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HK1075660B - Polycyclic compounds as potent alpha2-adrenoceptor antagonists - Google Patents

Polycyclic compounds as potent alpha2-adrenoceptor antagonists Download PDF

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Publication number
HK1075660B
HK1075660B HK05107766.2A HK05107766A HK1075660B HK 1075660 B HK1075660 B HK 1075660B HK 05107766 A HK05107766 A HK 05107766A HK 1075660 B HK1075660 B HK 1075660B
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HK
Hong Kong
Prior art keywords
alkyl
alpha
alkoxy
hexahydro
oxa
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HK05107766.2A
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Chinese (zh)
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HK1075660A1 (en
Inventor
David Din Belle
Reija Jokela
Arto Tolvanen
Antti Haapalinna
Arto Karjalainen
Jukka Sallinen
Jari Ratilainen
Original Assignee
Orion Corporation
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Priority claimed from FI20020642A external-priority patent/FI20020642A0/en
Application filed by Orion Corporation filed Critical Orion Corporation
Priority claimed from PCT/FI2003/000255 external-priority patent/WO2003082866A1/en
Publication of HK1075660A1 publication Critical patent/HK1075660A1/en
Publication of HK1075660B publication Critical patent/HK1075660B/en

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Description

As effective alpha2Polycyclic compounds of adrenoceptor antagonists
Technical Field
The present invention relates to pharmacologically active arylquinolizine derivatives and related compounds and their pharmaceutically acceptable salts and esters, to pharmaceutical compositions containing them and to their use as alpha-agonists2-use of an adrenoceptor antagonist.
Background
Some compounds are known in the art to exhibit alpha adrenergic activity. It is well recognized in the art that these compounds are useful in the treatment of a variety of diseases and conditions of the peripheral and Central Nervous System (CNS).
According to the basic principle of pharmacology, alpha can be applied to the kidneyGlandular receptors divided into alpha1Adrenoceptor and alpha2The adrenergic receptors, both of which can also be divided into subtypes. Three subtypes have been found in humans, and are designated as alpha according to genetic codes2AAdrenoceptor, alpha2BAdrenoceptor and alpha2CThe adrenergic receptor. Thus, pharmacologically in vivo alpha2Adrenoceptors are subdivided into three known subtypes, alpha2AAdrenoceptor, alpha2BAdrenoceptor and alpha2CThe adrenergic receptor. A fourth subtype, found in rodents and certain other animals, is pharmacologically defined as α2DAdrenoceptor corresponding to a genetically defined alpha2AThe adrenergic receptor.
α2Each subtype of adrenergic receptor has distinct tissue distribution and functional roles. For example, though α2AThe adrenergic receptors are widely distributed in various tissues, and alpha2CThe adrenergic receptors are only concentrated in the CNS, but both appear to play a role in specific behavioural and physiological responses governed by the CNS.
It is known that α is mentioned above2Compounds with non-specificity for either subtype of adrenergic receptor and for alpha2Compounds that are specific for a certain subtype of adrenergic receptors. For example, altimezole is a non-specific alpha2An adrenoceptor antagonist. Altemazole is described in EP-A-183492(cf. p.13, Compound XV) and Naunyn-Schmiedeberg' sArch Pharmacol.356(1997)570-582 by HaaparinnｃA, A. et al. Para-alpha useful for the treatment of psychiatric disorders such as stress-induced psychotic disorders is described in U.S. Pat. No. 5,902,8072CSelective antagonist compounds of the adrenergic receptor subtype. These compounds include MK-912 and BAM-1303. Furthermore, WO-A-9928300 discloses substituted imidazole derivatives p α2BAdrenoceptor or alpha2BAdrenergic receptors and alpha2CAdrenoceptors have a similar antagonistic effect. In addition, WO01/64645 also relates to alpha as2Quinoline derivatives of receptor antagonists, and to selective alpha2CA receptor antagonist. The entire contents of the documents cited in this paragraph are hereby incorporated by reference.
Several arylquinolizine derivatives and related compounds are described in the above documents, some of which have important pharmaceutical value. For example, U.S. Pat. Nos. 4,806,545 and 4,044,012 describe 1, 1-disubstituted indolo [2, 3-a ] as vasodilators and anti-hypoxic agents]Quinolinidines (quinolizidine). In addition, having an alpha is also described in U.S. Pat. No. 4,686,2262Substituted arylquinolizine derivatives having adrenoreceptor antagonism are useful as drugs for the treatment of depression, hypertension or diabetes or platelet aggregation inhibitors. Also, indolo [2, 3-a ] is related to central nervous system inhibitors in U.S. Pat. No. 3,492,303]Quinolinidines. Griffith, R.et al, in J.Compout. -AidedMol.Design13(1999)69-78, discuss the use for synthesizing alpha1AReceptor and alpha2Molecular models of receptor-specific ligands.
Disclosure of Invention
It is an object of the present invention to provide a composition which can be used for the treatment of diseases or conditions of the peripheral or central nervous system (alpha)2Therapeutically effective of receptor antagonists) of2An adrenoceptor antagonist. Accordingly, it is also an object of the present invention to provide other compounds which act as alpha in the treatment of mammals, including humans and animals2A compound which is a receptor antagonist.
The invention also provides as selectivity alpha2CCompounds as receptor antagonists for the treatment of various para-alpha2CCentral nervous system disorders or conditions for which receptor antagonists are effective.
Drawings
FIGS. 1a and 1b show the results of two different locomotor activity experiments, respectively, testing mice for locomotor activity after injection of vehicle or amphetamine (amph) (4. mu. mol/kg), respectively. Mice were treated with vehicle, non-selective alpha (20 minutes prior to amphetamine administration)2Subtype receptor antagonist altimezole (1 micromole/kg) or alpha2CReceptor antagonist, compound K (3 μmol/kg) (figure a) or compound L (3 μmol/kg) (figure b) were pretreated. Compared with the control vehicle + amphetamine group,＊p<0.05、＊＊p<0.01 and＊＊＊p<0.001 (one-way ANOVA + LSD-test).
FIG. 2 shows α in mice2Receptor agonist-induced sedation (determination of inhibition of movement). Non-selective alpha2Receptor subtype antagonist altimezole (Ati) antagonizes non-selective alpha2Sedation with the receptor subtype agonist dexmedetomidine (Dex; 50nmol/kg s.c.) and selectivity to alpha2CReceptor antagonists have no significant effect. (veh ═ vehicle). (compared to the control Dex + vehicle group,＊＊＊p<0.001)
FIG. 3 shows selectivity α in forced rat swimming experiments2CCompound K (3 micromoles/kg) and compound L (3 micromoles/kg) of the receptor antagonist, the non-selective antagonist altimezole (10 micromoles/kg) and the effects of the reference antidepressants desipramine (10 micromoles/kg) and fluoxetine (10 micromoles/kg). All other compounds, except altemezole, were enhanced in activity (compared to the control vehicle,＊＊＊p<0.001)。
FIGS. 4a and 4b show the effect of compounds K and L on inhibition of the startle reflex and pre-stimulation in rats. (Veh ═ vehicle). The differences between the PCP (phencyclidine) + vehicle group and the PCP + compounds K and L group are indicated by asterisks in figure 1.
FIGS. 5a and 5b show the effect of the non-selective antagonist altimeprazole (ati) on inhibition of the startle reflex and pre-stimulation in rats in the presence of phencyclidine (PCP); (veh ═ vehicle). Compared to the vehicle + PCP group, indicated by an asterisk in figure 1.
Detailed Description
One embodiment of the present invention includes the use of a compound of formula I or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for the treatment of alpha2The use of a receptor antagonist in the manufacture of a medicament for the treatment of a disease or condition for which it is effective,
wherein the content of the first and second substances,
x is CR2R2', O, S or NR2；
Z is-CHR8-(CH2)n-or a single bond;
R1is hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halogen, halo (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-, CN, NO2、NH2One or two (C)1-C6) An alkylamino group or a carboxyl group;
R2and R2' are each H, hydroxy or (C)1-C6) Alkyl or R2And R2' the carbon ring atoms to which they are attached form a carbonyl group;
R3is H, hydroxy, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl group, (C)3-C7) Cycloalkyl (C)1-C6) Alkyl, aryl (C)1-C6) Alkyl, aryloxy, aryl (C)1-C6) Alkoxy, aryloxy (C)1-C6) Alkyl, aryl(s) (iii)C1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, NH2Amino group (C)1-C6) Alkyl, mono-or di (C)1-C6) Alkylamino, mono-or di (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, (C)1-C6) alkyl-CO-, (C)1-C6) alkyl-CO-O-, (C)1-C6) alkyl-CO-O- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-, (C)1-C6) alkoxy-CO- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO- (C)1-C6) Alkoxy (C)1-C6) Alkyl, carbamoyl, mono-or di (C)1-C6) Alkylcarbamoyl, carboxy or (C)1-C6) alkyl-S- (C)1-C6) Alkyl group, wherein (C) is3-C7) Cycloalkyl or aryl is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxy, NH2CN or NO2Or R is3Or R4With R6Form bonds between the ring atoms to which they are attached;
R4is H, hydroxy, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R5is H, hydroxy, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl group, (C)3-C7) Cycloalkyl (C)1-C6) Alkyl, aryl (C)1-C6) Alkyl, aryloxy, aryl (C)1-C6) Alkoxy, aryloxy (C)1-C6) Alkyl, aryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)1-C6) alkyl-CO-O-, (C)1-C6) alkyl-CO-O- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO- (C)1-C6) Alkoxy (C)1-C6) Alkyl, carbamoyl, mono-or di (C)1-C6) Alkylcarbamoyl, carboxy or (C)1-C6) alkyl-S- (C)1-C6) Alkyl group, wherein (C) is3-C7) Cycloalkyl or aryl is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxy, NH2CN or NO2Or R is3And R4Form, with the carbon ring atoms to which they are attached, a fused five-to seven-membered ring formed from 1 to 3 substituents R9Substituted saturated carbocyclic ring, each R9Independently is hydroxyl, (C)1-C6) Alkyl, halogen, NH2、NO2、(C3-C7) Cycloalkyl, hydroxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, amino (C)1-C6) Alkyl, mono-or di (C)1-C6) Alkylamino, mono-or di (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, carboxyl, (C)1-C6) alkyl-CO-, (C)1-C6) alkyl-CO-O-, (C)1-C6) alkoxy-CO-, (C)1-C6) alkoxy-CO- (C)1-C6) Alkyl, carbamoyl, mono-or di (C)1-C6) Alkylcarbamoyl or oxo;
R6is H, hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy (C)1-C6) Alkyl or R6At the ring atom to which it is attached and R7A bond is formed between the attached ring atoms;
R7is H, hydroxy, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R8is H, hydroxy, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy (C)1-C6) Alkyl or, when n is 0, R7And R8With the carbon ring atoms to which they are attached forming a fused five-to seven-membered saturated carbocyclic ring, the carbocyclic ring formed being unsubstituted or substituted by 1 to 3 substituents R10Substituted, each substituent R10Independently is hydroxyl, (C)1-C6) Alkyl, halogen, NH2、NO2、(C3-C7) Cycloalkyl, hydroxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, amino (C)1-C6) Alkyl, mono-or di (C)1-C6) Alkylamino, mono-or di (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, carboxyl, (C)1-C6) alkyl-CO-, (C)1-C6) alkyl-CO-O-, (C)1-C6) alkoxy-CO-, (C)1-C6) alkoxy-CO- (C)1-C6) Alkyl, carbamoyl, mono-or di (C)1-C6) Alkylcarbamoyl or oxo;
R15is H, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, amino (C)1-C6) Alkyl, mono-or di (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, (C)1-C6) alkyl-CO-, (C)1-C6) alkyl-CO-O- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-, (C)1-C6) alkoxy-CO- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO- (C)1-C6) Alkoxy (C)1-C6) Alkyl, carbamoyl, mono-or di (C)1-C6) Alkylcarbamoyl or carboxyl;
R16is H or (C)1-C6) An alkyl group;
R7and R8To an adjacent carbon ring atom;
m is 0 to 2; and is
n is 0 or 1;
however, 1, 2,3, 4, 5, 10 b-hexahydro-10-thioxo-3 a-aza-cyclopenta [ a ] fluorenes (cyclopenta [ a ] fluorenes) are excluded.
In a possible subgroup of the compounds of the formula I, X is NR2。
In a further possible subgroup of the compounds of the formula I, m is 0, n is 0 and R2Is H, R3Is H, hydroxy, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl, halo (C)1-C6) Alkyl, (C)1-C6) alkyl-CO-, (C)1-C6) alkyl-CO-O- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-or (C)1-C6) alkoxy-CO- (C)1-C6) Alkyl radical, R4Is H, hydroxy, (C)1-C6) Alkyl or hydroxy (C)1-C6) Alkyl radical, R5Is H, hydroxy, (C)1-C6) Alkyl or (C)1-C6) Alkoxy radical, R6Is H or (C)1-C6) Alkyl and R7Is H, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group.
In a further possible subgroup of the compounds of the formula I, R3Is H or (C)1-C6) Alkyl and R4Is hydroxy or hydroxy (C)1-C6) An alkyl group.
In a further possible subgroup of the compounds of the formula I, R4And R5The carbon ring atoms to which they are attached form a fused six membered saturated carbocyclic ring.
In a further possible subgroup of the compounds of the formula I, R4And R6Forming bonds or R between the ring atoms to which they are attached6At the ring atom to which it is attached and R7The linking ring atoms form bonds therebetween.
In a further possible subgroup of compounds of the formula I, the compounds are 1 α -ethyl-1, 2,3, 4,6, 7, 12, 12b β -octahydro-indolo [2, 3-a ] quinolizin-1-ol, (1 β -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizin-1-yl) -methanol, 1 α -methyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-ol, (1 α -methyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol or 3,4, 4a beta, 5, 6, 7, 8, 13, 13b beta, 13c alpha-decahydro-2H-6 a, 13-diaza-indeno [1, 2-c ] phenanthren-1-one.
In a further possible subgroup of the compounds of the formula I, X is CR2R2’。
In other possible subgroups of the compounds of formula I, X is S.
In other possible subgroups of the compounds of formula I, X is O.
When X is OPossible subgroups of the compounds of the formula I include R5And R6A compound as defined above in the description of the use of the compound of formula I.
