JPS5883679A - Pharmacological novel 1,2,3,4,4a,5,10,10a- octahydro-benzo(g)quinoline derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention relates to octahydrobenzoquinoline derivatives, and more particularly to novel compounds having useful pharmacological activity. 2.8,4,4a,5.10.1Oa-octahydro-
The present invention relates to benzo[g]quinoline derivatives, methods for producing the derivatives, pharmacological compositions containing the derivatives, and uses of the derivatives as drugs. In particular, the present invention provides 6-, 5- and/or 7-oxy-5°benzo[g]quinolines (an amidated carboxyl group if required at the 8-position, an etherified hydroxymethyl group if required, a cyanomethyl (alkyl- or aryl-thiomethyl, sulfamoylamino or carbamoylamino groups) or physiologically hydrolyzed and physiologically acceptable esters thereof. The benzoCglquinoline nucleus of the compound of the present invention further has substituents,
That is, the above substituents include n-positions, especially the 6-position and/or the 7-position.
It can have a substituent at the position and the 3-position. The benzo[g]quinolines of the present invention are preferably unsubstituted at the 1-position or substituted with C1-4 alkyl. Suitably, there are no further substituents other than the C1-4 alkyl at the 1-position. The aryl in the arylthio group that can be present at the 3-position includes heterocyclic aryl groups such as pyridyl. 6
Preferred substituents in positions 2 and/or 7 are hydroxy or methoxy. A preferred substituent at the 3-position is substituent R4 described below. In the present invention, the following benzo[g]quinolines (I) and their physiologically hydrolyzed and physiologically acceptable n
Particularly preferred are esters: 3 [wherein B is a trans bond to the ring]. R1 and square are each individually hydrogen, hydroxy or methoxy (however, both of R1 and - do not have to be hydrogen); H is hydrogen or C1-4 alkyl; R4 is -COOH, -C)I20R5, - CH2CN,
-CON(R6)R7-CH2SR8,-N)180
2N(R9)Rlo or -NI(CON (R9)R
1o; R5 is hydrogen or C1-3 alkyl. R6 is hydrogen or 01-8 alkyl, and the buttock is hydrogen,
ClN3 alkyl, phenyl or pyridyl (phenyl and pyridyl optionally substituted with halogen, methyl or methoxy) or R6 and R7 taken together -(CH2)4-. -(CH2)5- or -(CH2) 2-0- (C
H2) 2-1R8 is C194 alkyl or ipyridyl (pyridyl may be optionally substituted with halogen, methyl or methoxy). R9 and Rlo are each individually hydrogen or C1-3
Alkyl or R6 and R7 together are -(
Represents CH2)4 or -(CH2)5-. ]. In the present invention, halogen includes fluorine, chlorine, and bromine. Pyridyl displaces 2-13- and 4-pyridyl. Physiologically hydrolyzed and physiologically tolerated
The esters are esters with acids or alcohols that can be hydrolyzed under physiological conditions to acids and alcohols and are themselves physiologically tolerable (non-toxic at the desired dosage). be. Such esters are acylated benzo[g]quinolines of the invention having one or more hydroxy groups (e.g. hydroxy and/or hydroxymethyl) in the 3-, 6- and/or 7-positions, and/or It can be obtained by esterification of the benzo[g]quinolines of the present invention having an acid residue (for example, a carboxyl group) at the 3-position. Such esters include esters of mono- and dicarboxylic acids, especially carboxylic acids having 2 to 5 carbon atoms, and esters with fatty alcohols having 1 to 4 carbon atoms. Preferably, the primary form of compound (I) and a combination thereof are preferred. 1. 2, R3 is C1-4 alkyl (particularly n-propyl), 3
, R4 is a group other than =coon (especially -CON(R6)
R7゜CH2S Rs, -NH802N(R9)Rlo
or -N)ICON(R9)R1゜, especially -CH28
R84 or -NH802N(R9)Rlo, especially -NH
802N(R9)R10), 4. R5 is hydrogen, 5. R6 is hydrogen, R7 is pyridyl substituted with halogen, methyl or methoxy if necessary (in particular, pyridyl substituted with halogen, methyl or methoxy if necessary) 6, R8 is C1-4 alkyl (especially methyl), 7, R9 is monohydrogen or C1-4 alkyl (
C1-4 alkyl, especially ethyl), Rlo is hydrogen or C1-4 alkyl (especially C1-4 alkyl, especially ethyl). The benzo[gl quinolines (I) of the present invention include the following first
The group includes compounds in which both R1 and R2 are hydroxy or both methoxy, or one of Rt and is hydrogen and the other is hydroxy or methoxy, and R3 is Ct4 alkyl. R4 car CH20H1"Cti2 CN, -CON (
Re,)R7, -C1i2S R8-NHbo2N
(R9) Rlo or -NHCON (Rta)
R1o, R6 are hydrogen or C1-3 alkyl, and R7 is a bilysyl substituted with halogen, methyl or methoxy. R8, R9 and Rlo are a compound Th having the same meaning as in formula (I). (I) and its physiologically hydrolyzed and physiologically acceptable esters. The benzo[g]quinolines (I) of the present invention include the following second group of compounds: Rh, R2 and R3 has the same meaning as the above formula (I), R
4 car C00I(, -CI(20H1-CH2CN,
-CON(R6)R7, -CH2SR8, -NH80
2N(R9)Rlo or -NHCON(R9)Rt
□, R6, R7, R8, R9 and Rlo have the same meanings as in formula (I), and a physiologically hydrolyzed and physiologically acceptable ester thereof. Furthermore, the benzo[g]quinolines (I) of the present invention include the following group of compounds: one of R1 and Sylvia is hydrogen, the other is hydroxy or methoxy, and R3 to R1o are the same as in formula (I). Compound (I) and its physiologically 7I0 hydrolyzable and physiologically acceptable esters. The compounds of the present invention can be used in free and salt forms, such as acid addition salts,
or, for example, when R4 is carboxyl, it can exist as a salt with a base. The present invention includes such compounds in free and salt (particularly pharmacologically acceptable salt) forms. Examples of compounds included in suitable pharmacologically acceptable salt forms include hydrochloride and maleate. Salts with pharmacologically acceptable bases include, for example, sodium salts. The substituent at the 3-position of the benzo[gl quinoline nucleus (R4 in formula (I)) of the compound of the present invention may be in either the α-configuration or the β-configuration. This nucleus has a trans configuration (for example, rings A and B in the formula ←, T are trans bonds, and therefore the hydrogens at positions 43 and 10a are also trans bonds with each other), so the compounds of the present invention are It exists as four isomers consisting of a pair of enantiomers. Furthermore, when other free radicals are present or when the free radical itself contains an optically active center, respective isomers exist. It is to be understood that the present invention encompasses both individual isomers and racemates (ie, mixtures of single enantiomeric isomer pairs) as well as other isomer mixtures. In formula (I), the only optically active centers present in the nucleus are the centers at positions 3, 4, and 101, giving four isomeric forms. These can be represented by the following structural formulas: (Ia) (Ib) ('Ic)
(id) The invention relates to individual isomers of formula (I), such as compounds (Ia), (Ib)
, (IC) or (Id) and mixtures thereof, especially (I
Includes racemic compounds of a) and (Ib) or (IC) and (Id). For pharmacological applications the individual isomers and racemates of the invention are preferred. Racemic mixtures are referred to throughout the specification (including the claims) as two sets of enantiomers present (e.g. 8α,
4aα, 10aβ or 3β, 4aα, tOaβ) (referred to as racemic compound). In addition to the above, the present invention can provide a method for producing a free or salt type compound of an octahydrobenzoquinoline derivative consisting of (al~([1) as described below. (a) 6 and/or 7 -Midogi;/ -tran
s -1゜2.3,4,4a,5.10.10a-octahydrogenzo[g]quinoline (the 1st position is unsubstituted,
A compound in which the 3-position is substituted with an amidated carboxyl group, optionally an etherified hydroxyl group, a cyanmethyl group, or an alkyl or arylthiomethyl group), or the above benzo[g]quinoline compound [ In the formula, B is a trans bond to the ring.R (and R
2 is each individually hydrogen or methoxy (however, R1'
and R2 do not both need to be hydrogen). R is -C■20R5, -CH2CN, -CON(R6
) R7, -CH2SR8, esterified 200O
H, or esterified -CH20H. R5, R6, R7 and R8 have the same meanings as in formula (I). ], the corresponding 6- and/or 7-midoxy tran
s-1,2,8,4,4a,5.10.10a-octahydro-benzo[g]quinoline or benzo[g]
A quinoline ester (a compound in which the 1st position is substituted with a benzyloxy group or a C1-4 alkoxy group), for example, the formula (■): X [In the formula, rings A and B are a trans bond. X represents Be, Jill or C1-4 Ayaki. R1., R2 and R4 have the same meaning as formula CI). ], the penyloxy group or C1-4 rubexy group (
(b) 6 and/or 7-midoxy trans
-1゜2.8,4,4a,5.10.1, Oa-octahydrogenzo[g]quinoline (the 1st position is, for example, C
(a compound substituted with 1 to 4 alkyl, whose 3-position is substituted with an amidated carboxyl group, optionally an etherified hydroxymethyl group, a cyanomethyl group, or an alkylmodyl arylthiomethyl group), or Physiologically hydrolyzed and physiologically acceptable esters of the above benzo[g]quinoline (compounds substituted at the 3-position with an esterified carboxyl group or an esterified hydroxylmethyl group), such as & (
I). a In the formula, rings A and B are trans-bonded. ~ is C1~4
Represents alkyl. Same meaning as Rt, R2 and Rtti formula (■1). ] In order to produce the compound represented by
-1, 2, 8, 4, 4a, 5.10. lOa -octahydro-benzo[glquinoline, or benzo'[g
]Quinoline ester (compound with no substitution at the 1st position)
A substituent is introduced into the 1-position of C1, for example, by alkylation.
