1.1g, 5.4mmol) suspension in 1N HCl (20ml) reflux 48 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, and the isolated by filtration crude product washs with ethanol development solid and with ether, filter to isolate product (650mg), mp.228-229 ℃.
Elementary analysis value of calculation measured value
C????????65.58?????65.38
H?????????6.75??????6.76
N?????????6.95??????6.92
Embodiment 22
6-methyl isophthalic acid-[(2,3, the 4-trimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Remove and use 2,3, outside the 4-TMB (20.0g), according to embodiment 21 preparation azalides (12.28g).
Azalide is (as above-mentioned preparation, 2.0g, 7.2mmol) and 5-methyltryptamine hydrochloride (1.1g, 5.4mmol) suspension in 1N HCl (20ml) reflux 48 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, and the isolated by filtration crude product washs with isopropyl alcohol development solid and with ether, filter to isolate product (1.36g), mp.214.5 ℃.
Elementary analysis value of calculation measured value
C????????65.58?????65.41
H?????????6.75??????6.70
N?????????6.95??????6.89
Embodiment 23
6-methyl isophthalic acid-[(2-methoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Remove and use outside the 2-methoxybenzaldehyde (20.0g), according to embodiment 21 preparation azalides (16.42g).
Azalide is (as above-mentioned preparation, 2.0g, 9.2mmol) and 5-methyltryptamine hydrochloride (1.5g, 6.9mmol) suspension in 1N HCl (20ml) reflux 48 hours under blanket of nitrogen, reactant mixture is chilled to room temperature, and the isolated by filtration crude product washs with isopropyl alcohol development solid and with ether, filter to isolate product (880mg), mp.252.8 ℃.
Elementary analysis value of calculation measured value
C?????????70.06????70.15
H??????6.76??????6.83
N??????8.17??????8.16
Embodiment 246-methyl isophthalic acid-[(2, the 4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
The method of describing according to embodiment 21 prepares azalide (7.55g), only is to use 2,4-dimethoxy benzaldehyde (20.0g).
Under nitrogen atmosphere, (2.0g is 8.1mmol) with 5-methyltryptamine hydrochloride (1.3g, 1N HCl (20ml) suspension reflux 6.1mmol) 48 hours with azalide (as above preparing).Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges is with silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with anhydrous HCl.By the product (361mg) that filters to isolate hydrochloride form.262.6 ℃ of fusing points.
Analytical calculation value measured value
C???????????????67.64???????????67.73
H????????????????6.76????????????6.85
N????????????????7.51????????????7.50
Embodiment 256-methyl isophthalic acid-[(2, the 5-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
The method of describing according to embodiment 21 prepares azalide (13.21g), only is to use 2,5-dimethoxy benzaldehyde (20.0g).
Under nitrogen atmosphere, (2.0g is 8.1mmol) with 5-methyltryptamine hydrochloride (1.3g, 1N HCl (20ml) suspension reflux 6.1mmol) 48 hours with azalide (as above preparing).Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges is with silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with anhydrous HCl.By the product (1.14g) that filters to isolate hydrochloride form.262 ℃ of fusing points.
Analytical calculation value measured value
C????????????67.64?????????67.36
H?????????6.76????????6.71
N?????????7.51????????7.25
Embodiment 266-methyl isophthalic acid-[(2,4, the 5-trimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
The method of describing according to embodiment 21 prepares azalide (8.36g), only is to use asarylaldehyde (20.0g).
Under nitrogen atmosphere, (2.0g is 7.2mmol) with 5-methyltryptamine hydrochloride (1.1g, 1N HCl (20ml) suspension reflux 5.4mmol) 48 hours with azalide (as above preparing).Reaction mixture is to room temperature, the isolated by filtration crude product.Wash with the isopropyl alcohol abrasive solid and with ether.The isolated by filtration product obtains product (299mg) by the ethanol/cyclohexane recrystallization.176.3 ℃ of fusing points.
Analytical calculation value measured value
C??????????65.58?????????65.51
H???????????6.75??????????6.73
N???????????6.95??????????6.87
Embodiment 276-(1-first and second bases)-1-[(2,3, the 4-trimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Under nitrogen atmosphere, with azalide (press among the embodiment 22 method preparation) (1.0g, 3.61mmol) and 5-isopropyl tryptamines hydrochloride (press among the embodiment 13 method preparation) (646mg, 1N HCl (20ml) suspension reflux 2.7mmol) 48 hours.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges is with silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with anhydrous HCl.By the product (315mg) that filters to isolate hydrochloride form.147.3 ℃ of fusing points.
Analytical calculation value measured value
C??????????66.89??????66.80
H???????????7.25???????7.01
N???????????6.50???????6.39
Embodiment 286-methyl isophthalic acid-[(3,4-dimethoxy-5-nitrobenzophenone) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
The method of describing according to embodiment 21 prepares azalide (16.9g), only is to use 3,4-dimethoxy-5-nitrobenzaldehyde (23.5g).
Under nitrogen atmosphere, (2.8g is 9.6mmol) with 5-methyltryptamine hydrochloride (2.0g, 1N HCl (20ml) suspension reflux 9.5mmol) 72 hours with azalide (as above preparing).Reaction mixture is to room temperature, the isolated by filtration crude product.Wash with the isopropyl alcohol abrasive solid and with ether.By filtering to isolate hydrochloride product (3.44), fusing point 239-243 ℃, m/e=381.
Analytical calculation value measured value
C????????60.36??????60.54
H?????????5.79???????5.66
N????????10.06??????10.12
Embodiment 296-methyl isophthalic acid-[(3-iodo-4,5-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
To the iodo vanillin that is stirring (10.0g, add in dimethyl formamide 35.96mmol) (50ml) cooling (0 ℃) solution Anhydrous potassium carbonate (20.0g, 148.86mmol), add then iodomethane (3.11ml, 50.0mmol).Mixture is warmed to room temperature and stirred 14 hours.Mixture is poured in the ether (500ml) water (3 * 150ml) washings.Use the dried over mgso organic facies, concentrating under reduced pressure obtains yellow oily 3-iodo-4, and 5-dimethoxy benzaldehyde (9.5g) leaves standstill and solidifies this grease, and this product need not to be further purified in use.
The method of describing according to embodiment 21 prepares azalide (11.1g), only is to use 3-iodo-4,5-dimethoxy benzaldehyde (9.5g), and use hippuric acid (6.41g) to replace acetylaminoacetic acid.
Under nitrogen atmosphere, (2.2g is 5.0mmol) with 5-methyltryptamine hydrochloride (1.0g, 1N HCl (100ml) suspension reflux 4.3mmol) 48 hours with azalide (as above preparing).Reaction mixture is to room temperature, with saturated potassium hydroxide aqueous solution neutralization and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid.By the product (134mg) that filters to isolate maleate, m/e=463.
Analytical calculation value measured value
C???????????51.92???????52.15
H????????????4.72????????4.72
N????????????4.84????????4.70
Embodiment 306-methyl isophthalic acid-[(3,4-dimethoxy-5-amino-phenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole dihydrochloride
(3.0g adds activatory zinc powder (4.64g) in acetic acid 7.2mmol) (40ml) solution to the nitro compound that is stirring (press among the embodiment 28 method preparation).At room temperature stirred reaction mixture is 2 hours, and water (200ml) dilutes and passes through diatomite filtration.Filtrate is used NH 4The neutralization of OH aqueous solution is also used chloroform extraction.Camera salt water washing is arranged, use dried over mgso.The organic facies that concentrating under reduced pressure merges, residue is dissolved in the ethyl acetate, handles with anhydrous HCl.The isolated by filtration product with the ether washing, grinds the product (2.41g) that obtains dihydrochloride with ethyl acetate.Fusing point 230-234 ℃, m/e=351.
Analytical calculation value measured value
C???????????59.44???????58.47
H????????????6.41????????6.31
N????????????9.90????????9.68
Embodiment 316-methyl isophthalic acid-[(3-methoxyl group-4-propoxyl group phenyl)-methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
To the vanillin that is stirring (30.0g, add in methanol 197mmol) (100ml) solution Anhydrous potassium carbonate (13.7g, 99mmol), add then allyl bromide, bromoallylene (17.0ml, 197mmol).Reflux mixture 5 hours.Reactant mixture filters and concentrating under reduced pressure obtains oily solid intermediate product (30.4g), and this product need not to be further purified in use.
The method of describing according to embodiment 21 prepares azalide (32.2g), only is to use 3-methoxyl group-4-allyl benzene formaldehyde (30.4g), and uses hippuric acid (28.3g) to replace acetylaminoacetic acid.
Under nitrogen atmosphere, (1.74g is 5.2mmol) with 5-methyltryptamine hydrochloride (1.1g, the 1N HCl (40ml) 5.2mmol) and the suspension reflux of ethanol (30ml) 18 hours with azalide (as above preparing).Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid.By filtering to isolate maleate product (560mg).m/e＝362。This product need not to be further purified in use.
Under intense agitation, (560mg adds unsaturated carbonate aqueous solutions of potassium (100ml) in chloroform 1.7mmol) (100ml) suspension to maleate.Chloroform (2 * 100ml) extractions are further used in layering, water.The organic facies anhydrous Na that merges 2SO 4Dry also concentrating under reduced pressure.Free alkali is dissolved in the ethanol, under the Raney nickel catalyst existence condition, carry out hydrogenation (25 ℃, 60psi).Filter to isolate catalyst, decompression concentrated solution obtains a viscosity grease, it is dissolved in the ethyl acetate and with maleic acid (140mg) handles.The isolated by filtration crude product.Obtain maleate product (170mg) with the ethyl acetate grinding of heat and with the ether washing.188 ℃ of fusing points, m/e=365.
Analytical calculation value measured value
C??????????67.48???????67.62
H???????????6.71????????6.66
N???????????5.83????????5.80
Embodiment 326-methyl isophthalic acid-[(4-dimethylaminophenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole dihydrochloride
With syringe to the chlorination methoxy triphenyl phosphonium that is stirring (13.79g, drip in 40.02mmol) anhydrous THF (150ml) cooling (78 ℃) suspension n-BuLi solution (25.2g, 1.6M, 40.02mmol).Stirred the orange colour suspension 15 minutes down at-78 ℃.In 10 minutes, (5.00g, THF 3.35mmol) (75ml) drips of solution is added in this inner salt with 4-dimethylamino benzaldehyde.Reactant mixture is warmed to room temperature gradually and stirred 14 hours.In mixture, add saturated NH 4Cl solution (100ml) is with ether (3 * 50ml) extractions.Use Na 2SO 4Dry organic facies and the concentrating under reduced pressure that merges.With 15% ethyl acetate/hexane eluting, silica gel chromatography purification, obtain olefin isomer mixture product (4.70g), this product need not to be further purified in use.
(891mg, 4.23mmol) (1.00g, the mixture heated of acetonitrile 5.64mmol) (20ml) and 1N HCl solution (150ml) refluxed 96 hours with 1-methoxyl group-4 '-dimethylamino styrene with the 5-methyltryptamine hydrochloride.Reactant mixture is cooled to room temperature, with unsaturated carbonate aqueous solutions of potassium neutralization and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (2.5%MeOH/ chloroform/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate, handles with anhydrous HCl.By the product (354mg) that filters to isolate dihydrochloride.275.4 ℃ of fusing points.
Analytical calculation value measured value
C?????????64.28??????64.21
H??????????6.94???????7.01
N?????????10.71??????10.74
Embodiment 336-methyl isophthalic acid-[(4-dibutylamino phenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole dihydrochloride
With syringe to the chlorination methoxy San Ben Phosphonium that is stirring (8.81g, drip in 25.7mmol) anhydrous THF (150ml) cooling (78 ℃) suspension n-BuLi solution (16.1g, 1.6M, 25.7mmol).Stirred the orange colour suspension 15 minutes down at-78 ℃.In 10 minutes, (5.00g, THF 2.14mmol) (75ml) drips of solution is added in this inner salt with 4-dibutylamino benzaldehyde.Reactant mixture is warmed to room temperature gradually and stirred 14 hours.Add saturated NH 4Cl solution (100ml), (3 * 50ml) extract this mixture with ether.Use Na 2S0 4Dry organic facies and the concentrating under reduced pressure that merges.The silica gel chromatography purification with 15% ethyl acetate/hexane eluting, obtains olefin isomer mixture product (3.47g), and this product need not to be further purified in use.
(605mg, 2.87mmol) (1.00g, the mixture heated of acetonitrile 3.83mmol) (20ml) and 1N HCl solution (150ml) refluxed 96 hours with 1-methoxyl group-4 '-dibutylamino styrene with the 5-methyltryptamine hydrochloride.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (2.5%MeOH/ chloroform/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate, handles with anhydrous HCl.By filtering to isolate dihydrochloride product (476mg).266.6 ℃ of fusing points.
Analytical calculation value measured value
C???????????68.05???????67.92
H????????????8.25????????8.22
N????????????8.82????????8.74
Embodiment 346-methyl isophthalic acid-[(3-fluoro-4-methoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
The method of describing according to embodiment 21 prepares azalide (0.330g), only is to use 3-fluoro-4-methoxybenzaldehyde (5.0g).
Under nitrogen atmosphere, (0.30g is 1.3mmol) with 5-methyltryptamine hydrochloride (0.27g, 1N HCl (20ml) suspension reflux 1.3mmol) 24 hours with azalide (as above preparing).Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with anhydrous HCl.By filtering to isolate hydrochloride product (170mg).m/e＝324。
Analytical calculation value measured value
C?????????66.57??????66.37
H??????????6.15???????6.16
N??????????7.76???????7.5
Embodiment 356-methyl isophthalic acid-[(3, the 4-3,5-dimethylphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
The method of describing according to embodiment 21 prepares azalide (11.3g), only is to use 3,4-dimethylbenzaldehyde (25.0g).
Under nitrogen atmosphere, (2.04g is 9.5mmol) with 5-methyltryptamine hydrochloride (2.0g, 1N HCl (80ml) suspension reflux 9.5mmol) 24 hours with azalide (as above preparing).Reaction mixture is to room temperature, the isolated by filtration crude product.The gained solid grinds with ethanol and washs with ether.By filtering to isolate hydrochloride product (1.89g), m/e=304.
Analytical calculation value measured value
C??????????73.99??????73.84
H???????????7.39???????7.35
N???????????8.21???????8.48
Embodiment 366-methyl isophthalic acid-[(2-chloro-3,4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
The method of describing according to embodiment 21 prepares azalide (5.26g), only is to use 2-chloro-3,4-dimethoxy benzaldehyde (10.45g).
Under nitrogen atmosphere, with the azalide of as above preparation (1.34g, 4.76mmol) and 5-methyltryptamine hydrochloride (1.0g, 1N HCl (30ml) suspension reflux 4.75mmol) 24 hours.Reaction mixture is to room temperature, the isolated by filtration crude product.Wash with ethanol grinding gained solid and with ether.By filtering to isolate hydrochloride product (1.19g), m/e=370,244 ℃ of fusing points (decomposition).
Analytical calculation value measured value
C???????61.92??????61.67
H????????5.94???????5.94
N????????6.88???????6.94
Embodiment 376-methyl isophthalic acid-[(2-chloro-3-methoxyl group-4-hydroxy phenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
The method of describing according to embodiment 21 prepares azalide (12.4g), only is to use 2-chloro-3-methoxyl group-4-hydroxy benzaldehyde (12.0g).
Under nitrogen atmosphere, with the azalide of as above preparation (1.29g, 4.82mmol) and 5-methyltryptamine hydrochloride (1.0g, 1N HCl (30ml) suspension reflux 4.75mmol) 24 hours.Reaction mixture is to room temperature, the isolated by filtration crude product.The gained solid grinds with ethanol and washs with ether.By filtering to isolate hydrochloride product (1.07g).240 ℃ of fusing points (decomposition).
Analytical calculation value measured value
C?????????61.07?????60.83
H??????????5.64??????5.71
N??????????7.12??????7.03
Embodiment 385-fluoro-6-methyl isophthalic acid-[(2-chloro-3,4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Under nitrogen atmosphere, with azalide (press among the embodiment 36 method preparation) (2.15g, 7.63mmol) and 4-fluoro-5-methyltryptamine hydrochloride (pressing preparation among the embodiment 9) (1.0g, 1N HCl (80ml) suspension reflux 4.75mmol) 24 hours.Reaction mixture is to room temperature, the isolated by filtration crude product.The gained solid grinds with ethanol and washs with ether.By filtering to isolate hydrochloride product (1.39g), m/e=388.
Analytical calculation value measured value
C???????59.30?????59.58
H????????5.45??????5.47
N????????6.59??????6.71
Embodiment 396-methyl isophthalic acid-(cyclohexyl methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Under nitrogen atmosphere, (631mg is 5.0mmol) with 5-methyltryptamine hydrochloride (1.0g, ethanol 4.3mmol) (20ml) suspension reflux 36 hours with cyclohexyl acetaldehyde.Reaction mixture is to room temperature, the isolated by filtration crude product.The gained solid grinds with ethanol and washs with ether.Filter to isolate product (731mg), m/e=282,230 ℃ of fusing points.
Analytical calculation value measured value
C?????????71.56?????71.27
H??????????8.53??????8.56
N??????????8.78??????8.64
Embodiment 40 (±) 6-methyl isophthalic acid-[(3, the 4-Dimethoxyphenyl)-1-ethyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt
To the chlorination methoxy triphenyl phosphonium that is stirring (118.9g, add in the suspension of 347mmol) anhydrous THF (2000ml) cooling (20 ℃) in batches uncle-butanols potassium (39.3g, 350mmol).Stirred the orange colour suspension 30 minutes down at-20 ℃.In 30 minutes, with 3, (50.0g, THF 275mmol) (500ml) drips of solution is added in this inner salt the 4-dimethoxy-acetophenone.Reactant mixture is warmed to room temperature gradually and stirred 2 hours.Add saturated NH 4Cl solution (500ml), (3 * 500ml) extract this mixture with ether.Use Na 2SO 4Dry organic facies and the concentrating under reduced pressure that merges.With 15% ethyl acetate/hexane eluting, silica gel chromatography purification, obtain olefin isomer mixture product (48.4g), this product need not to be further purified in use.
With 5-methyltryptamine hydrochloride (2.16g, 10.3mmol) and 1-methoxyl group-2-methyl-3 ', (2.13g, the mixture heated of methanol 10.3mmol) (12ml) and 1N HCl solution (108ml) refluxed 96 hours 4 '-dimethoxy styrene (as above preparing).Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (2.5%MeOH/ chloroform/0.2%NH 4OH is an eluent).Collection contains fraction and the concentrating under reduced pressure of product (higher diastereomer (upperdiastereomer)).Residue is dissolved in the ethyl acetate, handles with maleic acid.By filtering to isolate maleate product (260mg).Fusing point 187-90 ℃.
Analytical calculation value measured value
C????????66.94??????66.95
H?????????6.48???????6.35
N?????????6.00???????5.81
Embodiment 41 (±) 6,7-dimethyl-1-[(3,4-Dimethoxyphenyl)-the 1-ethyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt
Exist under the condition of wet chemical 5, (1.60g 7.12mmol) is transformed into its free alkali to 6-dimethyltryptamine hydrochloride (preparation among the embodiment 16) in chloroform.Dry this solution, with 1-methoxyl group-2-methyl-3 ', 4 '-dimethoxy styrene (preparation among the embodiment 40) (1.49g, 7.14mmol) and trifluoroacetic acid (1.62g 14.2mmol) handled also reflux 96 hours.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (2.5%MeOH/ chloroform/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product (higher diastereomer).Residue is dissolved in the ethyl acetate, handles with maleic acid.By filtering to isolate maleate product (560mg), 177 ℃ of fusing points (decomposition).
Analytical calculation value measured value
C???????67.48?????67.34
H????????6.71??????6.68
N????????5.83??????5.74
Embodiment 42 (±) 6-ethyl-1-[(3, the 4-Dimethoxyphenyl)-the 1-ethyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt
(2.0g 8.9mmol) is transformed into its free alkali in chloroform with 5-etryptamine hydrochloride (preparation among the embodiment 17) under having the condition of wet chemical.Dry this solution, with 1-methoxyl group-2-methyl-3 ', 4 '-dimethoxy styrene (preparation among the embodiment 40) (1.86g, 8.9mmol) and trifluoroacetic acid (2.03g 17.8mmol) handled also reflux 96 hours.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (2.5%MeOH/ chloroform/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product (higher diastereomer).Residue is dissolved in the ethyl acetate, handles with maleic acid.By filtering to isolate maleate product (430mg), m/e=364, fusing point 192-194 ℃ (decomposition).
Analytical calculation value measured value
C?????????67.48???????67.32
H??????????6.71????????6.72
N??????????5.83????????5.76
Embodiment 43 (±) 6-methyl isophthalic acid-[(3, the 4-Dimethoxyphenyl)-1-propyl group]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt
Under stirring condition, in methanesulfonic acid (203ml), slowly add phosphorus pentoxide (30.0g).Add the back and under nitrogen atmosphere, continued to stir the mixture 2 hours, until forming homogeneous phase.Once add 3 in this solution, (50g 0.28mol), then splashes into 2-methyl-2 to 4-Dimethoxyphenyl acetonitrile, and (72.1ml, 0.56mol), it splashes into speed with holding temperature be advisable (1 hour) to the 4-pentanediol between 25 to 30 ℃.After adding is finished, reactant mixture was at room temperature stirred 10 hours, in the impouring ice (500g).Make mixture be alkalescence with sodium hydroxide solution (50%), the adding speed of sodium hydroxide is lower than 35 ℃ with holding temperature and is advisable.(3 * 25ml) extraction mixture are used Na with ether 2SO 4The dry organic facies that merges, concentrating under reduced pressure obtains green solid.Distillation (Kugelrohr) obtains intermediate product (27.7g), and this product need not to be further purified in use.