When X is O, in a further possible subgroup of the compounds of the formula I, R5Is H, hydroxy, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl group, (C)3-C7) Cycloalkyl (C)1-C6) Alkyl, aryl (C)1-C6) Alkyl, aryloxy, aryl (C)1-C6) Alkoxy, aryloxy (C)1-C6) Alkyl, aryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)1-C6) alkyl-CO-O-, (C)1-C6) alkyl-CO-O- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO- (C)1-C6) Alkoxy (C)1-C6) Alkyl, carbamoyl, mono-or di (C)1-C6) Alkylcarbamoyl, carboxy or (C)1-C6) alkyl-S- (C)1-C6) Alkyl and R6Is H, hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy (C)1-C6) An alkyl group.
Another embodiment of the present invention provides novel compounds of formula IA, pharmaceutically acceptable salts or esters thereof:
wherein the content of the first and second substances,
x is CR2R2', O or S;
Z、R1、R2、R2’、R3-R10、R15and R16M and n are as defined in claim 1,
with the proviso that
a) When X is O, m is 0 and n is 0, then R3-R8Not hydrogen at the same time;
b) with the exception of the following compounds: 1, 2,3, 4, 5, 10 b-hexahydro-10-thia-3 a-aza-cyclopenta [ a ] fluorene;
1, 3,4, 5, 6, 11 b-hexahydro-2H-11-thia-4 a-aza-benzo [ a ] fluorene;
1- (1, 3,4, 5, 6, 11 b-hexahydro-2H-11-thia-4 a-aza-benzo [ a ] fluoren-1-yl) -ethanone or 1, 3,4, 5, 6, 11 b-hexahydro-2H-11-thia-4 a-aza-benzo [ a ] fluorene-1-carboxylic acid methyl ester; for example,
x is CR2R2'; or
X is O; or
X is S; or
R3Is hydroxy, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-or (C)1-C6) alkyl-CO-O- (C)1-C6) Alkyl and R4Is H, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group; or
R3Is hydroxy, hydroxy (C)1-C6) Alkyl or (C)1-C6) Alkoxy (C)1-C6) Alkyl and R4Is (C)1-C6) An alkyl group; or
R4And R5Form, together with the carbon ring atoms to which they are attached, a fused six-membered saturated carbocyclic ring; or
The compounds are 1 alpha-methyl-1, 3,4, 5, 6, 11 b-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-ol, (1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol, (-) - (1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol, (+) - (1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol, 1 alpha-isopropyl-1, 3,4, 5, 6, 11 b-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-ol, 1 alpha-ethyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-ol, (1 alpha-ethyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol, 1-methyl-1 α,3, 4,6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene, (1-hydroxymethyl-1, 3,4, 5, 6, 11 b-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol, 1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene, (-) -1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro 2H-11-oxa-4 a-aza-benzo [ a a ] fluorene, (+) -1-methoxymethyl-1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene, 1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene-1-carboxylic acid ethyl ester, 1-ethoxymethyl-1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene, (1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene [a] Fluoren-1-yl) -methanol, (-) - (1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol, (+) - (1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol, 1 α -ethyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene-1-carboxylic acid methyl ester, methyl ester, 1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene, (-) -1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene, (+) -1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene, (1 α -ethyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol, acetic acid 1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-ylmethyl ester or (1 α -methyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindeno [2, 1-a ] quinolizin-1-yl) -methanol.
Another embodiment of the present invention provides novel compounds of formula IB, pharmaceutically acceptable salts or esters thereof:
wherein the content of the first and second substances,
x is NR2；
R2Is (C)1-C6) An alkyl group;
Z、R1、R3-R10、R15、R16m and n are as defined in claim 1,
with the proviso that
a) When m is 0 or R1Methoxy radical and R4When H or ethyl, then R3Is not methoxy-CO;
b) with the exception of the following compounds: 12-methyl-1, 2,3, 4,6, 7, 12, 12 b-octahydro-indolo [2, 3-a ] quinolizine; 1-ethyl-12-methyl-1, 2,3, 4,6, 7, 12, 12 b-octahydro-indolo [2, 3-a ] quinolizine; 2, 3-diethyl-12-methyl-1, 2,3, 4,6, 7, 12, 12 b-octahydro-indolo [2, 3-a ] quinolizine; 12-methyl-1, 2,3, 4,6, 7, 12, 12 b-octahydro-indolo [2, 3-a ] quinolizin-1-ol; 2- (1-ethyl-12-methyl-1, 2,3, 4,6, 7, 12, 12 b-octahydro-indolo [2, 3-a ] quinolizin-1-yl) -ethanol; 11-methyl-2, 3, 5, 6, 11, 11 b-hexahydro-1H-indolino [8, 7-b ] indole; (11-methyl-2, 3, 5, 6, 11, 11 b-hexahydro-1H-indolino [8, 7-b ] indol-1-yl) -methanol; (1, 11-diethyl-2, 3, 5, 6, 11, 11 b-hexahydro-1H-indolizino [8, 7-b ] indol-1-yl) -methanol or 3- (1-ethyl-12-methyl-1, 2,3, 4,6, 7, 12, 12 b-octahydro-indolo [2, 3-a ] quinolizin-1-yl) -propionic acid methyl ester; for example
R3Is hydroxy, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl or (C)1-C6) Alkoxy (C)1-C6) Alkyl and R4Is H, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group; or
The compound is 1 alpha-ethyl-12-methyl-1, 2,3, 4,6, 7, 12b beta-octahydro-indolo [2, 3-a ] quinolizin-1-ol or 1 alpha-ethyl-12-ethyl-1, 2,3, 4,6, 7, 12b beta-octahydro-indolo [2, 3-a ] quinolizin-1-ol.
Another embodiment of the present invention provides novel compounds of formula IC, pharmaceutically acceptable salts or esters thereof:
wherein the content of the first and second substances,
x is NR2；
R2Is H;
z is-CHR8-(CH2)n-or a single bond;
n is 0;
R1、R3、R6-R9、R15、R16and m is as defined in claim 1;
r is 1-3;
with the proviso that the following compounds are excluded: 10-methyl-5, 7, 7a, 8, 9, 10, 11, 11a, 11b, 12-decahydro-6H-6 a, 12-diaza-indeno [1, 2-a ] fluorene; 3-hydroxy-1, 2,3, 4, 4a, 5, 6, 7, 8, 13, 13b, 13 c-dodecahydro-6 a, 13-diaza-indeno [1, 2-c ] phenanthrene-4-carboxylic acid methyl ester; 3-ethyl-1, 2, 3a, 4,6, 7, 12b, 12 c-octahydro-3H, 12H-indolo [2, 3-g ] cyclopenta [ a ] indolizine-2-carboxylic acid methyl ester;
1, 2, 3a, 4,6, 7, 12b, 12 c-octahydro-3H, 12H-indolo [2, 3-g ] cyclopenta [ a ] indolizine-2-carboxylic acid methyl ester or 12 c-ethyl-1, 3a, 4,6, 7, 12b, 12 c-octahydro-cyclopenta [1, 2] indolizine [8, 7-b ] indol-3 (2H) -one; for example
R is 1 and R3Is H, hydroxy, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group; or
The compound is 3,4, 4a beta, 5, 6, 7, 8, 13, 13b beta, 13c alpha-decahydro-2H-6 a, 13-diaza-indeno [1, 2-c ] phenanthrene-1-one, 1, 2,3, 4, 5, 6, 7, 8, 13, 13 b-decahydro-6 a, 13-diaza-indeno [1, 2-c ] phenanthrene, 1 alpha, 2,3, 4, 4a beta, 5, 6, 7, 8, 13, 13b beta, 13c alpha-dodecahydro-6 a, 13-diaza-indeno [1, 2-c ] phenanthrene-1-yl acetate or 1 beta, 2,3, 4, 4a beta, 5, 6, 7, 8, 13, 13b beta, 13c alpha-dodecahydro-6 a, 13-diaza-indeno [1 ], 2-c ] phenanthren-1-yl ester.
Another embodiment of the present invention provides novel compounds of formula ID, a pharmaceutically acceptable salt or ester thereof:
wherein the content of the first and second substances,
x is NR2；
R2Is H;
z is-CH- (CH)2)n-；
n is 0;
R1、R3-R10R15、R16and m is as defined in claim 1,
t is 0 to 3;
with the proviso that the following compounds are excluded: 1, 2,3, 4, 4a, 5, 6, 11, 11b, 12, 13, 13 a-dodecahydro-4 b, 11-diaza-indeno [2, 1-a ] phenanthrene; 1, 2,3, 4, 4a, 5, 6, 11, 11b, 12-decahydro-4 b, 11-diaza-indeno [2, 1-a ] phenanthrene; 9-methoxy-1, 2,3, 4, 4a, 5, 6, 11, 11b, 12-decahydro-4 b, 11-diaza-indeno [2, 1-a ] phenanthrene or methyl 1-hydroxy-1, 2,3, 4, 4a, 5, 6, 11, 11b, 12, 13, 13 a-dodecahydro-4 b, 11-diaza-indeno [2, 1-a ] phenanthrene-2-carboxylate.
Another embodiment of the present invention provides novel compounds of formula IE, pharmaceutically acceptable salts or esters thereof:
wherein
X is NR2；
R2Is H;
Z、R1、R3-R10、R15、R16and m is as defined in claim 1; n is a number of 1, and n is,
with the proviso that the following compounds are excluded: 2,3, 4, 5, 7, 8, 13, 13 b-octahydro-2, 3-diethyl-1H-aza [1 ', 2': 1, 2] pyrido [3, 4-b ] indole; acetic acid 2,3, 4, 5, 7, 8, 13, 13 b-octahydro-1H-azafuro [1 ', 2': 1, 2] pyrido [3, 4-b ] indol-2-ylmethyl ester; 2,3, 4, 5, 7, 8, 13, 13 b-octahydro-1H-azepino [1 ', 2': 1, 2] pyrido [3, 4-b ] indole-2- [ (phenylmethoxy) methyl ] or 2,3, 4, 5, 7, 8, 13, 13 b-octahydro-1H-azepino [1 ', 2': 1, 2] pyrido [3, 4-b ] indole-4-ethyl-2- [ (phenylmethoxy) methyl ]; for example
The compound is 2,3, 4, 5, 7, 8, 13, 13 b-octahydro-1H-aza * o [1 ', 2': 1, 2] pyrido [3, 4-b ] indoles.
Embodiments of other novel compounds provided herein are 2 β -methoxy-1, 2,3, 4,6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizine, 2 α -methoxy-1, 2,3, 4,6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizine, 1 α -ethyl-2 α -methyl-1, 2,3, 4,6, 7, 12, 12b β -octahydro-indolo [2, 3-a ] quinolizine-1-ol, 1 α -isopropyl-1, 2,3, 4,6, 7, 12, 12b β -octahydro-indolo [2, 3-a ] quinolizine-1-ol, (-) -1 α -isopropyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-ol, (+) -1 alpha-isopropyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-ol, 1 beta-isopropyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin, (1 alpha-isopropyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol, (1 alpha-n-propyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol, 2- (1 α,2, 3,4, 6, 7, 12, 12b β -octahydro-indolo [2, 3-a ] quinolizin-1-yl) -butan-2-ol, 1- (1, 2 α,3, 4,6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizin-2-yl) -propan-1-ol, 2- (1 α,2, 3,4, 6, 7, 12, 12b β -octahydro-indolo [2, 3-a ] quinolizin-1-yl) -propan-2-ol, 1-s-butyl-1, 2,3, 4,6, 7, 12, 12b β -octahydro-indolo [2, 3-a ] quinolizin-1-ol, 1-cyclohexyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-ol, 9-fluoro-1 α -isopropyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-ol, (1 α -methyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol, (-) - (1 α -methyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol, and mixtures thereof, (+) - (1. alpha. -methyl-1, 2,3, 4,6, 7, 12, 12 b. beta. -octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol, (1. alpha. -ethyl-1, 4,6, 7, 12, 12 b. beta. -hexahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol, 3. beta., 4. alpha. -dimethyl-1, 2,3, 4,6, 7, 12, 12 b. beta. -octahydroindolo [2, 3-a ] quinolizin, (1, 2. alpha., 3,4, 6, 7, 12, 12 b. alpha. -octahydroindoo [2, 3-a ] quinolizin-2-yl) -propan-2-ol, (1, 2. alpha., 3,4, 6, 7, 12, 12 b. beta. -octahydroindolo [2, 3-a ] quinolizin-2-yl) -propan-2-ol, (2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizin-2-yl) -methanol, (2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-2-yl) -methanol, (1 α -ethyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindoo [2, 3-a ] quinolizin-1-ylmethoxy) -acetic acid ethyl ester, 1- (2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizin-2-yl) -ethanone, 1- (2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizin-2-yl) -ethanol, 2- (2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizin-2-yl) -propan-2-ol, 2- (3-ethyl-1, 2 α,3 α,4, 6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizin-2-yl) -propan-2-ol, (3-ethyl-2-methyl-1 α,2 beta, 3 beta, 4,6, 7, 12, 12 beta-octahydro-indolo [2, 3-a ] quinolizin-1-yl) -methanol, 3-ethyl-1, 2-dimethyl-1 alpha, 2 beta, 3 beta, 4,6, 7, 12, 12b beta-octahydro-indolo [2, 3-a ] quinolizine, 1, 2-dimethyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydro-indolo [2, 3-a ] quinolizin-1 beta-ol, (1-ethyl-2-methyl-1 beta, 2 beta, 3 beta, 4,6, 7, 12, 12b alpha-octahydro-indolo [2, 3-a ] quinolizin-3-yl) -methanol, 1-beta-hydroxymethyl-1-methyl-1, methyl 2,3, 4,6, 7, 12, 12b β -octahydro-indolo [2, 3-a ] quinolizine-6 β -carboxylate, 5, 6, 7, 7a β,8, 9, 10, 11, 11a β, 11b α -decahydro-12-oxa-6 a-aza-indeno [1, 2-a ] fluorene, 2,3, 4, 4a β,5, 6, 7, 8, 13b β, 13c β -decahydro-1H-13-oxa-6 a-aza-indeno [1, 2-c ] phenanthrene, 2,3, 4, 4a β,5, 6, 7, 8, 13b α, 13c β -decahydro-1H-13-oxa-6 a-aza-indeno [1, 2-c ] phenanthrene, 2,3, 4, 4a β,5, 6, 7, 8, 13, 13b β -decahydro-1H-6 a, 13-diaza-indeno [1, 2-c ] phenanthrene-13 c β -ol, (-) -2, 3,4, 4a β,5, 6, 7, 8, 13, 13b β -decahydro-1H-6 a, 13-diaza-indeno [1, 2-c ] phenanthrene-13 c β -ol, (+) -2, 3,4, 4a β,5, 6, 7, 8, 13, 13b β -decahydro-1H-6 a, 13-diaza-indeno [1, 2-c ] phenanthrene-13 c β -ol, (2, 3,4, 4a β,5, 6, 7, 8, 13, 13b β -decahydro-1H-6 a, 13-diaza-indeno [1, 2-c ] phenanthrene) -13c β -methanol or 5, 6, 7, 7a, 11, 11b, 12-decahydro-6 a, 12-diaza-indeno [1, 2-a ] fluoren-11 a-ol.