~4 alkyl group is introduced, for example, the above compound (11)
alkylating to introduce a 01-4 alkyl group into the 1-position; (C) 6- and/or 7-midoxy trans
i. 2, f3,4,4a,5.10.10a-Octahydrohenzo[g]quinoline (a compound whose 3-position is substituted with a sulfamoylamino group or a carbamoylamino group), such as formula (I6) In the formula, rings A and B are a trans bond. Rj is -Ni
(802N (R9) Rlo or -NICON (R9
-) represents Rlo. R3, R9 and Rlo are of the formula (I
), R1' and R6 have the same meanings as formula (■1). ] In order to produce the compound represented by
s-1,2,3,4,4a,5.10.10a-octahydro-, benz[g]quinoline (a compound substituted with an amino group (-Nu-12) at the 3-position), for example, the formula (
m): 3'' 2 [In the formula, B is a trans bond to the ring. RI, R6 and R3 have the same meanings as in formula (I3). ] and aminosulfonic acids, aminocarboxylic acids or reactive derivatives thereof, such as formula (IVa) or (IVb
): HO-802-N(R9)Rlo(IVa))10-
CO-N(R9)Rlo (b) [wherein R9 and Rlo have the same meanings as in formula (, I). ] or a reactive derivative thereof; (d) 6- and/or 7-midoxy trans
-1゜2.8,4,4a,5.10.・1Oa-octahydro-benzo[g]quinolines (compounds in which the 8-position is substituted with a carboxyl group), for example, formula (■4)::
2 [In the formula, rings A and B are a trans bond. R1 and R
2 has the same meaning as formula (■1), and R3 has the same meaning as formula (I). ] To produce the compound shown in The corresponding 6 and/or 7-midoxy trans-
1,2,8,4,4a,5.10.101-octahydrogenzo[glquinoline (a compound substituted with an esterified carboxyl group at the 8-position), for example, the formula (
V): 3 ■ [In the formula, B is a trans bond to the ring. 2 represents an esterified carboxyl group. R1'. R crystal and R3 have the same meaning as formula [■4]. ]; (e1 6- and/or 7-oxy-tran of the present invention);
s-1,2,3,4,4a,5.10.10a-octahydro-benzo[g]gynoline (a compound having at least one hydroxyl group in its 6- and 7-positions), for example formula (■). In the 3C formula, rings A and B are a 4-torus bond. Rf and R are each individually hydrogen, hydroxy, or methoxy (at least one of Ri/ and R5 is hydroxy), and Rs sp and R4 have the same meanings as in formula (I). ], the corresponding 6 and/or 7-oxy-trans-1
, 2,8,4,4a, 5.10.1 Oa-octahydro-benzo[glquinoline (a compound having at least one methoxy group in its 6- and 7-positions), for example of the formula (
'Vl): 3 ■ [In the formula, B is a trans bond to the ring. R7 and R2 are each individually hydrogen, hydroxy or methoxy (at least one of R1' and R' is methoxy), R3 and R4 have the same meaning as in formula (I). ]; (f) 6 and/or 7-oxy-rrans -1,2°8.4,4a, 5.10
．． 1Oa-octahydro-ben:/[g]quinoline (with an amidated carboxyl at position 3), or 6- and/or 7-oxy-t of the present invention
rans-1, 2, 3, 4, 4a. 5.10,10a-Octahydrogenzo[g]quinolines for producing physiologically hydrolyzed and physiologically acceptable esters of 6 and/or 7-oxy-trans-1,2,
8゜4.4a, 5.10.10a -O99 HiFC2
- 7"[g]quinoline (a compound in which the 3-position is substituted with a carboxyl group) or a reactive derivative thereof, or the 6 and/or 7-oxy-trans-1 of the present invention, 2,9,4,4a,5.10
．． Acylation or esterification of 1oa-octahydro-benzo[glquinoline (e.g. a compound having one or more hydroxy and/or carboxyl groups in the 3-, 6- and/or 7-position) or a reactive derivative thereof, e.g. Reacting the benzo [compound (I) in which gllquinone R4 is a carboxyl group) or a reactive derivative thereof with an amine: HN (Rs ) R7 (R6 and R7 have the same meanings as in formula (I)), or Formula (I)
benzo[glquinoline (I
)) or benzo[glquinoline (compound (■) in which R4 is carboxy) of formula (I) or a reactive derivative thereof with a suitable acid or a reactive derivative thereof or a suitable alcohol; [A method for producing octahydrobenzoquinoline derivatives, which comprises recovering glquinoline or benzo[g]quinoline ester in free form or salt form. The above preparation method (al to (fl) can be carried out according to standard procedures known in the art. Preparation method (for al, benzyloxy and C1
~4 alkoxy (e.g. -X group of compound (rl))
can be eliminated by reductive cleavage, e.g. reduction in the presence of lead and acetic acid. The introduction of a substituent at the 1-position according to the production method tbl can be carried out, for example, by alkylation or acylation. C
Introduction of 1-4 is accomplished, for example, by direct alkylation, indirect alkylation, or acylation followed by addition of the amide native product. Direct alkylation can be carried out, for example, by reaction with the compound R5-Q (Q is a leavingable group, Ri represents C1-4 alkyl). Groups Q that can be eliminated include chlorine, bromine, iodine and organic sulfonic acid residues (eg methyl- or p-)luene-sulfonyloxy groups). The reaction is preferably carried out in the presence of an acid binder such as an alkali or alkaline earth metal carbonate and an inert organic bath or diluent such as dimethylformamide. :R:i
-cuo (C5 represents hydrogen or C1-3 alkyl) and a suitable catalyst (e.g. palladium/
This can be carried out by simultaneous hydrogenation in the presence of carbon. This reaction can be carried out using an inert organic solvent or diluent (
For example, the corresponding alcohol: Rg-CH20H)
It is appropriate to carry out the reaction in the presence of normal pressure or slightly increased pressure. Acylation and alkylation by reduction, for example, acid halide: R5-C0-tlal (R5 has the same meaning as above,
Hal may be chlorine or bromine) followed by reduction using, for example, lithium aluminum hydride or diborane as reducing agent. Preparation process (C) can be carried out by acylation using a suitable sulfamino or carbamic acid, such as the aforementioned compound (IVa) or (b) or a reactive derivative thereof. Suitable reactive derivatives include the corresponding acid chlorides or acid bromides. This reaction is suitably carried out in the presence of an organic base (eg triethylamine) in an inert organic solvent or diluent (eg chloroform) at room temperature or with slight salt addition. Hydrolysis in production process +d+ can be carried out by suitable alkali treatment or acid hydrolysis, such as trifluoro cI1. This can be carried out by treatment in the presence of an acid. The ether cleavage in the preparation process tel can be carried out, for example, in the presence of an inert organic solvent or diluent (methylene dichloride, 1) MP, etc.), by reaction with hydrogen bromide, boron bromide or sodium methyl sulfide. This reaction is carried out, for example, from -70 to 0°C (HBr, BBra)'t*H100'c to reflux temperature (Na 8 C
In the case of Ha), it is appropriate to carry out the reaction at a temperature of The formed hydroxyl group can be removed by conventional operations such as the manufacturing method f.