In argon gas atmosphere, in 15 minutes with syringe to the intermediate product of the above-mentioned preparation of stirring (27.2g, drip in THF 0.106mol) (400ml) cooling (78 ℃) solution n-BuLi solution (68.7ml, the hexane solution of 1.6M, 0.11mol).Drip off the back and stirred orange colour solution 30 minutes down at-78 ℃.(8.18ml 0.10mol), stirred gained solution 45 minutes down at-78 ℃ again to splash into bromoethane with syringe.(68.7ml, the hexane solution of 1.6M 0.11mol), stirred orange colour solution 2 hours to drip n-BuLi in 15 minutes.In mixture impouring ice/water (500ml), this solution is acidified to pH2-3 with 5N HCl solution.(2 * 100ml) extraction mixture discard extract with ether.Make water be alkalescence with sodium hydroxide solution (50%), use ice-cooled mixture in case of necessity.(2 * 200ml) extract alkaline water, use MgSO with ether 4The dry organic extract liquid that merges filters and concentrates and obtains oily solid product (12.08g), and this product need not to be further purified in use.
(12.0g adds 5N HCl solution, until pH7 in cooling (40 ℃) solution of THF 39.3mmol) (90ml) and ethanol (90ml) to the product of the above-mentioned preparation of stirring.In another flask, (2.12g, 55.4mmol) solution is dissolved in the water (20ml), has wherein added one 50% sodium hydroxide with sodium borohydride.Several parts of sodium borohydrides and 5N HCl solution alternately join in the reactant mixture, make it to keep pH6-8, and its adding speed is advisable between-35 to-45 ℃ with holding temperature.After adding reactant mixture was warmed to room temperature about 2 hours.Make reactant mixture be alkalescence with sodium hydroxide solution, with ether (3 * 100ml) extractions.The organic facies that merges with the salt water washing is also used MgS0 4Dry.Filter and remove to desolvate and obtain viscosity oily crude product (11.3g), this product need not to be further purified in use.
The crude product that above-mentioned reaction is obtained (11.3g, 36.8mmol) and oxalic acid dihydrate (15.1g, 120mmol) mixture heated in water (300ml) refluxed 12 hours.Cooling mixture is to room temperature, with chloroform (2 * 100ml) extractions.Use MgSO 4The dry organic facies that merges is filtered and the concentrated buttery aldehyde of orange colour that obtains.Distilling under reduced pressure (Kugelrohr) obtains pure light buttery aldehyde (4.97g).
(2.53g, 12.0mmol) with 2-ethyl-3 ', (2.49g, 12.0mmol) mixture heated in ethanol (30ml) refluxed 48 hours 4 '-dimethoxy benzene ethylhexanal (as above preparing) with the 5-methyltryptamine hydrochloride.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (2.5%MeOH/ chloroform/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product (higher Rf diastereomer).Residue is dissolved in the ethyl acetate, handles with maleic acid.By filtering to isolate maleate product (1.51g), m/e=364.
Analytical calculation value measured value
C?????????2.34??????2.47
H?????????5.84??????5.71
N?????????59????????58
Embodiment 442,6-dimethyl-1-[(2-chloro-3,4-Dimethoxyphenyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
With sodium hydroxide (49mg, 1.23mmol) processing 6-methyl isophthalic acid-[(2-chloro-3, the 4-Dimethoxyphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing (preparation among the embodiment 36) (500mg, 1.23mmol) aqueous solution, then with formic acid (0.91ml) and formalin (0.18ml) processing.Mixture heated refluxed 4 hours.Reaction mixture is to room temperature and concentrating under reduced pressure.Residue is distributed between wet chemical and ether.Use K 2CO 3Dry organic facies and concentrating under reduced pressure.Residue is dissolved in the ethyl acetate, handles with maleic acid.Filter to isolate maleate, obtain product (240mg), m/e=385 by the ethyl acetate/hexane recrystallization purifying.
Analytical calculation value measured value
C??????????62.34??????62.47
H???????????5.84???????5.71
N???????????5.59???????5.58
Embodiment 452-methyl-6-(1-Methylethyl)-1,2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-preparation of 9H-pyrido [3,4-b] indole maleate
With sodium hydroxide (83mg, 2.08mmol) processing 6-(1-Methylethyl)-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt (preparing among the embodiment 13) (500mg, 1.04mmol) aqueous solution, then with formic acid (0.77ml) and formalin (0.15ml) processing.Mixture heated refluxed 4 hours.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid.Filter to isolate maleate product (130mg), m/e=376.
Analytical calculation value measured value
C???????67.99?????67.88
H????????6.93??????6.73
N????????5.66??????5.69
Embodiment 46 (-)-(S)-6-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-[(3,4-Dimethoxyphenyl) methyl]-preparation of 9H-pyrido [3,4-b] indole hydrochloride thing
To the 6-methyl isophthalic acid that is stirring, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] (3.14g adds (S)-N, N-dimethyl-N '-(uncle 1--butoxy-3-methyl)-2-butyl carbonamidine (3.79g to indole in anhydrous dimethyl benzene (65ml) solution 16.9mmol), 17.7mmol), sulfonic acid (200mg) then camphorates.Gained vlil 72 hours.Reaction mixture is to room temperature and concentrating under reduced pressure.With fast silica gel chromatogram method purification residue (1: 3: 6 triethylamine: ethyl acetate: hexane is an eluent).Collection contains the fraction of product and concentrates and obtains viscosity oily product carbonamidine (5.99g), and this product need not to be further purified in use.
(25% oily dispersion liquid, 829mg add carbonamidine (5.99g, 16.8mmol) THF (45ml) solution that as above prepares in THF 20.2mmol) (10ml) cooling (0 ℃) suspension to the hydrofining that is stirring.In this mixture, add tetramethylethylenediamine (3.0ml, 20.2mmol), add again chloromethyl methyl ether (1.9ml, 25.2mmol).Continued to stir the mixture 1 hour and water (50ml) processing.Be distributed between ether and the water mixture and layering.(2 * 100ml) aqueous phase extracted are used K with ether 2CO 3The dry organic facies that merges concentrates and obtains orange colour oily product (6.73g), and this product need not to be further purified in use.
In 5 minutes, to the carbonamidine of the above-mentioned preparation of stirring (6.29g, splash in cooling (78 ℃) solution of anhydrous THF (100ml) 8.4mmol) n-BuLi (hexane solution of 1.7M, 10.1ml, 17.1mmol).Further agitating solution is 1 hour under-78 ℃, with 1-chloromethyl-3,4-dimethoxy benzene (3.35g, anhydrous THF (15ml) solution-treated 17.8mmol).Continued agitating solution 4 hours down at-78 ℃, solution is warmed to ambient temperature overnight.Add moisture THF (50ml), decompression concentrated solution.Be dissolved in residue in the chloroform and wash with water.Use Na 2CO 3Dry organic facies also concentrates.With fast silica gel chromatogram method purification crude product (1: 3: 6 triethylamine: ethyl acetate: hexane is an eluent).Collection contains the fraction of product (higher Rf), concentrates and obtains viscosity oily product (3.92g) (m/e=550), and this product need not to be further purified in use.
(3.92g adds 2N HCl (20ml) in THF 7.13mmol) (70ml) solution to the as above methoxy indole of preparation that is stirring.Stirred the mixture under the room temperature 24 hours, and again it was distributed between ether and the water.(2 * 25ml) strip aqueous with the organic facies that the salt water washing merges, are used Na with ether 2CO 3Drying, concentrating under reduced pressure.Residue is dissolved among the THF (20ml) and handles with 2 N sodium hydroxide solutions (6ml).After 2 hours, with chloroform (2 * 100ml) extractive reaction mixture.Use Na 2CO 3Dry organic facies also concentrates.Silica gel chromatography purification (1: 3: 6 triethylamine: ethyl acetate: hexane is an eluent) obtains viscosity oily product (1.85g) (m/e=505).
(1.37g adds entry (6ml) in the cooling of ethanol 5.41mmol) (50ml) (0 ℃) solution, adds ethyl acetate (6ml) and hydrazine hydrate (11ml) again to the carbonamidine that as above prepares that is stirring.Reaction vessel was placed cold closet (10 ℃) 72 hours.Mixture is warmed to room temperature and concentrating under reduced pressure.Crude product is dissolved in the chloroform (300ml), water (3 * 50ml) washings.Use Na 2CO 3Dry and the concentrated viscosity grease that obtains.Grease is dissolved in the ether also with anhydrous HCl processing.Filter to isolate hydrochlorate (560mg).Obtain the material of constant optical rotation by ethanol (2 *) recrystallization.The enantiomeric purity of being determined by chirality HPLC is greater than 98%ee, m/e=336.Bi Xuan @598nM=-118.0 (pyridine, C=1) Bi Xuan @365nM=-401.0 (pyridine, C=1)
Analytical calculation value measured value
C??????????67.64??????67.65
H???????????6.76???????6.70
N???????????7.51???????7.52
Embodiment 47 (+/-) 6-methyl isophthalic acid-(1-(4-methoxyl group naphthyl) methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
Figure A9519302900981
With 4-methoxyl group-1-naphthaldehyde (20.0g, 0.107mol), the N-acetyl-glycine (12.58g, 0.107mol) and sodium acetate (8.18g, acetic anhydride 0.107mol) (100ml) solution be heated to 100 ℃ 2 hours.Under nitrogen atmosphere, reaction mixture is to room temperature and stirred 10 hours.Under stirring condition, in mixture impouring ice (250ml).Filter to isolate product, water (3 * 50ml) and ether (3 * 50ml) washing, drying under reduced pressure obtains product (3.16g).
Under nitrogen atmosphere, with the azalide of above preparation (2.0g, 7.5mmol) and 5-methyltryptamine hydrochloride (1.18g, 1N HCl (20ml) suspension reflux 5.62mmol) 48 hours.Reaction mixture filters to isolate crude product to room temperature.(3 * 50ml) grind brown solid, with ether (3 * 50ml) washings with isopropyl alcohol.Obtain the required product of light solid, shaped (1.42g) by ethyl alcohol recrystallization, 271.7 ℃ of fusing points.
Analytical calculation value measured value
C????????73.36????73.60
H?????????6.41?????6.51
N?????????7.13?????7.20
Embodiment 48 (+/-) 6-methyl isophthalic acid-(1-(2-methoxyl group naphthyl) methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
With syringe to the chlorination methoxy triphenyl phosphonium that is stirring (11.05g, drip in the anhydrous THF of 150ml 32.2mmol) cooling (78 ℃) solution n-BuLi (20.14ml, the 1.6M hexane solution, 32.2mmol).After adding, solution stirred 15 minutes under this temperature.(5.0g, THF 26.9mmol) (75ml) solution splashes in the above-mentioned solution with 2-methoxyl group-1-naphthaldehyde by charging hopper.Add finish after, solution be warmed to room temperature and stirred 14 hours.Add saturated NH 4Cl solution (100ml) is distributed in mixture between ether and the water.Use Na 2SO 4The dry organic facies that merges is filtered and concentrating under reduced pressure.Thick residue is filled in filtration purification (silica gel, 40% ethyl acetate/hexane are eluent) after filtration and is obtained 5.0g enol ether mixture product, and this product need not to be further purified in use.
Water (1.0ml) and perchloric acid (solution of 1.5ml 60%) are handled enol ether (5.0g, ether 23.3mmol) (50ml) solution of above-mentioned preparation.At room temperature agitating solution is 72 hours.Solution neutralizes with chloroform (100ml) dilution and with saturated sodium bicarbonate solution.With chloroform (3 * 100ml) extraction mixture, the organic facies Na of merging 2SO 4Dry and concentrated.Obtain colorless oil (2-methoxyl group-1-naphthyl)-acetaldehyde (1.79g) with fast silica gel chromatogram method purification residue (5% ether/hexane is an eluent).
To the 5-methyltryptamine hydrochloride that is stirring (947mg, add in 20ml alcoholic solution 4.49mmol) (2-methoxyl group-1-naphthyl)-acetaldehyde (1.0g, 4.99mmol).Under nitrogen atmosphere, with vlil 40 hours.Reaction mixture filters to isolate crude product to room temperature.Obtain light solid product (705mg) (245.3 ℃ of fusing points) by ethanol/2-butanone recrystallization.
Analytical calculation value measured value
C?????????73.36???????73.29
H??????????6.41????????6.64
N??????????7.13????????7.12
Embodiment 49 (+/-) 6-methyl isophthalic acid-(1-naphthyl-1-ethyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt
Under stirring condition, in methanesulfonic acid (215ml), slowly add phosphorus pentoxide (31.8g).Add the back and under nitrogen atmosphere, continued to stir the mixture 2 hours, until forming homogeneous phase.(50g 0.3mol), then splashes into 2-methyl-2, and (76.4ml, 0.6mol), it splashes into speed and is advisable between 25 to 30 ℃ (1 hour) with holding temperature the 4-pentanediol once to add 1-naphthyl acetonitrile in this solution.After adding is finished, reactant mixture was at room temperature stirred 10 hours, in the impouring ice (500g).Make mixture be alkalescence with sodium hydroxide solution (50%), the adding speed of sodium hydroxide is lower than 35 ℃ with holding temperature and is advisable.(3 * 250ml) extraction mixture are used MgSO with ether 4The dry organic facies that merges, concentrating under reduced pressure obtains green solid.Obtain product (28.29g) by re-crystallizing in ethyl acetate, this product need not to be further purified in use.
Under argon gas atmosphere, in 15 minutes with syringe to the “ of the above-mentioned preparation of stirring Yi oxazine " (28.3g, drip in THF 0.106mol) (475ml) cooling (78 ℃) solution t-BuLi solution (68.4ml, the pentane solution of 1.7M, 0.116mol).Drip off the back and stirred orange colour solution 30 minutes down at-78 ℃.(6.6ml 0.106mol), stirred gained solution 45 minutes down at-78 ℃ again to splash into methyl iodide with syringe.(68.4ml, the pentane solution of 1.7M 0.116mol), stirred orange colour solution 2 hours to drip t-BuLi in 15 minutes again.In mixture impouring ice/water (500ml), this solution is acidified to pH2-3 with 5N HCl solution.(2 * 200ml) extraction mixture are got rid of these extracts with ether.Make water be alkalescence with sodium hydroxide solution (50%), use ice-cooled mixture in case of necessity.(2 * 200ml) extract alkaline water, use MgSO with ether 4The dry organic extract liquid that merges filters and concentrates and obtains oily solid product (13.15g), and this product need not to be further purified in use.
Figure A9519302901012
(13.15g adds 5N HCl solution, until pH7 in cooling (40 ℃) solution of THF 46.7mmol) (100ml) and ethanol (100ml) to the product of the above-mentioned preparation of stirring.In delivery flask, (2.52g, 65.8mmol) solution is dissolved in the water (20ml), has wherein added 1 50% sodium hydroxide with sodium borohydride.Several parts of sodium borohydrides and 5N HCl solution alternately join in the reactant mixture, keep pH6-8, and its adding speed is advisable between-35 to-45 ℃ with holding temperature.Add the back and in about 2 hours, reactant mixture is warmed to room temperature. make reactant mixture be alkalescence with sodium hydroxide solution, with ether (3 * 100ml) extractions.The organic facies that merges with the salt water washing is also used MgSO 4Dry.Filter and remove to desolvate and obtain viscosity oily crude product (13.2g), this product need not to be further purified in use.
Figure A9519302901021
The crude product that above-mentioned reaction is obtained (13.2g, 46.6mmol) and oxalic acid dihydrate (19.1g, 152mmol) mixture heated in water (380ml) refluxed 12 hours.Cooling mixture is to room temperature, with chloroform (2 * 100ml) extractions.Use MgSO 4The dry organic facies that merges is filtered and the concentrated buttery aldehyde of orange colour that obtains.Distilling under reduced pressure (Kugelrohr) obtains pure light buttery aldehyde (1.97g).
Under nitrogen atmosphere, with the 5-methyltryptamine hydrochloride (1.11g, 5.27mmol) and 2-(1-naphthyl)-propionic aldehyde (0.97g, 5.26mmol) vlil in 95% alcohol is 48 hours.Cooling mixture is to room temperature, and residue is distributed between wet chemical and the chloroform.Use MgSO 4Dry chloroform phase and concentrating under reduced pressure.With fast silica gel chromatogram method purification residue (chloroformic solution of 25%MeOH is an eluent), obtain higher isomer of 529mg Rf and the lower isomer of 200mg Rf.Respectively various diastereomers are dissolved in the ethyl acetate, handle with excessive maleic acid.Filter to isolate maleate, obtain 570mg isomer A and 30mg isomer B.The data of isomer A: m/e=340
Analytical calculation value measured value
C?????????73.66????????73.64
H??????????6.18?????????6.13
The data of N 6.14 6.44 isomer B: m/e=340
Analytical calculation value measured value
C?????????73.66????????73.41
H??????????6.18?????????6.04
N??????????6.14?????????5.89
Embodiment 50 (+/-) 6-(1, the 1-dimethyl ethyl)-1-(1-naphthyl-1-ethyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
(300g 2.13mol) is dissolved among the anhydrous THF (3l) with the 4-chlorobutanoylchloride.Add 2 in this solution, 6-lutidines (252ml) then adds 5%Pd/C (30g).This mixture is placed the Pa Er hydrogenator, and under 60psi hydrogen, vibrate 6 hours.Use the nitrogen purging mixture, filter, with THF (500ml) washing catalyst, concentrating under reduced pressure under the room temperature.Distillation obtains colourless liquid shape 4-chlorobutyraldehyde (148.3g).
(15.3g adds saturated sodium carbonate solution (250ml) in chloroform 91.95mmol) (250ml) suspension to the 4-isopropyl that is stirring-phenyl hydrazine hydrochloride thing monohydrate.Stirred the mixture 30 minutes, and became homogeneous phase, with chloroform (2 * 200ml) extractions until organic facies.Concentrate the organic facies that merges, obtain yellow oily hydrazine free alkali.This grease is dissolved in methanol (200ml) and the water (5ml), and (6.72g, 82mmol) (8.7g 82mmol) handles with the 4-chlorobutyraldehyde with sodium acetate.This mixture is placed in the sealable test tube, uses nitrogen purging 10 minutes.The sealing test tube is also inserted it in oil bath that is preheated to 100 ℃.Continue heating 18 hours.Cool off resulting dark solution to room temperature and concentrating under reduced pressure.Residue is distributed between chloroform/methanol (75/25 volume ratio) and the aqueous sodium carbonate.Concentrate organic facies, with the thick indolecthanamine of fast silica gel chromatogram method purification (with the chloroformic solution gradient elution that contains 0-25% methanol).Merging the fraction that contains product also concentrates.Grease is dissolved in the ether (300ml) that contains 1% methanol, with anhydrous HCl gas treatment.Filter to isolate hydrochlorate, with 2-propanol (50ml) and ether (100ml) washing, drying obtains light solid, shaped 5-isopropyl tryptamines hydrochloride (9.8g), and this product need not to be further purified in use.
Under nitrogen atmosphere, with 5-isopropyl tryptamines hydrochloride (1.24g, 5.19mmol) and 2-(1-naphthyl)-propionic aldehyde (0.95g, 5.16mmol) vlil in 95% ethanol is 48 hours.Reactant mixture is cooled to room temperature and concentrating under reduced pressure, and residue is distributed between wet chemical and the chloroform.Use MgSO 4Dry chloroform phase and concentrating under reduced pressure.With fast silica gel chromatogram method purification residue (chloroformic solution that contains 25% methanol is an eluent), obtain the impure lower isomer of Rf of higher isomer of 500mg Rf and 400mg.Main diastereomer is dissolved in the ethyl acetate, handles with excessive maleic acid.The isolated by filtration maleate obtains 400mg light color solid title product, m/e=369.
Analytical calculation value measured value
C??????????74.36????????74.58
H???????????6.66?????????6.64
N???????????5.78?????????5.81
Embodiment 51 (+/-) 6-methyl isophthalic acid-(1-naphthyl methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
With the 1-naphthaldehyde (25.0g, 0.16mol), acetylaminoacetic acid (19.0g, 0.162mol) and sodium acetate (13.1g, 100 ℃ of acetic anhydride 0.160mol) (147ml) solution heating 4 hours.Reaction mixture is to room temperature and under stirring condition in the impouring ice (300ml).Filter to isolate product, water (3 * 50ml) and ether (3 * 50ml) washing, drying under reduced pressure obtains product (11.82g).
Under nitrogen atmosphere, with the azalide of above preparation (3.15g, 13.3mmol) and 5-methyltryptamine hydrochloride (2.0g, 1N HCl (50ml) suspension reflux 9.5mmol) 24 hours.Reaction mixture filters to isolate crude product to room temperature.(3 * 50ml) grind brown solid and use ether (3 * 50ml) washings by isopropyl alcohol.Obtain the required light solid product of 1.94g by ethyl alcohol recrystallization.
Analytical calculation value measured value
C?????????76.12??????76.03
H??????????6.39???????6.22
N??????????7.72???????7.52
Embodiment 52 (+/-) 8-bromo-1-(1-naphthyl methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
(25.8g adds saturated sodium carbonate solution (500ml) in chloroform 115mmol) (500ml) suspension to the 2 bromo phenyl hydrazine hydrochloride that is stirring.Stirred the mixture 30 minutes, and became homogeneous phase, (2 * 200ml) extractions of reuse chloroform until organic facies.The organic facies that concentrate to merge obtains yellow oily hydrazine free alkali. grease is dissolved in the methanol (100ml), and with 4-chlorobutyraldehyde (the method among the embodiment 4 of press prepares) (12.3g, 115ml) processing at leisure.Mixture is placed sealable test tube, use nitrogen purging 10 minutes.The sealing test tube also is placed in the oil bath that is preheated to 95 ℃.Continue heating 18 hours.Cooling gained dark solution is to room temperature and concentrating under reduced pressure.Residue is distributed between chloroform/methanol (75/25 volume ratio) and the aqueous sodium carbonate.Concentrate organic facies, with the thick indolecthanamine of fast silica gel chromatogram method purification (with containing the alcoholic acid chloroformic solution gradient elution of 0-25%).Merging the fraction that contains product also concentrates.Grease is dissolved in the ether (300ml) that contains 1% methanol, with anhydrous HCl gas treatment.Filter to isolate hydrochlorate, with 2-propanol (50ml) and ether (100ml) washing, drying obtains light solid 7-bromo-tryptamines hydrochloride (3.6g), and this product need not to be further purified in use.