The terms used herein have the following meanings:
the term "halo" or "halogen" as used herein as a group per se or as part of another group refers to chloro, bromo, fluoro or iodo.
The term "carboxy" as used herein refers to the-COOH group.
The term "oxo" as used herein refers to an ═ O group.
The term "(C) as used herein as the radical per se or as part of another radical1-C6) Alkyl "refers to a straight or branched carbon chain having 1 to 6 carbon atoms. (C)1-C6) Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like.
The term "(C) as used herein as a radical per se or as part of another radical2-C6) Alkenyl "means a straight or branched chain group having 2 to 6 carbon atoms and containing a double bond.
The term "(C) as used herein as a radical per se or as part of another radical3-C7) Cycloalkyl "refers to a saturated cyclic hydrocarbon group having 3 to 7 carbon atoms. Typical examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "(C) as used herein3-C7) Cycloalkyl (C)1-C6) Alkyl "means (C) as defined herein1-C6) (C) as defined herein, wherein the alkyl group is attached to the parent molecular moiety3-C7) A cycloalkyl group.
The term "aryl" as used herein as a group per se or as part of another group refers to monocyclic or bicyclic aryl groups having 6 to 12 carbon atoms. Typical examples of aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
The term "aryl (C) as used herein as a radical per se or as part of another radical1-C6) Alkyl "means (C) as defined herein1-C6) An aryl group, as defined herein, appended to the parent molecular moiety is an alkyl group.
The term "aryloxy" as used herein either as a group per se or as part of another group, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an-O-group.
The term "aryl (C) as used herein as a radical per se or as part of another radical1-C6) Alkoxy "means (C) as defined herein1-C6) An aryl group, as defined herein, having an alkoxy group attached to the parent molecular moiety.
The term "aryloxy (C) as used herein1-C6) Alkyl means (C) as defined herein1-C6) An aryloxy group, as defined herein, to which the alkyl group is attached to the parent molecular moiety.
The term "aryl (C) as used herein1-C6) Alkoxy (C)1-C6) Alkyl "means (C) as defined herein1-C6) Aryl (C) as defined herein, wherein the alkyl group is attached to the parent molecular moiety1-C6) An alkoxy group.
The term "hydroxy" as used herein as a group per se or as part of another group refers to an-OH group.
The term "hydroxy (C) as used herein as a radical per se or as part of another radical1-C6) Alkyl "means (C) as defined herein1-C6) Having alkyl groups bound to the parent molecular moietyAt least one hydroxyl group as defined herein. Hydroxy (C)1-C6) Typical examples of alkyl groups include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-methyl-1-hydroxyethyl, 1-methyl-1-hydroxypropyl, and the like.
The term "halo (C) as used herein1-C6) Alkyl "means (C) as defined herein1-C6) One or more halogens, as defined herein, attached to the parent molecular moiety is an alkyl group. Halo (C)1-C6) Typical examples of alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl, and the like.
The term "amino" as used herein as a group per se or as part of another group means-NH2A group.
All terms herein "amino (C)1-C6) Alkyl "means (C) as defined herein1-C6) An alkyl group is an amino group, as defined herein, appended to the parent molecular moiety. Amino (C)1-C6) Typical examples of alkyl groups include, but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl, 1-methyl-1-aminoethyl, and the like.
The term "mono-or di (C) as used herein as a radical per se or as part of another radical1-C6) Alkylamino "refers to one or two of (C) as defined herein attached to the parent molecular moiety through an amino group as defined herein1-C6) An alkyl group. One or two (C)1-C6) Typical examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, and the like.
All terms herein "mono or di (C)1-C6) Alkylamino radical (C)1-C6) Alkyl "means (C) as defined herein1-C6) Alkyl groups and parent moleculesPartially linked mono-or di (C) as defined herein1-C6) An alkylamino group. One or two (C)1-C6) Alkylamino radical (C)1-C6) Typical examples of alkyl groups include, but are not limited to, N-dimethylaminomethyl, N-diethylaminomethyl, N-methylaminoethyl, N-methylaminopropyl, N-ethyl-N-methylaminomethyl, and the like.
The term "(C) as used herein as a radical per se or as part of another radical1-C6) Alkoxy "means (C) as defined herein attached to the parent molecular moiety through an-O-group1-C6) An alkyl group. (C)1-C6) Typical examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
The term "(C) as used herein as a radical per se or as part of another radical1-C6) Alkoxy (C)1-C6) Alkyl "means (C) as defined herein1-C6) (C) wherein the alkyl group is attached to the parent molecular moiety1-C6) An alkoxy group. (C)1-C6) Alkoxy (C)1-C6) Typical examples of alkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-dimethoxypropyl, 2, 4-dimethoxybutyl, and the like.
The term "hydroxy (C) as used herein as a radical per se or as part of another radical1-C6) Alkoxy "means (C) as defined herein1-C6) An alkoxy group is a hydroxy group, as defined herein, appended to the parent molecular moiety.
The term "hydroxy (C) as used herein1-C6) Alkoxy (C)1-C6) Alkyl "means (C) as defined herein1-C6) Hydroxy (C) as defined herein, wherein the alkyl group is attached to the parent molecular moiety1-C6) An alkoxy group.
The term "carbamoyl" as used herein as a group per se or as part of another group refers to-CONH2A group.
All terms herein "mono or di (C)1-C6) -alkylcarbamoyl "means one or two (C) groups as defined herein attached to the parent molecular moiety through a-HNCO-or-NCO-group1-C6) An alkyl group. One or two (C)1-C6) Typical examples of the-alkylcarbamoyl group include, but are not limited to, an N-methylcarbamoyl group, an N-ethylcarbamoyl group, an N-propylcarbamoyl group, an N, N-dimethylcarbamoyl group, an N, N-diethylcarbamoyl group and the like.
Compounds of formula I and formula IA, IB, IC, ID and IE and their pharmaceutically acceptable salts and esters are, unless otherwise indicated, referred to as the compounds of the invention as follows.
The present invention includes within its scope all possible isomers of the compounds, including geometric isomers such as the Z and E isomers (cis and trans isomers), as well as optical isomers such as diastereomers and enantiomers. Furthermore, within the scope of the present invention, the present invention encompasses both the individual isomers and any mixtures thereof, such as racemic mixtures. The individual isomers can be obtained by starting from the corresponding isomeric forms or the final compound can be isolated after the end of the preparation according to customary separation methods. For separating optical isomers such as enantiomers from the mixture, a common resolution method such as fractional crystallization can be employed.
Pharmaceutically acceptable salts are known in the pharmaceutical art, e.g., acid addition salts with organic and inorganic acids. Examples of such salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, sulfonate, formate, tartrate, maleate, citrate, benzoate, salicylate, and ascorbate. Pharmaceutically acceptable esters can be prepared by known methods using pharmaceutically acceptable acids which are customary in the pharmaceutical art and retain their pharmacological properties in free form, if such esters are suitable. Examples of such esters include, but are not limited to, esters of aliphatic or aromatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl esters.
The compounds of the present invention can be prepared by methods analogous to or according to those disclosed in the literature, using appropriate starting materials. The starting materials of formulae II, III and IV are commercially available or can be prepared by various synthetic methods disclosed in the literature.
For example, arylalkylamines of the formula (II) used as starting materials
Wherein R is1X is NH, O, CH, as defined above2Or S.
When X is O, the amine of formula (II) can be prepared by, for example, the method disclosed in U.S. patent specification No. 4,710,504. When X is CH2The compounds of formula (II) may be prepared by the method described in J.Med.chem.10(1967) 856-859. When X is S, the compounds of formula (II) can be prepared by decarboxylation of the corresponding 3- (thianaphthen-3-yl) -L-alanine.
Other compounds useful as starting materials include compounds of formula (III)
Wherein R is3As defined above, R11Is OH or halogen.
Furthermore, the compounds used as starting materials also include compounds of the formula (IV)
Wherein R is3-R7And Z is as defined above, Y is O or NH. The compound of formula (IV) is prepared according to the method described in Tetrahedron33(1977) 1803-1808. Similarly, the lactone (Y ═ O) can be replaced with the corresponding acid chloride. When R is3And R5When forming the ring, the compounds of formula (IV) can be prepared by partial reduction of the corresponding anhydride.
Compounds of formula (I) wherein X is NH, O or S are typically prepared, for example, according to a procedure analogous to or employing the following scheme 1:
scheme 1
Wherein R is1、R3-R7And Z is as defined above.
According to the reaction scheme 1, the amine (II) is alkylated with a compound of formula (III) under basic conditions as described in Gazz. Chim. Ital.111(1981)257-267 to give the amide compound (V), which is converted to the enamine (VII) via beta-carboline (V) by a Bischler-Napieralski reaction followed by reaction of the compound of formula (VI) with a 1, 3-dihaloalkane to form the ring D. Finally, the compounds of formula (I) can be obtained by the following reaction:
1) oxidizing enamine (VII) with potassium iodide, air, or
2) Enamine (VII) is reacted with formaldehyde in the presence of Hunig's base at 60 ℃.
Scheme 2 illustrates the preparation of X as NR2、O、CH2Or S, of the formula (I),
scheme 2
Wherein X is NR2、O、CH2Or S, R1-R7And Z is as defined above.
In scheme 2, an arylalkylamine of formula (II) wherein X is NH, is reacted according to the method described in Tetrahedron33(1977)1803-18082、O、CH2Or S) with a compound of formula (IV) (or the corresponding acid chloride) to give the amide compound (VIII). Intermediate (VIII) is subjected to Bischler-Napieralski cyclization to give enamine (IX), which can be converted to the compound of formula (I).
Alkylation of compounds of formula (I) wherein X is NH with an alkyl halide at room temperature in the presence of a suitable base according to scheme 3 below (Heterocycles27(1988) 1179-1190):
scheme 3
Wherein R is1-R7And Z is as defined above.
Scheme 4 illustrates other methods for preparing compounds of formula (I):
scheme 4
Wherein R is2Is BOC and R1、R5And R6As defined above.
In scheme 4, pyridine is alkylated with tryptophanyl bromide (X) to give pyridinium salt (XI), which is partially reduced to give the compound of formula (XII). Protection of the compound of formula (XII) with di-tert-butyl dicarbonate under basic conditions gives the compound of formula (XIII). The resulting intermediate was subjected to a Polonovski-Potier reaction and cyclized with MeOH/HCl to yield the compound of formula (I).
The preparation of compounds of formula (I) (wherein X is O, S or NH, R) is shown in scheme 5 below1And R3-R8As defined above) of the other methods:
scheme 5
In scheme 5, the derivative (XIV) is subjected to oxidative cyclization with mercuric acetate to give enamine (XV) according to the method described by Heterocycles32(1991) 489-497. The intermediate is oxidized or treated with formaldehyde as in scheme 1 or reduced with sodium borohydride to give the compound of formula (I).
Scheme 6 illustrates the preparation of wherein R6And R7Other methods of forming a bond for a compound of formula (I):
scheme 6
Wherein X is NH and R3Is a lower alkyl group.
3, 4-dihydro- β -carboline (XVI) is subjected to a heter-Diels-Alder reaction with a dienyl ester (XVII) prepared by the Wittig reaction as described in Can.J.chem.65(1987) 670-356 according to the method described in J.org.chem.52(1987)353-356 to give a compound of formula (XVIII) which is then reduced to the alcohol of formula (I).
Scheme 7 illustrates additional methods for preparing compounds of formula (I).
Scheme 7
X, R therein1、R3、R7And z is as defined above. R12Can be H or OCH3And R is13May be an alkyl or aryl group.
In scheme 7, R was prepared according to the method described in J.chem.Soc., chem.Commun. (1995)2317-12A compound of formula (XIX) which is H, prepared according to the method described in J.chem.Soc. (C) (1971)736-74312Is OCH3A compound of formula (XIX). Reacting the compound of formula (XIX) with a Grignard reagent to give the compound of formula (I). When R in the formula (XIX)12When H, the other R in formula (I)13The radical is also H.
Scheme 8 illustrates a novel process for the preparation of certain compounds of formula (I).
Scheme 8
X, R therein1、R3And z is as defined above, R14A lower alkyl group.
In scheme 8, tetrahydropyridine (XX), prepared according to the method described in J.chem.Soc. (C) (1971)736-743, is deprotonated with a strong base to give the anion (XXI). Alkylation of the anion followed by cyclization with an acid affords compounds of formula (XXII). By LiAlH4Reduction of a compound of formula (XXII) gives a compound of formula (I).
Resolution of racemic compounds of formula (I) is carried out by converting the compound of formula (I) into a mixture of diastereomeric salts by reaction with an optically active acid (e.g. D-tartaric acid, dibenzoyl-D-tartaric acid, etc.) and separating the diastereomers by crystallization.
It will be apparent to those skilled in the art that in the above reactions, any starting materials or intermediates may be protected, if desired, in a manner known in the chemical arts. The protecting functional groups are then removed by conventional means.
It should be noted that the synthetic methods described above are intended to illustrate the preparation of the compounds of the invention and are in no way limiting, i.e. other synthetic methods within the scope known to the skilled person may also be employed.
If desired, the compounds of the present invention can be converted into their pharmaceutically acceptable salt or ester forms by methods known in the art.
The present invention will be explained in more detail in the following examples. However, these examples are only for illustrating the present invention and do not limit the scope of the invention defined in the claims.
Example 1
1-propyl-4, 9-dihydro-3H-beta-carboline
8.00g (50.0mmol) of tryptamine are dissolved in 150ml of ethyl acetate and 4.80ml (52.0mmol) of n-butyric acid are slowly added. After standing at 0 ℃ for 4 hours, the reaction mixture was filtered to give 12.30g (49.5mmol) of tryptamine butyrate, which was melted. The melt was heated to 200 ℃ and held at this temperature for 30 minutes. The water formed was removed with a Dean-Stark apparatus. After cooling, the melt is mixed with 120ml of toluene, 23.5ml (257.7mmol) of phosphorus oxychloride which has just been distilled off are added and the reaction mixture is refluxed for 4 hours. The solution was evaporated in vacuo and the dark oil was mixed with 20% acetic acid solution (3 × 50 ml). The solid was filtered off and the aqueous solution was made basic by adding 25% ammonium hydroxide with cooling and extracted with dichloromethane (3 × 50 ml). The combined organic phases are dried over sodium sulfate, the drying agent is filtered off and the filtrate is evaporated to give the title compound which is purified by column chromatography (silica gel, dichloromethane/methanol, 95: 5).