It can be easily converted to other oxy substituents by acylation according to fl. Amidation or ester formation in process (f) is a conventional procedure in the art, e.g. when acylating hydroxy groups, with a reactive derivative of the selected acid (e.g. acid chloride or anhydride). When the carboxyl group at the 3-position is amidated or esterified, it can be carried out, for example, by reacting the corresponding 3-carbonyl halide or anhydride with a selected amidation or alcohol. Starting materials used in the above production method, such as compound (II
), (Ill), (V) Oyohi (Vl) Ha, Exist in various isomeric forms corresponding to the above-mentioned isomers explained for biological substance (I). The preparation of each of the above compounds can be carried out using starting materials in one individual enantiomeric form or in the form of a mixture (in particular a racemic mixture thereof). The starting materials used are advantageously in racemic form. These starting materials can be produced by the methods described below. If a diastereomeric mixture of starting materials is used, the product is also of the diastereomeric mixture type. The diastereomers can be separated, for example, by chromatography, to obtain the racemic compound uncontaminated by the diastereomer. By dividing the obtained racemic compound using the known JJJ force method, for example, by forming an acid salt with optically active m, and separating the resulting diastereomeric salt, Individual optically active enantiomers can be obtained. The compound of the present invention can be recovered as a free form or a salt, such as an acid salt, from the reaction mixture initially prepared. The production of the starting material in production method 1al, for example, the production of compound (11), can be carried out according to the anti-Ls system shown below.YY ( Racemic compound v") (racemic compound v'〃) In the above reaction process diagram, R1', R1 and
'), each Y is C1-4 alkyl or aryl (especially phenyl), or both Y together are 03-4 alkylene, R11 is C1-4 alkyl (especially methyl, inpropyl or (dL-)) -tv). Each step in the above reaction process diagram can be carried out according to known techniques, for example, the examples given below. The starting material (■) is known or can be produced by suctioning using a method similar to a known method. Example 1

[As explained in [, the penultimate protoparabolite (a compound in which B is a cis or trans bond to the ring (V')) is a racemic compound (Vm) with only traces.
including. However, the amount of racemic compound <V”) present is
For example, in an alkaline medium (for example, Example 5a below),
It can be easily increased by turning it into shrimp. R1 or methyl is preferable for shrimp formation. Isolation of the racemic compound is conveniently carried out at the stage of formula (V'), but isolation may be carried out at a later stage of the synthesis if necessary. Similarly, racemic compounds (V“) and (V#
) can be used directly in the next reaction step or can be separated into individual enantiomers and this enantiomeric form used in the next reaction. The compound (V') in which rings A and B form a trans bond is the above-mentioned compound (V). When the group COOR1 is a physiologically hydrolyzable and physiologically acceptable ester group, these compounds are included within the scope of said compound (n). Compound (n) can be obtained from compound (V) by the following production method: fil compound (V)
on -c to obtain a compound (...); (1:) Etherify the compound obtained in (1) above to obtain a compound (11) in which R14 or -CI (20R5, R5'' is C1-4 alkyl) (++i+Mesylation of the purified compound obtained from (1) d above to obtain a corresponding compound in which the direct group at the 3-position is C1 (3so20C112-), and this compound and the compound: R85F■
to form a compound (1) in which R4 is -C112SR8
1); 6Vl above +m+ +C is mesylated, and the product is reacted with an alkali metal cyanide to obtain compound (II) in which R'4 is -CH2CN; 100N (4%)
%; trans-esterification of +vD compound (V) and further R
Compound (II) where 5 is esterified n-COOH
(vll) The compound obtained in (1) above is acylated to obtain a compound (b) in which R4 is esterified -CH20H. Reactions (1) to (vif) can all be carried out according to standard procedures, such as those described in the Examples below. Compound (ffl) can be obtained from compound (V) according to standard procedures, such as the Curtius reaction. All of the above intermediates except for compound (■) are new and form part of the present invention. In addition to the pharmacological usefulness described below, various compounds (
I) is yet another compound (1)! i! ! Its usefulness as an intermediate for manufacturing should be evaluated. For example, compounds (I'), (I2). and (Step 3) can be used as a starting material for the production method (el), and compound (I) can be used as a starting material for the production method (fl). In the examples, abbreviations have the following meanings: DMF-dimethylformamide, i(MP T-hexamethylphosphotriamide, MeOH=methanol, Et
OH=ethanol, T)IF=tetrahydrofuran, M
S-Mass Spectrometry. Example 1 8α-methoxycarbonyl-6-methoxy-1° [g]
Preparation of gynoline (racemic compound) 85 Jnl of niacetic acid and 18-l-methoxy-3α-methoxycarbonyl-
6-Methokiller 1.2.3.4°4aα, 5,10. l
3.5 g of Oaβ-octahydrohenzo[g]quinoline (racemic compound) was dissolved, and because of this bath 179 g of powder bed zinc was dissolved.
Add. The mixture is stirred at room temperature for about 15 hours, filtered and concentrated. The whole residue is taken up in methylene chloride and refiltered, and the residue is washed with methylene chloride. '/P axillary was extracted with IN potassium bicarbonate/water and the organic layer was dried over sodium sulfate and evaporated to give the title compound as a yellow oil. Leave this to crystallize. Melting point 66-68°C6 The starting material in the above production method is obtained by the following method. fal l, Preparation of 1-bis(phenylthio)-5-methoxy-2-tetralone 70 g of 5-methoxy-2-tetralone, 150 g of benzenesulfone@S-phenyl ester and 120 g of sodium acetate were mixed in 1100 methanol in a room width room. Stir for 24 hours. The title compound precipitates during the course of the reaction. The reaction mixture is concentrated to 1/2 volume, cooled to 100C, and filtered to give the title compound. Melting point 189~l 41 'C0 (b) β-[1,2,8,4-tetrahydro-1,1-
Bis(phenylthio)-2-oxo-5-methoxy-3
-Naphthyl]-a-methylidene-propionic acid[--Preparation of butyl ester 1.6 N solution of n-butyllithium in nihexane, 5
To B-, 12.6% of diimpropylamine in 240% of diethyl ether is added at -70°C. Mixture 15
Leave to warm to -20°C for a minute and recool to -90°C. Do not let the temperature rise above about -70℃. The product of the above (al step) 28.4 ftDTHF 25
0. nt/nMPT25-I fully request the bath solution. After completing the application, the mixture was left at -70°C for 60 minutes and diluted with THF50. n
Add 19.8 f of 2-promomethyl aphlyl mi-t-butyl ester in l. The temperature is raised to -20°C. An excess of 2N hydrochloric acid is added, the resulting mixture is extracted partitioned between methylene chloride/water, the organic layer is dried over sodium sulfate and evaporated to give the title compound as a yellow oil. This is crystallized from 7 ethyl ether/hexane at -20°C. Melting point: 120-121'C0 F2,
700- and water 800. In z, add fresh amalgamated aluminum △ rum powder 140II to 1ooy of the product of above it I a (bi). While stirring the mixture add 2
Heat to 50°C for an hour. The mixture is cooled, methylene chloride is added, and then filtered. The residue is washed several times with methylene chloride, the filtrate is evaporated and the residue is extracted partitioned between methylene chloride/water. The organic layer was dried with sodium sulfate,
Evaporate. Recrystallization of the residue from diethyl ether/hexane at -20°C (preferably using seed crystals previously obtained) gives the title compound. Melting point 95-9
6℃. (dlβ-(1,2,8,4-tetrahydro-2-methoxyimino-5-methoxy-3-naphthyl)-α-methylidene-propion vi [-Preparation of butyl ester) In 1600 methanol, the above steps Product 7 of (C)
9f, O-methylhydroxylamine Yin salt 41.5
fI and Hydrogen Phosphate Disu)IJiumOdiice Hydrate 44
Stir 5 g at room temperature for 4 hours. evaporate the reaction mixture;
The residue is partitioned and extracted between methylene chloride/water. The organic layer is dried over sodium sulfate, evaporated and recrystallized from hexane to give the title compound. Melting point 72-73°C. Preparation of (elβ-(1,2,8,4-tetrahydro-2-methoxyamino-5-methoxy-3-naphthyl)-α-methylidene-propionic acid [-butyl ester) Methanol 2200-
Add sodium cyanoborohydride 52y to the solution. During the reaction process, add methanolic 7.5 N hydrochloric acid to maintain the pf (3 to 4), and complete the reaction after 22 hours. Add a buffer solution to adjust the pH to 7, and evaporate the reaction mixture. Extraction with methylene chloride. After drying the organic layer over sodium sulfate and evaporation, the title compound is obtained as diastereo Y-. The results of thin-layer chromatography analysis already indicate the presence of a small fraction of the above product. ff) 1-methoxy-3-[-butyloxycarpho=
Lou 6-J Togi: /-1, 2, 8, 4, 4a, 5, 10
, 10a - Preparation of octahytrobenzo[g]quinoline The product of the above step tel 61. Potassium hydrogen phosphate in 1200 methanol solution of 96. Add Ofi. The mixture is stirred at room temperature for 3 days, evaporated and partitioned between methylene chloride/water. sulfurizing the organic layer) IJ
Dry over 300 ml and evaporate to give the title compound as a brown oil. Thin layer chromatography shows that the product is a diastereomeric mixture consisting of four pairs of enantiomers. These are expressed by the following formulas, respectively AfA) ~ fl)
Separate into 1. Each of the four racemic formulas represents the structure of one of the two enantiomers present. (racemic compound) melting point = 100-1 OrC (racemic compound) melting point = 104-105G (racemic compound) melting point -1
15-117°C (racemic compound) melting point = 83-84°
The diastereomeric mixture initially obtained consists primarily of racemic compounds (B) and (D), and contains a small amount of racemic compound (A') and traces of racemic compound (C). The four racemic compounds (A) to (D) can be easily separated by medium pressure liquid chromatography. (gl 1-methoxy-3σ-force l levoxy-6-medoxy 1.2.8.4.4 aα, 5,10,10aβ
- Production of octahytrobenzo[gl quinoline (racemic compound) Racemic compound (B) obtained in the above step (f)
Dissolve 4g in trifluoroacetic acid and dissolve the solution at room temperature.