Under nitrogen atmosphere, with azalide (press among the embodiment 5 method preparation) (55g, 6.53mmol) and 7-bromo-tryptamines hydrochloride (1.50g, 1N HCl (100ml) suspension reflux 5.44mmol) 24 hours.Reaction mixture filters to isolate crude product to room temperature.(3 * 50ml) grind brown solid, with ether (3 * 50ml) washings by isopropyl alcohol.Obtain the required light solid product of 260mg by ethyl alcohol recrystallization.(fusing point=231-233 ℃ is decomposed)
Analytical calculation value measured value
C?????????61.77???????61.48
H??????????4.71????????4.63
N??????????6.55????????6.73
Embodiment 53 (+/-) 8-bromo-1-(1-naphthyl methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
(25.8g adds saturated sodium carbonate solution (500ml) in chloroform 115mmol) (500ml) suspension to the 2 bromo phenyl hydrazine hydrochloride that is stirring.Stirred the mixture 30 minutes, and became homogeneous phase, (2 * 200ml) extractions of reuse chloroform until organic facies.Concentrate the organic facies that merges and obtain yellow oily hydrazine free alkali.Grease is dissolved in the methanol (100ml), and (12.3g 115ml) handles at leisure with 4-chlorobutyraldehyde (press among the embodiment 4 method preparation).Mixture is placed sealable test tube, use nitrogen purging 10 minutes.Seal test tube and be placed on and be preheated to 95 ℃ in the oil bath.Continue heating 18 hours.The dark solution of cooling gained is to room temperature and concentrating under reduced pressure.Residue is distributed between chloroform/methanol (75/25 volume ratio) and the aqueous sodium carbonate.Concentrate organic facies, with the thick indolecthanamine of fast silica gel chromatogram method purification (with containing the alcoholic acid chloroformic solution gradient elution of 0-25%).Merging the fraction that contains product also concentrates.Grease is dissolved in the ether (300ml) that contains 1% methanol, with anhydrous HCl gas treatment.Filter to isolate hydrochlorate, with 2-propanol (50ml) and ether (100ml) washing, drying obtains light solid 7-bromo-tryptamines hydrochloride (3.6g), and this product need not to be further purified in use.
Under nitrogen atmosphere, with azalide (press among the embodiment 5 method preparation) (55g, 6.53mmol) and 7-bromo-tryptamines hydrochloride (1.50g, 1N HCl (100ml) suspension reflux 5.44mmol) 24 hours.Reaction mixture filters to isolate crude product to room temperature.(3 * 50ml) grind brown solid, with ether (3 * 50ml) washings by isopropyl alcohol.Obtain the required light solid product of 260mg by ethyl alcohol recrystallization.(fusing point 231-233 ℃ is decomposed)
Analytical calculation value measured value
C?????????61.77???????61.48
H??????????4.71????????4.63
N??????????6.55????????6.73
Embodiment 54 (+/-) 8-methoxyl group-1-(1-naphthyl methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole butene dioic acid salt
To the 2-methoxybenzene hydrazonium salt acidulants (14.44g that is stirring, 4-chlorobutyraldehyde (the 9.0g that adds preparation among the embodiment 5 above in THF 83mmol) (600ml) cooling (0 ℃) suspension, 84mmol), drip triethylamine (8.6g, THF 85mmol) (20ml) solution then.Remove cooling bath after adding, agitating solution 1 hour.Filter reaction mixture is with THF (100ml) washing leaching cake.The filtrate that merges is condensed into orange colour grease, this grease is dissolved in methanol (150ml) and the water (5ml).Solution is transferred in the sealable test tube, uses nitrogen purging 10 minutes.The sealing test tube also is placed in the oil bath that is preheated to 95 ℃.Continue heating after 14 hours, reaction mixture is to room temperature and concentrating under reduced pressure.Residue is distributed in unsaturated carbonate aqueous solutions of potassium and 3: 1 chloroforms: between the 2-propanol.Use Na 2SO 4Dry organic facies also concentrates.With fast silica gel chromatogram method purification residue (15% methanol, 0.2%NH 4The chloroformic solution of OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the methanol, and with anhydrous HCl gas treatment and the concentrated stable foam (4.04g) that obtains 7-methoxytryptamine hydrochloride, this product need not to be further purified in use.
Under nitrogen atmosphere, (1.30g is 5.5mmol) with 7-methoxytryptamine hydrochloride (1.08g, 1N HCl (100ml) suspension reflux 4.8mmol) 48 hours with azalide (preparing as the method among the embodiment 5).Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium, chloroform extraction.Removal of solvent under reduced pressure, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid.Filter to isolate maleate product (880mg), (fusing point=226-227 ℃ is decomposed).
Analytical calculation value measured value
C?????????70.73??????70.61
H??????????5.72???????5.77
N??????????6.11???????6.03
Embodiment 55 (+/-) 6-bromo-1-(1-naphthyl methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole butene dioic acid salt
Under nitrogen atmosphere, with azalide (press among the embodiment 5 method preparation) (1.4g, 5.9mmol) and 5-bromine tryptamines hydrochloride (1.77g, 1N HCl (100ml) suspension reflux 6.4mmol) 24 hours.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.Removal of solvent under reduced pressure, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid.By filtering to isolate maleate product (540mg), (fusing point=234-235 ℃ is decomposed), m/e=390.
Analytical calculation value measured value
C??????????61.55??????61.38
H???????????4.57???????4.64
N???????????5.52???????5.29
Embodiment 56 (+/-) 7-methyl-8-bromo-1-(1-naphthyl methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
According to the method for the 2-bromo-4-procarbazine hydrochloride of preparation among the embodiment 7, preparation 2-bromo-3-procarbazine hydrochloride (23g) only is to use 2-bromo-3-monomethylaniline. as initiation material.
Figure A9519302901091
According to the method for the 5-methyl-7-bromo-tryptamines hydrochloride of preparation among the embodiment 7, preparation 6-methyl-7-tryptamines hydrochloride (2.42g) only is to use 2-bromo-3-procarbazine hydrochloride as initiation material.
Under nitrogen atmosphere, with azalide (press among the embodiment 5 method preparation) (1.07g, 4.51mmol) and 6-methyl-7-bromine tryptamines hydrochloride (1.22g, 1NHCl 4.21mmol) (70ml) suspension reflux 65 hours.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.Removal of solvent under reduced pressure, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with anhydrous HCl.By filtering to isolate hydrochloride product (840mg), (fusing point=276-279 ℃ is decomposed).
Analytical calculation value measured value
C??????????62.53??????62.79
H???????????5.02???????4.96
N???????????6.34???????6.19
Embodiment 57 (+/-) 6-cyclohexyl-1-(1-naphthyl methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
According to the method for preparing 2-bromo-4-procarbazine hydrochloride among the embodiment 7, preparation 4-cyclohexyl benzene hydrazonium salt acidulants (35.6g) only is to use 4-cyclohexyl aniline as initiation material.
Figure A9519302901101
According to the method for preparing 5-methyl-7-bromo-tryptamines hydrochloride among the embodiment 7, preparation 5-cyclohexyl tryptamines hydrochloride (1.29g) only is to use 4-cyclohexyl benzene hydrazonium salt acidulants as initiation material.
Under nitrogen atmosphere, (1.09g is 4.59mmol) with 5-cyclohexyl tryptamines hydrochloride (1.28g, 1N HCl (70ml) suspension reflux 4.59mmol) 14 hours with azalide (preparing as the method among the embodiment 5).Reaction mixture filters to isolate crude product to room temperature.Obtain the required product of 690mg light color solid salt hydrochlorate, m/e=395 by this solid of ethanol (2 *) recrystallization.
Analytical calculation value measured value
C???????????78.03??????78.26
H????????????7.25???????7.06
N????????????6.50???????6.48
Embodiment 58 (+/-) 2,6-dimethyl-1-(1-naphthyl methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing
5-methyl isophthalic acid-(the 1-naphthyl methyl)-1 of preparation in previous embodiment 5,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing (adding formic acid (4.1ml) and formalin (37% aqueous solution of 0.8ml) among the 2.00g, aqueous solution 5.51mmol) (200ml).Mixture heated refluxed 72 hours.Make solution be alkalescence with the unsaturated carbonate aqueous solutions of potassium, with chloroform (2 * 100ml) extractions.With dry organic facies and the concentrating under reduced pressure that merges of potassium carbonate.Silica gel chromatography purification crude product (chloroform is an eluent).Fraction and concentrating under reduced pressure that collection contains product obtain viscosity grease.This grease is dissolved in the ether, handles with anhydrous HCl.Filter to isolate the hydrochlorate of gained, drying obtains title product (1.34g), m/e=340.
Analytical calculation value measured value
C?????????76.48???????76.58
H??????????6.68????????6.63
N??????????7.43????????7.28
Embodiment 59 (+/-) 5-fluoro-6-methyl isophthalic acid-(1-naphthyl methyl)-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt
According to the method for preparing 2-bromo-4-procarbazine hydrochloride among the embodiment 7, preparation 3-fluoro-4-procarbazine hydrochloride (23.4g) only is to use 3-fluoro-4-monomethylaniline. as initiation material.
According to the method for preparing 5-methyl-7-bromo-tryptamines hydrochloride among the embodiment 7, preparation 4-fluoro-5-methyltryptamine hydrochloride (2.20g) only is to use 3-fluoro-4-procarbazine hydrochloride (6.00g) as initiation material.
Under nitrogen atmosphere, with azalide (press among the embodiment 5 method preparation) (2.3g, 9.6mmol) and 4-fluoro-5-methyltryptamine hydrochloride (2.2g, 1N HCl (40ml) suspension reflux 9.6mmol) 24 hours.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.Removal of solvent under reduced pressure, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product. and residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid.By filtering to isolate maleate product (520mg).
Analytical calculation value measured value
C???????70.42???????70.45
H????????5.47????????5.41
N????????6.08????????6.10
Embodiment 60 (+/-) 7,8,9, the preparation of 10-tetrahydrochysene-10-(1-naphthyl methyl)-11H-benzo [g] pyrido [3,4-b] indole (Z)-2-butylene diacid salt
Figure A9519302901121
According to the method for preparing 5-methyl-7-bromine tryptamines hydrochloride among the embodiment 7, preparation 6,7-benzo tryptamines hydrochloride (2.85g) only is to use 1-naphthyl-hydrazonium salt acidulants (6.00g) as initiation material.
Under nitrogen atmosphere, with azalide (press among the embodiment 5 method preparation) (2.75g, 11.6mmo1) and 6,7-benzo tryptamines hydrochloride (2.85g, 1N HCl (50ml) suspension reflux 11.6mmol) 24 hours.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.Removal of solvent under reduced pressure, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid.By filtering to isolate maleate product (300mg), m/e=363.
Analytical calculation value measured value
C???????75.30?????75.04
H????????5.48??????5.36
N????????5.85??????5.76
Embodiment 61 (+/-) 6-(1, the 1-dimethyl ethyl)-1,2,3, the preparation of 4-tetrahydrochysene-1-(1-naphthyl methyl)-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt
Figure A9519302901131
According to the method for preparing 5-methyl-7-bromine tryptamines hydrochloride among the embodiment 7, preparation 5-(1, the 1-dimethyl ethyl)-tryptamines hydrochloride (2.95g) only is to use 4-(1, the 1-dimethyl ethyl)-phenyl hydrazine hydrochloride thing (6.00g) as initiation material.
Under nitrogen atmosphere, with azalide (press among the embodiment 5 method preparation) (1.25g, 5.26mmol) and 5-(1, the 1-dimethyl ethyl)-tryptamines hydrochloride (1.33g, 1N HCl (50ml) suspension reflux 5.26mmol) 24 hours.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.Removal of solvent under reduced pressure, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid.By filtering to isolate maleate product (700mg), m/e=369.
Analytical calculation value measured value
C???????74.36?????74.08
H????????6.66??????6.69
N????????5.78??????5.69
Embodiment 62 (+/-) 6-(1-Methylethyl)-1,2,3, the preparation of 4-tetrahydrochysene-1-(1-naphthyl methyl)-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt
Under nitrogen atmosphere, with azalide (press among the embodiment 5 method preparation) (1.75g, 7.38mmol) and 5-isopropyl tryptamines hydrochloride (press among the embodiment 4 method preparation) (1.76g, 1N HCl (40ml) suspension reflux 7.37mmol) 24 hours.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.Removal of solvent under reduced pressure, silica gel chromatography purification residue (ethyl acetate/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate that contains 1% methanol, handles with maleic acid.By filtering to isolate maleate product (671mg), m/e=355.
Analytical calculation value measured value
C???????74.02?????74.08
H????????6.43??????6.21
N????????5.95??????5.83
Embodiment 63 (+/-) 6,9-dimethyl-1,2,3, the preparation of 4-tetrahydrochysene-1-(1-naphthyl methyl)-9H-pyrido [3,4-b] indole hydrochloride thing
(10.0g adds saturated sodium carbonate liquor (300ml) in chloroform 43.2mmol) (300ml) suspension to the 5-methyltryptamine hydrochloride that is stirring.At room temperature stirred the mixture 1 hour.Separate two layers, with chloroform (2 * 100ml) strip aqueous.Use Na 2SO 4The dry organic facies that merges also concentrates.Residue is dissolved in the toluene (300ml), and (7.05g 47.6mmol) handles with phthalic anhydride.Reflux solution is 14 hours under azeotropic water removing (by the Dean-Stark water knockout drum) condition.Cooling solution obtains light cystose crude product to room temperature and concentrated.Obtain phthalimide white solid (13.52g) by ethyl alcohol recrystallization, this product need not to be further purified in use.
In 30 minutes, (25% oily dispersion liquid, 8.24g add phthalimide (13.02g, THF 42.8mmol) (150ml) solution that as above prepares in anhydrous THF (50ml) suspension 51.3mmol) to the hydrofining that is stirring.Continued after adding to stir the mixture 1 hour.Add tetramethylethylenediamine (7.7ml, 51.3mmol), add again methyl iodide (4.0ml, 63.8mmol).After 1 hour, make the reaction all standing, then with ether (2 * 100ml) extractions by adding entry (200ml).Use MgSO 4The dry organic facies that merges concentrates and obtains yellow solid shape product (14g), and this product need not to be further purified in use.
(3.4ml 109mmol) handles phthalimide (14g, methanol 42.8mmol) (85ml) solution that makes in the above-mentioned steps with hydrazine.Mixture heated was refluxed 2 hours.Reaction mixture is handled with dense HCl (7ml) and methanol (25ml) to room temperature, and reheat refluxed 14 hours.After being cooled to room temperature, mixture is distributed between chloroform (200ml) and the aqueous sodium carbonate (200ml).(2 * 100ml) aqueous phase extracted merge organic facies to the reuse chloroform, use Na 2SO 4Dry and concentrated.With the fast silica gel chromatogram method purification crude product (chloroformic solution/0.2%NH that contains 0-25% methanol 4OH is an eluent).Collection contains the fraction of product and concentrates.Residue is dissolved in the ether, handles with anhydrous HCl.Filter to isolate brown solid product 1,5-dimethyl-tryptamines hydrochloride (6.08g), this product need not to be further purified in use.
Under nitrogen atmosphere, will as the azalide of the method among the embodiment 5 preparation (1.06g, 4.45mmol) and 1,5-dimethyltryptamine hydrochloride (1.00g, 1N HCl (50ml) suspension reflux 4.47mmol) 48 hours.Reaction mixture filters to isolate crude product to room temperature.(3 * 50ml) grind brown solid and use ether (3 * 50ml) washings with isopropyl alcohol.Ethyl alcohol recrystallization obtains the required light solid product of 710mg, m/e=340.
Analytical calculation value measured value
C????????76.48?????76.78
H?????????6.68??????6.58
N?????????7.43??????7.50
Embodiment 64 (-)-(S)-6-methyl isophthalic acid, 2,3, the preparation of 4-tetrahydrochysene-1-(1-naphthyl methyl)-9H-pyrido [3,4-b] indole hydrochloride thing
To the 6-methyl isophthalic acid that is stirring, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] (3.14g adds (S)-N, N-dimethyl-N '-(uncle 1--butoxy-3-methyl)-2-butyl carbonamidine (3.79g to indole in anhydrous dimethyl benzene (65ml) solution 16.9mmol), 17.7mmol), sulfonic acid (200mg) then camphorates.Gained vlil 72 hours.Reaction mixture is to room temperature and concentrating under reduced pressure.With fast silica gel chromatogram method purification residue (1: 3: 6 triethylamine: ethyl acetate: hexane is an eluent).Collection contains the fraction of product and concentrates and obtains viscosity oily product carbonamidine (5.99g), and this product need not to be further purified in use.
(25% oily dispersion liquid, 829mg add carbonamidine (5.99g, 16.8mmol) THF (45ml) solution that as above prepares in THF 20.2mmol) (10ml) cooling (0 ℃) suspension to the hydrofining that is stirring.In this mixture, add tetramethylethylenediamine (3.0ml, 20.2mmol), add again chloromethyl methyl ether (1.9ml, 25.2mmol).Continued to stir the mixture 1 hour and water (50ml) processing.Be distributed between ether and the water mixture and layering.(2 * 100ml) aqueous phase extracted are used K with ether 2CO 3The dry organic facies that merges concentrates and obtains orange colour oily product (6.73g), and this product need not to be further purified in use.
In 5 minutes, to the carbonamidine of the above-mentioned preparation of stirring (3.36g, 8.4mmol) splash in the cooling of anhydrous THF (55ml) (78 ℃) solution n-BuLi (hexane solution of 1.7M, 5.4ml, 9.18mmol).Further agitating solution is 1 hour under-78 ℃, with 1-chloromethyl-naphthalene (1.62g, anhydrous THF (10ml) solution-treated 9.18mmol).Continued agitating solution 4 hours down at-78 ℃, solution is warmed to ambient temperature overnight.Add aqueous THF (50ml), decompression concentrated solution.Be dissolved in residue in the chloroform and wash with water.Use Na 2CO 3Dry organic facies also concentrates.With fast silica gel chromatogram method purification crude product (1: 3: 6 triethylamine: ethyl acetate: hexane is an eluent).Collection contains the fraction of product, concentrates and obtains viscosity oily product (3.48g) (m/e=539), and this product need not to be further purified in use.
(3.48g adds 2N HCl (30ml) in THF 6.45mmol) (30ml) solution to the as above methoxy indole of preparation that is stirring.Stirred the mixture under the room temperature 24 hours, and again it was distributed between ether and the water.(2 * 25ml) strip aqueous with the organic facies that the salt water washing merges, are used Na with ether 2CO 3Drying, concentrating under reduced pressure.Residue is dissolved among the THF (20ml) also with 2N sodium hydroxide solution (6ml) processing.After 2 hours, with chloroform (2 * 100ml) extractive reaction mixture.At Na 2CO 3Go up dry organic facies, concentrate and obtain viscosity oily product (2.68g) (m/e=495).
(2.68g adds entry (12ml) in ethanol 5.41mmol) (100ml) cooling (0 ℃) solution, adds acetic acid (12ml) and hydrazine hydrate (22ml) again to the as above carbonamidine of preparation that is stirring.Reaction vessel was placed cold closet (10 ℃) 72 hours.Mixture is warmed to room temperature and concentrating under reduced pressure.Crude product is dissolved in the chloroform (300ml), water (3 * 50ml) washings.At Na 2CO 3The last dry and concentrated viscosity grease that obtains.Grease is dissolved in the ether also with anhydrous HCl processing.Filter to isolate hydrochlorate (1.50g).Obtain the material of constant optical rotation by ethanol (2 *) recrystallization.The enantiomeric purity of being determined by chirality HPLC is greater than 95%ee.m/e＝326。Bi Xuan @589nM=-40.21 (pyridine, C=1) Bi Xuan @365nM=+80.43 (pyridine, C=1)
Analytical calculation value measured value
C????????76.12?????75.96
H?????????6.39??????6.56
N?????????7.72??????7.44
Embodiment 656-methyl isophthalic acid-[(4-dimethylamino-naphthyl) methyl]-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole dihydrochloride-hydrate
With syringe to the chlorination methoxy triphenyl phosphonium that is stirring (10.32g, drip in 30.1mmol) anhydrous THF (150ml) cooling (78 ℃) suspension n-BuLi solution (18.8g, 1.6M, 30.1mmol).Stirred the orange colour suspension 15 minutes down at-78 ℃.In 10 minutes, (5.00g, THF 25.1mmol) (75ml) drips of solution is added in this inner salt with 4-dimethylamino-1-naphthaldehyde.Reactant mixture is warmed to room temperature gradually and stirred 14 hours.Add saturated NH 4Cl solution (100ml), (3 * 50ml) extract this mixture with ether.Use Na 2SO 4Dry organic facies and the concentrating under reduced pressure that merges.With 15% ethyl acetate/hexane eluting, silica gel chromatography purification, obtain the product (5.43g) of olefin isomer mixture, this product need not to be further purified in use.
(695mg, 3.3mmol) (1.00g, the mixture heated of acetonitrile 4.4mmol) (20ml) and 1NHCl solution (150ml) refluxed 96 hours with 1-methoxyl group-4 '-dimethylamino-benzo styrene with the 5-methyltryptamine hydrochloride.In the time of 4 hours, add the dense HCl of 1ml.Reaction mixture is to room temperature, with the neutralization of unsaturated carbonate aqueous solutions of potassium and use chloroform extraction.The organic facies that concentrating under reduced pressure merges, silica gel chromatography purification residue (2.5%MeOH/ chloroform/0.2%NH 4OH is an eluent).Collection contains the fraction and the concentrating under reduced pressure of product.Residue is dissolved in the ethyl acetate, handles with anhydrous HCl.By the product (1.22g) that filters to isolate dihydrochloride monohydrate, 231.3 ℃ of fusing points.
Analytical calculation value measured value
C???????65.21??????65.30
H????????6.79???????6.60
N????????9.13???????9.03
Embodiment 667-methyl-8-bromo-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
Figure A9519302901171
3.0g 6-methyl-7-bromo-1H-indole-3-ethylamine salt acidulants sample dissolution in hot water, is added the aqueous solution of Acetic acid,oxo-,monohydrate monohydrate (1.10g).With KOH or hydrochloric acid conditioning solution to pH 4.Solid suspension adds dense HCl at leisure in water, the mixture boiling.Collect solid, wash with water and vacuum drying.Solid is distributed between 1N NaOH and the chloroform.Dry and concentrated organic moiety, the residue that obtains silica gel chromatography purification is with the chloroformic solution eluting that contains methanol.Collect required fraction and be condensed into solid, it is dissolved in the methanol, dilute with the HCl gas treatment and with ether.Collect solid, with ether washing and dry.Productive rate: 48% fusing point: 321 ℃ of elementary analysis: C47.83; H4.89; N9.30.