NMR：1.00(t，3H)，1.75(m，2H)，2.66(t，2H)，2.87(t，2H)，3.90(t，2H)，7.00-7.62(m，4H)，8.94(br s，1H)。
MS：212(28％)，211(12％)，197(25％)，184(100％)，169(13％)。
Example 2
1-isobutyl-4, 9-dihydro-3H-beta-carbolines
The procedure of example 1 was repeated except that isovaleric acid was used instead of n-butyric acid.
NMR：0.98(d，6H)，2.16(m，1H)，2.54(d，2H)，2.86(t，2H)，3.89(t，2H)，7.00-7.62(m，4H)，8.60(br s，1H)。
MS：226(16％)，211(18％)，184(100％)，169(13％)。
Example 3
1-butyl-4, 9-dihydro-3H-beta-carboline
The procedure of example 1 was repeated except that n-pentanoic acid was used instead of n-butanoic acid.
NMR：1.00(t，3H)，7.00-7.62(m，4H)，8.64(br s，1H)。
MS：226(18％)，211(18％)，184(100％)，169(14％)。
Example 4
1- (2-methyl-butyl) -4, 9-dihydro-3H-beta-carboline
The procedure of example 1 was repeated except for using 3-methylvaleric acid instead of n-butyric acid.
NMR：0.84(t，3H)，0.87(d，3H)，7.05-7.60(m，4H)，12.2(br s，1H)。
MS：240(9％)，225(10％)，211(10％)，185(13％)，184(100％)，183(14％)，155(24％)。
Example 5
1-cyclohexylmethyl-4, 9-dihydro-3H-beta-carbolines
The procedure of example 1 was repeated except for using cyclohexylacetic acid instead of n-butyric acid.
NMR：1.0-1.9(m，11H)，2.56(d，2H)，2.85(m，2H)，3.88(m，2H)，7.14-7.63(m，4H)，8.55(brs，1H)。
MS：266(8％)，185(15％)，184(100％)，183(12％)，155(17％)。
Example 6
1 beta-isopropyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizine
2.56g (11.5mmol)4, 9-dihydro-1-isobutyl-3-H-pyrido [3, 4-b ] indole (example 2), 2ml N-ethyldiisopropylamine and 1.35ml (13.8mmol) 1-bromo-3-chloropropane are dissolved in 50ml acetonitrile. The mixture was refluxed for 8 hours under argon. After evaporation of the solvent, 20ml of methanol and 1.3g (34.5mmol) of sodium borohydride were added. The reaction mixture was stirred at room temperature for 1 hour and then 20ml of water were added. The reaction mixture was extracted with dichloromethane (3 × 50 ml). The combined organic phases are dried over sodium sulfate, the drying agent is filtered off and the filtrate is evaporated to give the title compound which is purified by column chromatography (silica gel, dichloromethane/methanol, 95: 5).
NMR：1.02(br s，6H)，7.11(t，1H)，7.18(t，1H)，7.35(d，1H)，7.48(d，1H)，7.85(br s，1H)。
MS：267(100％)，253(20％)，197(35％)，170(30％)，169(30％)。
Example 7
2- (1 alpha, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-yl) -butan-2-ol
0.11ml (0.8mmol) of ethylmagnesium bromide (1.0M) are added at-60 ℃ to a solution of 190mg (0.7mmol) of 1- (12, 3,4, 6, 7, 12, 12 b-octahydro-indolo [2, 3-a ] quinolizin-1-yl) -ketene in 5ml of dichloromethane (Tetrahedron Lett.30(1989) 719-722). The reaction mixture was stirred at this temperature for 30 minutes and at room temperature for 2 hours. Water (10ml) was then added and the reaction mixture was extracted with dichloromethane (3 × 50 ml). The combined organic phases are dried over sodium sulfate, the drying agent is filtered off and the filtrate is evaporated to give the title compound which is purified by column chromatography (silica gel, dichloromethane/methanol, 95: 5).
NMR：0.97(t，3H)，1.30(s，3H)，4.69(br s，1H)，7.00-7.50(m，4H)，8.36(brs，1H)。
MS：297(100％)，281(30％)，269(35％)，225(28％)，197(45％)，170(35％)，169(34％)。
Example 8
2- (1 α,2, 3,4, 6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-yl) -propan-2-ol the procedure of example 7 was repeated except that methyl magnesium bromide was used instead of ethyl magnesium bromide.
NMR：1.37(s，3H)，1.42(s，3H)，4.73(br s，1H)，7.00-7.50(m，4H)，8.18(br s，1H)。
MS：283(100％)，267(42％)，225(33％)，197(60％)，170(50％)，169(50％)。
Example 9
1 alpha-isopropyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-ol (Compound A)
5.13g (23.0mmol) of 4, 9-dihydro-1-isopropyl-3-H-pyrido [3, 4-b ] indole, 4ml of N-ethyldiisopropylamine and 2.7ml (27.6mmol) of 1-bromo-3-chloropropane are dissolved in 100ml of acetonitrile. The mixture was refluxed for 8 hours under argon. The black solution was concentrated to an oil and treated with 20% sodium hydroxide. After stirring for 10 min, the solution was extracted with dichloromethane (3 × 50 ml). The combined organic phases were dried over sodium sulfate, the drying agent was filtered off and the filtrate was evaporated to give the corresponding enamine, which was dissolved in 100ml acetonitrile. 7.0g (27.6mmol) iodine and 4.6g (27.6mmol) potassium iodide were added. The reaction mixture was stirred under air protected from light for 3 hours. After evaporation of the solvent, 50ml of methanol are added and, with cooling, 2.6g (69mmol) of sodium borohydride are added. The reaction mixture was stirred at room temperature for 1 hour, and then 20ml of water was added. The reaction mixture was extracted with dichloromethane (3 × 50 ml). The combined organic phases are dried over sodium sulfate, the drying agent is filtered off and the filtrate is evaporated to give the title compound which is purified by column chromatography (silica gel, dichloromethane/methanol, 95: 5).
N MR：0.47(d，3H)，0.90(d，3H)，3.48(br s，1H)，7.00-7.50(m，4H)，8.92(br s，1H)。
MS：284(14％)，239(13％)，171(100％)，170(16％)，169(33％)。
Example 10
1 alpha-Ethyl-2 alpha-methyl-1, 2,3, 4,6, 7, 12, 12 beta-octahydro-indolo [2, 3-a ] quinolizin-1-ol (Compound B)
The procedure of example 9 was repeated except for using 4, 9-dihydro-1-propyl-3-H-pyrido [3, 4-b ] indole in place of 4, 9-dihydro-1-isopropyl-3-H-pyrido [3, 4-b ] indole and 1, 3-dibromobutane in place of 1-bromo-3-chloropropane.
NMR：0.69(t，3H)，1.00(d，3H)，3.20(br s，1H)，7.00-7.60(m，4H)，9.04(br s，1H)。
MS：284(5％)，267(15％)，225(100％)，210(15％)，195(15％)，182(72％)，171(41％)，170(22％)，169(32％)。
Example 11
9-fluoro-1 alpha-isopropyl-1, 2,3, 4,6, 7, 12, 12 beta-octahydro-indolo [2, 3-a ] quinolizin-1-ol
The procedure of example 9 was repeated except for using 6-fluoro-1-isobutyl-4, 9-dihydro-3H-pyrido [3, 4-b ] indole (prepared from 5-fluorotryptamine according to the method described in example 2) instead of 4, 9-dihydro-1-isobutyl-3H-pyrido [3, 4-b ] indole.
NMR：0.45(d，3H)，0.89(d，3H)，3.32(s，1H)，6.8-7.25(m，3H)，8.94(brs，1H)。
MS：302(26％)，203(13％)，189(100％)，161(26％)。
Example 12
1-s-butyl-1, 2,3, 4,6, 7, 12, 12b β -octahydro-indolo [2, 3-a ] quinolizin-1-ol (isomer mixture) (Compound C)
The procedure of example 9 was repeated except for substituting 1- (2-methylbutyl) -4, 9-dihydro-3H-pyrido [3, 4-b ] indole for 4, 9-dihydro-1-isobutyl-3H-pyrido [3, 4-b ] indole.
NMR: 0.48(d, 3H, major isomer), 0.69(t, 3H, minor isomer), 0.82(t, 3H, major isomer), 0.92(d, 3H, minor isomer), 3.30(s, 1H), 7.0-7.5(m, 4H), 8.88(brs, 1H, minor isomer), 8.93(br s, IH, major isomer).
MS：298(23％)，172(24％)，171(100％)，170(15％)，169(23％)，143(29％)。
Example 13
1-cyclohexyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydro-indolo [2, 3-a ] quinolizin-1-ol
The procedure of example 9 was repeated except for using 1-cyclohexylmethyl-4, 9-dihydro-3H-pyrido [3, 4-b ] indole in place of 4, 9-dihydro-1-isobutyl-3H-pyrido [3, 4-b ] indole.
NMR：3.35(brs，1H)，7.02-7.55(m，4H)，8.98(brs，1H)。
MS：324(21％)，172(12％)，171(100％)，170(10％)，169(15％)，143(22％)。
Example 14
(1 alpha-isopropyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydro-indolo [2, 3-a ] quinolizin-1-yl) -methanol
The procedure of example 9 was repeated except that 40% water-soluble formaldehyde was used instead of iodine and potassium iodide oxyalkylene amine and the reaction mixture was heated under reflux for 3 hours and the solvent was evaporated. The residue was diluted with ethyl acetate and washed with brine. The combined organic phases are dried over sodium sulfate, the drying agent is filtered off and the filtrate is evaporated to give the title compound which is purified by column chromatography (silica gel, dichloromethane/methanol, 98: 2).
NMR：0.58(br s，3H)，0.82(d，3H)，3.07(br s，1H)，3.62(d，1H)，4.13(d，1H)，7.00-7.50(m，4H)，9.41(br s，1H)。
MS：298(100％)，297(55％)，281(60％)，170(75％)，169(52％)。
Example 15
(1 alpha-n-propyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol
The procedure of example 14 was repeated except for substituting 4, 9-dihydro-1-butyl-3-H-pyrido [3, 4-b ] indole for 4, 9-dihydro-1-isobutyl-3-H-pyrido [3, 4-b ] indole.
NMR：0.81(t，3H)，3.34(br s，1H)，3.65(d，1H)，3.82(d，1H)，7.00-7.50(m，4H)，10.07(br s，1H)。
MS：298(100％)，297(65％)，281(67％)，170(75％)，169(52％)。
Example 16
(1 alpha-methyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol
The procedure of example 14 was repeated except for substituting 1-ethyl-4, 9-dihydro-3H-pyrido [3, 4-b ] indole for 4, 9-dihydro-1-isobutyl-3H-pyrido [3, 4-b ] indole.
NMR：0.91(s，3H)，3.37(br s，1H)，3.70(d，1H)，3.76(d，1H)，7.0-7.6(m，4H)，9.78(br s，1H)。
MS：270(97％)，269(100％)，253(53％)，197(48％)，170(68％)，169(62％)。
Example 17
(1 alpha-ethyl-1, 4,6, 7, 12, 12b beta-hexahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol
A mixture of 0.34g (2.0mmol) of 3, 4-dihydro-beta-carboline and 0.39g (2.5mmol) of ethyl 2-ethylpenta-2, 4-dienoate in 5ml of chlorobenzene was refluxed for 16 hours. The solvent was evaporated and the residue was subjected to column chromatography (silica gel, dichloromethane/methanol, 99: 1) to give an ester intermediate. This compound was reduced by a conventional method using lithium aluminum hydride in anhydrous tetrahydrofuran to give the title compound.
NMR：0.82(t，3H)，3.69(d，1H)，3.70(br s，1H)，3.90(d，1H)，5.42(ddd，1H)，5.97(ddd，1H)，7.0-7.5(m，4H)，10.02(br s，1H)。
MS：282(31％)，171(14％)，170(100％)，169(52％)。
Example 18
2 beta-methoxy-1, 2,3, 4,6, 7, 12, 12b alpha-octahydro-indolo [2, 3-a ] quinolizine and
2 alpha-methoxy-1, 2,3, 4,6, 7, 12, 12b alpha-octahydro-indolo [2, 3-a ]]Quinolizine (Compound D) 1.16g (14.7mmol) of pyridine and 3.0g (13.4mmol) of tryptophanyl bromide were dissolved in 15ml of anhydrous ether. The reaction mixture was heated with stirring at 60 ℃ until the solvent completely evaporated. The reaction mixture was then heated at 100 ℃ for 2 hours to give the corresponding pyridinium bromide salt. The product is dissolved in 100ml of methanol and 1.52g (40.1mmol) of sodium borohydride are added portionwise with cooling. The reaction mixture was stirred at room temperature for 4 hours, then 20ml of water were added. The reaction mixture was extracted with dichloromethane (3 × 30 ml). The combined organic phases were dried over sodium sulfate, the drying agent was filtered off and the filtrate was evaporated. The residue was dissolved in 100ml of anhydrous dichloromethane and 2.91g (13.3mmol) of di-tert-butyl dicarbonate and 0.149g (1.2mmol) of 4- (dimethylamino) pyridine were added. The reaction mixture was stirred at room temperature under argon for 2 hours. Evaporating the solvent and removing the residuePurification is carried out by column chromatography (silica gel, dichloromethane/methanol, 98: 2). The resulting viscous oil was dissolved in 40ml dichloromethane and 2.54g (13.3mmol) mCPBA was added. After stirring the solution at 0 ℃ for 2 hours, the solvent is evaporated and the crude product is purified by column chromatography (silica gel, dichloromethane/methanol, 98: 2) to give BocNb-an oxide.
3.0ml of trifluoroacetic anhydride are slowly added at 0 ℃ to 0.59g (1.7mmol) of Boc N dissolved in 15ml of dichloromethane, which is stirredb-oxide solution. The cooling bath was removed and after stirring at room temperature for a further 2 hours, the solvent was evaporated. Hydrogen chloride gas saturated methanol was added and the mixture was refluxed for 2 hours. Base treatment and purification by column chromatography (silica gel, dichloromethane/methanol, 98: 2) gave two ethers.
2 β -methoxy-1, 2,3, 4,6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizine:
NMR：1.54(ddd，1H)，3.24(dd，1H)，3.38(dddd，1H)，3.43(s，3H)，7.00-7.50(m，4H)，7.77(br s，1H).