Leave for 5 minutes. The reaction mixture is dried under reduced pressure and the title compound is recrystallized as a gray solid. Melting point 196-197°C0'th) 1-methoxy-
3α-methoxy power! Reponile 6-Methoxy River, 2
．． 3.4.4 aα, 5, 10. Preparation of lOaβ-octahytrobenzo[glquinolino (racemic, compound)] An excess of a mixture of diasomethane and diethyl ether is added to a solution of the crude product 6.6F obtained in the above step fgl in ichmethylene 50-. After concentrating and evaporating the reaction mixture under reduced pressure, the title compound was obtained as a brown solid. This crude product is used directly in the next step. Melting point after recrystallization: 111-112°C0 Example 2 1-n-7′-pill-3α-methoxyca I levonyl-6
-Medoxy 1.2.8.4.4 aα, 5, 10. l
Production of Oaβ-octahydro-benzo[g]quino-1-one (racemic compound): -3α-methoxycarbonyl-6-methoxy-1°2.8
,4,4allt,5.10.101/-octahydro-benzo[g]quinoline (racemic compound prepared in Example 1)8. Dissolve in Ofi, n-propatool 3o-. Add n-propionaldehyde 8ffItf,
Hydrogenate using 10% palladium/carbon at 1.2 F and stirring for about 15 hours. After filtering and evaporating the reaction mixture,
The title compound was obtained as a yellow oil. This stuff solidifies slowly. Melting point 81-83°CQ Example 8 l-n-propyl-3α-diethylsulfamoylamino-6-methoxy-1,2,8,4,4aα, 5.
IO. Preparation of 10aβ-octahydro-benzo-Cglquino (racemic compound) Ni-diethylsulfamoyl chloride 1.9f Chloropho/
l/450 wtmH, 1-n-propyl-3α-7
Mi/-5-methoxy-1,2,8,4,4ad, 5.1
0゜10aβ-octahydro-benzo[glquinoline(
Racemic Va) 1.5g and triethylamide 73, Om
Z is added and the mixture is stirred at 50° C. for about 15 hours + lJ. 5° of IN carbonated sodium solution is added and the mixture is stirred at room temperature for 2 hours and extracted partitioned between methylene chloride/water. The organic layer was dried over sulfuric acid, evaporated and purified by chromatography to give the title compound as a yellow oil. -2 from diethyl ether/hexane
Crystallizes at 0"C. Melting point 88-89'C0 The starting material in this example can be obtained in the following manner: fall-n-propyl-3α-carbazoyl-6-midoxy 1,2,8,4 .4aα, 5,10.10a
Preparation of β-octahydro-benzo[g]quinoline (racemic compound) 1-n-propyl-3ct-methoxycarbonyl-6-
) ) 'fushi-, 2, 8, 4, 4ad, 5, 10.
lOaβ-, t-phtahydro-benzo[g]quinoline (racemic compound prepared according to Example 2) 185- in methanol at 60 rrt 1&K, hydrazine-1-
18.54 is added and the mixture is stirred at 50° C. for about 15 hours. After concentrating and drying under high vacuum, the residue is dissolved in diethyl ether, dried over sodium sulfate and evaporated to give the title compound as a yellow oil. Leave this to crystallize. Melting point 84-86°C. (bll-nL propyl-3α-amino-6-medoxy 1.2.8.4.4 aα,s,io,toaβ-octahydro-benzoCg) Production of quinoline (racemic compound) To 2.5 v of THF 8□ solution, add nitrosyl IN solution 8-, which is agglomerated in THF.The reaction is completed within 5 minutes.The mixture is boiled under reflux for 1 hour, and 2N hydrochloric acid 50- is added. The solution was boiled under reflux for 2 hours, cooled and evaporated, and the residue was adjusted to Pi (12) by adding 2N sodium hydroxide and extracted with methylene chloride. The organic layer was extracted with potassium carbonate. Dry and evaporate to give the title compound as a brown oil, which is used directly in the next step. Example 4 1-n-7'ipyr-3α-diethylsulfamoylamino-6-hydroxy -1, 2, 3, 4, 4aα,
5゜10.10a β-octahydro-benzo[gl Preparation of quinoline (racemic compound) 1-n-□propyl-3α-diethylsulfamoylamino-6-methoxy-1,2,a, 4.42α,5,
10゜10aβ-octahydro-benzo[g]quinoline (racemic compound obtained according to Example 3) Into a 1.9F methylene chloride 7〇 solution, a mixture of 2.7㎜ of boron tribromide and 30㎜ of methylene chloride was added. , at -80°C. The mixture was stirred at -30 to -10 °C for 4.5 hours, 100 - of IN potassium bicarbonate was added, the mixture was diluted with methylene chloride and the mixture was diluted with methylene chloride. Extract several times. The organic layer was washed with water until it became neutral, and then dried with sulfuric acid (IJ), and the formation of a brown foamy substance progressed. Dissolve this nf in methylene chloride/methanol (l:1) 80-, add methanolic 7N hydrochloric acid 9-, and dissolve the whole? - Boil at reflux for 15 minutes.゛Concentrate this, partition and extract between methylene chloride/IN sodium hydroxide, wash with water until the organic layer becomes neutral, and add sulfuric acid.)
Dry with IJum and evaporate. The combined residue was taken up in boiling diethyl ether/hexane, cooled and filtered once to give the title compound as a beige powder. Melting point 122.5~
124°C0 Example 5 3β-, methylthiomethyl-6-medoxy 1,2°8
, 4.4 aσ, 5,10,10aβ-Octahydrogenzo[g]Quinoline (racemic compound) Production Knee 17
Methoxy-3β-methyldithiomethyl-6-methoxy-
1,2,8,4,4aα,5,10,10aβ-octahydro-benzo[g]quinoline (racemization=product>2゜4
Dissolve f in 24rnl of acetic acid and 12ml of water, and add 11.6N of zinc powder to this m solution. The mixture is stirred at room temperature for about 15 hours, filtered and the P solution is concentrated. Dissolve the residue in methylene chloride and filter again. The ipH was extracted with 1N aqueous potassium bicarbonate solution, and the organic layer was dried and evaporated to give the title compound. Melting point: 107.5-108.5°C0 The starting material for this production can be obtained by the following method. +a+ 1-methoxy-3β-methoxycarbonyl-6
-Methoxy-1,2,8,4,4aα,5,10,10
Preparation of aβ-octahydro-benzo[g]quinoline (racemic compound) Ni-l-methoxy-3α-methoxycarbonyl-6-methoxy-1,2,3,4,4aα,5,10,10aβ-octahydro-benzo[g ] Quinoline (Real @VA+ 1
(obtained by hl) 8.59 was mixed with methanol/water (
9:1) in a 1N solution of sodium hydroxide at room temperature for 2 days. Through this reaction, the methoxycarbonyl group is hydrolyzed, and the 3-position is partially converted to shrimp. The reaction mixture was strained, 4N hydrochloric acid was added, and the mixture was poured.
2 and extracted several times with methylene chloride/methanol (95:5). The organic layer is dried and distilled, and the crude product is reacted with a diazomethane filter and evaporated. By repeating this operation twice, shrimp formation is completed and the title compound is obtained. This is finally crystallized from t'L1r ether/hexane. Melting point ios~109"c. (bl l-methoxy-3β-hydroxymethyl-6-
Medoxy 1.2.8.4.4 aα, 5, 10. lO
Preparation of aβ-octahydro-benzo[g]quinoline (racemic compound) Lithium aluminum hydride in Tt[F2O,j 0°5
The above (al production Th 1
Add 1V TtiF50mj/valley solution. The mixture was stirred for a further 2 hours at room temperature, and 0.6 i of water, 0.6 i of 20% sodium hydroxide, and then 2 − of water were carefully added.