Embodiment 678-methoxyl group-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
With preparing required product with embodiment 66 essentially identical methods, just initiation material is 7-methoxyl group-1H-indolecthanamine.Fusing point: 207-209 ℃ elementary analysis: C60.17; H5.56; N8.60.
Embodiment 688-methoxyl group-2 (N)-propyl group-1,2,3, the preparation of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole
Figure A9519302901181
Prepare 8-methoxyl group-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole according to essentially identical method with embodiment 66 descriptions.With 0.36g indole sample and 1gK 2CO 3Contact, the mixture nitrogen purging.With 40ml CH 3The CN sample joins in the gained mixture, adds 0.12ml1-iodopropane sample again.Mixture remains in the nitrogen atmosphere and lucifuge stirs.Extraction gained mixture is with organic facies drying, evaporation and chromatogram purification.Evaporate required fraction, it is dissolved in methanol: in the ethyl acetate.The gained mixture is joined in the diethyl ether solution that is stirring solution gas HCl bubbling.Vacuum drying gained solid, recrystallization and evaporation obtain required product.Output: 0.10g fusing point: 282-28 elementary analysis: C64.45; H7.67; N9.91
Embodiment 698-methoxyl group-2 (N)-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole
Figure A9519302901191
8-methoxyl group-1,2,3, the sample of 4-tetrahydrochysene-9H-pyrido [3,4-b]-indole is pressed embodiment 66 described preparations basically.Stir indole (1g), NaOAc (0.34g), NaBH 3CN (0.53g), methanol (50ml) and HOAc (1.0g) add the indole mixture to 1.36g (37%, in 10ml methanol) sample.
With acid reaction is stopped, making it to be alkalescence, extraction, organic facies drying, evaporation and chromatogram purification.Required fraction is through evaporation and be dissolved in methanol/ethyl acetate, and the mixture that obtains is added the HCl that contains ether, collects the solid and the vacuum drying that obtain.M.P.:291-294 ℃ of elementary analysis: C62.06 of productive rate: 0.84g (79%); H6.97; N11.32.
Embodiment 708-methoxyl group-2 (N)-cyclopropyl methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole
Figure A9519302901192
Prepare required product with suitable reagent with by embodiment 69 described methods.Productive rate: 88%M.P.:285-287 ℃ elementary analysis: C65.76; H7.47; N9.47.
Embodiment 71
Figure A9519302901201
Prepare required product with suitable reagent with by embodiment 69 described methods.Productive rate: 48%M.P.:321 ℃ elementary analysis: C47.83; H4.89; N9.30.
Embodiment 727,8-dimethyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole
2.30g 6,7-dimethyl-1H-indole-ethamine heating for dissolving adds the solution of 1.03g glyoxalic acid sample in 10ml water in the mixture of water and isopropyl alcohol in flask, makes the solution cooling and add potassium hydroxide to make it to be alkalescence, agitating solution 48 hours.The solid that isolated by filtration obtains washes with water.Solid is dissolved in 50ml water, adds concentrated hydrochloric acid lentamente and make it acidify, begin heating and add the 5ml concentrated hydrochloric acid again.Decantation obtains solid, makes it to be dissolved in 10ml water, adds potassium hydroxide and makes this solution be alkalescence, with 1: 3 isopropyl alcohol: chloroform extraction.Separation and concentrated organic layer obtain heavy-gravity oil, and it is used chromatogram purification.This oil is dissolved in ethyl acetate, forms hydrochlorate, filter to isolate hydrochlorate with gasiform HCl bubbling in solution, dry in vacuum drying oven.Productive rate: 54%M.P.:330 ℃ elementary analysis: C65.75; H7.29; N11.62.
Embodiment 736-methyl-8-bromo-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole
Prepare required 6-methyl-8-bromo-1,2,3 with suitable reagent with by embodiment 72 described methods, 4-tetrahydrochysene-9H-pyrido [3,4-b]-indole.Productive rate: 57%M.P.:346 ℃ elementary analysis: C48.04; H4.68; N9.30.
Embodiment 746,8-two fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole
With suitable reagent and prepare by embodiment 72 described methods required 6,8-two fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole.Productive rate: 5%M.P.:350 ℃ elementary analysis: C53.90; H4.26; N9.52.
Embodiment 758-bromo-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole
Prepare required 8-bromo-1,2,3 with suitable reagent with by embodiment 72 described methods, 4-tetrahydrochysene-9H-pyrido [3,4-b]-indole.Productive rate: 4%M.P.:337.8 ℃ elementary analysis: C46.17; H4.26; N9.52.
Basically the method by embodiment 72 prepares following chemical compound.8-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole productive rate: 48%M.P.:329.5 ℃ elementary analysis: C58.58; H5.43; N12.37.6-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4 one b]-indole productive rate: 63%M.P.:317.9 ℃.6-bromo-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole productive rate: 19%M.P.:310.9 ℃.6-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole productive rate: 38%M.P.:316.6 ℃.Productive rate: 54%M.P.:330 ℃ elementary analysis: C65.75; H7.29; N11.62.
Embodiment 767-methyl-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole
Except being 6-methyl-7-chloro-1H-indole-3-ethylamine salt acidulants, starting material prepares required product by embodiment 1 described method basically.Productive rate: 70%.
The material that obtains seethes with excitement in ethanol, collects the product that obtains, with washing with alcohol and vacuum drying.Productive rate: 58%M.P.:330-334 ℃ elementary analysis: C55.88; H5.47; N10.93.
Basically the method by the foregoing description 76 prepares following chemical compound.7-methyl-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole M.P.:350-352 ℃ elementary analysis: C55.65; H5.68; N10.39.8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole M.P.:335-337 ℃ elementary analysis: C53.93; H4.88; N11.09.7-bromo-8-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole M.P.:323-325 ℃ elementary analysis: C47.85; H4.84; N9.08.
Embodiment 777-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole
In the presence of Pd/C, ethanol and triethylamine, make 7-methyl-8-bromo-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-sample and the H-H reaction of indole, the material that obtains after filtration, concentrate and extraction, the organic facies drying, concentrate and vacuum drying, the solid that obtains is dissolved in the hydrochloric acid that methanol and adding contain ether, collect the solid of white, with ether washing and vacuum drying.Productive rate: 56%M.P.; 310-312 ℃ of elementary analysis: C64.79; H6.89; N12.47.
Embodiment 788-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b]-indole
Basically prepare required product by embodiment 77 described methods.Productive rate: 46%M.P.; 318-320 ℃ of elementary analysis: C64.53; H6.94; N12.43.
Embodiment 797-bromo-1H-indole-3-ethamine
25.8g 2-bromophenyl hydrazonium salt acidulants is distributed in 1N NaOH and the chloroform, separates organic facies, contain the water section chloroform extraction, the organic facies drying (Na of merging 2SO 4) and concentrate the buttery free hydrazine of generation.
Above-mentioned oil stirred in 100ml methanol add 4-neoprene anhydride (12.3g) simultaneously, the mixture that obtains is transferred to tube sealing and uses nitrogen purging, tube sealing, reactant mixture heated 14 hours in 95 ℃ of oil baths.Make reactant mixture cooling, concentrate the residue that obtains and be distributed in 1NNaOH and the chloroform, the organic facies drying of merging and be condensed into oil.Oil is carried out chromatogram purification with silica gel,, concentrate the shared oil that heats up in a steamer that contains product, be dissolved in oil in a small amount in the methanol and add the HCl that contains ether, collect solid, with the ether washing with at 50 ℃ of vacuum dryings with containing the chloroform gradient elution of 0-10% methanol.Output: 7.32g productive rate: 23%M.P.:260-262 ℃ elementary analysis: C43.55; H4.41; N10.03.
Embodiment 807-fluoro-1H-indole-3-ethamine
Basically press the hereinafter required 7-fluoro-1H-indole-3-ethamine of embodiment 81 described preparations, just with 2-fluorophenyl hydrazonium salt acidulants (25.5g).In addition, last purification requires reverse hplc.Productive rate: 4gM.P.:187-189 ℃ elementary analysis: C55.12; H5.48; N12.60.
Embodiment 817-methoxyl group-1H-indole-3-ethamine
15.8g 2-methoxyphenyl hydrazonium salt acidulants and 26.3g 4-phthalimido n-butyraldehyde diethyl acetal are stirred in ethanol, and mixture heated refluxed 2 hours, made the reactant mixture cooling and was condensed into residue.
The residue that obtains is dissolved in 750ml ethanol, adds the hydrate of 15.5g hydrazine, mixture heated was refluxed 14 hours.Add 70ml 5N HCl sample and make the mixture cooling, make refrigerative mixture be condensed into residue.Residue is distributed in 1N HCl and the chloroform, isolates the organic facies part, contain the water section chloroform extraction, the organic extract liquid drying (Na of merging 2SO 4) and be condensed into oil.Oil is carried out chromatogram purification with silica gel,, concentrate the shared oil that heats up in a steamer that contains product, be dissolved in oil in a small amount in the methanol and add the HCl that contains ether, collect solid, obtain white solid with the ether washing with at 50 ℃ of vacuum dryings with containing the chloroform gradient elution of 0-10% methanol.Productive rate: 7.5gM.P.:198-200 ℃ elementary analysis: C57.51; H6.75; N12.10.
Embodiment 827-chloro-1H-indole-3-ethamine
10.0g 2-chlorphenyl hydrazonium salt acidulants and 17.9g 4-phthalimido n-butyraldehyde diethyl acetal are stirred with 1ml 5N HCl in 200ml ethanol, mixture is condensed into residue, this residue stirs in dichloromethane in a small amount, collects xanchromatic solid and at 40 ℃ of vacuum dryings.This solid stirs in 500ml ethanol, adds the hydrate of 14g hydrazine, and mixture heated was refluxed 14 hours.Add 60ml 5N HCl sample and mixture heated was refluxed 1 hour.Make the mixture cooling, and be condensed into residue.Residue is distributed in 1N HCl and the chloroform, isolates the organic layer part, water-bearing layer chloroform extraction, the extract drying (Na of merging 2SO 4) and be condensed into oil.Oil is carried out chromatogram purification with silica gel, with the 0-10% methanol-chloroform gradient elution that contains 0.2% ammonium hydroxide, concentrate the shared oil that heats up in a steamer contain product, be dissolved in oil in a small amount in the methanol and add the HCl that contains ether, collect solid, with the ether washing with at 50 ℃ of vacuum dryings.M.P.:227-229 ℃ of elementary analysis: C51.76 of productive rate: 3.2g (25%); H5.29; N11.97
Embodiment 835-methyl-7-chloro-1H-indole-3-ethamine
Figure A9519302901261
Basically press the required product of embodiment 82 described preparations.M.P.:279-281 ℃ of elementary analysis: C54.05 of productive rate: 4.3g (34%); H5.85; N11.33
Embodiment 841H-benzo (G) indole-3-ethamine
Figure A9519302901262
Basically prepare 1H-benzo (G) indole-3-ethamine by embodiment 82 described methods.M.P.:305-307 ℃ of elementary analysis: C68.43 of productive rate: 3.5g (17%); H6.30; N11.08.
Embodiment 856-methyl-7-chloro-1H-indole-3-ethamine and 6-bromo-7-Methyl-1H-indole-3-ethamine
Figure A9519302901271
Basically prepare 6-methyl-7-chloro-1H-indole-3-ethamine by embodiment 82 described identical methods.M.P.:290 ℃ of elementary analysis: C54.10 of productive rate: 3.0g (24%); H5.88; N11.66.
With suitable initiation material, press embodiment 82 described preparation 6-bromo-7-Methyl-1H-indole-3-ethamine basically.M.P.:251 ℃ of elementary analysis: C45.85 of productive rate: 1.6g (56%); H4.97; N9.71.
Embodiment 866-Methyl-1H-indole-3-ethamine
Figure A9519302901272
In the presence of ethanol and triethylamine, make 6-methyl-7-bromo-1H-indole-3-ethamine and Pd/CH 2Contact, the material that evaporation obtains is allocated in alkali/CHCl with it 3Between.Organic facies drying, concentrated and dry is dissolved in the material that obtains methanol and adds the HCl that contains ether, and the material that obtains is through washing and vacuum distilling.M.P.:232-236 ℃ of elementary analysis: C62.84; H7.24; N13.20.
Embodiment 875-methyl-7-bromo-1H-indole-3-ethamine
By suitable starting material with prepare 5-methyl-7-bromo-1H-indole-3-ethamine, productive rate: 16% with embodiment 79 described methods basically.
0.6g 5-methyl-7-bromo-1H-indole-3-ethylamine salt acidulants is changed into free alkali and uses the silica gel chromatography purification, compile and evaporate required fraction, the material that obtains is dissolved in ethyl acetate, filtration, dilutes with ether and maleic acid methanol solution, and product is also dry with ether crystallization, filtration.Productive rate: 67%M.P.:185-187 ℃ elementary analysis: C49.09; H4.85; N7.71.
Embodiment 886,7-dimethyl-1H-indole-3-ethamine
By suitable starting material with basically with embodiment 79 described method preparations 6,7-dimethyl-1H-indole-3-ethamine is used K 2CO 3Handle purification 6,7-dimethyl-1H-indole-3-ethamine is also with chloroform/isopropyl alcohol extraction in 3: 1.Organic facies drying, evaporation and chromatogram purification compile and evaporate required fraction, and required fraction mixes with ethyl acetate, and the material that obtains is with ether and the dilution of maleic acid methanol solution, and solid grinds in ether and drying.M.P.:171-173 ℃ of elementary analysis: C63.20; H6.75; N8.89.
Embodiment 896-methyl-7-bromo-1H-indole-3-ethamine
By suitable starting material with prepare 6-methyl-7-bromo-1H-indole-3-ethamine, productive rate: 8.6% with embodiment 79 described methods basically.
6-methyl-7-bromo-1H-indole-3-ethamine is dissolved in ebullient ethanol and slowly cools to room temperature.Reduce solvent, the material that obtains washs after filtration and with ether, and the material that obtains obtains required material once more after filtration and with the ether washing.M.P.:288-290 ℃ of elementary analysis: C45.54; H4.80; N9.47.
In embodiment 90-110, wherein used ether is before use with the distillation of benzophenone sodium ketyl.All reactions all are to carry out under positive argon pressure.With Bruker AC-200P (200MHz) record 1H-NMR and 13The C-NMR data obtain IR spectrum with Nicolet510 P-FT (film and KBr).Fusing point is measured with the Buchi instrument, and does not proofread and correct.TLC analyzes and to use Merck TLC, the glass plate precoating F 254Silica gel 60 (UV, 254nm and iodine).Used in chromatograph 230-400 order silica gel (Merck) carries out.N-BOC-aziridine (2a-d) is by corresponding alkene method preparation routinely.
Preparation example 2 indole starting materials
Indole starting material hereinafter (1a, 1b, and 1c) is (1a) that buys, press Bartoli method preparation (1b) [Bartoli, G. etc., Tetrahedron Lett., 1989,30,2129] or by 2-iodo-4, the synthetic 1c of 6-dimethylaniline (5 )).The method is by following process description:
2-iodo-4, the synthetic of 6-dimethylaniline (5 ) can be finished by following: in Ar gas, to 5 (24mmol), CuI (0.05 equivalent) and (PPh 3) 2PdCl 2(0.05 equivalent) adds trimethyl silyl acetylene (trimethylsilylacetylene) (1.1 equivalent) in the suspension of 30ml anhydrous triethylamine, and the mixture that obtains was stirred 3 hours.Then, solvent removed in vacuo, the residue purification by flash chromatography is that eluent obtains 6 with quantitative productive rate with hexane/ethyl acetate (3: 1).Serosity in the 50ml anhydrous dimethyl formamide is at 100 ℃ 6 (23mmol) and CuI (2 equivalent), and heating is 2.5 hours in the Ar atmosphere.Be cooled to room temperature after-filtration reactant mixture, solid washs secondary with ether (20ml), and organic facies washes (3 * 50ml) with water, use dried over sodium sulfate, solvent evaporation is to doing the crude product purification by flash chromatography, with hexane/ethyl acetate (3: 1) is that eluent provides 1c (1.5g, 45%).
The method for preparing embodiment 90-107 chemical compound is with following process description:
Figure A9519302901301
aX″＝5-Me?????n 30＝4R，R′＝H(95)aX″＝5-Me??????aX″＝5-Me?????n 30＝3(90)???bX″＝7-Cl?????n 30＝4R，R′＝H(96)bX″＝7-Cl??????bX″＝7-Cl?????n 30＝3(91)???cX″＝5-Me?????n 30＝3R＝3，4-(OMe)2Bn，R′＝H(97)cX″＝5，7-diMe?cX″＝5，7-Me 2n 30＝3???????dX″＝7-C1?????n 30＝3R＝3，4-(OMe)2Bn，R′＝H(98)
dX″＝5-Me?????n 30＝4(92)???eX″＝5，7-Me2?n 30＝3R＝3，4-(OMe) 2Bn，R′＝H(99)
eX″＝7-Cl?????n 30＝4(93)???fX″＝5-Me?????n 30＝4R＝3，4-(OMe) 2Bn，R′＝H(100)
fX″＝5，7-Me 2n 30＝4(94)???gX″＝7-Cl?????n 30＝4R＝3，4-(OMe) 2Bn，R′＝H(101)
gX″＝5-Me?????n 30＝5???????hX″＝5，7-Me2?n 30＝4R＝3，4-(OMe) 2Bn，R′＝H(102)
iX″＝5-Me?????n 30＝5R＝3，4-(OMe) 2Bn，R′＝H(103)
jX″＝5-Me?????n 30＝3R＝1-naphthylmethyl，R′＝H(104)
kX″＝5-Me?????n 30＝4R＝1-naphthylmehyl，R′＝H(105)
lX″＝5，7-Me2?n 30＝4R＝1-naphthylmethyl，R′＝H(106)
mX″＝5-Me?????n 30＝4R，R′＝???????????????????(107)
Figure A9519302901302
Embodiment 90 trans-3-(2-amino-cyclopenta)-5-methylindole, hydrochloride
Anhydrous ether solution to the 10ml of corresponding indole 1a (5mmol) in argon atmospher adds 3M methyl-magnesium-bromide (1.5 equivalent), and the chemical compound that obtains was in stirring at room 45 minutes.Then,, in the Ar atmosphere this mixture is added with pipe in the 5ml absolute ether of copper bromide (I)-dimethyl sulfoxine complex (0.2 equivalent), under same temperature, stirred the mixture 30 minutes at-30 ℃.After this mixture is cooled to-78 ℃, the corresponding aziridine 2a (1.5 equivalent) that is dissolved in absolute ether is added wherein, make all mixture reach room temperature and stir and spend the night.With 10ml ammonium chloride saturated solution reaction is stopped, separate each layer, (2 * 10ml) extract water with ether/ethyl acetate (1: 1), the organic extract liquid anhydrous sodium sulfate drying that merges, vacuum is removed solvent, the residue purification by flash chromatography is an eluent with hexane/ethyl acetate (3: 1).The tryptamines of corresponding N-BOC protection is dissolved in dichloromethane/ether, solution with dry hydrogen chloride saturated and stirring at room temperature spend the night.The final evaporation solvent, crude product is title compound (3a) with dichloromethane/ether/carbinol mixture (2: 3: 1) washing purification through identifying product.Productive rate:
85％.Mp：＞200℃. 1H?NMR(CD 3OD)，δ：7.35(s，1H)，7.23-7.12(m，??2H)，6.91(d，J＝7.5Hz，1H)，3.73(m，1H)，3.27(m，1H)，2.38-2.10(m，5H)，2.05-1.70??(m，4H). 13C?NMR(CD 3OD)，δ：136.98，128.93，127.84，124.27，123.13，119.01，??114.19，112.37，58.56，43.93，33.10，31.30，23.07，21.73.IR(KBr)：3304，2963，1593，??1510，1481，800cm -1.MS(EI)：214(M +-HCl，28)，197(70)，170(14)，144(42)，126??(49)，105(33)，84(100).
Embodiment 91 trans-3-(2-amino-cyclopenta)-7-chloro-indole, hydrochloride
Preparing title compound (3b) with embodiment 90 described substantially the same methods, but the indole starting material is a formula 1b chemical compound.Productive rate:
37％.Mp：＞200℃. 1H?NMR(CD 3OD)，δ：7，56(d，J＝7.7Hz，1H)，7.31(s，1H)，7.12(dJ＝7.3Hz，1H)，7.01(t，J＝7.8Hz，1H)，3.77(q，J＝7.9Hz，1H)，3.40-3.25(m，1H)，2.40-2.15(m，2H)，.2.05-1.70(m，4H). 13C?NMR(CD 3OD)，δ：135.48，129.53，124.28，122.13，120.79，118.40，118.02，116.18，58.55，43.79，33.32，31.36，23.11.IR(KBr)：3422，3298，3040，2972，2909，1495cm -1.MS(EI)：235(M +-Cl，100)，218(28)，165(7).
Embodiment 92 trans-3-(2-amino-cyclohexyl)-5-methylindole, hydrochloride
To prepare title compound (3d) with embodiment 90 described substantially the same methods.Productive rate:
80％.Mp：＞200℃. 1H?NMR(CD 3OD)，δ：7，44(s，1H)，7.27(d，J＝8.3??Hz，1H)，7.18(s，1H)，6.95(dd，J＝8.3?and?1.2Hz，1H)，3.55-3.40(m，1H)，2.86(dt，??J＝4.3?and?11.3Hz，1H)，2.42(s，3H)，2.25-2.12(m，1H)，2.10-1.79(m，4H)，1.75-1.40??(m，3H). 13C?NMR(CD 3OD)，δ：136.97，129.12，127.74，124.42，123.73，119.09，.??114.77，112.48，56.22，41.61，34.75，32.42，26.93，25.79，21.73.IR(KBr)：3400，3283，??3021，2936，2861，1491cm -1.MS(EI)：229(M +-Cl，100).