MS：256(100％)，255(86％)，255(59％)，197(35％)，169(30％).
2 α -methoxy-1, 2,3, 4,6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizine:
NMR：3.41(s，3H)，3.67(br s，1H)，3.68(br d，1H)，7.00-7.50(m，4H)，7.72(br s，1H).
MS：256(100％)，255(75％)，255(70％)，223(45％)，197(40％)，170(45％)，169(65％).
example 19
1- (1, 2 alpha, 3,4, 6, 7, 12, 12b alpha-octahydroindolo [2, 3-a ] quinolizin-2-yl) -propan-1-ol
0.22ml (1.7mmol) of 1M ethylmagnesium bromide was added at-60 ℃ to a solution of 0.086g (0.3mmol) of 1, 2,3, 4,6, 7, 12, 12 b-octahydro-indolo [2, 3-a ] quinolizine-2-carbaldehyde in 2ml of dichloromethane (J.chem.Soc.chem.Commun.22(1995) 2317-2318). The reaction mixture was stirred under argon for 4 hours. Treatment with aqueous sodium hydroxide solution, followed by extraction with dichloromethane and purification by column chromatography (silica gel, dichloromethane/methanol, 98: 2) gives the title compound.
NMR：1.02(t，3H)，1.93(br d，1H)，2.30(br d，1H)，6.80-7.40(m，4H).
MS：284(95％)，283(100％)，225(80％)，169(36％).
Example 20
(1, 2 alpha, 3,4, 6, 7, 12, 12b alpha-octahydroindolo [2, 3-a ] quinolizin-2-yl) -propan-2-ol
1ml (3.0mmol) of methylmagnesium chloride solution (3M in tetrahydrofuran) was added dropwise to a solution of 88mg (0.31mmol) of 1, 2 α,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] -quinolizine-2-carboxylic acid methyl ester dissolved in 3ml of anhydrous tetrahydrofuran. The resulting solution was then refluxed for 90 minutes. The mixture was then worked up as in the example to give the crude alcohol which was purified by column chromatography (silica gel, dichloromethane/methanol, 95: 5) to give the title compound.
NMR：1.20(s，3H)，1.25(s，3H)，3.28(br d，1H)，7.0-7.5(m，4H)。
MS：284(86％)，283(65％)，225(100％)。
Example 21
(1, 2 alpha, 3,4, 6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-2-yl) -propan-2-ol
A solution of 64mg (0.23mmol) of methyl 1, 2 α,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] -quinolizine-2-carboxylate and 0.7ml (2.1mmol) of methylmagnesium chloride (3M in tetrahydrofuran), dissolved in 3ml of anhydrous tetrahydrofuran, is refluxed for 90 minutes as in example 20. After workup in the manner described above, column chromatography (silica gel, dichloromethane/methanol, 90: 10) gives the title compound.
NMR：1.17(s，3H)，1.18(s，3H)，4.57(br s，1H)，7.0-7.5(m，4H)，8.65(brs，1H)。
MS：284(58％)，283(53％)，225(100％)。
Example 22
(2 alpha-ethyl-1, 2,3, 4,6, 7, 12, 12b alpha-octahydroindolo [2, 3-a ] quinolizin-2-yl) -methanol
2.0ml (3.6mmol) of n-butyllithium (1.8M in hexane) are added at-50 ℃ to a stirred solution of 0.36g (3.6mmol) of diisopropylamine in 4ml of anhydrous tetrahydrofuran. The mixture was heated to-30 ℃ (15 minutes) and then cooled to-70 ℃. At this temperature 0.64g (3.6mmol) hexamethylphosphoramide was added. Stirring is continued for 30 minutes at this temperature, then 0.42g (1.48mmol) of 1- [2- (3-indolyl) ethyl ] -1, 2, 5, 6-tetrahydropyridine-4-carboxylic acid methyl ester dissolved in 7ml of tetrahydrofuran are added. After stirring at-70 ℃ for 20 minutes, the mixture was heated to-40 ℃ (15 minutes). At this temperature 0.3g (3.6mmol) of ethyl iodide was added and stirring continued for 1 hour. The cooling bath was removed and stirred for an additional 15 minutes and the mixture was quenched with 5% aqueous ammonia. The aqueous phase was extracted with dichloromethane (3 × 20ml) and the combined organic phases were washed with water. Drying over sodium sulfate, filtration and evaporation of the solvent gave the crude enamine, which was dissolved in 50ml of methanol saturated with hydrogen chloride and the resulting solution was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was treated with aqueous sodium bicarbonate. Following the normal extraction procedure (dichloromethane), the solvent was evaporated to give the crude product, which was subjected to column chromatography (silica gel, dichloromethane/methanol, 98: 2) to give the ester intermediate, methyl 2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizine-2-carboxylate. The compound is then treated with lithium aluminium hydride in anhydrous tetrahydrofuran by conventional methods and subjected to column chromatography (silica gel, dichloromethane/methanol, 95: 5) to give the title compound.
NMR：0.90(t，3H)，3.29(d，1H)，3.43(d，IH)，3.52(br d，1H)，7.0-7.5(m，4H)。
MS：284(100％)，283(98％)，253(33％)，197(37％)，170(33％)，169(40％)，156(34％)。
Example 23
(2 alpha-ethyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-2-yl) -methanol
A solution of 51mg (0.16mmol) of the ester intermediate (methyl 2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizine-2-carboxylate) obtained in example 22 dissolved in 4ml of trifluoroacetic acid was refluxed for 16 hours under argon. The acid was evaporated and the residue was treated with aqueous sodium bicarbonate. Extraction (dichloromethane) by the normal procedure gave a crude mixture of the two diastereomers (20: 80), methyl 2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizine-2-carboxylate and methyl 2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizine-2-carboxylate. The latter isomer is separated by column chromatography (silica gel, dichloromethane/methanol, 99: 1) and then reduced in anhydrous tetrahydrofuran with lithium aluminium hydride by conventional methods. Purification as above yielded the title alcohol.
NMR：0.87(t，3H)，3.51(d，1H)，3.78(d，1H)，7.0-7.5(m，4H)。
MS：284(95％)，283(100％)，253(30％)，197(30％)，170(17％)，169(23％)，156(19％)。
Example 24
1- (2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizin-2-yl) -ketene and
2- (2 alpha-ethyl-1, 2,3, 4,6, 7, 12, 12b alpha-octahydroindolo [2, 3-a ] quinolizin-2-yl) -propan-2-ol
230mg (0.74mmol) of the ester intermediate (methyl 2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizine-2-carboxylate) obtained in example 22 dissolved in anhydrous tetrahydrofuran (9ml) and 3.7ml (11.1mmol) of methylmagnesium chloride (3M in tetrahydrofuran) were refluxed overnight as in example 20. After customary work-up, column chromatography (silica gel, dichloromethane/methanol, 98: 2-95: 5) gives a mixture of the two compounds in a ratio of 5: 1.
1- (2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizin-2-yl) -ketene:
NMR：0.82(t，3H)，2.14(s，3H)，3.44(br d，1H)，7.05-7.50(m，4H)，8.05(br s，1H)。
MS：296(83％)，295(62％)，253(100％)，184(95％)。
2- (2 α -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizin-2-yl) -propan-2-ol:
NMR：1.05(t，3H)，1.24(s，6H)，3.42(br d，1H)，7.05-7.50(m，4H)，7.88(br s，1H)。
MS：312(48％)，311(37％)，253(100％)。
example 25
1- (2 alpha-ethyl-1, 2,3, 4,6, 7, 12, 12b alpha-octahydroindolo [2, 3-a ] quinolizin-2-yl) -ethanol
Reduction of the ketone obtained from the above reaction with sodium borohydride in methanol by conventional methods gives the title alcohol as an inseparable mixture of diastereomers.
NMR: 0.95(t, 3H, minor isomer), 1.18(t, 3H, major isomer), 3.61(q, 1H, minor isomer), 3.67(q, 1H, major isomer).
MS：298(100％)，297(64％)，253(87％)。
Example 26
2,3, 4, 5, 7, 8, 13, 13 b-octahydro-1H-aza * o [1 ', 2': 1, 2] pyrido [3, 4-b ] indoles (Compound E)
0.14g (1.2mmol) of epsilon-caprolactam was added to a solution of 0.20g (1.2mmol) of tryptamine in 5.0ml of xylene. The mixture was refluxed for 7 hours. After evaporation of the solvent, the residue was dissolved in 5.0ml of toluene, 0.65ml of freshly distilled phosphorus oxychloride was added and the reaction mixture was refluxed for 9 hours. The solution was evaporated in vacuo and the residue was mixed with 20% acetic acid solution (3 × 10 ml). The solid was filtered off, the aqueous solution was made basic with 25% ammonium hydroxide (pH11) and extracted with dichloromethane (3 × 20ml) under cooling. 6.0ml of 4M sodium hydroxide was added to the combined organic phases and the mixture was refluxed for 1 hour. The organic phase was dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated to give an oil which was dissolved in 30ml of methanol. 0.2g (5.6mmol) of sodium borohydride was added to the cooled solution. The mixture was stirred at room temperature for 1 hour. Water was added slowly and the reaction mixture was extracted with dichloromethane (3 × 20 ml). The organic phase is dried over sodium sulfate, the drying agent is filtered off and the solvent is evaporated to give the title compound which is purified by column chromatography (silica gel, dichloromethane/methanol, 95: 5).
NMR：4.03(br d，1H)，7.11-7.46(m，4H)，8.05(br s，1H)。
MS：240(52％)，239(100％)，198(10％)，170(24％)。
Example 27
1 alpha-ethyl-12-methyl-1, 2,3, 4,6, 7, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-ol
0.02ml (0.3mmoles) of methyl iodide are added to a solution of 0.05g (0.1mmol) of 1 α -ethyl-1 β -hydroxy-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizine and 0.05g (0.9mmol) of KOH in 1.0ml of acetone. The reaction mixture was stirred at room temperature for 1 hour. Water was added slowly and the reaction mixture was extracted with dichloromethane (3 × 20 ml). The combined organic phases are dried over sodium sulfate, the drying agent is filtered off and the filtrate is evaporated to give the title compound which can be purified by column chromatography (silica gel, dichloromethane/methanol, 95: 5).
NMR：0.71(t，3H)，1.01(m，2H)，3.59(br s，1H)，3.72(s，3H)，7.00-7.50(m，4H)。
MS：284(21％)，283(100％)，185(60％)，170(10％)。
Example 28
1 alpha-ethyl-12-ethyl-1, 2,3, 4,6, 7, 12b beta-octahydro-indolo [2, 3-a ] quinolizin-1-ol
The procedure of example 27 was repeated except that iodoethane was substituted for iodomethane.
NMR：0.71(t，3H)，1.00(m，2H)，1.07(t，3H)，3.60(s，1H)，4.20(m，1H)，4.64(m，1H)，7.00-7.50(m，4H)。
MS：298(29％)，297(19％)，199(100％)，171(33％)。
Example 29
1 alpha-methyl-1, 3,4, 5, 6, 11 b-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-ol
0.34g (3.0mmol) of α -methyl- δ -valerolactone was added to a solution of 0.48g (3.0mmol) of 2- (3-benzo [ b ] furanyl) ethylamine dissolved in 5.0ml of xylene. The mixture was refluxed for 7.5 hours. After evaporation of the solvent, the residue is dissolved in 6.0ml of toluene, 0.72ml of freshly distilled phosphorus oxychloride is added and the reaction mixture is refluxed for 11 hours. The solution was evaporated in vacuo and the resulting oil was mixed with 20% acetic acid solution (3 × 20 ml). The solid was filtered off, the aqueous solution was made basic with 25% ammonium hydroxide (pH11) and extracted with dichloromethane (3 × 20ml) under cooling. 12.5ml of 4M sodium hydroxide were added to the combined organic phases and the mixture was refluxed for 1 hour. The organic phase was dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated to give the corresponding enamine, which was oxidized as described in example 9.
NMR：1.18(s，3H)，3.25(br d，1H)，7.10-7.50(m，4H)。
MS：257(25％)，242(10％)，172(100％)。
Example 30
(1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol
The procedure of example 29 was repeated except that 40% aqueous formaldehyde was slowly added to the enamine formed. The reaction mixture was refluxed for 3.5 hours and the solvent was evaporated. Dilute with ethyl acetate and rinse the residue with brine. The organic phase is dried over sodium sulfate, the drying agent is filtered off and the filtrate is evaporated to give the title compound which can be purified by column chromatography (silica gel, dichloromethane/methanol, 98: 2).
NMR：0.89(s，3H)，3.40(br s，1H)，3.62(d，1H)，4.29(d，1H)，7.10-7.50(m，4H)。
MS：271(69％)，270(100％)，198(45％)，171(52％)，170(60％)。
Example 31
1 alpha-isopropyl-1, 3,4, 5, 6, 11 b-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-ol
The procedure of example 9 was repeated except that 2- (3-benzo [ b ] furanyl) ethylamine was used instead of tryptamine.
NMR：1.00(m，6H)，7.25(m，2H)，7.44(m，2H)。
MS：285(23％)，242(10％)，198(10％)，186(23％)，172(100％)。
Example 32
1 alpha-ethyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-ol
The procedure of example 29 was repeated except that α -ethyl- δ -valerolactone was substituted for α -methyl- δ -valerolactone.
NMR：0.73(t，3H)，3.22(br s，1H)，7.00-7.30(m，2H)，7.40-7.55(m，2H)。
MS：271(15％)，186(18％)，173(11％)，172(100％)，170(28％)。
Example 33
(1 alpha-ethyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol
The procedure of example 30 was repeated except that α -ethyl- δ -valerolactone was substituted for α -methyl- δ -valerolactone.
NMR：0.62(t，3H)，3.48(br s，1H)，3.52(d，1H)，4.06(d，1H)，7.00-7.30(m，2H)，7.40-7.55(m，2H)。
MS：285(56％)，284(100％)，268(19％)，198(36％)，172(20％)，171(44％)，170(54％)。
Example 34
5, 6, 7, 7a, 11, 11b, 12-decahydro-6 a, 12-diaza-indeno [1, 2-a ] fluoren-11 a-ol
The procedure of example 29 was repeated except that tryptamine and hexahydroisobenzofuran-1-one were substituted for 2- (3-benzo [ b ] furanyl) ethylamine and α -methyl- δ -valerolactone.