0゛. After 10 minutes, the mixture is filtered and the p-liquid is evaporated to give the title compound as a white powder. Melting point 149-15
1℃. (C11-methoxy-3β-mesyloxymethyl-6-
Methoxy-1,2,3,4,4aα, 5.10. lO
Preparation of aβ-octahydro-benzo[gl quinoline (racemate) niemethanesulfonyl chloride 1.6-(0°C). A mixture of 2.8 g of the product from the above step (bl) and 40-pyridine is added. After the mixture is left at room temperature for about 15 hours,
INN Denden Hydrogen) Add IJum 20- to make the whole 30
Stir for a minute. The reaction mixture was m&Ied with methylene chloride/
Distribute extraction between water. The organic layer is dried and evaporated and the residue is crystallized from ethyl acetate to give the title compound. Melting point 1
88-189°C01dl 1-methoxy-3β-methylthiomethyl-6-medoxy 1.2,8,4.4aα
, 5.10.10 Preparation of β-octahydro-benzo[g]quinoline (racemic compound) Hydrogenation of methyl mercaptan 4- in DMF 20-
Add 2.5 g of IJum (50% suspension in oil). The suspension of product 3y of step fcl above is then added to zero with OoC and the mixture is stirred for 2 hours while cooling with water. The reaction mixture is placed under high vacuum and the residue is extracted partitioned between methylene chloride/water. The organic layer is dried and evaporated to give the title compound. The product is directly used in the next step reaction. Leprosy example 6 1-0-propyl-3β-methylthiomethyl-6-medoxy 1.2.8.4.4a (t, 5.10.10aβ
- Production of octahydrobenzo[glquinoline (racemic compound)] 3β-methylthiomethyl-6-midoxyl, 2°8,
Iodide n
- 0.874 propyl and 1.9 g of potassium carbonate in 7JO
The mixture was then stirred at room temperature for about 15 hours, filtered and dried under high vacuum. The residue was partitioned and extracted between methylene chloride/water, the organic layer was dried, evaporated and the product obtained as a yellow oil crystallized on standing to give the title compound. Melting point 74-75°C. Example 7 l-n-propyl-3β-methylthiomethy/L)-6
-Hydroxy-1,2,8,4,4aσ,5,10,1
Preparation of 0aβ-octahydro-benzo[g]quinoline (racemic compound) 1-n-propyl-3β-methylthiomethyl-6-medoxy 1.2.8.4.4 aα, 5,10,10aβ
-Octahydro-benzo[g]quinoline (racemic compound obtained by the method of Example 6)2. Of is commonly understood as methylene chloride 100-, and boron tribromide 3.6- methylene chloride 80 ml 1 K + 130 ° C is simplified. The mixture is stirred at -30 to -1O<0>C for 5 hours. Add 6≦125 of potassium hydrogen carbonate, adjust the pi (l 2) by adding 2N sodium hydroxide, and extract the mixture several times with methylene chloride. Wash the organic layer, which becomes neutral, with water. Then, dry and adjust with sodium sulfate (a yellow precipitate will form).
1:1) 100-JK is absorbed, methanolic 7N hydrochloric acid solution lO- is added and the mixture is boiled under reflux for 10 minutes. The resulting mixture was condensed and partitioned between methylene chloride/l sodium hydroxide. Wash the organic layer until neutral, dry and evaporate. The solid residue was taken up in diethyl ether and collected with '/Fi to give the title compound as a beige powder. Melting point 173-174°C0 Specific example 8 3α-methoxycarbonyl-7-methoxy-1°2,
B, 4.4 aα, 5.10.10aβ-Octahydro-benzo[g]quinoline (racemic compound) Production The title compound was obtained via the intermediate F by carrying out the same operation as in Example 1 above. Ta. (a)1. l-bis(phenylthio)-6-methoxy-2-tetralone, melting point 97-99°C0 (blβ-[
1,2,8,4-tetrahydro-1,1-bis(phenylthio)-2-oxo-6-medoxy-3-naphthyl]
-α-methylidene-propionic acid [-buti tv f, f
Le, d1 point lts ~ 119-C. (C) β-(1,2,8,4-tetrahydro-2-okino-6-methoxy-3-naphthyl)-α-methylidene-
Propionic acid [-butyl ester, melting point 58-60°C. (d) β-(1,2,8,4-tetrahydro-2-methoxyimino-6-methoxy-8-naphthyl)-α-methylidene-propionic acid [-butyl ester. Yellow oil. (elβ-(1,2,8,4-tetrahydro-2-methoxyamino-6-methoxy-8-naphthyl)-α-methylisonopropio7M[-butyl ester. Stereomer% compound: l-methoxy-3~[-butyloxycarbonyl-7~methoxy-1,2,8,4゜4a,5
,10,1Oa-octahytologenzo[glquinoline: tAl l-methoxy-3β-(-butyloxycarbonyl-7-methoxy:/-1,2,8,4,4aβ,5,
10,10aβ-octahydrobenzo[glquinoline (racemic compound), melting point 75°C, fBl l-methoxy-8α-[-butyloxycarbonyl-7-methoxy-1,2,8,4,4aα, 5.1
0.10aβ-octahydro-benzo[glquinoline(
racemic compound), melting point 94°C, (C) 1-methoxy-3β-[-butyloxycarbonyl-7-methoxy-1,2,3,4,4aα, 5.10
．． 10aβ-octahydrobenzo[gl gynoline (racemic compound), melting point 118'C1 IDI 1-methoxy-3α-[-butyloquinecarbonyl-7-methoxy-1,2,8,4,4aβ,5,1
0,10aβ-octahydro-benzo[glquinoline(
racemic compound), melting point 91'C0 The initial diastereomeric mixture consists primarily of racemates (B) and (D), with a small amount of (A) and traces of (C). Single solid racemic compounds can be easily separated by medium pressure liquid chromatography. Using the racemic compound, the following compound synthesis method was performed. Igl 1-methoxy-8α-carboxy-7-medoxy 1.2,8,4,4aα, 5.10. loaβ-
Octahydro-benzo[g]quinoline (racemic compound h>
. (h) l-methoxy-3α-methoxycarbonyl-7
-methoxy-1,2,8,4,4aα, 5.10. l
Oaβ-octahydro-benzo[glquinoline (racemate), mp 101 to tOa°C (starting material). Example 9 l-n-propyl-3α-methoxycarbonyl-7-methoxy-1,2J, 4.4aα, 5.10.10aβ-
Octahydro-benzo[g]quinoline (racemic compound)
The product of Example 8 above was used as a starting material, and the same treatment as in Example 2 was carried out to obtain the labeled Shimono Fang? It's 0. MS: M”=817゜Real IMVAll. 1-n-7'Rohi/L/-3α-diethylsulfamoylami7-7-medoxy 1.2.8.4.4 aα
, 5,10°10aβ-Octahitorobenzo[glJ&I Preparation of Quinoline (Racemic Compound) The product of Example 9 above was taken as starting material I7 and treated as in Example 3 to obtain the following compound The title compound was obtained as an oily substance via the body. fal l -n-propyl-3α-carbazoyl-7
- Midoxie 1.2.8.4.4 aα, 5.10
．． 10 aβ-71-ri'9hydro-benzo[g]quinolino (racemic compound), oil. (bl 1-n-propyl-3α-amino-7-medki:/-1, 2, 8, 4, 4a (, 5, 10, 10a
β-octahydro-benzoCg]quinoline (racemic compound). Example 11 1-n-propyl-8α-diethylsulfamoylamino-7-hydroxy-1,2,8,4,4aα, 5゜10.10aβ-octahydrobensogog]quinoline (racemic compound) Production The product of Example 1O above was used as the raw material and the same treatment as in Example 4 was carried out to obtain a standardized product. Melting point 21
0-211'C (as hydrochloride). Example 12' Preparation of 8β-methylthiomethyl-7-medoxy1.2°8.4,4a (r, 5.10.lOaβ-octahydrogenzoCg)quinoline (racemic compound) Example 8 (h ) was used as a starting material, the same treatment as in Example 5 was carried out, and the title compound was obtained as an oily substance via the following Nakaura body. (a) 1-Methoxy-3β-methoxyluponine I Lehrmethoxy-1,2,8,4,4aα,5,10.I
Qaβ-octahydro-benzo[g]quinoline (racemate), melting point 74-76°C0 (bl 1-methoxy-3β-hydroxymethyl-7-
Medoxy 1.2, 8, 4.4aα, 5, 10, 10a
β-octahydro-benzo[g]quinoline (racemate). fcl t-methoxy-3β-mesyloxymethyl-7
- Midokini l, 2.8.4.4 aα, 5,10.
lOaβ-yi-phtahydro-benzo[g]quinoline (
racemic compound). fdl l-methoxy-3β-methylthiomethyl-7-
Medoxie 1.2. :(,4,4aα,5,10,10
aβ-octahydro-benzo[glquinoline (racemized-1+), melting point 92-94°c0 Example 15 l-n-propyl-8β-methylthiomethyl-7-midoxy 1.2.8,4,4aα,5. 10. lOa
Preparation of β-octahydro-benzo[g]quinoline (racemic compound) a. Using the product of Example 12 above as a starting material, the same treatment as in Example 6 was carried out to give the title compound. Melting point 23
6-238°C (as hydrochloride). Example 14 1-n-propyl-3β-methylthiomethyl-7-hydroxy-1,2,8,4,4aα, 5,10,10aβ
-Preparation of octahydro-benzo[g]quinoline (racemate) A 50% suspension of sodium hydride (>49 in oil, washed several times with hexane, L) suspended in MF50-. Methyl mercaptan 12-1 then 1-n-propyl-
8β-methylthiomethyl-7-midoxy 1, 2.8.