Embodiment 93 trans-3-(2-amino-cyclohexyl)-7-chloro-indole, hydrochloride (3e)
To prepare title compound (3e) with embodiment 90 described substantially the same methods.Productive rate:
43％.Mp：＞2?00℃. 1H?NMR(CD 3OD)，3：7，63(d，J＝7.8Hz，1H)，7.35(s，1H)，7.14(d，J＝7.4Hz，1H)，7.02(t，J＝7.7Hz，1H)，3.60-3.40(s，1H)，3.08-2.91(m，1H)，2.30-2.10(m，1H)，2.05-1.80(m，4H)，1.75-1.45(m，3H). 13C?NMR(CD 3OD)，δ：135.43，129.41?125.00，122.15，120.87，118.53，118.09，116.70，56.12，41.43，34.74，32.37，26.80，25.68.IR(KBr)：2938，2859，1429，1341，779，735cm -1.MS(EI)：249(M +-Cl，100).
Embodiment 94 trans-3-(2-amino-cyclohexyl)-5, the 7-dimethyl indole, hydrochloride is trans-3-(2-amino-cyclopenta)-5,7-dimethyl indole, hydrochloride
Preparing title compound (3f) with embodiment 90 described substantially the same methods, but indole is 1c, and aziridine is 2b.Productive rate:
45％.Mp：＞200℃. 1H?NMR(CD 3OD)，δ：7，27(s，1H)，7.19(s，1H)，6.77(s，1H)，3.42(dt，J＝11.0?and?4.2Hz，1H)，2.85(dt，J＝11.4?and?4.2Hz，1H)，2.44(s，3H)，2.39(s，3H)，2.30-2.10(m，1H)，2.08-1.83(m，4H)，1.70-1.40(m，3H). 13C?NMR(CD 3OD)，δ：136.39，129.37，127.39，125.01，123.56，121.94，116.78，115.16，56.28，41.70，34.71，32.40，26.93，25.80，21.72，16.93.IR(KBr)：3420，3279，3013，2934，2861，1505cm -1.MS(EI)：242(M +-HCl，62)，225(25)，199(23)，184(20)，171(38)，158(100)，145(18)，128(12)，115(12)，97(12).
Prepare trans-3-(2-amino-cyclopenta)-5 with essentially identical method, the 7-dimethyl indole, hydrochloride (3c), but aziridine is 2a.Productive rate:
63％. 1H?NMR(DMSO-d 6)，δ：10.8(s，1H)，8.12(broads，3H)，7.30-7.20(m，2H)，6.70(s，1H)，3.70-3.55(m，1H)，3.55-3.20(m，1H)，2.38(s，3H)，2.36(s，3H)，2.30-2.10(m，2H)，2.00-1.60(m，4H).
Embodiment 95 anti-form-1 0-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-c] quinoline also, hydrochloride
Make tryptamines hydrochloride (3a) 10ml distilled water suspension heating for dissolving (1.3mmol), the 1ml aqueous solution that in this solution, adds Acetic acid,oxo-,monohydrate (1.43mmol), the 1ml distilled water solution that then adds KOH (1.3mmol) lentamente makes pH=4, and the solution that obtains was stirring at room 1 hour.After this, drip the hydrochloric acid (0.5ml) of supply of commodities, the chemical compound that backflow obtains 30 minutes added another part hydrochloric acid (0.5ml) and reaction mixture refluxed 15 minutes again.At last, reactant mixture is cooled to room temperature, leaches, then water and washing with alcohol title compound tetrahydrochysene-b-carboline (4a).Productive rate:
81％，Mp：＞200℃， 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，9.92??(broads，1H)，9.68(broads，1H)，7.38(s，1H)，7.23(d，J＝8.3Hz，1H)，6.88(d，J＝??7.8Hz，1H)，4.50-4.22(m，2H)，3.18-2.95(m，2H)，2.80-2.65(m，1H)，2.34(s，3H)，??2.30-2.15(m，1H)，1.98-1.80(m，2H)，1.80-1.20(4H). 13C?NMR(DMSO-d 6)，δ：??134.75127.31，126.49，125.64，122.65，119.11，111.14，108.82，58.99，37.18，29.42，??28.84，24.94，24.43，21.28.IR(KBr)：3391，3266，2936，2861，2801，2762cm -1.MS??(EI)：241(M +-Cl，100).
Embodiment 96 trans-8-chloro-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-c] quinoline also, hydrochloride
Make tryptamines hydrochloride (3b) 10ml distilled water suspension heating for dissolving (1.3mmol), the 1ml aqueous solution that in this solution, adds Acetic acid,oxo-,monohydrate (1.43mmol), the 1ml distilled water solution that then adds KOH (1.3mmol) lentamente makes pH=4, and the solution that obtains was stirring at room 1 hour.After this, drip the hydrochloric acid (0.5ml) of supply of commodities, the chemical compound that obtains 30 minutes of refluxing adds another part hydrochloric acid again. (0.5ml) and reaction mixture refluxed 15 minutes.At last, reactant mixture is cooled to room temperature, leaches, then water and washing with alcohol title compound tetrahydrochysene-b-carboline (4b).Productive rate:
45％.Mp：＞200℃. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，10.05(broads，1H)，9.87(broads，1H)，7.58(d，J＝7.8Hz，1H)，7.16(d，J＝7.6Hz，1H)，6.98(t，J＝7.9Hz，1H)，4.60-4.20(m，2H)，3.18-2.95(m，2H)，2.90-2.70(m，1H)，2.25-2.18(m，1H)，1.98-1.75(m，2H)，1.65-1.20(4H). 13C?NMR(DMSO-d 6)，δ：133.17128.18，127.23，120.65，120.03，118.55，115.78，110.73，58.74，36.93，29.16，28.77，24.88，24.36.IR(KBr)：3422，3231，2936，2861，2760，1429cm -1.MS(EI)：261(M +-Cl，30)，241(100).
Embodiment 97 trans-5-(3, the 4-Dimethoxyphenyl)-9-methyl isophthalic acid, 2,3,4,4a, 5,6,10c-octahydro Pentamethylene. is [a] pyrido [3,4-b] indole also, hydrochloride (4c)
Corresponding tryptamines hydrochloride (3a) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
88％.Mp：187-191℃. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，10.38(broads，1H)，9.25(broads，1H)，7.50-7.15(m，3H)，7.15-6.80(m，3H)，5.0-4.70(broads，1H)，3.75(s，6H)，3.40-2.80(m)，2.49(s，3H)，2.20-1.70(m，4H)，1.55-1.30(broads，1H). 13C?NMR(DMSO-d 6)，δ：148.73147.90，134.45，130.24，128.17，127.64，125.44，123.03，121.78，118.43，113.69，111.95，111.27，110.64，62.01，57.50，55.51，37.49，25.52，25.14，21.30，20.73.IR(KBr)：3438，3237，2942，1518，1264，1248cm -1.MS(EI)：377(M +-Cl，100).
Embodiment 98 trans-7-chloro-5-(3, the 4-Dimethoxyphenyl)-1,2,3,4,4a, 5,6,10c-octahydro Pentamethylene. is [a] pyrido [3,4-b] l diindyl also, hydrochloride (4d)
Corresponding tryptamines hydrochloride (3b) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
52％.Mp：＞230℃dec. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，10.40(broads，1H)，9.30(broads，1H)，7.60-7.42(m，1H)，7.38-6.90(m，5H)，4.90-4.75(broads，1H)，3.78(s，3H)，3.76(s，3H)，3.40-3.00(m)，2.15-1.80(m，4H)，1.60-1.35(broads，1H). 13C?NMR(DMSO-d 6)，δ：148.70，147.91，132.95，131.78，128.25，127.02，121.75，121.11，120.41，117.96，116.05，113.54，112.72，111.99，61.74，57.45，55.50，37.27，25.24，25.07，20.77.IR(KBr)：3588，3438，1518，1290cm -1.MS(EI)：398(M ++2-HCl，40)，396(M +-HCl，100).
Embodiment 99 trans-5-(3, the 4-Dimethoxyphenyl)-7,9-dimethyl-1,2,3,4,4a, 5,6,10c-octahydro cyclopentano [a] pyrido [3,4-b] indole, hydrochloride (4e)
Corresponding tryptamines hydrochloride (3c) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
87％.Mp：＞200℃. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，10.20(broads，1H)，9.20(broads，1H)，7.29(s，1H)，7.20-6.95(m，3H)，6.75(s，1H)，4.90-4.70(broads，1H)，3.78(s，6H)，3.30-2.90(m)，2.48(s，3H)，2.34(s，3H)，2.10-1.70(m，4H)，1.60-1.30(broads，1H). 13C?NMR(DMSO-d 6)，δ：148：73147.90，134.01，129.98，128.31，127.84，125.10，123.82，121.75，120.42，116.03，113.58，111.99，111.21，61.94，57.62，55.52，37.60，25.57，25.17，21.23，20.75，17.07.IR(KBr)：3447，2910，1520
cm -1.MS(EI)：391(M +-Cl，100)，239(35).
Embodiment 100 trans-6-(3, the 4-Dimethoxyphenyl)-10-methyl-, 2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-c] quinoline also, hydrochloride (4f)
Corresponding tryptamines hydrochloride (3d) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
85％.Mp：197-200℃. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，8.90(broads，1H)，7.42(s，1H)，7.28(d，J＝8.3Hz，1H)，7.16(s，1H)，7.05-6.90(m，3H)，4.95-4.80(broads，1H)，3.73(s，6H)，3.66-3.59(m，1H)，3.25-2.80(m，4H)，2.35(s，3H)，2.20-2.10(m，1H)，1.95-1.20(m，6H). 13C?NMR(DMSO-d 6)，δ：148.67147.91，134.92，134.76，129.72，127.85，127.45，125.43，122.91，121.85，119.43，113.59，111.90，111.30，109.45，59.98，55.47，55.40，37.08，36.65，29.48，28.24，24.94，24.41，21.32.IR(KBr)：3439，2936，1516，1464，1453，1265cm -1.MS(EI)：391(M +-Cl，100).
Embodiment 101 trans-8-chloro-6-(3, the 4-Dimethoxyphenyl)-9-methyl-2,3,4,4a, 5,6,7,10c-octahydro-1H-cyclopentano pyrido [2,3-c] quinoline, hydrochloride (4g)
Corresponding tryptamines hydrochloride (3e) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
47％.Mp：＞250℃. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，9.75(broads，1H)，8.90(broads，1H)，7.64(d，J＝7.9Hz，1H)，7.20(d，J＝7.8Hz?1H)，7.15-7.00(m，4H)，4.90-4.80(broads，1H)，3.74(s，6H)，3.70-3.60(m，1H)，3.25-2.85(m，4H)，2.20-2.15(m，1H)，1.95-1.25(m，6H). 13C?NMR(DMSO-d 6)，δ：148.72，148.00，133.46，131.35，128.00，127.08，121.86，121.13，120.28，119.01，115.99，113.41，111.98，111.66，59.62，55.53，55.42，54.98，37.24，36.49，29.23，28.25，24.88，24.34.IR(KBr)：3428，2938，1518，1250?cm -1.MS(EI)：410(M +-HCl，100).
Embodiment 102 trans-6-(3, the 4-Dimethoxyphenyl)-8,10-dimethyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-c] quinoline also, hydrochloride (4h)
Corresponding tryptamines hydrochloride (3f) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
78％.Mp：198-202℃. 1H?NMR(DMSO-d 6)，δ：10.88(s，1H)，9.81(broads，1H)，8.78(broads，1H)，7.24(s，1H)，7.20(s，1H)，7.10-6.90(m，2H)，6.73(s，1H)，4.90-4.75(broads，1H)，3.74(s，6H)，3.25-3.10(m，2H)，3.10-2.80(m，2H)，2.45(s，3H)，2.32(s，3H)，2.20-2.10(m，1H)，2.00-1.80(m，3H)，1.60-1.10(m，3H). 13C?NMR(DMSO-d 6)，δ：148.65147.87，134.44，129.55，128.17，127.59，125.13，123.68，121.90，120.36，117.05，113.64，111.89，110.04，59.89，55.78，55.41，37.17，36.56，29.47，28.21，24.94，24.43，21.26，17.09.IR(KBr)：3450，2936，1516，1493，1264，1240cm -1.MS(EI)：405(M +-Cl，100).
Embodiment 103 trans-7-(3, the 4-Dimethoxyphenyl)-11-methyl isophthalic acid, 2,3,4,5,5a, 6,7,8,12a-decahydro ring heptan is [a] pyrido [3,4-b] indole also, hydrochloride (4i)
Corresponding tryptamines hydrochloride (3g) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
35％.Mp：187-190℃. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，9.66(broads，1H)，7.29-7.25(m，2H)，6.92(d，J＝7.8Hz，1H)，6.81(d，J＝8.2Hz，1H)，6.65-6.56(m，2H)4.80-4.70(broads，1H)，3.66(s，3H)，3.43(s，3H)，3.00-2.90(m，1H)，2.90-2.70(m，1H)，2.35(s，3H)，2.35-2.20(m，1H)，1.80-1.30(m，8H)，0.85-0.65(m，1H). 13C?NMR(DMSO-d 6)，δ：148.56147.96，135.12，128.81，128.05，127.27，125.32，123.09，121.73，118.97，113.32，111.85，111.31，110.51，55.60，55.08，54.97，51.48，36.97，36.24，32.74，31.88，26.37，24.88，24.14，21.30.IR(KBr)：3414，3343，2932，2859，1516，1265?cm -1.MS(EI)：405(M +-Cl，100)，335(20).
Embodiment 104 trans-9-methyl-5-(1-menaphthyl)-1,2,3,4,4a, 5,6,10c-octahydro ring heptan is [a] pyrido [3,4-b] l diindyl also, hydrochloride (4j)
Corresponding tryptamines hydrochloride (3a) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
78％.?Mp：＞200℃. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，10.45(broads，1H)，9.03(broads，1H)，8.46(d，J＝7.9?Hz，1H)，8.12-7.90(m，3H)，7.70-7.40(m，3H)，7.40-7.25(m，2H)，6.96(d，J＝8.0Hz，1H)，5.15-4.90(broads，1H)，4.45-4.30(m，1H)，3.65-3.50(m)，3.15-2.95(m，1H)，2.38(s，3H)，2.00-1.70(m，4H)，1.60-1.35(broads，1H). 13C?NMR(DMSO-d 6)，δ：134.59，133.86，131.63，131.32，129.92，129.18，128.86，128.07，127.74，126.38，125.96，125.83，125.48，124.08，123.20，118.52，111.31，110.97，61.78，55.76，37.40，35.13，25.49，25.12，21.32，20.67.IR(KBr)：3445，3231，2949，2878，2780，793cm -1.MS(EI)：367(M +-C1，100).
Embodiment 105 anti-form-1 0-methyl-6-(1-menaphthyl)-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-c] quinoline also, hydrochloride (4k)
Corresponding tryptamines hydrochloride (3d) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
80％.Mp：＞200℃. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，8.40(d，J＝7.8Hz，1H)，8.01(d，J＝7.5Hz，1H)，7.92(d，J＝8，2Hz，1H)，7.74(d，J＝6.8Hz，1H)，7.70-7.40(m，4H)，7.35(d，J＝8.4Hz，1H)，6.97(d，J＝8.2Hz，1H)，5.15-4.90(broads，1H)，4.50-4.30(m，1H)，3.50-3.10(m，2H)，3.10-2.82(m，2H)，2.38(s，3H)，2.10-1.20(m，7H). 13C?NMR(DMSO-d 6)，δ：135.05，134.90，133.85，131.79，131.28，129.36，128.93，128.07，127.56，126.33，125.94，125.83，125.41，124.02，123.10，119.54，111.27，109.61，59.72，53.97，36.73，35.27，29.47，28.37，24.92，24.36，21.34.IR(KBr)：3447，3235，2936，2857，1450，790cm -1.MS(EI)：381(M +-Cl，100).
Embodiment 106 is trans-8,10-dimethyl-6-(1-menaphthyl)-2,3,4, and 4a, 5,6,7,11c-octahydro-1H-indole is [2,3-c] quinoline also, hydrochloride (4l)
Corresponding tryptamines hydrochloride (3f) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
77％.Mp：＞200℃. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，10.11??(broads，1H)，8.52(d，J＝8.2Hz，1H)，8.35(broads，1H)，8.02(d，J＝7.3Hz，1H)，??7.92(d，J＝7.9Hz，1H)，7.82(d，J＝6.9Hz，1H)，7.71-7.46(m，3H)，7.29(s，1H)，6.78??(s，1H)，5.10-4.90(broads，1H)，4.70-4.50(m，1H)，3.40-3.20(m，2H)，3.10-2.80(m，??2H)，2.51(s，3H)，2.34(s，3H)，2.05-1.90(m，1H)，1.80-1.70(m，2H)，1.60-1.20(m，??4H). 13C?NMR(DMSO-d 6)，δ：134.57，133.87，131.95，131.42，129.29，129.11，128.81，??128.04，127.71，126.21，125.91，125.83，125.14，124.46，123.91，120.46，117.14，110.25，??59.65，54.03，36.66，35.25，29.47，28.32，24.94，24.35，21.26，17.30.IR(KBr)：3449，??2934，2859，2791，1449，779cm -1.MS(EI)：395(M +-Cl，100).
Embodiment 107 trans-spiral shells-6,6-[2-(3, the 4-dimethoxy)-1,2,3,4-tetralyl]-10-methyl-2,3,4,4a, 5,6,7,11a-octahydro-1H-indole is [2,3-c] chinidine also, hydrochloride (4m)
Corresponding tryptamines hydrochloride (3a) (1mmol) was refluxed 72 hours in Ar atmosphere with the corresponding 4-alkylidene-2-Jia oxazolin-suspension of 5-ketone (1.2mmol) in 1N hydrochloric acid (3ml), after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).The epimer mixture, productive rate:
89％. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，??10.12(broads，1H)，8.72(broads，1H)，7.42(s，1H)，7.21(s，1H)，6.90-6.60(s，3H)，??3.75(s，3H)，3.71(s，3H)，3.30-2.80(m，5H)，2.35(s，3H)，2.00-1.20(m，6H). 13C??NMR(DMSO-d 6)，δ：147.44，134.84，134.32，133.98，127.42，126.53，126.35，125.25，??125.13，123.60，123.25，122.98，119.56，119.43，112.05，111.48，111.27，108.78，108.60，??57.83，57.50，56.07，55.56，36.40，31.91，30.74，29.39，29.21，28.73，28.41，24.92，24.38，??23.83，21.30.IR(KBr)：3440，2950，1518，1200，1110，cm -1.MS(EI)：417(M +-Cl，??100).
Embodiment 108 anti-form-1s-(3, the 4-Dimethoxyphenyl)-3,4,6-trimethyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole, hydrochloride (4n)
Basically the method by embodiment 90 prepares trans-3-(2-amino-1,2-dimethyl ethyl)-5-methylindole, hydrochloride (3h), and still, aziridine is 2c.Productive rate:
71%. 1H NMR (CD 3OD), δ: 7,45 (s, 1H), 7.32 (d, J=8.3Hz, 1H), 7.19 (s, 1H), 7.00 (dd, J=8.4 and 1.5Hz, 1H), 3.66 (t, J=6.9Hz, 1H), 3.28 (t, J=7.3Hz, 1H), 2.47 (s, 3H), 1.48 (d, J=7.2Hz, 3H), 1.38 (d, J=6.6Hz, 3H). 13C NMR (CD 3OD), δ: 136.89,129.19,127.68,124.46,123.69,119.09,115.41,112.44,53.51,36.62,21.71,17.06,16.49. make corresponding tryptamines hydrochloride (3h) (1mmol) with corresponding 6,7-dimethoxy-1,2,3,4-naphthane-the suspension of 2-ketone (1.2mmol) in 1N hydrochloric acid (3ml) refluxed 72 hours in Ar atmosphere, after this, make reactant mixture reach room temperature, leach, rough solid purification by flash chromatography is an eluent with methylene chloride (9: 1).Productive rate:
32％.Mp：195-199℃. 1H?NMR(DMSO-d 6)，δ：＞11.0(s，1H)，9.40(broads，1H)，8.90(broads，1H)，7.40(s，1H)，7.30(d，J＝8.2Hz，1H)，7.08(s，1H)，6.96-6.90(m，3H)，4.90-4.80(broads，1H)，3.73(s，3H)，3.72(s，3H)，3.70-3.60(m，2H)，3.20-3.00(m，3H)，2.37(s，3H)，1.46(broads，3H)，1.40(broads，3H). 13CNMR(DMSO-d 6)，δ：148.66147.93，135.00，129.21，127.40，125.40，122.97，121.82，119.07，113.56，111.95，111.24，110.34，57.32，55.43，55.33，54.60，36.46，32.56，21.24，17.06，15.92.IR(KBr)：3438，2936，1518，1464，1265，1242，1040cm -1.MS(EI)：365(M +-Cl，100).
Embodiment 109 cis-3-(2-amino-cyclohexyl)-5-methylindole, hydrochloride cis-6-(3, the 4-Dimethoxyphenyl)-10-methyl-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-c] quinoline also, hydrochloride (4o)
Press Scmuszkovicz, J. etc., Tetrahedron, the method for describing in 1991,47,8653 begins to prepare title compound (3i) by 5-methylindole (1a).Mp：86-90℃. 1H?NMR(CD 3OD)，δ：7，38(s，1H)，7.26(d，J＝8.3Hz，1H)，7.11(s，1H)，6.96(d，J＝8.2，1H)，3.90-3.70(m，1H)，3.55-3.38(m，1H)，2.42(s，3H)，2.40-2.35(m，1H)，2.10-1.79(m，4H)，1.75-1.50(m，3H). 13C?NMR(CD 3OD)，δ：136.75，129.27，127.88，124.63，123.51，118.71，114.49，112.34，52.60，36.79，29.52，26.44，25.85，21.68，21.00.IR(KBr)：3401，3017，2932，2863，1561，1489cm -1.MS(EI)：229(M +-Cl，100).
Following formula has illustrated the preparation method of end product (4o):
Figure A9519302901411
Mp:167-171 ℃. 1H NMR (DMSO-d 6), δ:＞11.0 (s, 1H), 8.87 (broads, 2H), and 7.29-7.20 (m, 3H), 7.12-6.85 (m, 3H), and 4.95-4.80 (broads, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.70-3.60 (m), 3.25-3.00 (m, 1H), 2.36 (s, 3H), 2.40-2.00 (m), 1.95-1.20 (m, 6H). 13CNMR (DMSO-d 6), δ: 148.67147.87,134.80,128.71,128.43,127.63,125.45,123.32,121.75,117.82,113.59,111.91,111.30,111.34,56.99,55.46,55.12,36.12,36.65,28.42,27.49,24.94,24.39,21.23,19.17.IR (KBr): 3439,2934,1516,1263cm -1.MS (EI): 390 (M +-ClH, 100).