NMR：4.45(br d，1H)，7.00-7.60(m，4H)，9.11(br s，1H)。
MS：296(8％)，143(100％)，130(81％)。
Example 35
1, 2,3, 4, 4a, 5, 6, 7, 8, 13-decahydro-6 a, 13-diaza-indeno [1, 2-c ] phenanthrene
A solution of 1.6g of mercuric acetate and 1.88g of disodium ethylenediaminetetraacetate dihydrate dissolved in 40ml of water was added to a solution of 0.356g (1.26mmol) of N- [2- (3-indolyl) ethyl ] decahydroisoquinoline dissolved in 20ml of ethanol and the resulting mixture was refluxed for 3 hours. The cooled mixture was made basic with dilute ammonium hydroxide (pH11) and extracted with dichloromethane (3x30 ml). The organic phase was dried over sodium sulfate, filtered and the filtrate was concentrated to give crude enamine (mixture of regioisomers) which was used directly in the next step (cf. example 36). Purified enamine was obtained by column chromatography (silica gel, dichloromethane/methanol/triethylamine, 98: 1).
Example 36
2,3, 4, 4a β,5, 6, 7, 8, 13, 13b β -decahydro-1H-6 a, 13-diaza-indeno [1, 2-c ] phenanthrene-13 c β -ol (Compound F)
0.42g (1.51mmol) of the crude enamine from example 35 was treated with 0.21g of potassium iodide and 0.32g of iodine in 30ml of acetonitrile as in example 9. After reduction with 0.29g of sodium borohydride in 30ml of methanol, the crude product is purified by column chromatography (silica gel, dichloromethane/methanol, 99: 1) to give the purified alcohol.
NMR：3.18(br s，1H)，7.0-7.55(m，4H)，9.18(br s，1H).。
MS：296(25％)，295(10％)，185(15％)，171(100％)。
Example 37
(2, 3,4, 4a β,5, 6, 7, 8, 13, 13b β -decahydro-1H-6 a, 13-diaza-indeno [1, 2-c ] phenanthryl) -13c β -methanol
150mg (1.51mmol) of the purified enamine described above (from example 35), 2ml of 36% aqueous formaldehyde solution and 0.2ml of N-ethyldiisopropylamine solution in 10ml of acetonitrile are refluxed for 3 hours. After work-up, the crude product is purified by column chromatography (silica gel, dichloromethane/methanol, 98: 2) to give the purified alcohol.
NMR：3.29(br s，1H)，3.98(d，1H)，4.17(d，1H)，7.0-7.5(m，4H)，10.05(br s，1H)。
MS：310(88％)，309(100％)，293(34％)，197(67％)，184(35％)，170(90％)，169(77％)。
Example 38
3 beta, 4 alpha-dimethyl-1, 2,3, 4,6, 7, 12, 12 beta-octahydro-indolo [2, 3-a ] quinolizine
A solution of 2.1g of mercuric acetate and 2.46g of disodium ethylenediaminetetraacetate dihydrate dissolved in 50ml of water was added to a solution of 0.422g (1.65mmol) of N- [2 '- (3' -indolyl) ethyl [ -2, 3-dimethylpiperidine dissolved in 25ml of ethanol and the resulting mixture was refluxed for 3 hours. The cooled mixture was made basic with dilute ammonium hydroxide and extracted with dichloromethane. Drying over sodium sulfate, filtration and evaporation of the solvent gave the crude enamine, which was dissolved in 30ml methanol and cooled with an ice bath. A few drops of acetic acid were added and 0.322g of sodium borohydride were added in portions. After stirring for 1.5 hours, the mixture is worked up in the customary manner to give the crude product which is purified by column chromatography (silica gel, dichloromethane/methanol (98.5: 1.5).
NMR：0.89(d，3H)，0.96(d，3H)，3.76(br d，1H)，7.0-7.5(m，4H)，7.71(brs，1H)。
MS：254(95％)，253(100％)，239(30％)，170(31％)，169(36％)。
Example 39
(1 alpha-ethyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-ylmethoxy) -acetic acid ethyl ester
A solution of 0.02g (0.07mmol) (1. beta. -ethyl-1, 2,3, 4,6, 7, 12, 12 b. alpha. -octahydro-indolo [2, 3-a ] quinolizin-1-yl) -methanol (Gazz. Chim. Ital.111(1981) 257) 267) in N, N-dimethylformamide-toluene (1ml, 1: 1) was added to 6.8mg (0.28mmol) of sodium hydride, previously washed with heptane. The reaction mixture was stirred at room temperature for 1 hour, then ethyl bromoacetate (0.009ml, 0.084mmol) dissolved in toluene (1ml) was added dropwise. Stirring was continued at room temperature for 3 hours. Water was added slowly and the reaction mixture was extracted with dichloromethane (3 × 20 ml). The combined organic phases are dried over magnesium sulfate, the drying agent is filtered off and the filtrate is evaporated to give the title compound which can be purified by column chromatography (silica gel, dichloromethane/methanol, 95: 5).
NMR：0.61(t，3H)，1.28(t，3H)，3.49(s，1H)，4.25(d，1H)，4.30(q，2H)，4.55(d，1H)，6.93(t，1H)，7.03(t，1H)，7.35(d，1H)，7.38(d，1H)，10.64(s，1H)。
MS：370(40％)，369(30％)，283(12％)，267(100％)，197(12％)，170(12％)，169(16％)。
Example 40
5, 6, 7, 7a beta, 8, 9, 10, 11, 11a beta, 11b alpha-decahydro-12-oxa-6 a-aza-indeno [1, 2-a ] fluorene
0.13g (0.87mmol) of cis-1, 2-cyclohexanedicarboxylic anhydride is added to a solution of 0.70g (0.43mmol) of 2- (3-benzo [ b ] furanyl) ethylamine dissolved in 30ml of chlorobenzene. The mixture was irradiated in a microwave oven (1000W, T130 ℃) for 30 minutes. Chlorobenzene was removed by ethanol (5ml) and 82.7mg (2.18mmol) of sodium borohydride were added. After stirring the mixture at room temperature for 18 hours, water was added and the product was isolated in the usual manner. Trifluoroacetic acid (0.12ml, 1.53mmol) in dichloromethane (10ml) was added and the reaction mixture was stirred at room temperature for 2 h. Base treatment (4M sodium hydroxide) gave the amide intermediate which was dissolved in diethyl ether (15ml), 0.1g (2.63mmol) of lithium aluminium hydride was added and the reaction mixture was refluxed for 1.5 h. Water was added slowly with cooling. After standard extraction methods, the crude product is purified by column chromatography (silica gel, dichloromethane/methanol, 90: 10).
NMR：1.77(m，2H)，2.07(m，1H)，2.29(m，1H)，2.48(m，1H)，3.04(m，1H)，3.20(m，1H)，4.13(s，1H)，7.18-7.50(m，4H)。
MS：267(46％)，266(100％)，185(52％)，170(12％)。
EXAMPLE 41
1-methyl-1 alpha, 3,4, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene (Compound G)
The procedure of example 26 was repeated except that α -methyl- δ -valerolactone and 2- (3-benzo [ b ] furanyl) ethylamine were used instead of e-caprolactam and tryptamine, respectively.
NMR：0.88(d，3H)，3.34(br s，1H)，7.19-7.43(m，4H)。
MS：241(40％)，240(50％)，226(100％)，198(10％)，170(68％)，170(24％)。
Example 42
(1-hydroxymethyl-1, 3,4, 5, 6, 11 b-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol
The procedure of example 41 was repeated except that delta-valerolactone was substituted for alpha-methyl-delta-valerolactone and the resulting enamine was treated with formaldehyde as in example 14.
NMR：3.30(d，1H)，3.76(d，1H)，3.79(d，1H)，3.82(s，1H)，4.31(d，1H)，7.18-7.50(m，4H)。
MS：287(56％)，286(60％)，270(40％)，256(100％)，198(34％)，172(26％)，170(54％)。
Example 43
1-methoxymethyl-1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene
173.1mg (0.64mmol) of the alcoholic solution described in example 30 dissolved in 5ml of tetrahydrofuran are added to 153.0mg (6.38mmol) of sodium hydride previously rinsed with heptane. The reaction mixture was stirred at 35 ℃ for 1 hour, and then a solution of 0.04ml (0.64mmol) of iodomethane dissolved in tetrahydrofuran (5ml) was added dropwise. Stirring was continued for 1 hour. Water was added slowly and the reaction mixture was extracted with dichloromethane (3 × 20 ml). The combined organic phases are dried over sodium sulfate, the drying agent is filtered off and the filtrate is evaporated to give the title compound which can be purified by column chromatography (silica gel, dichloromethane/methanol, 90: 10).
NMR：0.74(s，3H)，3.29(s，3H)，3.36(d，1H)，3.89(d，1H)，7.20-7.52(m，4H)。
MS：285(80％)，284(100％)，270(20％)，254(98％)，198(35％)，171(82％)，170(70％)。
Example 44
2,3, 4, 4a beta, 5, 6, 7, 8, 13b beta, 13c beta-decahydro-1H-13-oxa-6 a-aza-indeno [1, 2-c ] phenanthrene and 2,3, 4, 4a beta, 5, 6, 7, 8, 13b alpha, 13c beta-decahydro-1H-13-oxa-6 a-aza-indeno [1, 2-c ] phenanthrene
The procedure of example 41 was repeated except that cis-octahydro-isochromen-1-one was substituted for α -methyl- δ -valerolactone. The two isomers are separated by column chromatography (silica gel, ethyl acetate/heptane, 70: 30).
2,3, 4, 4a β,5, 6, 7, 8, 13b β, 13c β -decahydro-1H-13-oxa-6 a-aza-indeno [1, 2-c ] phenanthrene:
NMR：3.28(s，1H)，7.17-7.53(m，4H)。
MS：281(40％)，280(100％)，238(15％)，198(12％)，170(24％)。
2,3, 4, 4a β,5, 6, 7, 8, 13b α, 13c β -decahydro-1H-13-oxa-6 a-aza-indeno [1, 2-c ] phenanthrene:
NMR：2.75(d，1H)，7.15-7.43(m，4H)。
MS：281(38％)，280(100％)，198(16％)，170(30％)。
example 45
1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene-1-carboxylic acid ethyl ester
0.56g (2.33mmol) of 5-chloro-2-ethoxycarbonyl-2-methylpentanoyl chloride (prepared according to the procedure described in J.org.chem.45(1980)32-34 for the corresponding 2-ethyl derivative) in dichloromethane (4ml) was added to a mixture of 0.375g (2.33mmol) of 2- (3-benzo [ b ] furanyl) ethylamine and triethylamine (0.97ml, 7.0mmol) in dichloromethane (3 ml). After stirring at room temperature for 45 minutes, water was added and the mixture was extracted with dichloromethane. Drying over sodium sulfate, filtration of the drying agent and evaporation of the solvent gave the crude amide which was purified by column chromatography (ethyl acetate/heptane, 1: 1). The purified amide (0.3g, 0.82mmol) was dissolved in toluene (3ml) and 0.38ml (4.1mmol) of phosphorus oxychloride was added. After refluxing the mixture for 2 hours, it was evaporated to dryness. The residue was dissolved in methanol (3ml) and 57mg (1.5mmol) of sodium borohydride were added in portions. After stirring at room temperature for 1 hour, water was added and the mixture was extracted with ethyl acetate. Drying over sodium sulfate, filtration and evaporation gave the crude ester which was purified by column chromatography (silica gel, ethyl acetate/heptane, 1: 1).
NMR：0.65(t，3H)，1.55(s，3H)，3.30(br s，1H)，7.16-7.50(m，4H)。
MS：313(70％)，312(100％)，284(22％)，240(32％)，198(80％)，171(35％)，170(95％)。
Example 46
1-ethoxymethyl-1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene
The procedure of example 43 was repeated except that iodoethane was substituted for iodomethane.
NMR：0.74(s，3H)，1.17(t，3H)，3.37(s，1H)，3.38(d，1H)，3.54(q，2H)，3.96(d，1H)，7.10-7.60(m，4H)。
MS：299(70％)，298(92％)，270(40％)，254(100％)，198(34％)，171(86％)，170(72％)。
Example 47
(1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol
0.86g (2.74mmol) of the ester described in example 45 in anhydrous tetrahydrofuran (10ml) were added to a suspension of 0.31g (8.23mmol) of lithium aluminium hydride in anhydrous tetrahydrofuran (10 ml). The reaction mixture was refluxed for 1 hour. Water was added slowly and the reaction mixture was extracted with ethyl acetate (3 × 20 ml). The combined organic phases are dried over magnesium sulfate, filtered and the filtrate is evaporated to give the desired compound which is purified by column chromatography (silica gel, ethyl acetate/heptane, 50: 50).
NMR：1.30(s，3H)，2.98(br s，1H)，3.21(d，1H)，3.69(d，1H)，4.33(s，1H)，7.15-7.55(m，4H)。
MS：271(52％)，270(100％)，198(34％)，172(20％)，171(44％)，170(66％)。
Example 48
(1 alpha-methyl-1, 2,3, 4,6, 7, 12, 12b alpha-octahydroindeno [2, 1-a ] quinolizin-1-yl) -methanol
The procedures of examples 45 and 47 were repeated except that 2- (3H-inden-1-yl) -ethylamine was used in place of 2- (3-benzo [ b ] furanyl) ethylamine.
NMR：0.82(s，3H)，3.07(br s，1H)，3.23(d，1H)，3.39(d，1H)，3.52(d，1H)，3.70(d，1H)，7.05-7.35(m，4H)。
MS：269(43％)，268(100％)，252(29％)，196(36％)，168(40％)。
Example 49
1 alpha-Ethyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene-1-carboxylic acid methyl ester
The procedure of example 45 was repeated except for substituting 5-chloro-2-ethoxycarbonyl-2-ethylpentanoyl chloride for 5-chloro-2-ethoxycarbonyl-2-methylpentanoyl chloride.
NMR：0.90(t，3H)，6.90-7.58(m，4H)。
MS：327(72％)，326(100％)，312(20％)，298(20％)，254(30％)，198(54％)，172(60％)，170(90％)。
Example 50
1-methoxymethyl-1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene
The procedure of example 43 was repeated except that the alcohol in example 47 described above was used as a starting compound.
NMR：1.44(s，3H)，2.99(d，1H)，3.15(br s，1H)，3.22(s，3H)，3.70(d，1H)，7.18-7.50(m，4H)。
MS：285(84％)，284(100％)，270(14％)，254(92％)，198(34％)，171(74％)，170(50％)。
Example 51
(1 alpha-ethyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol
The procedure of example 47 was repeated except that the ester in example 49 described above was used as the starting compound.