4.4 aα,5,10,10aβ-octahydro-benzo[glquinoline (prepared according to Example 13)
Add a small amount of 8.5 I/ml DMF solution in small portions. The mixture is stirred at 160° C. for 5 hours, cooled and the DMF removed under high vacuum. The residue is commonly understood as methylene chloride, and the first 2
Extract twice with N-hydrochloric acid and then saturated sodium bicarbonate.b The resulting solution is dried over sodium sulfate, evaporated and purified by chromatography, the main fraction being extracted with methylene chloride/
Recrystallization from hexane gave the title compound. Melt 182
~184°C0 Example 15 3β-methoxycarbonyl-6-methoxy-1°2,8
．． 4.4 aα, 5,10,10aβ-octahy”drobenzo[gl quinoline (racemic compound) W synthesis 1
-methoxy-3β-methoxycarbonyl-6-methoxy-1,2,8,4,4aα, 5,10. lOa β-octahydro-ben 11 g 3 quinoline (racemic compound of Example 5(a)) 12.2 g acetic acid/water (2:'1) 180
Add zinc dust 601) to the rnl bath and stir the mixture at room temperature for 8 days. Run+yI+ The product was isolated as in 1 to give the title compound. Example 16 1-Methyl-3β-methoxysulfonyl-6-methoxy-1,2,3,4,4aα, 5,10. lOa β-octahydro-benz゛[g]quinoline (racemic compound) 'M crush Knee above @Production of Example 15\/Alof methanol 180
, z#; 35% aqueous formaldehyde solution 56- is added to the mixture and the mixture is hydrogenated for about 15 hours using 1.2 g of parasicum/carbon as a catalyst. Take the product /II. gaj
The solution was concentrated, the residue was partitioned and extracted between methylene chloride/IN potassium bicarbonate solution, and the organic layer was dried over sulfuric acid and evaporated to give the title compound. Melting point after recrystallization: 93-94°C0 Example 17 1-Methyl-8β-methodicarbonyl-6-hydroxy-1,2,8,4,4aα, 5. to, loaβ-octahydro-benzo[glquinoline (racemic Th)
Preparation of the product of Example 16 above: 1.2 fI of methylene chloride 10
A solution of 2.4 mt of boron tribromide in methylene chloride was added to the 0-solution at -20°C, and the mixture was heated to -5 to -1.
Stir at 0°C for 8 hours. Add 50ml of water (raise the temperature to room temperature). This suspension was boiled once in a methanolic IN hydrochloric acid solution for 1 hour, then evaporated, washed with water until the organic layer became neutral, dried over sodium sulfate, and evaporated. The title compound was obtained as a shaped powder. Melting point 1
82°c. Example] 8 1-Methyl-3β-carboxy-6-hydro [Jxy-1
, 2,8,4,4ad, 5.10.101 Preparation of β-octahydrohenzo[g]quinoline (racemic compound) Ethanol lOm of the product o,'iy of Example 17 above
10 ml of ethanolic IN potassium hydroxide solution are added and the solution is boiled under reflux for 11 hours. After cooling, the mixture is neutralized by adding 7.5 hours of methanolic 1N hydrochloric acid solution and evaporated. The residue was suspended in 2 ml of water, and the insoluble portion was separated to obtain the title compound. Melting point 250
~260°C (decomposition). Example 19 6-hydroxy-N-(2-methoxy-5-pyridyl)
-1-methyl-1,2,8,4,4aα, 5,10. l
Oaβ-octahydro-benzo[g]quinoline-3β-
Preparation of carboxamide (racemic compound) Product 1.1' of Example 18 above and A7) IJ Le 35Wll
Add 1°35rnl of trifluoroacetic anhydride to the liquid
and trifluoroacetic acid 74 molar solution in acetonitrile are added at -20°C (addition causes disintegration of the suspended material). The mixture was stirred for 40 min at 0 °C and −20
Recool to °C, 5-amino-2-methoxypyridine 1
．． Add 4g of Pyririf 12m/solution. Mixture Oo
Stir for an additional 4 hours at C. The resulting bath liquor is partitioned between methylene chloride/water, the organic layer is dried over sodium sulfate and evaporated (unreacted insoluble starting material is partitioned off, which is then collected separately). The residue was purified by chromatography to give the title compound. Melting point 209-211'
0゜Example 20 8β-methoxycarbonyl-7-methoxy-1゜2,8
．． 4.4 aα, 5,10,10aβ-octahydro-
Preparation of benzo[glquinoline (racemate) The product of Example 121al above was used as the starting material and treated in the same manner as in Example 15 to filter out the title compound.゛Melting point tl
O'c. Example 21 1-Methyl-8β-methylcarbonyl-7-medoxy 1.2.8.4.4 aα, 5,10. Preparation of lOaβ-octahydro-benzo[glquinoline (racemic compound) The product of Example 20 above was used as starting material and treated as in Example 16 to give the title compound. Example 22 1-Methylv-3β-methoxycarbonyl-7-hydroxy 1.2.8.4.4 aα, 5,10. ]]Oa
Preparation of β-octahydrobenzog]quinoline (racemic compound) The product of Example 21 above was used as starting material and treated as in Example 17 to give the title compound. Melting point 197~
199℃. Example 23 1-methyl-3β-carboxy-7-hydroxy-1,
2, 8, 4, 4aα, 5.10. lOaβ-octahydro-benzo[g]quinoline (racemic compound)'il
The product of Example 22 above was used as starting material and treated as in Example 18 to give the title compound. Melting point 194-196°c0 Example 24 7-hydroxy-N-(2-methoxy-5-pyridyl)
-1-methyl-1,2,8,4,4aα,5,10,1
0aβ-octahydo-benzo[g]quinoline-3β-
Preparation of carfoxamide (racemic compound) The product of Example 23 above was used as a starting material and treated in the same manner as in Example 19 to obtain the title compound. Melting point 244-246°
C0 Example 25 1-n-propyl-8α-diethylsulfamoylamino-T6-1 benzoyloxy-1,2,8,4°4a
α, 5.10. lOaβ-octahydro-benzo [g]
Preparation of quinolin (racemic compound) The product of Example 4 was added to a solution of 1.5 F in 200 °C of pyridine with 4.4 t of benzoyl chloride at 0°C. The mixture is stirred for 1 hour with water cooling, condensed and the residue is partitioned between methylene chloride/water. The organic layer was dried over sodium sulfate and evaporated, and the residue was recrystallized from ether to obtain the hydrochloride-formed compound. Melting point: 166-168°C. The final benzo[glquinoline products 6 of the present invention, particularly benzo[g]quinolines (I) and their pharmacologically acceptable salts, retain useful pharmacological properties as shown in animal studies. In particular, the compounds of the present invention can be used, for example, at 0.5%. O1~8.0
Suppression of pregnancy (ovum implantation) by administration to acid rats 5 days after insemination at a dose of 4/kf (subcutaneous administration) and e.g. 0.001 to 0.1 mg/kg (subcutaneous administration) Inhibition tests for both C and C exhibit inhibitory activity on prolactin secretion, as shown by inhibition of serum prolactin concentrations as determined by RIA 4 hours after administration in male rats. (1978)]. The benzo[g]quinolines and salts thereof of the present invention can be used as prolactin secretion inhibitors, for example, for the treatment of conditions or disorders in which prolactin secretion levels are decreased, such as lactation, including postpartum hyperlactation. treatment of prolactin-dependent menstrual irregularities, including amenorrhea, suppressive treatments for lactation, including postpartum lactation and pathological lactation, and hyperprolactinemia in men and women.
Uses are suggested for the treatment of sexual dysfunction (naernic) and prolactinoma (prolactinoma). The suggested daily dosage for such use is approximately 0.
25 to 10 da, conveniently administered in divided doses 2 to 4 times per day or as sustained release. Suitable unit dosage forms, such as oral dosage forms, contain about 0% of the active ingredient in free form or in pharmacologically acceptable salt form.
．． 05~5~ together with a pharmacologically acceptable diluent or carrier. In addition to the above, the final benzo[g]1-noline products of the present invention, particularly benzo[g]quinolines (I) and their pharmacologically acceptable salts, are capable of substantianigra 6-hydroxydopamine. )' by injecting it into the black neostriatum (neostriatum).