As mentioned above, The compounds of this invention is useful on blocking 5-hydroxytryptamine or other 5-HT 2A, 5-HT 2BAnd/or 5-HT 1CThe effect of receptor stimulating agent.Therefore, the present invention also provides 5-HT in the blocking-up mammal 2A, 5-HT 2BOr 5-HT 1CThe method of receptor comprises to needs and blocks 5-HT respectively 2A, 5-HT 2BOr 5-HT 1CThe The compounds of this invention of the administration blocking-up receptor dosage of receptor.
A concrete application implementation scheme of the present invention provides 5-HT 2BThe selective coordination body of receptor.To 5-HT 2BReceptor has the chemical compound of high-affinity usually to 5-HT 1CReceptor also has the activity of intersection.Now, 5-HT 2BReceptor can with above determine to 5-HT 2BReceptor stimulating agent has the The compounds of this invention of the amount of application of blocking effect optionally to regulate.Optionally affinity can make treatment that less side effect and the therapeutic agent that can help supervene are arranged.
To 5-HT 2BReceptor demonstrates active chemical compound and can be used for treatment and 5-HT 2BThe adjusting diseases associated of receptor.For example, has 5-HT 2BThe chemical compound of antagonistic activity can be alleviated the spasm of colon.Therefore, these chemical compounds can be used for treating intestinal dysfunction comprise irritable bowel trace integration disease with the relevant syndrome of irritable bowel trace integration disease.The spasmolytic effect of these chemical compounds can be alleviated the abdominal pain relevant with intestinal dysfunction.In addition, 5-HT 2BReceptor also is positioned other organ such as brain, bladder, blood vessel, harmonization of the stomach uterus, and additional conditions are 5-HT 2BBe vehicular 5-HT 2B
To 5-HT 2AReceptor demonstrates active chemical compound and can be used for treatment and prevention and 5-HT 2AThe adjusting diseases associated of receptor.The example of these diseases comprises hypertension, sleep disorder, causes unreal activity, psychosis, anxiety, depression, thermoregulation, apositia and hypotension.Leonard, B.E., international clinical psychopharmacology (International ClinicalPsychopharmacology), 7,13-21 (1992).
Term " receptor blocking dosage " is meant that blocking-up is selected from 5-HT in mammal 2A, 5-HT 2BAnd 5-HT 1CThe amount of the required chemical compound of target receptor.Reactive compound is effective in very wide dosage range.For example, the dosage of every day can be about 0.05 to the scope of about 250mg/kg body weight usually.With one or many dosage treatment adult disease the time, preferably about 0.5 to the scope of about 100mg/kg body weight, about 5 to about 60mg/kg body weight and about 10 to about 50mg/kg body weight be particularly preferred.But; obviously; the actual dosage of chemical compound be by the doctor comprise according to relevant condition needs treatments disease, selection give drug compound, age, body weight and the reaction of individual patient, the order of severity of patient symptom; and the route of administration of selecting decides, so the protection domain that above-mentioned dosage range does not limit the present invention in any way.Chemical compound is can various approach for example oral, percutaneous, subcutaneous, intranasal, intramuscular and intravenous administration.
The compounds of this invention can be not the directly administration with the form of any preparation, but preferably use with the form of the pharmaceutical preparation that contains pharmaceutically acceptable excipient and at least a The compounds of this invention.It is about 0.1 to about 90.0% The compounds of this invention that this compositions contains weight ratio.As mentioned above, the present invention also provides the pharmaceutical preparation that contains The compounds of this invention and pharmaceutically acceptable excipient.
In the preparation of the present composition, normally make active component and can be that the excipient of carrier or diluent is mixed together, or with the carrier dilution, or to pack into can be in capsule, medicine bag, paper or other container.When carrier used as diluent, it can be solid, semisolid or its effect fluent material as carrier, excipient or active component medium.Therefore, the form of compositions can be tablet, pill, powder, lozenge, medicine bag, cachet, elixir, emulsion, solution, syrup, suspension, aerosol (as solid or in liquid medium), and soft or hard gelatin capsule.
If desired, The compounds of this invention can be carried by percutaneous.Transdermal penetration reinforcing agent and delivery system are that skilled technician is known, and above-mentioned reinforcing agent and system can comprise plaster and analog thereof.
The example of appropriate carriers, excipient and diluent comprises lactose, glucose, sucrose, Sorbitol, mannitol, starch, acacin, calcium phosphate, alginate esters, calcium silicates, microcrystalline Cellulose, polyvinylpyrrolidone, cellulose, Tragacanth, gelatin, syrup, methylcellulose, methyl-and propyl hydroxy-benzoate, Talcum, magnesium stearate, water, and mineral oil.Preparation can also comprise wetting agent, emulsifying agent, suspending agent, antistaling agent, sweeting agent or flavouring agent.Use methods known in the art, preparation of the present invention can be formed in the dosage form to rapid release, slow release or delayed release of active elements after patient's medication.
Chemical compound of the present invention can discharge with percutaneous delivery system and excipient percutaneous.Most preferably The compounds of this invention mixes with penetration enhancers, mixes plaster and similar delivery system, and described penetration enhancers includes but not limited to propylene glycol, Polyethylene Glycol, monolaurate and azacycloalkyl-2-ketone.Percutaneous preparation can add other excipient that comprises gellant, emulsifying agent and buffering solution if desired.
To oral administration, it is desirable to The compounds of this invention and carrier and mixing diluents and the be shaped tablet or the gelatine capsule of packing into.
Preferably compositions is made unit dosage form, every dosage contains about 1 to about 500mg, more usually about active component of 5 to about 300mg.Term " unit dosage form " is meant the physiological individual to the suitable single dosage of people and other mammiferous experimenter, each unit contains the active substance with the suitable bonded scheduled volume of pharmaceutical carrier, and this scheduled volume is the amount that can produce required therapeutical effect through calculating.
Reactive compound is effective in very wide dosage range.For example, the dosage of every day can be about 0.05 to the scope of about 250mg/kg body weight usually.With one or many dosage treatment adult disease the time, preferably about 0.5 to the scope of about 100mg/kg body weight, about 5 to about 60mg/kg body weight and about 10 to about 50mg/kg body weight be particularly preferred.But; obviously; the actual dosage of chemical compound be by the doctor comprise according to relevant condition needs treatments disease, selection give drug compound, age, body weight and the reaction of individual patient, the order of severity of patient symptom; and the route of administration of selecting decides, so the protection domain that above-mentioned dosage range does not limit the present invention in any way.Chemical compound is can various approach for example oral, percutaneous, subcutaneous, intranasal, intramuscular, rectum and intravenous administration.
Most preferably reactive compound is become with the The compounds of this invention of unit dosage form or the pharmaceutical composition of its salt or its solvate with the pharmaceutical carrier preparation.Some examples of unit dosage form are the solution of the parenteral of tablet, pill, powder, moisture or water-free oral solvent and suspending agent, the device and the plaster of percutaneous conveying and the container of packing into, contain one or more dosage units in this container and can be divided into single dosage again.Suitable pharmaceutical carrier and/or diluent comprise gelatine capsule, comprise the sugar of lactose and sucrose, as the starch of corn starch and potato starch, as sodium carboxymethyl cellulose, ethyl cellulose, the cellulose derivative of methylcellulose and cellulose ethanoate phthalic acid ester, gelatin, Talcum, stearic acid, magnesium stearate is as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum sesami, olive oil, the vegetable oil of Semen Maydis oil and cupu oil, propylene glycol, glycerol, Sorbitol, Polyethylene Glycol, water, agar, alginic acid, isotonic saline solution, phosphate buffer solution, lactic acid, glycolic, microcrystalline Cellulose, Kaolin, mannitol, dicalcium phosphate, sodium chloride, magnesium stearate, cross-linked carboxymethyl cellulose, alginic acid, primojel, lauryl sulfate, and other material that can be compatible in pharmaceutical preparation.With biodegradable polymer or other known method reactive compound is made microgranule.The compositions that compositions can be made quick dissolving, slowly discharge or target is carried with known preparation technique.Compositions of the present invention can contain other component, for example coloring agent, flavouring agent and/or antistaling agent.Compositions can also contain other therapeutic agent, for example antacid or analgesic.
The finished product of making comprises packaging material.Preferred packaging material preferably include container.Select preferred container and packaging material to select with bonded characteristic.For example, preferred container can be glass, plastics, paper tinsel, envelope blister package, transparent wrapper, amber packing, and can combine with other known drug packing technique.Can also comprise as Cotton Gossypii silica gel or other desiccant and/or metering device in the packing.The finished product of making comprises label, is to be used for the treatment of and 5-HT in order to the explanation compositions 2BReceptor for stimulating imbalance diseases associated, most preferred disease is selected from urinary incontinence, bladder function is bad, uterine function is bad, cardiovascular disease and respiratory disorder.
For enforcement of the present invention is described more fully, the example of formulations below providing.These embodiment only illustrate and do not limit protection scope of the present invention.Can use arbitrary chemical compound of the present invention as reactive compound in the preparation.
Preparation 1
Prepare hard gelatin capsule with following component:
Each capsule concentration
In amount wt% (+/-) 6-ethyl-8-chloro-1-[(3,4-dimethoxy benzene ylmethyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing 250mg 55.0 dry starch 200mg 43.0 magnesium stearate 10mg 2.0
460mg????????100.0
Said components mixed and with the amount of the 460mg hard gelatin capsule of packing into.
Preparation 2
The capsule that each capsule contains the 20mg medicine is prepared as follows:
Each capsule concentration
Amount wt%6-methyl-8--ethyl-1-[(3-bromo-4-chloro-phenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt 20mg 10.0 starch 89mg 44.5 microcrystalline Cellulose 89mg 44.5 magnesium stearate 2mg 1.0
200mg????????100.0
Active component, cellulose, starch and magnesium stearate are mixed, by the No.45 U.S. sieve and the hard gelatin capsule of packing into.
Preparation 3
The capsule that each capsule contains the 100mg medicine is prepared as follows:
Each capsule concentration
Amount wt%5-fluoro-6-methyl isophthalic acid-[1-(3-methylamino phenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt 100mg 30.0 Tween-81 50mg 0.02 starch powder 250mg 69.8
400mg???????100.0
With the said components gelatine capsule that thoroughly mixes and pack into.
Preparation 4
Every preparation tablets that contains the 100mg active component is as follows:
Every amount concentration
Wt%6-fluoro-8-phenoxy group-1-[1-(4-ethoxyl phenenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt 0mg 10.0 starch 5mg, 45.0 microcrystalline Cellulose 5mg, 35.0 polyvinylpyrrolidones (10% aqueous solution) 4mg 4.0 carboxymethyl starch sodium 4.5mg 4.5 magnesium stearate 0.5mg 0.5 Talcum 1mg 1.0
100mg???????100.0
U.S. No.45 sieve and abundant mixing that active component, starch and cellulose pass through, the powder mixes that makes polyvinylpyrrolidonesolution solution and obtain then by U.S. No.14 sieve, is also sieved the granule that so obtains 50-60 ℃ of drying by U.S. No.18.Carboxymethyl cellulose, magnesium stearate and Talcum are added in the granule by U.S. No.60 sieve in advance, after the mixing granule is pressed into the tablet of heavy 100mg on tablet machine.
Preparation 5
It is as follows to prepare tablet with following compositions:
Every amount concentration
Wt%5,6-two fluoro-1-[(1, the 3-dimethylamino phenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-succinate 250mg 38.0 microcrystalline Cellulose 400mg 60.0 fumed silica 10mg 1.5 stearic acid 5mg 0.5
665mg?????????100.0
The tablet that each component is mixed and is pressed into heavy 665mg.
Preparation 6
The suspension preparation that every 5ml dosage contains the 5mg medicine is as follows:
Every 5ml's
Suspension 3-methyl-5-chloro-6-methyl isophthalic acid-[(1, the 3-dimethylamino phenyl) methyl]-1,2,3, an amount of (q.v.) water of an amount of (q.v.) coloring agent of 4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt 5mg sodium carboxymethyl cellulose 50mg syrup 1.25ml benzoic acid solution 0.10ml flavouring agent adds to 5ml
The U.S. No.45 sieve that medicine is passed through also mixes to form uniformly with sodium carboxymethyl cellulose and syrup and sticks with paste, and with a part of water dilution and under agitation add in the paste, the water of adding capacity makes it the volume that reaches required with benzoic acid solution, flavouring agent and coloring agent.
Preparation 7
Preparation contains the aerosol of following compositions:
Concentration
Wt%5-propyl group-6-ethyl-1-[(3, the 4-Dimethoxyphenyl) methyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole hydrochloride thing 0.25 ethanol 29.75 propellants 22 (F-22) 70.00
100.00
Reactive compound is mixed with ethanol, the mixture that obtains adds a part of propellant 22, is cooled to-30 ℃ and be transferred in the filling device, then the required amount rustless steel container of packing into, propellant with surplus further dilutes, and then loads onto valve unit on container.
Preparation 8
Being prepared as follows of injection:
Every crowd amount 6-(1-Methylethyl)-1,2,3,4-tetrahydrochysene-1-[1-(4-dimethylamino naphthyl) methyl]-Devazepide is an amount of for 9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt 50mg injection
Chemical compound or its suitable salt are dissolved in for example ethanol,, filter back solution five equilibrium pack into ampoule or phial by 2 microns filter.
Preparation 9
Every preparation tablets that contains the 10mg active component is as follows:
Every amount concentration
Wt%7,8,9,10-tetrahydrochysene-10-[1-(2-methylamino naphthyl) methyl]-11H-benzo [g] pyrido [3,4-b] indole (Z)-2-butylene diacid salt 6g 2.0 corn starch 200g 78.0 microcrystalline Cellulose 46g 18.0Sterotex Powder HM 4g 1.5 pure water 300ml
100mg????100.0
Active component, starch and cellulose lumped together in planetary-type mixer and mixed 2 minutes, in compositions, add water and mixed 1 minute, the mixture that obtains is dispersed in that dish is gone up and in 50 ℃ of hot-airs drying till humidity is 1% to 2%.Then, dried mixture is ground in the Fitz grinding machine, by the #RH2B sieve, is added back in the mixture of grinding again.With mixture rolling 5 minutes, with suitably punch die compacting 50mg, the 150mg of size and the tablet of 200mg.
Preparation 10
Prepare capsule with following component:
Each capsule concentration
Amount weight wt% (+/-) 6-methyl isophthalic acid-[1-(3-ethylamino naphthyl)-1-ethyl]-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole (Z)-2-butylene diacid salt 200mg 49.0 lactose USP 200mg 49.0Sterotex Powder 10mg 2.0
410mg????100.0
Said components mixed and with the amount of the 410mg hard gelatin capsule of packing into.
Preparation 11
Prepare hard gelatin capsule with following component:
Each capsule concentration
Amount weight wt% trans-9-methyl-5-(1-naphthyl methyl)-1,2,3,4,4a, 5,6,10c-octahydro-Pentamethylene. is [a] pyrido [3,4-b] indole also, hydrochloride 250mg 55.0 dry starch 200mg 43.0 magnesium stearate 10mg 2.0
460mg?????100.0
Said components mixed and with the amount of the 460mg hard gelatin capsule of packing into.
Preparation 12
Preparing each capsule, to contain the capsule of 20mg medicine as follows:
Each capsule concentration
Amount weight wt% spiral shell-6-[2-(3, the 5-dimethoxy)-1,2,3, the 4-tetralyl]-1,2,3,4,4a, 5,6,10c-octahydro-1H-indole is [2,3-c] quinuclidine also, hydrochloride 20mg 10.0 starch 89mg 44.5 microcrystalline Cellulose 89mg 44.5 magnesium stearate 2mg 1.0
200mg??????100.0
Active component, cellulose, starch and magnesium stearate are mixed, by the U.S. No.45 sieve and the hard gelatin capsule of packing into.
Preparation 13
Preparing each capsule, to contain the capsule of 100mg medicine as follows:
Each capsule concentration
Amount weight wt% spiral shell-6-[2-(3-fluoro-4-methoxyl group)-1,2,3, the 4-tetralyl]-1,2,3,4,4a, 5,6,11a-octahydro-1H-indole also [2,3-c] quinine, hydrochloride 100mg 30.0 Tween-81 50mg 0.02 starch powder 250mg 69.98
350mg???100.0
Empty gelatine capsule fully mixes mentioned component and packs into.
Preparation 14
Every preparation tablets that contains the 10mg active component is as follows:
Every amount concentration
Wt%8-fluoro-10-phenoxy group-6-(1 naphthyl methyl)-1,2,3,4,4a, 5,6,7,11c-octahydro-1H-indole also [2,3-c] quinoline, tartrate 10mg 10.0 starch 45mg, 45.0 microcrystalline Cellulose 35mg, 35.0 polyvinylpyrrolidones (10% aqueous solution) 4mg 4.0 carboxymethyl starch sodium 4.5mg 4.5 magnesium stearate 0.5mg 0.5 Talcum 1mg 1.0
100mg??????100.0
Active component, starch and cellulose by U.S. No.45 sieve and abundant mixing, are made polyvinylpyrrolidonesolution solution and the powder mixes that obtains,, the granule that so obtains is also passed through U.S. No.18 sieve 50-60 ℃ of drying then by U.S. No.14 sieve.Carboxymethyl cellulose, magnesium stearate and Talcum in advance by U.S. No.60 sieve, are pressed into granule the tablet of heavy 100mg on tablet machine after the mixing.
Preparation 15
It is as follows to prepare tablet with following compositions:
Every amount concentration
Wt%8-methyl isophthalic acid 0-methoxyl group-6-(1-naphthyl ethyl)-2,3,4,4a, 5,6,7,11c-octahydro-1H-indole is [2,3-c] quinoline 250mg 38.0 microcrystalline Cellulose 400mg 60.0 fumed silica 10mg 1.5 stearic acid 5mg 0.5 also
665mg???100.0
The tablet that each component is mixed and is pressed into heavy 665mg.
Preparation 16
The suspension preparation that every 5ml dosage contains the 5mg medicine is as follows:
Every 5ml
Suspension 8-chloro-10-cyclopropyl-6-(1-naphthyl ethyl)-2,3,4,4a, 5,6,7,11c,-octahydro-1H-indole also an amount of (q.v.) water of an amount of (q.v.) coloring agent of [2,3-c] quinoline 5mg sodium carboxymethyl cellulose 50mg syrup 1.25ml benzoic acid solution 0.10ml flavouring agent adds to 5ml
The U.S. No.45 sieve that medicine is passed through also mixes to form uniformly with sodium carboxymethyl cellulose and syrup and sticks with paste, and with a part of water dilution and under agitation add in the paste, the water of adding capacity makes it the volume that reaches required with benzoic acid solution, flavouring agent and coloring agent.
Preparation 17
Preparation contains the aerosol of following compositions:
Concentration
Wt% spiral shell-6-[2-(3-ethyl-4-ethyoxyl)-1,2,3, the 4-tetralyl]-10-methyl-2,3,4,4a, 5,6,7,11a-octahydro-1H-indole also [2,3-c] quinuclidine, maleate 0.25 ethanol 29.75 propellants 22 (F-22) 70.00
100.00
Reactive compound is mixed with ethanol, the mixture that obtains adds a part of propellant 22, is cooled to-30 ℃ and be transferred in the filling device, then the required amount rustless steel container of packing into, propellant with surplus further dilutes, and then loads onto valve unit on container.
Preparation 18
It is as follows to prepare tablet with following compositions:
Every amount concentration
Wt% spiral shell-6-[2-(3-ethyl-4-ethyoxyl)-1,2,3,4-tetrahydrochysene-6-methyl-naphthyl]-10-methyl-2,3,4,4a, 5,6,7,11a-octahydro-1H-indole also [2,3-c] quinine, maleate 250mg 38.0 microcrystalline Cellulose 400mg 60.0 fumed silica 10mg 1.5 stearic acid 5mg 0.5
665mg????100.0
The tablet that each component is mixed and is pressed into heavy 665mg.
Carry out The compounds of this invention to 5-HT with following method 1cThe test of receptor affinity.IA. the preparation of biological reagent
Take out Medulla Bovis seu Bubali after the massacre at once, in ice, separate the choroid plexus (chroid plexus) that cuts.The male Sprague-Dawley rat (Harlan Industries, Cumberland IN) of body weight 125-150g is beheaded and killed, take out each brain immediately, in ice, separate and cut cerebral cortex (cerebralcortex).This tissue of homogenize in the 0.32mol/L of 9 times of volumes sucrose, with the speed of 1,000 * g centrifugal 10 minutes, supernatant centrifugal 20 minutes with the speed of 17,000 * g.Particulate matter is suspended in the 50mM Tris-HCl (pH7.4) of 100 times of volumes,, with 50,000 * g centrifugal 10 minutes, said method is repeated 3 times 37 ℃ of hatchings 10 minutes.Last particulate matter-70 ℃ freezing, and in 2 weeks, use, make particulate matter rehydration with normal saline buffer solution before the use.II. test method
Carry out 5-HT by the method for having described 1cAnd 5-HT 2The radiation coordination of receptor is in conjunction with test.Test can be undertaken by following document is described: Hoyer D, serotonin 5-HT 1The functional relationship of recognition site, receptor research magazine (J.Receptor Res), 8,59-81 (1988) and HoyerD, Engel G, 5-HT in rat and the Medulla sus domestica film 1And 5-HT 2The KalkmanHO molecular pharmacology of recognition site: with [ 3H] 5-HT, [ 3H] 8-OH-DPAT, (-) [ 125I] iodocyanopindolol, [ 3H] mesulergineand[ 3H] radioligand that carries out of ketanserin is in conjunction with research, European pharmacology's magazine (Eur.J.Pharmacol.118), 13-23 (1985).