NMR：1.00(t，3H)，2.93(m，2H)，3.29(s，1H)，7.15-7.60(m，4H)。
MS：286(90％)，285(68％)，284(100％)，268(16％)，198(22％)，171(22％)，170(36％)。
Example 52
1-beta-hydroxymethyl-1-methyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydro-indolo [2, 3-a ] quinolizine-6 beta-carboxylic acid methyl ester
The preparation of (1 β -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizin-1-yl) -methanol (Gazz. Chim. Ital.111(1981) 257-.
NMR：0.74(s，3H)，3.39(s，3H)，3.46(d，1H)，3.97(d，1H)，4.38(br s，1H)，7.00-7.50(m，4H)，8.90(br s，1H)。
MS：328(26％)，327(100％)，299(38％)，268(32％)，170(10％)，169(24％)。
Example 53
Resolution of 1 alpha-isopropyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] quinolizin-1-ol
0.3g (1.1mmol) (+ -) -1 alpha-isopropyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] dissolved in 15ml acetone]Quinazine-1-ol and 0.16g (1.1mmol) L-tartaric acid solution were refluxed for 30 minutes. Standing overnight at room temperature gave 200mg of a solid precipitate. After two recrystallizations from methanol, the collected L-tartrate salt was partitioned between dichloromethane and 10% sodium hydroxide solution, dried over sodium sulfate and evaporated to yield 116.6mg (-) -1 α -isopropyl-1, 2,3, 4,6, 7, 12, 12b β-octahydroindolo [2, 3-a ]]Quinolizin-1-ol, its [ alpha ]]D ═ 64.5 ° (c, 0.011 in CHCl)3In (1). The other corresponding isomer (+) -1 alpha-isopropyl-1, 2,3, 4,6, 7, 12, 12b beta-octahydroindolo [2, 3-a ] is separated from the mother liquor in the same way]Quinolizin-1-ol [ alpha ]]D ═ 64.5 ° (c, 0.011 in CHCl)3In (1).
Example 54
Resolution of (1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol
The procedure of example 53 was repeated except that (+) -diacetyl-L-tartaric anhydride and isopropanol were used instead of L-tartaric acid and acetone. The purity of the separated enantiomers was determined by chiral HPLC (column: d A I C EL CHEMICAL INDUSTRIES, LTD CHIRACEL OJ, size: 0.46cm × 25cm, flow rate: 0.5 ml/min, mobile phase: n-hexane (Merck Uvasol for chromatography)/isopropanol (Rathburn, HPLC grade) (100: 20), UV detection wavelength of 272nm, retention time: 8.8 min [ (+) - (1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol ] and 11.1 min [ (-) - (1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol ].
Example 55
Isolation of (1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol
The procedure of example 53 was repeated except for using (-) -di-p-toluoyl-L-tartaric acid monohydrate and ethyl acetate instead of L-tartaric acid and acetone. The optical purity of the separated enantiomers was determined by chiral HPLC (column: DAICEL CHEMICAL INDUSTRIES, LTDCHIRACEL OJ, size: 0.46cm × 25cm, flow rate: 0.8 ml/min, mobile phase: n-hexane (Merck Uvasol for chromatography)/isopropanol (Rathburn, HPLC grade) (180: 20), UV detection wavelength: 254nm, retention time: 7.8 min [ (+) - (1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol ] and 12.6 min [ (-) - (1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol ].
Example 56
1-methoxymethyl-1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene isomers
Except that the purified isomer (+) - (1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] is derived from example 54]Fluoren-1-yl) -methanol and (-) - (1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a]Fluoren-1-yl) -methanol the procedure of example 43 was repeated, substituting the alcohols described in example 30, respectively. The optical purity of the product was determined by chiral HPLC (column: ROC KLAND TECHNOLOGIES, INS ULTRON ES-OVM, size: 4.6 cm. times.15 cm, flow rate: 0.8 ml/min, mobile phase: 0.04M KH2PO4(pH 4.6)/acetonitrile (Merck Lichorolv Isocratic grade for liquid chromatography) (90: 10), retention time: 3.8 min [ (-) -1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ]]Fluorene compounds]And [ (+) -1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] for 5.8 minutes]Fluorene compounds]。
Example 57
1-methoxymethyl-1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene isomers
The procedure of example 43 was repeated except for purifying the corresponding isomers (+) - (1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol and (-) - (1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol from example 55, respectively, in place of the alcohol described in example 30. The optical purity of the product was determined by chiral HPLC (column: DAICEL CHEMICAL INDUSTRIES, LTD CHIRACEL OJ, size: 0.46 cm. times.25 cm, flow rate: 0.8 ml/min, mobile phase: n-hexane (Merck Uvasol for Spectroscopy for chromatography), retention time: 5.6 min [ (+) -1-methoxymethyl-1. alpha. -methyl-1, 3,4, 5, 6, 11 b. alpha. -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene ] and 6.3 min [ (-) -1-methoxymethyl-1. alpha. -methyl-1, 3,4, 5, 6, 11 b. alpha. -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluorene ].
The following known compounds were prepared analogously or according to methods known in the literature.
1 α -methyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-ol (compound H): the procedure of example 6 was repeated except that 1-ethyl-4, 9-dihydro-3H-pyrido [3, 4-b ] indole (J.chem.Soc., Perkin Trans I (1977) 2109-one 2115) was used instead of 1-isobutyl-4, 9-dihydro-3H-pyrido [3, 4-b ] indole.
2 β -methyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-2-ol and 2 α -methyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-2-ol were prepared according to the procedures described in J.org.chem.56(1991)2701-2712 and chem.Ber.106(1973) 3106-3118. 1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1 α -ol and 1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1 β -ol were prepared according to the procedure described in chem.pharm.Bull.34(1986) 3713-one 3721. 1, 2,3, 4,6, 7, 12, 12 b-octahydroindolo [2, 3-a ] quinolizine was prepared according to the method described in j.chem.soc., chem.comm. (1972) 461. 1, 4,6, 7, 12, 12 b-hexahydroindolo [2, 3-a ] quinolizine (Compound I) was prepared according to the method described in Tetrahedron45(1989) 3975-. 3,4, 6, 7, 12, 12 b-hexahydroindolo [2, 3-a ] quinolizine and 1-ethyl-3, 4,6, 7, 12, 12 b-hexahydroindolo [2, 3-a ] quinolizine were prepared according to the method described in Bull. Soc. Chim. Fr.7-8(1976) 1222. 1 α -Ethyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizine and 1 β -Ethyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindoo [2, 3-a ] quinolizine (Compound J) were prepared according to the procedure described in Tetrahedron45(1989) 7615-7630. 1 α -Ethyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-ol (compound K) and (1 β -ethyl-1, 2,3, 4,6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol (compound L) were prepared according to the method described in Gazz. Chim. Ital.111(1981) 257-one 267. (1 β -ethyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol (compound M) was prepared according to the method described in Indian j.chem., sect.b22(1983) 531. 3-Ethyl-2-methyl-1, 4,6, 7, 12, 12 b-hexahydro-indolo [2, 3-a ] quinolizine (Compound N) and 3 α -ethyl-2 α -methyl-1, 2,3, 4,6, 7, 12, 12 b-octahydroindolo [2, 3-a ] quinolizine were prepared according to the method described in Tetrahedron46(1990) 2633-2650. 2,3, 5, 6, 7, 11, 11 b-hexahydro-1H-indolizino [8, 7-b ] indole was prepared according to the method described in J.org.chem.53(1988) 4236. (1 β,2, 3,4, 6, 7, 12, 12b α -octahydroindolo [2, 3-a ] quinolizin-1-yl) -methanol (compound O) was prepared by reduction of the related ester synthesized as described in Tetrahedron52(1996) 9925. 1- (1 α,2, 3,4, 6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-yl) -ethanol (compound P) was prepared by reduction of the relevant ketone synthesized as described in Tetrahedron Lett.30(1989) 719. 1 β -propyl-1, 2,3, 4,6, 7, 12, 12b β -octahydro-indolo [2, 3-a ] quinolizine was prepared according to the method described in j.org.chem.34(1969) 330. 1 α -ethyl-1 β -methyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizine was prepared according to the method described in J.chem.Res. (S) (1995) 382. 2 β -tert-butyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizine and 2 β -tert-butyl-1, 2,3, 4,6, 7, 12, 12b α -octahydro-indolo [2, 3-a ] quinolizine (compound Q) were prepared according to the method described in Tetrahedron45(1989) 3975. 2-tert-butyl-1, 4,6, 7, 12, 12 b-hexahydroindolo [2, 3-a ] quinolizine and 2-tert-butyl-3, 4,6, 7, 12, 12 b-hexahydroindolo [2, 3-a ] quinolizine were prepared according to the method described in Tetrahedron47(1991) 2879-2894. (-) -1 α -Ethyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-ol and (+) -1 α -Ethyl-1, 2,3, 4,6, 7, 12, 12b β -octahydroindolo [2, 3-a ] quinolizin-1-ol are obtained by resolution of the racemic mixture (Compound K).
As mentioned above, the compounds of the invention exhibit remarkable pharmacological properties, namely with respect to α2Adrenergic receptors exhibit affinity. The above pharmacological activity of the compounds of the present invention will be demonstrated by pharmacological experiments as shown below.
Experiment I: radioligands and alpha2-binding of adrenergic receptors
Compounds of the invention and alpha2Examples of-adrenoreceptor binding are shown in table 1. For all alpha2The majority of these compounds are high affinity ligands for the receptor, but some of them appear to be alpha2C-selectivity of receptor subtype.
Table 1: by expressing human alpha2Determination of Ki values by radioligand experiments on cells of the adrenoreceptor subtype
Compound (I) Affinity (Ki; nM)
ABCDEFGHIJKLMNOPQ α-receptors α-receptors α-receptors
4801307102930514962801502103598544013038029027 33016058081110 not found 4546052024520470111027041040 not found 61258717267022238575311811046110906.4
Experiment II: alpha in vitro2Antagonism of the adrenergic receptor
Determination of alpha in binding experiments2CFunctional activity of two compounds (K and L) selective for receptors, in order that the compounds inhibit the activation by epinephrine35S-GTP gamma S and G protein (located in human alpha)2-stable transfection of the adrenoreceptor subtype onto CHO cell membranes) to (Jasper, J.R. et al, biochem. Pharmacol.55(7) (1998) 1035-44). The antagonism of compound K and compound L is shown in table 2. The results show that these compounds are alpha2C-selective antagonists of receptor subtypes.
Table 2: compounds K and L for human alpha2Average antagonism (KB) of the adrenoceptor subtype
Compound (I) Antagonistic force (KB; nM)
KL α-receptors α-receptors α-receptors
295320 35175 234，2
α2CIn vivo Effect of receptor-Selective Compounds
The presence of para-alpha is not known in the art2CWhat effect the selective antagonism of the receptor will produce in vivo. To prove for alpha2CThe effect of specific antagonism of the receptor on the CNS in mice and rats, the inventors have selected two different behavioural patterns, namely d-amphetamine-induced locomotor activity and forced swim experiments, based on prior knowledge and previous experience. These methods are selected essentially from the published values for alpha2CTheoretical inference of receptor antagonists is based; the inference is that, due to the lack of appropriate ligands, expression of alpha is being investigated2CGene-modified mice based on adrenoceptors (Scheinin, M. et al, Life Sci68(19-20) (2001) 2277-85).
Experiment III: d-amphetamine-induced locomotor activity assay
Having a non-functional alpha2CGene-modified mice (α) for adrenoceptors2C- "reject (knockout)"; alpha is alpha2CKO) is more sensitive to the effect of the psychostimulant d-amphetamine in enhancing locomotion, while on the other hand alpha is present in mice2COverexpression of the adrenoceptor (. alpha.)2COE) can lead to the opposite effect, i.e.to a reduction in the influence of the activator (Scheinin, M. et al, Life Sci68(19-20) (2001) 2277-85). Therefore, can infer alpha2CAntagonists enhance the motor action of d-amphetamine.
Amphetamine (4 micromoles/kg s.c.) or with α of the invention may be administered to experimental groups of mice (n-10-12/dose group)2C-antagonismAnti-agent (3 micromole/kg s.c.) or with para-alpha2CAlpha non-selective for receptor subtype2The above reasoning was verified by co-administration of antagonists (1 micromole/kg s.c.) (Haaparinna, A. et al, Nauyn-Schmiedeberg's research. Pharmacol.356(1997)570-582) followed by observation of the locomotor activity of the mice using a fully automatic infrared detector for motility studies (PAS CageRack, San Diego Instruments, San Diego, Calif., USA). As expected, selectivity α2CBoth experimental groups of receptor antagonists enhanced the mobility of mice (FIG. 1a + b), and with respect to α2The expected agreement of the antagonist. Subtype nonselective alpha2Antagonists also potentiate the effect of d-amphetamine. However, the compounds tested did not alter the basal locomotor activity of the mice (dose range 0.1-10 mg/kg.c.).
Experiment IV: for alpha2Antagonism of agonist-induced sedation
Non-selective alpha in rodents2One of the main effects of agonists is to cause deep sedation. This effect (using alpha) can be used2Determination of the inhibition of locomotion by the agonist dexmedetomidine) in alpha2C(Scheinin, M. et al, Life Sci68(19-20) (2001) 2277-85). On the other hand, in alpha2AAlpha in mice with disruption of the adrenoceptor Gene2Agonists, however, do not have a sedative effect (Hunter, J.C. et al, British Journal of Pharmacology122(7) (1997) 1339-44). Therefore, due to α2Sedation by agonists is generally attributed to alpha2AThe adrenergic receptor, therefore it can be concluded that2CAntagonists do not significantly modulate alpha2-agonist-induced sedation. This inference can be verified experimentally by administering dexmedetomidine alpha2CMice pretreated with the antagonist (compound K or compound L) or with the subtype non-selective antagonist altimezole (Haaparinna, A. et al, Nauyn-Schmiedeberg's Arch. Pharmacol.356(1997) 570-582). As expected, α2CThe antagonist has no obvious effect, while the altemezole effectively antagonizes the effect of dexmedetomidineThe application is as follows. The results demonstrate that for alpha2CThe compounds of the invention selective for the alpha receptor2AReceptor no antagonism (figure 2).