) of the dopamine pathway (unilateral
) Talat [U. Ungerstedt: Acta physiol
, 8cand, 5uppl. 867, pp. 69-93 (1978)], for example, when administered intraperitoneally at an amount of 0.05 to 2.0 per groan, the contralateral rotation that is logically derived. (contralateral rotation
Dopamine [+1 activity (dop
aminergic activity). The compound of the invention also exhibits a stereotypy in apomorphine stereotypy when administered, for example, at doses of about 9 to 10 q/d. The benzo[g]quinolines and salts thereof of the present invention have several applications as dopaminergic agents, such as for the treatment of Parkinson's disease. The suggested daily dosage for this use is from about 1 to 40, with this n
It is convenient to administer in divided doses 2 to 4 times a day or as a sustained release form. Suitable unit dosage forms, such as oral dosage forms, may contain from about 0.25 to about 20% of the active ingredient in free or pharmacologically acceptable salt form together with a pharmacologically acceptable diluent or carrier. It consists of Additionally, the final benzo[g]quinoline products of the present invention, particularly benzo[g]quinolines (I) and their pharmacologically acceptable acid addition salts, can reduce blood pressure in anesthetized dogs and reduce the upper intestinal tract. It exhibits dopamine receptor stimulating activity as shown by the induction of mesenteric and renal vascular resistance reduction. In this test, dogs anesthetized with Nemptal are used. Blood pressure is measured by a catheter inserted into the femoral artery, and heart rate is monitored by electrocardiogram. The next highest dose of imprenaline (0.5 μf/'?) was administered intravenously 8 times, and blood pressure and heart rate were measured. Ten minutes after the eighth dose of imprenaline, the test substance was administered by injection into the femoral artery, followed by an additional 5 minutes, 15 minutes, 35 minutes, and 7 minutes.
After 5, 155 and 315 minutes, administration of imprenaline is repeated at the same dose and the degree of inhibition of isoprenaline-induced tachycardia is determined by continuous measurement of heart rate and blood pressure. The compound of the present invention was tested in the above test, for example 2
．． It has been shown that intravenous administration at doses of 5 to 100 μf/kf causes a decrease in blood pressure and a decrease in superior mesenteric and renal vascular resistance. Several benzo[gl quinolines and salts thereof of the present invention have been indicated for use as dopamine receptor stimulants, for example, for the treatment or prevention of coronary artery disease, such as congestive heart failure, as well as hypertension and acidic renal failure. Ru. The suggested daily dosage for this use is about 1 to
500 to 500, conveniently administered as a sustained-release tubular tap in divided doses 2 to 4 times per day. Suitable unit dosage forms, such as oral dosage forms, contain about 0.2'5 of the active ingredient in free form or in pharmacologically acceptable salt form.
~2Eomy together with a pharmacologically acceptable diluent or carrier. As mentioned above, the bensogoquinolines of the present invention can be administered in free form or in their pharmacologically acceptable salt form (particularly in their pharmacologically acceptable acid addition salt form). I can do it. The salt form of the compound exhibits the same level of activity as the free form. As described above, the present invention relates to the following compounds. Treatment methods and pharmacological compositions can also be provided. If the 1.3 position or n position is required, a carpoquine group, which may be amidated, a hydroxymethyl group, which may be etherified, if necessary, a cyanomethyl group, an alkyl or arylthiomethyl group, a sulfamoylamino group or a carbamoyl group. 6 which is substituted with an amino group and has the following uses:
and/or 7-oxy-trans -1,2%l
, 4, 4a, 5.10. l Qa -octahydro-
Compounds of benzo[gl-quinolines, especially the free or pharmacologically acceptable salts of the said benzo[gl-quinolines (I) or their physiologically hydrolyzed and physiologically acceptable esters: 1.1 Prolactin secretion inhibitors, especially 1, 1.1 Hyperlactinemia, premenstrual disorder, hyperrolactinemia (hyperprolactinemia)
) sexual dysfunction or prolactin tumors (prol a
A prolactin secretion inhibitor for use in the treatment of ct inoma) or as a galactinemic agent. 1.2 Dopaminergic
agent), especially 1, 2.1 Dopaminergic agents for use in the treatment of Parkinson's disease, and 1.8 Dopamine receptor stimulators, especially 1, 8.1 Coronary artery disease, especially for the treatment of congestive heart failure or Dopamine receptor stimulant for use in prophylaxis and treatment of hypertension or acidarthropathy. 2. A method of treatment comprising administering to a patient an effective amount of benzo[gl quinoline, ester or salt as defined in 1 above, for treating conditions or diseases, especially those having an etiology consisting of or associated with prolactin secretion. 11 above.
A method for treating a condition or disease according to item 1, a method for treating Parkinson's disease, or a method for preventing or treating a condition or disease specified in item 1.11 above. 8. A pharmaceutical composition comprising the benzo[g]quinoline, ester or salt described in Section 8.1jd1 together with a pharmacologically acceptable diluent or carrier. Patent applicant: Sand Akchengesellschaft, patent attorney Aoyama Aoyama, and 1 other person

Claims (1)

[Claims] 1.6 and/or 7-oxy-trans -1
, 2゜8.4,4a,5,6.10.10a-octahydrohenzo[g]quinolines, if the 3-position is required, an amidated carboxyl group, if necessary, the ni-f Free benzenes [gl quinolines, Physiologically hydrolysable and physiologically acceptable esters and salts thereof. Free compounds in which the 2 and 1 positions are unsubstituted or substituted with a C1-4 alkyl group, physiologically hydrolyzed and physiologically acceptable esters thereof, and salts thereof The benzo [gl quinolines described in item 1]. 3. The benzene according to claim 2, which is a free compound represented by the formula (■): 3 , physiologically hydrolyzed and physiologically acceptable esters thereof, and salts thereof. [gl quinolines [wherein, rings A and B are trans-bonded]. R1 and R2 are each individually hydrogen, hydroxy or methoxy (both R1 and R2 may not be hydrogen); R3 is hydrogen or C1-4 alkyl; R4 is -C0011, -Ct120R5 ,-C112C
N, -CON(R6)R7, -CI-12SR8, -N
u(802N(R9)Rlo-f 7tH-NHCON
(R9)Rlo, to is hydrogen or C1-3a, right, to is hydrogen or C1-3 alkyl, and buttocks are hydrogen, ClN3 alkyl, phenyl or pyridyl, phenyl and pyridyl are halogen, methyl, if necessary. Alternatively, it may be substituted with methoxy. ), or - and the buttocks together -(CH2)4-1-(
CH2)5- or -(CH2)2-0-(CH2)2
-1~ is C1-4 alkyl or pyridyl (pyridyl may be substituted with halogen, methyl or methoxy if necessary), R9 and Rlo are each individually hydrogen or 01-3
Alkyl or R6 and buttocks are combined -(C
I(2) represents 4- or -(CH2)s-. ]. 4. The compound according to any one of claims 1 to 8, which is a racemic compound. 5, R1 and ~ are both hydroxy, or both are methoxy, 7 or either R1 and ~ are hydrogen, the other is hydroxy or methoxy, R3 is C1+v4 alkyl. R4 is -CH2O■, -CH2CN, -CON (R6)
R7゜-CH2SR8,-Ni(80゜N(Ro)Rl
o or -NtICON(R9)klo, R6 represents hydrogen or pyridyl optionally substituted with halogen, methyl or methoxy; R8, R9 and Rlo are 8J:14; The benzo[g]quinoline according to claim 3, which is a free compound (■) having the same meaning, physiologically hydrolyzed and physiologically acceptable esters thereof, and acid addition salts thereof. kind. 6. The compound according to claim 5, which is a racemic compound type 1. 't, R1, R2, R3 each have the same meaning as the third term,