In order to carry out 5-HT 1cThe test of receptor, under the room temperature in polystyrene tube the 50nM Tris-HCl buffer solution of the test compound that progressively strengthens concentration, pH7.4 and tritium-labeled mesulergine (2.0nM) ( 3The H ligand) merge, the choroid plexus tissue that adds resuspending makes the reaction beginning, and this choroid plexus is organized in 37 ℃ of pre-cultivations 20 minutes.Reactant mixture was cultivated 15 minutes in 37 ℃ of water-baths.
Filter (Brandel CellHarvestor) fast with Whatman GF/B glass filter, this filter is preliminary wetting in the Tris of pH7.4 buffer solution.This filter is with the Tris buffer solution washing of the ice-cold pH7.4 of 5ml 2 times then, and the filter after the washing is put into the container of scintillation counter, adding 10ml Redysolv, and (Brandel), sample is counted in Searle D-300-β enumerator.Mean error and standard deviation with the value counting statistics of following three test determinations of certain condition.The meansigma methods that obtains three times or repeatedly measure respectively.Reactant mixture is 15 minutes at 37 ℃ incubation time.
Obtain radiating coordination in conjunction with suppressing to reach 50% o'clock concentration (IC with computer auxiliary regression analysis 50) and the Hill coefficient.The radiation coordination is in conjunction with research:
By transformant system film.Centrifugally under the speed of 4 ℃ and 2200 * g obtain representing vegetative rat 5-HT 2BThe cell suspending liquid of receptor.Kursar J.D., D.L.Nelson, D.B.Wainscott, M.L.Cohen, and M.Baez, Mol.Pharmacol., 42:549-557 (1992).At 50mM Tris-HCl, pH7.4 (0.5 * 10 particulate matter 9Cell/30ml) middle vortex stirs the film that preparation is used for the combination test.Then with this suspensions of tissues in centrifugal 10 minutes of the speed of 39,800 * g (under 4 ℃).The method has repeated washing altogether three times, is cultivating 10 minutes in 37 ℃ between the washing for the first time and for the second time.Last particulate matter is at 67ml Tris-HCl, and (initial cell number is 20-40 and 1200.5 ten thousand cells/ml to pH7.4, represents 5-HT low and relative higher level respectively 2BRecipient cell) (Tekmar Cincinnati, OH) homogenize is 15 seconds, places 65 with tissue mashing machine (Tissumizer) in.
[ 3H] 5-HT is in conjunction with research.(Beckman Instruments, Fullerton CA) carry out the combination test automatically, and test is with cumulative volume 0.8ml triplicate with Biomek 1000.Contain [ 3H] 5-HT, pargyline, CaCl 2With 400 μ l pH of L-ascorbic acid be the water diluent that adds film suspension 200 μ l (0.04-0.27mg protein) and 200 μ l medicines among 7.4 the 67mM Tris-HCl, pargyline, CaCl 2Be respectively 10 μ M, 3mM and 0.1% with the final concentration of L-ascorbic acid.Test tube is cultivated 2 hours (confirming all to reach under these conditions bonded balance) 37 ℃ of cultivations 15 minutes or at 0 ℃, use Brandel Cell Harvestor (Model MB-48R then; Brandel; Gaithersburg, MD) filter fast by Whatman GF/B filter, this filter preliminary wetting and with pre-cooling among the Tris-HCl of ice-cold pH7.4 in 0.5% polymine, this filter is 7.4 50mM Tris-HCl washing 4 times fast with the ice-cold pH of 1ml then.With liquid scintillation meter (Ready Protein) measure capture on the filter [ 3H] amount of 5-HT, and with Biomek1000 (Beckman Instruments, Fullerton CA) carry out the combination test automatically, and test is with cumulative volume 0.8ml triplicate.Contain [ 3H] 5-HT, pargyline, CaCl 2With 400 μ l pH of L-ascorbic acid be the water diluent that adds film suspension 200 μ l (0.04-0.27mg protein) and 200 μ l medicines among 7.4 the 67mM Tris-HCl, pargyline, CaCl 2Be respectively 10 μ m, 3mM and 0.1% with the final concentration of L-ascorbic acid.Test tube is cultivated 2 hours (confirming all to reach under these conditions bonded balance) 37 ℃ of cultivations 15 minutes or at 0 ℃, use Brandel Cell Harvestor (Model MB-48R then; Brandel; Gaithersburg, MD) filter fast by Whatman GF/B filter, this filter preliminary wetting and with pre-cooling among the Tris-HCl of ice-cold pH7.4 in 0.5% polymine, this filter is 7.4 50mM Tris-HCl washing 4 times fast with the ice-cold pH of 1ml then.With liquid scintillation meter (Ready Protein and Beckman) measure capture on the filter [ 3H] amount of 5-HT, and with the best combination of the combination model of position of part F-test determination or two positions.De Lean, A., A.A.Hancock, and R.J.Lefkowitz, Mol.Pharmacol.21:5-16 (1981).Following formula is used for the combination model of a position: Bound = B max × [ L ] K d + [ L ]
Wherein the bound=specificity bonded [ 3H] amount of 5-HT, B MaxThe maximum number of=binding site, K d=balance dissociation constant, and [L]=free [ 3H] concentration of 5-HT, perhaps two position combination models: Bound = B max 1 × [ L ] K d 1 + [ L ] + B max 2 × [ L ] K d 2 + [ L ]
Wherein the bound=specificity bonded [ 3H] amount of 5-HT, B Max1The maximum number of=high-affinity binding site, B Max2The maximum number of=low-affinity binding site, K D1=high-affinity position balance dissociation constant, K D2=low-affinity binding site equilibrium dissociation constant, and [L]=free [ 3H] concentration of 5-HT.Measured the 1C that obtains by competition experiments by the nonlinear regression analysis of four parameter mathematical formulaes 50Value, IP 3The incorporating parametric of standard curve and by IP 3The EC that test obtains 50And E MaxValue (Systet, SvstetInt, Evanston, IL) Delean, A., A.A.Hancock, and R.J.Lefkowitz, molecular pharmacology (Mol.Pharmacol.), 21:5-16 (1981).Cheng, Y., and W.H.Prusoff, biochemical pharmacology (Biochem.Pharmacol.), 22:3099-3108 (1973).
Test described basic skills and test chemical compound of the present invention with above radiating coordination, and be incorporated into Table I.Value in the Table I is with the K of calculating as indicated above iExpression, the blank value of Table I is meant that this chemical compound does not carry out corresponding test.
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=6.62SEM=0.09 N=4
Figure A9519302901562
AVG.=6.28SEM=0.91 N=4
Figure A9519302901563
AVG.=12.20SEM=1.54 N=3
Figure A9519302901564
AVG.=6.87SEM=0.55 N=3
Table 1
5-HT 2BCell 5-HT 2A
[ 3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=18.98=0.90=5.12SEM=7.56=0.32=1.21 N=6=5=5
Figure A9519302901572
AVG.=15.11=15.09=2.05SEM=2.43=2.26=0.29 N=6=5=5
Figure A9519302901573
AVG.=24.49SEM=? N=2 AVG.=35.13SEM=? N=1
Table 1
5-HT 2BCell 5-HTX
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iHuman K iRat structure 5-HT 2B5-HTX 2B5-HT 2A5-HT 2A
Figure A9519302901581
AVG.=15.53SEM=? N=1 215403 transisomer LAVG.=10.24=74.49=8.91SEM=5.05=6.34=0.64 N=4=3=3 215047 isomer LAVG.=11.36=107.74=12.44SEM=4.21=16.32=2.29 N=4=3=3 215046 isomer UAVG.=8.61=15.80=2.39SEM=4.21=3.03=0.26 N=4=3=3
Table 1
5HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901591
215404 transisomer UAVG.=9.35=18.60=2.44SEM=4.36=2.42=0.35 N=4=3=3
Figure A9519302901592
AVG.=1=32.71SEM=1.93=0.84 N=2=2
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOT
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=4115.29SEM=311.55 N=3
Figure A9519302901602
AVG.=5153.15SEM=? N=1
Figure A9519302901603
AVG.=3019.67SEM=? N=1
Figure A9519302901604
AVG.=1501.95SEM=? N=1
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901611
AVG.=862.41SEM=? N=1 AVG.=936.34SEM=? N=1
Figure A9519302901613
AVG.=1752.56SEM=? N=1 AVG.=79.27=215.15=6158.98SEM=5.39=4.97=2084.19 N=6=2=2
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A And structure body 1HBrAVG.=0.00=4749.52=2229.48SEM=?=?=? N=1=1=1
Figure A9519302901622
AVG.==508.94=354.03SEM==45.08=41.34 N==3=3
Figure A9519302901623
AVG.==784.17=127.21SEM==32.35=28.34 N==3=3
Figure A9519302901624
AVG.==256.63=5690.86SEM==9.56=560.80 N==3=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.==1018.01=6028.85SEM==?=? N==1=1 AVG.==1789.87=0.00SEM==?=? N==1=1
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901641
AVG.=37.58SEM=4.76 N=3
Figure A9519302901642
AVG.=11.34=33.67=14.22SEM=2.24=2.01=2.36 N=3=3=3 AVG.=32.03SEM=3.49 N=4 AVG.=283.84SEM=13.48 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=10.47=11.91SEM=1.46=1.09 N=4=3
Figure A9519302901652
AVG.=130.79SEM=18.70 N=4 AVG.=10.19=9.84=7.77=15.80SEM=1.99=2.33=0.59=1.90 N=6=5=3=3 AVG.=9.15SEM=1.47 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=146.84=127.84=120.16SEM=13.49=15.96=? N=7=3=1 AVG.=169.22SEM=50.27 N=4 AVG.=39.28SEM=14.04 N=4 AVG.=112.90SEM=5.61 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=474.74SEM=80.54 N=5
Figure A9519302901672
AVG.=60.96SEM=16.54 N=5 AVG.=32.78SEM=4.99 N=3
Figure A9519302901674
AVG.=5.65SEM=0.55 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901681
AVG.=6.21SEM=0.55 N=6
Figure A9519302901682
AVG.=40.64SEM=4.45 N=3
Figure A9519302901683
AVG.=15.37SEM=1.67 N=3
Figure A9519302901684
AVG.=30.18SEM=0.90 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901691
AVG.=84.49SEM=8.44 N=3
Figure A9519302901692
AVG.=38.48SEM=3.77 N=3 AVG.=49.29SEM=? N=1
Figure A9519302901694
AVG.=6.52SEM=0.60 N=2
Table 1
5-HT 2B-cell 5-HT 2A
[3H] 5-hydroxy tryptamine [125] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901701
AVG.=49.92SEM=11.09 N=2 Kreatinin sulfate AVG.=41.62SEM=10.13 N=2
Figure A9519302901703
Kreatinin sulfate AVG.=4571.89SEM=499.67 N=2
Figure A9519302901704
AVG.=154.84SEM=? N=1
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901711
AVG.=20.85SEM=5.29 N=2
Figure A9519302901712
AVG.=62.43SEM=7.52 N=3
Figure A9519302901713
AVG.=102.06SEM=1.62 N=2 AVG.=14.78SEM=? N=1
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=7.94=11.21=27.55=20.70SEM=0.52=?=0.62=3.48 N=6=1=3=3 AVG.=336.55SEM=? N=1
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901731
AVG.=4.50=3.79SEM=0.47=0.80 N=12=8 AVG.=3.58SEM=1.67 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=3.17=21.74=15.74SEM=0.36=0.74=1.41 N=3=3=3 AVG.=34.49SEM=2.85 N=4
Figure A9519302901743
Isomer AAVG.=5.61=1.40=44.46SEM=0.91=0.08=0.75 N=5=5=3
Figure A9519302901744
Isomer BAVG.=30.07=5.55=372.81SEM=8.51=0.40=23.51 N=5=4=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOT
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A5-HT 2A
Figure A9519302901751
AVG.=8.16=1.50=23.39SEM=2.16=0.35=3.81 N=4=4=3 AVG.=3.10=0.79=28.07SEM=0.20=0.06=2.30 N=3=7=3 AVG.=5.39SEM=0.68 N=3 AVG.=28.37SEM=2.08 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901761
AVG.=3.94=1.29=5.62SEM=0.88=0.12=0.63 N=3=3=3 AVG.=39.70SEM=5.09 N=3 AVG.=1463.01SEM=110.95 N=4
Figure A9519302901764
AVG.=14.18SEM=1.74 N=4
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxyl color [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-ET 2A
Figure A9519302901771
AVG.=44.91SEM=1.48 N=3
Figure A9519302901772
AVG.=5.02=1.64=0.83SEM=0.51=0.23=0.10 N=3=4=3
Figure A9519302901773
AVG.=4.82SEM=0.23 N=3 AVG.=2.16SEM=0.33 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=228.87SEM=18.34 N=3
Figure A9519302901782
AVG.=6.42=2.01=23.08SEM=0.78=?=? N=3=1=1
Figure A9519302901783
AVG.=4.38SEM=1.25 N=3
Figure A9519302901784
AVG.=3.31=0.74=4.63SEM=0.31=0.04=0.26 N=3=3=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=219.79SEM=20.68 N=3
Figure A9519302901792
AVG.=4609.36SEM=316.40 N=3
Figure A9519302901793
AVG.=379.15SEM=16.72 N=3 AVG.=114.16SEM=7.17 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-H 2A5-HT 2A AVG.=404.85SEM=51.64 N=3 AVG.=97.53SEM=? N=1
Figure A9519302901803
AVG.=71.75SEM=? N=1
Figure A9519302901804
AVG.=70.71SEM=10.08 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901811
AVG.=15.83SEM=1.73 N=3 AVG.=13.98=16.43=41.71=47.00SEM=1.00=?=7.42=5.15 N=3=1=4=3
Figure A9519302901813
AVG.=6.20=9.68=22.72=25.61SEM=0.62=1.12=2.15=3.43 N=3=3=6=3 AVG.=62.09SEM=1.76 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901821
AVG.=57.89SEM=7.60 N=3 AVG.=32.44SEM=3.48 N=3 AVG.=322.26SEM=35.50 N=3
Figure A9519302901824
AVG.=25.63SEM=2.59 N=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901831
AVG.=78.46SEM=1.22 N=2
Figure A9519302901832
AVG.=60.10SEM=2.07 N=3
Figure A9519302901833
AVG.=2.69=2.68=20.61=15.49SEM=0.24=0.24=1.28=0.79 N=6=4=4=3
Figure A9519302901834
AVG.=3.19=0.84=0.93SEM=0.33=0.15=0.07 N=3=4=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.=8.77SEM=? N=1
Figure A9519302901842
AVG.=5652.17SEM=? N=1
Figure A9519302901843
AVG.=15.26=10.15=17.76SEM=?=2.19=0.68 N=1=4=3
Figure A9519302901844
AVG.==1.69=49.70SEM==?=? N==1=1
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] D0I
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.==2.08=6.71SEM==?=? N==1=1 AVG.==0.37=12.23SEM==?=? N==1=1 AVG.==0.87=17.48SEM==?=? N==1=1
Figure A9519302901854
AVG.==1.47=54.85SEM==?=? N==1=!
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A AVG.==3.46=201.26SEM==?=? N==1=1
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOT
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901871
255747, trans AVG.=44.65=12.44=1.25=5.36SEM=25.15=1.70=0.56=1.85 N=5=3=5=5 278458, cis AVG.=22.29=4.30=11.33=1.57SEM=6.65=0.30=3.26=0.49 N=5=3=5=5 253535 (trans) AVG.=30.90=6.24=21.18=2.82SEM=4.52=0.29=3.78=0.40 N=3=3=3=3
Table 1
5-HT 2BCell 5-HT 2A
[3H] 5-hydroxy tryptamine [125I] DOI
K iRat K iPeople K iPeople K iRat structure 5-HT 2B5-HT 2B5-HT 2A5-HT 2A
Figure A9519302901881
AVG.==7.87=0.60SEM==-=-N==1=1
Figure A9519302901882
AVG.==2.24=21.92SEM==-=-N==1=1
Following test cell line human body cell chemical compound 5HT 2BCell 5HT 2ACell 5HT 2CCell embodiment 100 16.44 292.58 351.96 embodiment 105 22.07 86.48 195.44 embodiment 102 168.49 917.17 2172.86 embodiment 106 367.41 263.94 1108.87 embodiment 104 11.35 32.99 52.06 embodiment 97 9.56 123.93 220.51 embodiment 99 106.17 556.40 1117.00 embodiment 107 177.89 362.79 325.10 isomers 107 (1) 142.80 152.65 137.76 isomers 107 (2) 2894.33 1967.05 6211.80 embodiment 101 121.19 172.03 783.35 embodiment 98 52.54 53.65 202.60 embodiment 96 667.82 277.62 976.73 embodiment 95 839.63 3443.51 2641.21 embodiment 103 3520.31 1447.65 9247.06
The 5-HT of vitro tissue 2BTest method:
Put to death male Wistar rat (150-375g by the cervical region dislocation; LaboratorySupply, Indianapolis, IN), the position of the length direction at the bottom of the preparation stomach is used in vitro tests.Obtain 4 goods at the bottom of the stomach by a rat.Cohen，M.L.，J.Pharmacol.Exp.?Ther.，233：75-79(1985)。Tissue is placed on the organ bath that contains 10mi Modified K rebs solution, and the composition of this solution (millimolar concentration) is: NaCl, 118.2; KCl, 4.6; CaCl 2H 2O, 1.6; KH 2PO 4, 1.2; MgSO 41.2; Dextrose, 10.0; And NaHCO 3, 24.8.Tissue bath's solution remains on 37 ℃ and with 95% O 2With 5% CO 2Balance.Best static force (4g) place down above-mentioned tissue and before the contact test chemical compound about 1 hour of balance, the record isometric contraction of representing with the change of power (is the unit with the gram) on the Beckman power record system of Statham UC-3 pick off is being equipped with.Measure apparent antagonist dissociation constant:
After washing previous concentration off at the bottom of 15-20 minute progressively improves concentration to have obtained the 5-hydroxy tryptamine stomach function regulating in the non-accumulation of other agonist shrink concentration-response curve.Each agonist concentration contacts about 2 minutes with tissue, measures the peak response of every kind of compound concentration.EC 50Value is decided to be the concentration of a half agonist that can produce maximum collapse.After obtaining the contrast response, tissue was cultivated the response of replication 5-hydroxy tryptamine in the presence of antagonist then 1 hour with the buffer solution or the antagonist of debita spissitudo.Each is organized and only uses a kind of agonist and a kind of antagonist concentration determination concentration-response.In general, successive agonist response is constant (mean dose is than being 1.28+/-0.21) under the situation that has buffered to exist.
Measure the apparent antagonist binding constant (K of each antagonist concentration by following formula B):
K B=[B]/(dosage is than-1) wherein [B] is the concentration of antagonist, and dosage is than the ED that is agonist under antagonist exists 50ED divided by contrast 50Generally speaking, the translation of concentration-response curve occurs in the presence of antagonist, the result is with K BNegative logarithm represent (promptly-logK B).Calculating is finished with known method.
The in vitro tests of some chemical compound of the present invention the results are shown in Table II, and the value in the Table II is with-logK B± standard error (number of data point) expression.5-HT 2BThe negative logarithm of value representation antagonist concentration, under this concentration can at the bottom of the stomach of rat with 5-HT 2BReceptor is to produce moving to right of twice on the concentration-response curve of 5-hydroxy tryptamine of media.Similarly, 5-HT 2AThe negative logarithm of value representation antagonist concentration, under this concentration can in the jugular vein of rat with 5-HT 2AReceptor is to produce moving to right of twice on the concentration-response curve of 5-hydroxy tryptamine of media.The blank value of Table II is meant that this chemical compound does not carry out described test.
Table II
Embodiment number ???????????5-HT 2B(substrate) ??????????5-HT 2A(jugular vein)
??????1 9.00±0.07??(3)
??????2
??????3 8.78±0.24??(4)
??????4 8.92±0.29??(4)
??????5
??????6 9.60±0.13??(7)
??????7 9.02±0.35??(3)
??????8 8.45±0.24??(3)
??????9 9.30±0.12??(7)
??????10 9.22±0.05??(3)
??????11 ＜7.52?(4)
??????12 9.29±0.18??(4)
??????13 8.50±0.13??(4)
??????14 9.61±0.22??(5)
??????15 9.34±0.12??(3)
??????16 9.71±0.14??(6) 8.15±0.28??(3)
??????17 9.46±0.11??(6) 7.66±0.13??(4)
??????18 8.80±0.17??(3)
??????19 10.12±0.18?(3)
??????20 9.48±0.30??(4) 7.21±0.20??(4)
??????21
??????22 8.21±0.43??(3)
??????23
??????24
??????25
??????26
??????27
??????28 8.55±0.10??(4)
??????29 8.12±0.16??(7)
??????30 8.89±0.12??(4)
??????31 8.95±0.17??(3) 7.29±0.09??(4)
??????32
Table II (continuing)
Embodiment number ???????????5-HT 2B(substrate) ??????????5-HT 2A(jugular vein)
????33
????34 9.42±0.18??(5)
????35 *9.06±0.27??(3)
????36 9.80±0.15??(4) 8.14±0.10??(6)
????37 9.19±0.14??(4)
????38
????39 8.32±0.17??(3)
????40 9.75±0.11??(6)
????41 9.81±0.18??(3) 7.94±0.15??(6)
????42 9.56±0.22??(3)
????43 9.44±0.16??(6)
????44 8.40±0.40??(3)
????45 8.14±0.32??(3)
????46 9.37±0.11??(8) 8.22±0.07??(12)
????47
????48 ??**
????49 *10.41±0.22??(5)
????50 8.40±0.28??(3)
????51 9.75±0.11??(8) 8.07±0.10??(8)
????52 *9.10±0.28??(3)
????53 ??**
????54 ??**
????55 8.95±0.07??(4)
????56 *7.53±1.08??(4)
????57 ＜8.0?(3)
????58 ＜7.52?(4)
????59 9.69±0.21??(7)
????60 8.92±0.04??(4)
????61 8.44±0.22??(4)
????62 8.58±0.23??(3)
????63 9.09±0.23??(3)
????64 9.73±0.05??(3)
*Approximately be worth *The functional in vitro tests of the noncompetitive inhibitor of 30nM
Put to death Sprague-Dawley rat (200-250g by the cervical region dislocation; LaboratorySupply, Indianapolis IN), takes out one section 8cm DC, and with ice-cold Modified K reb ' s solution washing, the composition of this solution (millimolar concentration) is: NaCl, 118.2; KCl, 4.6; CaCl 2H 2O, 1.6; KH 2PO 4, 1.2; MgSO 41.2; Dextrose, 10.0; And NaHCO 3, 24.8.Colon is fixed on the Glass rod, takes out the Musclar layer of the length direction link to each other with the flesh enteric plexus, be placed on the organ bath that contains above-mentioned Modified K reb ' s solution, solution remains on 37 ℃ also with 95% O 2With 5% CO 2Balance.The tension force that tissue is placed 2g down and made it to stablize 1 hour, with grass FT03 pick off and MI 2The isometric contraction that-computer power recording system record is represented with the change of power (unit gram).After washing previous concentration off, progressively improved concentration and can obtain 5-hydroxy tryptamine accumulation contraction concentration-response curve every 10-15 minute.Each agonist concentration contacts 5 minutes with tissue, measures the peak response and the digitized of every kind of compound concentration.EC 50Value is decided to be the concentration of a half agonist that can produce maximum collapse.After obtaining the contrast response, tissue was cultivated the response of replication 5-hydroxy tryptamine in the presence of antagonist then 15 minutes with the antagonist of debita spissitudo.Each is organized only with a kind of antagonist concentration determination concentration-response.Determine the apparent antagonist dissociation constant (K of each antagonist concentration by following formula B):
K B=[B]/(dosage is than-1) wherein [B] is the concentration of antagonist, and dosage is than the ED that is agonist under antagonist exists 50ED divided by contrast 50The result is with K BNegative logarithm represent (promptly-logK B) (Br.J.Pharmacol.Methods4:4165, (1980)).