Experiment V: forced swimming experiment
Forced swim tests (FST, Porsolt's test) are commonly used for pharmacological activity screening of novel antidepressants. In this experiment, the antidepressant enhanced the mobility of the animals relative to the untreated control group. In FST, α2C-more active and alpha expression in KO mice2COE mice have reduced mobility (U.S. Pat. No. 5,902,807 and Scheinin, M. et al, Life Sci68(19-20) (2001) 2277-85). Thus, FST is the test specificity α2CWhether the receptor antagonist has a similar antidepressant action (i.e. activity enhancing properties). FIG. 3 shows, for example, studies on transgenic mice (Scheinin, M. et al, Life Sci68(19-20) (2001)2277-85) and the newly published a2CAntagonists (WO01/64645), two alpha values being shown in this experiment2CHow the receptor compound enhances mobility. The positive control groups desipramine and fluoxetine (clinically effective antidepressants) also acted in the same way. As expected (WO01/64645), subtype nonselective alpha2The antagonist altemezole does not have a similar antidepressant effect.
Experiment VI: pre-stimulus (prepulse) inhibition of startle reflex
The pre-stimulus inhibition (PPI) of the startle reflex refers to the attenuation of the startle reflex caused by a low-intensity non-startle stimulus (pre-stimulus), which occurs shortly before the startle stimulus. PPIs commonly found in all mammals, including rats and humans, serve as an indicator of an operational sensory motor gate (Swerdlow, N.R. et al, The archives of general sensory physiology 51(1994)139- "154). In general, the function of PPIs can be disrupted by psychostimulants such as d-amphetamine or phencyclidine (PCP), and can also be reversed by clinically effective antipsychotics.
In previous studies, α2C-mutation and attenuation of KOPPI related, demonstrated alpha2Cthe-OE enhances PPI. That is, α2CMice with altered receptor expression genes are associated to some extent with altered PPI, which suggests that alpha is2CAntagonists can attenuate PPI (Scheinin, M. et al, Life Sci68(19-20) (2001) 2277-85). This inference can be tested by comparing compound K and compound L with PCP (PPI-disrupted), respectively.
In an experimental setup for startle studies (SR-LAB, San Diego Instruments, CA, USA), rats in the experimental group (n 10/group) for the determination of the acoustic startle reflex and PPI were dosed with α 20 minutes prior to the determination2CAntagonists, PCP or vehicle administered 10 minutes before. Discovery of alpha2CAntagonists can reduce the destruction of PPIs by PCP (fig. 3). This was unexpected and contrary to the reasoning of transgenic studies. And optionally alpha2CNon-selective alpha compared to antagonist2The antagonist altimezole has different actions: altimezole did not enhance PPI, but it enhanced the startle reflex itself (i.e. startle without pre-stimulation) (fig. 4).
In summary, the results in this section show that alpha is selective in a sense in vitro2CAntagonists also exhibit a selectivity in vivo2CAntagonists, this being by way of a preexisting para-alpha2CKnowledge of antagonism to infer. However, as expected, α2CAntagonists do not attenuate PPIs but rather enhance PPIs, which discovery is unexpected and adds to the novelty value of the effectiveness of the compounds of the present invention.
The compounds according to the invention can be used for the treatment of any alpha2Antagonists therapeutically effective diseases or conditions. These compounds are also useful for reversing alpha2-agonist induced effects. Thus, the compounds of the present invention are useful in the treatment of various Central Nervous System (CNS) disorders, i.e., different neurological, psychiatric and cognitive disorders (e.g., depression, anxiety, post-traumatic stress disorder, schizophrenia, parkinson's disease and other movement disorders). In addition, they are useful in the treatment of various peripheral disorders such as diabetes, orthostatic hypotension, lipidsMetabolic disorders (such as obesity), raynaud's disease, or sexual dysfunction in both men and women.
Selectivity of the invention alpha2CAntagonists may be used to treat a variety of alpha2CAntagonists are useful in the treatment of disorders or symptoms of CNS systems such as relief of symptoms of various psychiatric disorders caused by stress, parkinson's disease, depression, negative symptoms of schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder and anxiety disorders.
In addition, in view of the invention α2CDiscovery of antagonist action on PCP (destroying PPI) is novel and previously undisclosed, Selective alpha2CReceptor compounds are also useful for the treatment of disorders and diseases associated with sensorimotor gate deficits, particularly those in which sensorimotor gate deficits cause attention and comprehension dysfunction leading to sensory dyslexia (sensory flooding) and cognitive loss (cognitive fragmentation). These include, but are not limited to, schizophrenia, obsessive-compulsive disorders, tourette's syndrome, blepharospasm and other focal dystonias, temporal lobe epilepsy with psychosis, drug-induced psychosis (e.g., psychosis associated with chronic use of dopaminergic drugs) (Braff, d.l., et al, psychopharmacography (berl)156(2-3) (2001)234-258), huntington's chorea, parkinson's disease, disorders caused by fluctuations in sex hormone levels (e.g., premenstrual syndrome), and panic disorder.
In addition, symptoms associated with the above disorders or diseases include, but are not limited to, hallucinations, delusions, paraphasia, excitement, cognitive disorders of psychosis (including thought and language deficits), social withdrawal, withdrawal syndromes associated with smoking, alcohol abuse, or drug abuse (including delirium). These symptoms can also be observed in the animal in abnormal circumstances, such as during departure from the owner or transportation.
Due to the alpha of the invention2CSelectivity of action of the antagonist, so that it has no or little non-selective alpha2Adverse effects of antagonism, such as increased blood pressure, increased heart rate, salivation, gastrointestinal secretion, anxiety and startle reflex (Ruffolo, r.r.j. et al, Ann)u Rev Pharmacol Toxicol32(1993)243-279)。
The compounds of the present invention may be administered enterally, topically or parenterally in any pharmaceutical formulation containing at least one active compound of formula I in a pharmaceutically acceptable effective amount, in association with pharmaceutically acceptable diluents, carriers and/or excipients known in the art. Methods for the production of such pharmaceutical preparations are well known in the art.
The dosage required for the treatment of a patient will vary depending on the compound given, the species, age and sex of the patient, the particular disease being treated, and the route and mode of administration, and can be readily determined by one skilled in the art. Thus, for adult mammals, a typical dosage for oral administration is from 5 μ g/kg to 100mg/kg per day, while for parenteral administration is from 0.5 μ g/kg to 10 mg/kg.
The invention also provides the use of a compound of the invention or an ester or salt thereof as alpha2-an antagonist. In addition, the method also provides the step of alpha2Antagonists (e.g.. alpha.)2CAntagonists) are useful in the treatment of diseases or conditions, such as central nervous system diseases or conditions. In this method, an effective amount of a compound of the present invention is administered to a patient in need of treatment. The invention also provides the use of a compound of the invention in the manufacture of a medicament for use in the above method.
Those skilled in the art will appreciate that changes may be made to the embodiments of the application without departing from the broader inventive concept. It will also be appreciated by those skilled in the art that the invention is not limited to the specifically disclosed embodiments, but encompasses modifications within the spirit and scope of the invention.

Claims (13)

1. A compound of formula IA, a pharmaceutically acceptable salt or ester thereof:
wherein the content of the first and second substances,
x is CR2R2', O or S;
z is-CHR8-(CH2)n-；
R1Is hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halogen, halo (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-, CN, NO2、NH2One or two (C)1-C6) An alkylamino group or a carboxyl group;
R2and R2' independently is H, hydroxy or (C)1-C6) Alkyl or R2And R2' the carbon ring atoms to which they are attached form a carbonyl group;
R3is hydroxy, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl group, (C)3-C7) Cycloalkyl (C)1-C6) Alkyl, aryl (C)1-C6) Alkyl, aryloxy, aryl (C)1-C6) Alkoxy, aryloxy (C)1-C6) Alkyl, aryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, NH2Amino group (C)1-C6) Alkyl, mono-or di (C)1-C6) Alkylamino, mono-or di (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, (C)1-C6) alkyl-CO-, (C)1-C6) alkyl-CO-O-, (C)1-C6) alkyl-CO-O- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-, (C)1-C6) alkoxy-CO- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO- (C)1-C6) Alkoxy (C)1-C6) Alkyl, carbamoyl, mono-or di (C)1-C6) Alkylcarbamoyl, carboxy or (C)1-C6) alkyl-S- (C)1-C6) Alkyl group, wherein (C) is3-C7) Cycloalkyl or aryl is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxy, NH2CN or NO2Or R is3Or R4With R6Form bonds between the ring atoms to which they are attached;
R4is hydroxy, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R5is H, hydroxy, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl group, (C)3-C7) Cycloalkyl (C)1-C6) Alkyl, aryl (C)1-C6) Alkyl, aryloxy, aryl (C)1-C6) Alkoxy, aryloxy (C)1-C6) Alkyl, aryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)1-C6) alkyl-CO-O-, (C)1-C6) alkyl-CO-O- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO- (C)1-C6) Alkoxy (C)1-C6) Alkyl, carbamoyl, mono-or di (C)1-C6) Alkylcarbamoyl, carboxy or (C)1-C6) alkyl-S- (C)1-C6) Alkyl group, wherein (C) is3-C7) Cycloalkyl or aryl is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxy, NH2CN or NO2Or R is3And R4Form, with the carbon ring atoms to which they are attached, a fused five-to seven-membered ring formed from 1-3 substituentsR9Substituted saturated carbocyclic ring, each R9Independently is hydroxyl, (C)1-C6) Alkyl, halogen, NH2、NO2、(C3-C7) Cycloalkyl, hydroxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, amino (C)1-C6) Alkyl, mono-or di (C)1-C6) Alkylamino, mono-or di (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, carboxyl, (C)1-C6) alkyl-CO-, (C)1-C6) alkyl-CO-O-, (C)1-C6) alkoxy-CO-, (C)1-C6) alkoxy-CO- (C)1-C6) Alkyl, carbamoyl, mono-or di (C)1-C6) Alkylcarbamoyl or oxo;
R6is H, hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy (C)1-C6) Alkyl or R6At the ring atom to which it is attached and R7A bond is formed between the attached ring atoms;
R7is H, hydroxy, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R8is H, hydroxy, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R15is H, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, amino (C)1-C6) Alkyl, mono-or di (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, (C)1-C6) alkyl-CO-, (C)1-C6) alkyl-CO-O- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-, (C)1-C6) alkoxy-CO- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO- (C)1-C6) Alkoxy (C)1-C6) Alkyl, carbamoyl, mono-or di (C)1-C6) Alkylcarbamoyl or carboxyl;
R16is H or (C)1-C6) An alkyl group;
R7and R8To an adjacent carbon ring atom;
m is 0 to 2; and is
n is 0.
2. The compound according to claim 1, wherein X is CR2R2’。
3. A compound according to claim 1, wherein X is O.
4. A compound according to claim 1, wherein X is S.
5. A compound according to any one of claims 1 to 4, wherein R3Is hydroxy, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-or (C)1-C6) alkyl-CO-O- (C)1-C6) Alkyl and R4Is (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group.
6. Compounds according to any one of claims 1 to 5, wherein R3Is hydroxy, hydroxy (C)1-C6) Alkyl or (C)1-C6) Alkoxy (C)1-C6) Alkyl and R4Is (C)1-C6) An alkyl group.
7. Compounds according to any one of claims 1 to 4, wherein R4And R5The carbon ring atoms to which they are attached form a fused six membered saturated carbocyclic ring.
8. The compound according to claim 1, wherein the compound is 1 α -methyl-1, 3,4, 5, 6, 11 b-hexahydro-2H-11-oxa-4 a-aza-benzo [ α ] fluoren-1-ol, (1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ α ] fluoren-1-yl) -methanol, (-) - (1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ α ] fluoren-1-yl) -methanol, (+) - (1 α -methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] fluoren-1-yl) -methanol, 1 alpha-isopropyl-1, 3,4, 5, 6, 11 b-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] fluoren-1-ol, 1 alpha-ethyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] fluoren-1-ol, (1 alpha-ethyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] fluoren-1-yl) -methanol, 1 alpha-ethyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] fluoren-1-, (1-hydroxymethyl-1, 3,4, 5, 6, 11 b-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] fluoren-1-yl) -methanol, 1-methoxymethyl-1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] fluorene, (-) -1-methoxymethyl-1 alpha-methyl
-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ α ]]Fluorene, (+) -1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ α ] -n]Fluorene, a,Methyl radical
-1，3，4，5，6，11balpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] -n]Fluorene-1-carboxylic acid ethyl ester, 1-ethoxymethyl-1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] -n]Fluorene, (1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] -n]Fluoren-1-yl) -methanol, (-) - (1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] -, and its preparation]Fluoren-1-yl) -methanol, (+) - (1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ alpha ] -l]Fluoren-1-yl) -methanol,Ethyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a]Fluorene-1-carboxylic acid methyl ester, 1-methoxymethyl-1 alpha-methyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a]Fluorene, (-) -1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a [ -a ]]Fluorene, (+) -1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b α -hexahydro-2H-11-oxa-4 a-aza-benzo [ a]Fluorene, (1 alpha-ethyl-1, 3,4, 5, 6, 11b alpha-hexahydro-2H-11-oxa-4 a-aza-benzo [ a)]Fluoren-1-yl) -methanol, acetic acid 1 alpha-methyl-1, 3,4, 5, 6, 11b beta-hexahydro-2H-11-oxa-4 a-aza-benzo [ a]Fluoren-1-ylmethyl ester or (1 alpha-methyl-1, 2,3, 4,6, 7, 12, 12b alpha-octahydroindeno [2, 1-a ]]Quinolizin-1-yl) -methanol.
9. The compound of any one of claims 1, 3, 5, 6 and 8 wherein said compound is (-) - (1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-aza-benzo [ a ] fluoren-1-yl) -methanol.
10. A compound according to any one of claims 1, 3, 5, 6 and 8, wherein the compound is (-) -1-methoxymethyl-1 α -methyl-1, 3,4, 5, 6, 11b β -hexahydro-2H-11-oxa-4 a-azabenzo [ a ] fluorene.
11. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 10 and a pharmaceutically acceptable diluent, carrier and/or excipient.
12. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for use as a selective α -2C antagonist.
13. Use according to claim 12 for the preparation of a medicament for the treatment of: stress-induced psychotic disorders, Parkinson's disease, depression, schizophrenia, attention-deficit hyperactivity disorder, post-traumatic stress disorder, anxiety disorders, obsessive compulsive disorders, Marigold syndrome, blepharospasm and other focal dystonias, temporal lobe epilepsy with psychosis, drug-induced psychosis, Huntington's chorea, disorders arising from fluctuations in sex hormone levels, and panic disorder.
HK05107766.2A 2002-04-03 2003-04-03 Polycyclic compounds as potent alpha2-adrenoceptor antagonists HK1075660B (en)

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FI20020642A FI20020642A0 (en) 2002-04-03 2002-04-03 Polycyclic compounds as potent alpha2-adrenoceptor antagonists
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