Above-mentioned functional in vitro tests method is used for test compound of the present invention.With the outer Table III that the results are shown in that obtains of testing of function gonosome, value representation wherein is pK iAnd pA 2(iogK B).Following table has illustrated the result (pK that chemical compound obtains in above-mentioned radiation coordination test i), and the result (pA that outside the above-mentioned functions gonosome, obtains in the test 2).
Table III chemical compound pK iPA 2Embodiment 73 7.85 8.0 embodiment 49 8.4 8.2 embodiment 20 8.51 7.8 embodiment 72 7.8 7.5 embodiment 41 8.19 7.2 embodiment 17 8.09 6.2 embodiment 22 8.27 4.87-methyl-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole 8.57 8.36-bromo-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole 7.21 8.26-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indole 7.157.2 in vivo test research
With Sprague-Dawley rat (250-300g) overnight fasting.With input endoperitoneal urethane (250mg) anesthetized rat, open the abdominal cavity, stress rule pick off is sutured in the antimesenteric edge of colon.Sensor orientation is with the contraction of record ring-type muscle.The temperature of animal body is kept with heating cushion.Inserting venous duct in jugular vein is used for drug administration and monitors Blood pressure of carotid artery simultaneously.The output of stress rule pick off is mapped on Beckman power recorder.Baseline motility (Motility) 30 minutes gave vehicle Control dosage when finishing in 30 minutes, write down 15 minutes motilities again.Respond with-5-hydroxy tryptamine dosage.With the 5-hydroxy tryptamine dosage of giving again at interval in 15 minutes progressively to improve.Calculate ED 50Value, this value is the dosage that can produce the half maximum collapse.In the antagonist test, use former ED 50Dosage is with the establishment of the test that confirms to be done.Then, give antagonist dosage, monitoring motility 15 minutes.After monitoring 15 minutes.Give ED 50Dosage obtains motility index (Motility Index) by the shrinkage amplitude of measuring in shrinking number and multiply by at certain time intervals.Calculate inhibition percent by carrier (no antagonism) treatment batch total.The minima of 3 rats is used for various concentration, compiles the data of different animals and determines ED 50Value.
By above-mentioned In vivo assay Cells proof The compounds of this invention activity is arranged, for example the ED of the chemical compound of embodiment 73 50Value is 3.2mg/kg, in the body.

Claims (42)

1. mammiferous method of treatment, this mammal suffers from or easily trouble and dysfunction or not normal 5-HT 2BThe disease that receptor for stimulating is relevant, this method comprise use effective dose and 5-HT 2BThe chemical compound that is selected from following formula I-X of acceptor interaction or its pharmaceutically acceptable salt or solvate:
Formula I chemical compound:
Figure A9519302900021
Wherein:
Q is hydrogen or (CHR 2) R 4
R 1Be hydrogen or C 1-C 3Alkyl;
R 2Be hydrogen or C 1-C 6Alkyl;
R 3Be hydrogen or C 1-C 3Alkyl;
R 4Be C 5-C 8Cycloalkyl, the C of replacement 5-C 8Cycloalkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, the dicyclo of dicyclo or replacement;
A is selected from following groups:
Wherein:
R 6And R 7Be respectively hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5
M is 1 or 2;
R 5Be hydrogen or C 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 8Be selected from R respectively 6, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl; Or
R 6And R 7Carbon atom with the A group forms 5-8 unit carbocyclic ring;
Formula II chemical compound:
Wherein:
R 8Be selected from hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 2-C 6) alkyl, halo (C 1-C 6) thiazolinyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, OR 5, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, and C 7-C 20Aralkyl;
R 5Be respectively hydrogen or C 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 9And R 10Be selected from hydrogen respectively, C 1-C 6Alkyl, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl;
R 11Be selected from C 1-C 4Alkyl, OR 5 ', fluorine, bromine, iodine, and chlorine;
R 12 'Be selected from hydrogen and C 1-C 4Alkyl;
The formula III chemical compound:
Figure A9519302900041
Wherein:
R 12Be C 1-C 4Alkyl and pi-allyl;
R 13Be-O-or-N (R 15)-;
R 15Be hydrogen or C 1-C 4Alkyl;
R 14Be C 1-C 4Alkyl, hydroxyl C 1-C 4Alkyl, C 3-C 7Cycloalkyl and the C that is replaced by hydroxyl or methoxyl group 3-C 7Cycloalkyl;
Formula IV chemical compound: Wherein: R 15' be C 1-C 4Alkyl; R 16Be pi-allyl or C 1-C 4Straight chained alkyl; R 17Be hydrogen or C 1-C 4Straight chained alkyl; R 18Be hydrogen, C 1-C 4Alkyl, hydroxyl, or C 1-C 4Alkoxyl; M ' is 0,1,2 or 3; Formula V chemical compound:
Figure A9519302900052
Wherein: R 19Be C 1-C 4Alkyl; R 20Be pi-allyl or C 1-C 4Straight chained alkyl; R 21Be hydrogen or C 1-C 4The straight chain alkanoyl; R 22Be pyridine radicals or imidazole radicals; Alk is from straight or branched C 1-C 5The deutero-divalent organic base of alkane; Formula VI chemical compound:
Figure A9519302900061
Wherein: R 23Be C 1-C 3Alkyl or pi-allyl; R 24Be C 1-C 3Hydroxy alkyl or C 1-C 3The dihydroxy alkyl; R 25Be hydrogen or CH 3Formula VII chemical compound: Formula VIII chemical compound:
Figure A9519302900071
Wherein: R 25 'Be hydrogen or methoxyl group; Formula IX chemical compound:
Wherein:
Y bForm the replacement that is selected from following groups or do not replace 5 yuan of heterocycles of aromatics with the carbon atom that it connected,
Figure A9519302900073
R 26Be hydrogen, C 1-C 3Alkyl, pi-allyl or R 27Be hydrogen, C 1-C 3Alkyl, pi-allyl,
Or (CH 2) N '-X ";
N ' is 1 to 5;
X " be the phenyl that replaces arbitrarily, C 1-C 3Alkoxyl, or C 1-C 3Alkylthio group;
R 28And R 29Be respectively hydrogen, C 1-C 3Alkyl, C 1-C 3Alkoxyl, hydroxyl, C 1-C 3Alkylthio group, halogen, CN, phenyl; Or formation-(CH together 2) P "-;
P " be 3 to 6;
Y aBe-CH 2-,-O-,-S (O) M "-;
M " be 0,1, or 2; And
Formula X chemical compound:
Figure A9519302900083
2. the process of claim 1 wherein that chemical compound is selected from formula I, II, and IX.
3. the method for claim 2, its Chinese style IX chemical compound has following array structure:
Figure A9519302900091
R wherein 26, R 27, R 28, R 29, and Y aDefinition as above.
4. the method for claim 2, wherein chemical compound is selected from following compounds or its pharmaceutical salts or solvate: 2-(two n-propylamine bases)-8-(isothiazole-3-yl)-1,2,3,4-naphthane, 2-ethylamino-8-(isoxazole-3-base)-1,2,3, the 4-naphthane, 2-(N-methyl-N-benzyl amino)-8-(5-n-pro-pyl-1,2,3-oxadiazole-4-yl)-1,2,3, the 4-naphthane, 2-diallyl amino-8-(pyrazole-3-yl)-1,2,3, the 4-naphthane, 2-lignocaine-8-(1,3,4-oxadiazole-2-yl)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-8-(3-Methoxy Pyridine-2-yl)-1,2,3,4-naphthane, 2-benzyl methylamino-8-(3-Methoxy Pyridine-2-yl)-1,2,3, the 4-naphthane, 2-benzyl methylamino-8-(benzofuran-2-yl)-1,2,3, the 4-naphthane, 2-dimethylamino-8-(1,3,5-triazine-2-yl)-1,2,3, the 4-naphthane, 2-(two cyclopropyl methylaminos)-8-(oxazole-4-yl)-1,2,3,4-naphthane, 2-ethylamino-8-(1,2,3-oxadiazole-4-yl)-sulfo--1,2,3,4-naphthane, 2-n-butyl amine base-8-(5-methoxy pyrimidine-2-yl)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-8-(5-Lv oxazole-2-yl)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-8-(pyrimidine-2-base)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-8-(2-aminopyrimidine-4-yl)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-8-(3-phenyl-1,2,4-oxadiazole-5-yl)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-8-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-8-(pyrazine-2-yl)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-6-(bromo-pyrazine-2-yl)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-8-(benzothiazole-2-yl)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-8-(benzoxazole-2-yl)-1,2,3, the 4-naphthane, 2-(two n-propylamine bases)-8-(indol-3-yl)-1,2,3, the 4-naphthane, 3-(two n-propylamine bases)-5-(isoxazole-2-yl)-1,2,3, the 4-naphthane, 3-(two n-propylamine bases)-5-(isoxazole-2-yl)-benzodihydropyran, 5-(isoxazole-5-base)-and 3-(dipropyl amino) benzodihydropyran, 5-(3-methyl-isoxazole-5-yl)-3-(dipropyl amino) benzodihydropyran, 5-(4-methyl-isoxazole-5-yl)-3-(dipropyl amino) benzodihydropyran, 5-(3,4-dimethyl isoxazole-5-yl)-and 3-(dipropyl amino) benzodihydropyran, 5-(3-methyl-isoxazole-5-yl)-3-(dipropyl amino) sulfo-benzodihydropyran, 5-(4-methyl-isoxazole-5-yl)-3-(dipropyl amino) sulfo-benzodihydropyran, 5-(3,4-dimethyl isoxazole-5-yl)-3-(dipropyl amino) sulfo-benzodihydropyran, and 8-(4,5,6, the 7-tetrahydro benzo [c] isoxazole-1-yl)-2-(dimethylamino) naphthane.
5. the method for claim 2, chemical compound wherein is formula I or formula II chemical compound.
6. the process of claim 1 wherein and 5-HT 2BThe chemical compound of acceptor interaction is 5-HT 2BReceptor antagonist.
7. the method for claim 5, chemical compound wherein is selected from following compounds or its pharmaceutical salts or solvate: 7-bromo-8-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6-isopropyl-8-methoxyl group-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 5-chloro-8-ethyoxyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6-chloro-7-methyl-8-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 5-dimethylamino-8-hydroxyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6-nitro-8-butyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 7-cyclohexyl-8-hydroxyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6-[3-methyl-cyclohexyl base]-the 8-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6-benzyl-8-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 5-cyclohexyl methyl-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6-carboxyl-8-bromo-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6-ethyoxyl-8-isopropyl-3-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6,8-two chloro-4-menaphthyls-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6,8-dimethyl-3,4-dimethyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 7,8-two fluoro-2 (N)-methyl isophthalic acids, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6,8-dibutyl-2 (N)-cyclopropyl methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6,8-two bromo-2 (N)-cyclohexenyl group methyl isophthalic acids, 2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 8-chloro-2 (N)-benzyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 8-fluoro-4-methyl-2 (N)-cyclohexyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, 6-methylamine-8-chloro-3-isopropyl-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole, and 6-chloromethyl-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4b]-indole.
8. the disease that the process of claim 1 wherein comprises urinary incontinence, vesical dysfunction, uterine dysfunction, cardiovascular disorder, respiratory disorder and intestinal dysfunction.
9. the method for claim 8, disease wherein is an intestinal dysfunction.
10. the method for claim 9, intestinal dysfunction wherein comprises the irritable bowel syndrome, ichlasia, low side (lower) sphincter of gullet tension force is too high, tachygastria, the hypermotility relevant with the irritable bowel syndrome, and constipation.
11. the method for claim 2, disease wherein comprises urinary incontinence, vesical dysfunction, uterine dysfunction, cardiovascular disorder, respiratory disorder and intestinal dysfunction.
12. the method for claim 8, disease wherein is a cardiovascular disorder.
13. the method for claim 8, disease wherein are vesical dysfunction or urinary incontinence.
14. the method for claim 8, disease wherein is a respiratory disorder.
15. the method for claim 8, disease wherein is a migraine.
16. the chemical compound that the process of claim 1 wherein comprises formula III, IV, V and VI chemical compound.
17. the method for blocking-up 5-HT2B receptor in mammalian body, comprise use blocking-up 5-HT2B receptor dosage be selected from above-mentioned formula I, II, III, IV, V, VI, VII, VIII, the chemical compound of IX and X or its pharmaceutically acceptable salt or solvate.
18. in mammalian body, block 5-HT selectively 2BThe method of receptor comprises that use is to 5-HT 2BReceptor selectively is selected from above-mentioned formula I, II, III, IV, V, VI, VII, the chemical compound of VIII and IX or its pharmaceutically acceptable salt or solvate.
19. the human 5-HT of blocking-up in human body 2BThe method of receptor comprises and uses blocking-up 5-HT 2BThe above-mentioned formula I of receptor dosage, II, III, IV, V, VI, VII, the chemical compound of VIII and IX or its pharmaceutically acceptable salt or solvate.
20. the goods of a medicine comprise that packaging material and one or more are contained in the medicament in the said packaging material, wherein said medicament is to treatment and 5-HT 2BIt is effective to regulate relevant disease, and is selected from above-mentioned formula I, II, III, IV, V, VI, VII, VIII, the chemical compound of IX and X or its pharmaceutically acceptable salt or solvate; Said lapping comprises a label, and it points out that said medicament can be used for the treatment of and 5-HT 2BReceptor for stimulating dysfunction or not normal relevant disease.
21. the chemical compound of a formula XI
Figure A9519302900131
Wherein: Q ' is selected from hydrogen, R 34(CHR 2) R 4R 34Be selected from the spiral shell dicyclo, the spiral shell dicyclo of replacement, the dicyclo of dicyclo or replacement; R 1Be hydrogen or C 1-C 3Alkyl; R 2Be hydrogen or C 1-C 6Alkyl; R 3Be hydrogen or C 1-C 3Alkyl;
R 4Be C 5-C 8Cycloalkyl, the C of replacement 5-C 8Cycloalkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, the dicyclo of dicyclo or replacement;
A is selected from following group:
Figure A9519302900141
Wherein:
R 6And R 7Be respectively hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5
M is 1 or 2;
R 5Be respectively hydrogen or C 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 8Be selected from R respectively 6, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl; Or
R 6And R 7Carbon atom with the A group forms 5-8 unit carbocyclic ring;
R 30And R 31Form 3-8 unit carbocyclic ring together; Or
R 30And R 31Be selected from C respectively 1-C 6Alkyl and C 2-C 6Thiazolinyl; Or its drug acceptable salt or solvate.
22. the chemical compound of claim 21, wherein R 30And R 31Form 3-8 unit carbocyclic ring together.
23. the chemical compound of claim 22, wherein Q is (CHR 2) R 4
24. the chemical compound of claim 23, wherein R 4It is the dicyclo of dicyclo or replacement.
25. the chemical compound of claim 22, wherein Q is R 34
26. the chemical compound of claim 25, wherein A is structure I V.
27. the chemical compound of claim 21, wherein R 30And R 31Be selected from C respectively 1-C 6Alkyl and C 2-C 6Alkenyl; Q is (CHR 2) R 4
28. the chemical compound of claim 27, wherein R 4It is the dicyclo of dicyclo or replacement.
29. the chemical compound of claim 21, wherein R 1Be selected from C 3-C 8Cycloalkyl, the C of replacement 3-C 8Cycloalkyl, and C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl.
30. the chemical compound of claim 29, wherein R 30And R 31Be selected from C respectively 1-C 6Alkyl and C 2-C 6Alkenyl.
31. formula XII chemical compound
Figure A9519302900151
A is selected from following groups:
Figure A9519302900152
Wherein:
R 6And R 7Be respectively hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) thiazolinyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5
M is 1 or 2;
R 8Be selected from hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 2-C 6) alkyl, halo (C 1-C 6) thiazolinyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, and C 7-C 20Aralkyl;
R 5Be respectively hydrogen or C 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 6And R 7Carbon atom with the A group forms 5-8 unit carbocyclic ring;
R 9And R 10Be selected from hydrogen respectively, C 1-C 6Alkyl, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl;
R 11Be selected from C 1-C 4Alkyl, OR 5 ', fluorine, bromine, iodine, and chlorine;
R 30And R 31Form 3-8 unit carbocyclic ring together; Or
R 30And R 31Be selected from C respectively 1-C 6Alkyl and C 2-C 6Alkenyl; Or its drug acceptable salt or solvate.
32. the chemical compound of claim 31, wherein R 30And R 31Form 3-8 unit carbocyclic ring together.
33. the chemical compound of claim 32, wherein R 9And R 10Be respectively hydrogen.
34. the chemical compound of claim 31, wherein A is IIa or IIIa.
35. the chemical compound of claim 31, wherein A is IV; R 6, R 7And R 8Be selected from hydrogen respectively, C 1-C 6Alkyl, C 2-C 6Alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2And-SR 5, its condition is R at least 6, R 7And R 8One of them should be selected from C 1-C 6Alkyl, C 2-C 6Alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2And-SR 5
36. the chemical compound of claim 35, wherein R 30And R 31Form 3-8 unit carbocyclic ring together.
37. mammal suffers from or easily trouble and dysfunction or not normal 5-HT in treatment 2BReceptor for stimulating has the method for related disorders, comprises the chemical compound that uses effective dose, this chemical compound and 5-HT 2BAcceptor interaction also is selected from the chemical compound of formula XI:
Figure A9519302900171
Wherein:
Q ' is selected from hydrogen, R 34(CHR 2) R 4
R 34Be selected from the spiral shell dicyclo, the spiral shell dicyclo of replacement, the dicyclo of dicyclo or replacement;
R 1Be hydrogen or C 1-C 3Alkyl;
R 2Be hydrogen or C 1-C 6Alkyl;
R 3Be hydrogen or C 1-C 3Alkyl;
R 4Be C 5-C 8Cycloalkyl, the C of replacement 5-C 8Cycloalkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, the dicyclo of dicyclo or replacement;
A is selected from following groups:
Figure A9519302900172
Figure A9519302900181
Wherein:
R 6And R 7Be respectively hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5
M is 1 or 2;
R 5Be respectively hydrogen or C 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 8Be selected from R 6, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl; Or
R 6And R 7Carbon atom with the A group forms 5-8 unit carbocyclic ring;
R 30And R 31Form 3-8 unit carbocyclic ring together; Or
R 30And R 31Be selected from C respectively 1-C 6Alkyl and C 2-C 6Alkenyl; With
The chemical compound of formula XII:
Figure A9519302900182
A is selected from following groups:
Figure A9519302900191
Wherein:
R 6And R 7Be respectively hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 1-C 6) alkyl, halo (C 2-C 6) thiazolinyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5
M is 1 or 2;
R 8Be selected from hydrogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, halogen, halo (C 2-C 6) alkyl, halo (C 1-C 6) alkenyl, COR 5, C 1-C 10Alkanoyl, CO 2R 5 ', (C 1-C 6Alkyl) mAmino, NO 2,-SR 5, or OR 5, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group, the C of replacement 5-C 8Cycloalkenyl group, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, and C 7-C 20Aralkyl;
R 5Be respectively hydrogen or C 1-C 4Alkyl;
R 5 'Be C 1-C 4Alkyl;
R 6And R 7Carbon atom with the A group forms 5-8 unit carbocyclic ring;
R 9And R 10Be selected from hydrogen respectively, C 1-C 6Alkyl, the C of replacement 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl-(C 1-C 3) alkyl, C 5-C 8Cycloalkenyl group-(C 1-C 3) alkyl, C 7-C 20Aralkyl;
R 11Be selected from C 1-C 4Alkyl, OR 5 ', fluorine, bromine, iodine, and chlorine;
R 30And R 31Form 3-8 unit carbocyclic ring together; Or
R 30And R 31Be selected from C respectively 1-C 6Alkyl and C 2-C 6Alkenyl; Or its drug acceptable salt or solvate.
38. the method for claim 37 is wherein with 5-HT 2BThe chemical compound of acceptor interaction is 5-HT 2BReceptor antagonist.
39. in mammalian body, block 5-HT 2BThe method of receptor comprises and uses blocking-up 5-HT 2BThe above-mentioned formula XI of receptor dosage and the chemical compound of XII or its pharmaceutically acceptable salt or solvate.
40. in mammalian body, block 5-HT selectively 2BThe method of receptor comprises and uses the 5-HT that is selected from above-mentioned formula XI and XII 2BThe alternative cpd of receptor or its pharmaceutically acceptable salt or solvate.
41. on human body, block 5-HT 2BThe method of receptor comprises and uses blocking-up 5-HT 2BThe above-mentioned formula XI of receptor dosage and the chemical compound of XII or its pharmaceutically acceptable salt or solvate.
42. a pharmaceutical preparation comprises as the above-mentioned formula XI of active component and chemical compound or its pharmaceutically acceptable salt or the solvate of XII, and one or more pharmaceutically acceptable carrier.
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