R4 is -CUOt(, -Cf(20f(, -CH2CN
, -CON(R6)R7, -CH2SR8, -N)1
802N (R9) Rlo or -NLICON (R9)
represents Rlo, R6, R7, R8, R9 and Rlo
Claim 3, which is a compound having the same meaning as in claim 3, its physiologically/JO-hydrolyzed and physiologically acceptable esters, their free form and their acid addition salt form. Benzo[g]quinolines (■
). 8. The compound according to claim 7, which is racemic. 9,1-n-propyl-3α-diethylsulfamoyl7mi/-6-hy)-0x-1,2,8,4,4
a, 5°10.10a β-octahydro-benzo [gl
Free form of quinoline (racemic compound) or its acid addition salt form. io, aβ-methylthiomethyl-7-methoxy=1
．． 2, 8, 4, 4aα, 5.10. toaβ-octahydrogenzo[glquinoline (racemic compound); 1-
n-propyl-3β-methylthiomethyl-7-medoxy 1.2,8,4,4a(t, 5.10.10aβ
-octahydrogenzo[glquinoline (racemic compound); l-n-propyl-3β-methylthiomethyl-7-hydroxy-1,2,8,4,4aα, 5.1
0.10aβ-octahydro-benzo[glquinoline(
racemic compound) or its acid addition salt form. 11,8α-methoxycarbonyl-6-methoxy-1,
2,8,4,4aα,5,10,10aβ-octahydrogenzo[g]quinoline (racemic compound); 1-
1-Propyl-3α-methoxycarbonyl-6-methoxy-1,2,8,4,4aα,5,10,10aβ-octahydro-ben:/[g]quinoline (racemic compound)
;1-n-propyl-3α-diethylsulfamoylamino-6-methoxy-1,2,a, 4.4 aα, 5
,10. lOaβ-octahydro-benzo[g]quinoline (racemic compound); 3β-methylthiomethyl-6-medoxy 1.2.3.4.4 aα, 5,10,10a
β-octahydro-benzo[g)quinoline (racemized f
)';l n-propyl-3β-methylthiomethyl-6,-methoxy-1,2,8,4,4aα,5,10
．． 10aβ-octahydro-benzo[g]quinoline (racemic compound, ); 1-n-propyl-3β-methylthiomethyl-6-hydroxy-1,2,8,4,4aα
, 5,10.10aβ-octahydro-benzo[glquinoline (racemic Th); 3α-methoxycarbonyl-7-methoxy-1,2°8,4.4 aα,5,10
,10aβ-octahydrohenzo[g]quinoline (racemic compound);1-n-propyl-3α-methoxycarbonyl-7-methoxy-1.2,8,4,4aα,5,
10,10aβ-octahydro-benzo[glquinoline (racemic compound); 1-n-propyl-3α-diethylsulfamoylamino-7-methoxy-1,2,8,4
,4aα,5,10,10aβ-octahydro-benzo[g]quinoline (racemic compound)il-n-propyl-
3α-diethylsulfamoylamino-7-hydroxy-1,2,8,4,4aα. 5.10,10aβ-octahydro-benzo[g]quinoline (racemate); and 7-hydroxy-N-(
2-methoxy-5-pyridyl)-1-methyl-1,2
, 8,4,4aα+ 5+ 10+ 10 aβ-octahydro-benzo[glQuinoline-8β-carboxamide (racemic compound) or an acid addition salt thereof. 12.3β-methoxycarbonyl-6-methoxy-1,
2,8,4,4aα,5,10,10aβ-octahydro-benzo[glquinoline (racemic compound); 1-methyl-3β-methoxycarbonyl-6-methoxy-1,2
,8,4,4a(g,5,10,10aβ-octahydro-benzo[g]quinoline (racemic compound);1-methyI,1.2,8,4,4aα,5.10.10aβ-octahydro- Benzo[g]quinolino (racemic compound!?+
I) i 1-methyl-3β-carboxy-6-hydroxyl 1.2.3.4゜4aα; -5,10,101β
-Octahydro-benzo[g]quinoline (racemic compound); 6-hydroxy-N-(2-methoxy-5-pyridyl)-1-methyl-1,2,8,4,4aα, 5.10
．． lOaβ-octahydro-benzo[g]quinoline-
3β-carboxamide (racemic compound); 3β-methoxycarbonyl-7-methoxy-1,2,3,4,4aα
, 5,10,10aβ-octahydro-benzoCg3quinoline (racemic compound); l-methyl-3β-methoxycarbonyl-7-methoxy-1,2,3,4,4aα,
5,10. '10aβ-octahydrobenzo[g]quinoline (racemic compound); l-methyl-3β-methoxycarbonyl-7-hydroxy-1,2,8,4; 4aα
, 5,10,10aβ-octahydro-benzo[g]quinoline (racemic compound); 1-methyl-3β-carboxyne-7-hydroxy=1,2. '8.4.4 aα
, 5,10,10aβ-octahydro-benzo[glquinoline (racemic compound) series and 1-n-propyl-3
α-diethylsulfamoylamino-6-penzoyloxy-1.2.8.4.4 aα, 5°10.10a
A free type or an acid addition salt type compound thereof selected from β-octahydrobenzo[g]quinoline (racemic compound). 18, (R16 and/or 7-midoxy tra
ns-1, 2, 8, 4, 4a, 5. to, 10a-
Octahydrogenzo[glquinoline (unsubstituted in the 1st position and substituted in the 3rd position with an amidated carboxyl group, optionally an etherified hydroxymethyl group, a cyanomethyl group or an alkyl or arylthiomethyl group) or physiologically hydrolyzed and physiologically acceptable esters (carboxyl group esterified at the 3-position or esterified hydroxymethyl group) of the above-mentioned benzo[g]quinoline (For example, formula (11):' [In the formula, rings A and B are a trans bond. R1' and R2 are each individually hydrogen or methoxy (however, R1
' and R2 need not both be hydrogen), R4' is -CH20R5, -CH2CN, -CoN (R
,)R7, -CH2SR8, esterified 100O
H, or esterified one CH201 (represents R5, R6, R7 and R8 have the same meanings as in Section 3), the corresponding 6 and/or 7-midoxy trans-
1, 2, 8, 4, 4a, 5, 10. toa-octahydro-benzo[glquinoline module or benzo[g]quinoline ester (the benzyloxy group or C1
~4-alkoxy-substituted compounds), for example, formula (
II) ,: OX [wherein B is a trans bond to the ring. X represents benzyl or C1-4 alkyl. R1', R2 and R4' have the same meanings as in formula (■1). ]+The indicated compound,
(b) 6 and/or 7-midoxy trans-
1゜2.1,4,4a,5.10.10a-octahydro-benzo[g]quinoline (the 1st position is, for example, C1-
(a compound substituted with 4 alkyl, whose 3-position is substituted with an amidated carboxyl group, optionally an etherified hydroxymethyl group, a cyanomethyl group, or an alkyl or arylthiomethyl group), or the above Physiologically hydrolyzed and physiologically acceptable esters of benzo[glquinoline (compounds substituted in the 3-position with an esterified carboxyl group or an esterified hydroxymethyl group), such as those of the formula (■ 2
): [In the formula, rings A and B are a trans bond. ■q is 0
Represents 1-4 alkyl. R1', R2 and R4' are the corresponding 6 and/or 7-midoxy trans-
1, 2, 8, 4, 4a, 5.10. 1 of toa-octahydro-benzo[g]quinolin or benzo[g]quinoline ester (compound not substituted at position 1)
By introducing a servo group at the C1-4 position, for example, alkylating it,
Introducing an alkyl group, for example, the above compound (I')
e Alkylated to create a C1-4 alkyl group at the 1st position. (C) 6- and/or 7-midoxy trans -
1゜2.8,4,4a,5.10.101-octahydro-benzo[g]quinoline (a compound in which the 3-position of ``S'' is substituted with a sulfamoylamino group or a carbamoylamino group), for example, formula (I5) :″ 3 ■ [In the formula, rings A and !:B are trans bonds. R4″ is -NH802N(R9) R1o4 or -NHCON(
R9) Represents Rlo. R3, R9 and Rlo are the third
R1' and R2 have the same meanings as in formula (11). ] To produce the compound shown in The corresponding 6 and/or 7-midoxy trans-
1,2,8,4,4a, 5.10.101-octahydro-benzo[glquinoline (the 3rd position is an amino group (-
Compounds substituted with NH2), for example formula (flI)
:c In the formula, rings A and B are trans and su bonds. R1',
R2 and R3 have the same meanings as in formula (■3). ] and aminosulfonic acids, aminocarboxylic acids or reactive derivatives thereof, such as formula (IVa) or (
IVb): HO-8,,C)2-N(R9)Rlo(IVa)H
O-CO-N(R9)Rlo(IVb) [wherein R9 and Rlo have the same meanings as in the third term. ]" or a reactive derivative thereof; (d) 6- and/or 7-midoxytrans-
1゜2.8,4,4a,5.10.10a-octahydrogenzo[g]quinolines (compounds in which the 3-position is substituted with a carboxyl group), for example, formula (I'): R　[formula Inside, rings A and B are trans-bonded. R1' and ~ have the same meanings as in Formula (Technical Engineering 1), and ~ has the same meanings as in the third term. ] To produce the compound represented by the corresponding 6 and/or 7-i toxic trans-
1,2,'8,4,4a,5,10.10a-octavitro-benzocarboxyl group), for example, formula (V): 3 ■ 2 [In the formula, rings A and B are trans bond be. 2 represents an esterified carboxyl group. R1', R2 and R3 have the same meanings as in formula (■4). ) is hydrolyzed;
anS- 1.2, 3, 4, 4a, 5, 10, lO
a-Octahydro-benzo[g]quinoline (a compound having at least one hydroxyl group in its 6- and 7-positions), for example formula (I5): in which B to the ring is a trans bond. R1// and R2' are each individually hydrogen, hydroxy or methoxy (provided that at least one of R1'' and R2'' is °hydroxy). R3 and R4 have the same meaning as in Section 3. ] In order to produce the compound represented by
1.2,8,4,4a,5,10,lOa-octahydro-benzo[g]quinoline (compounds having at least one Mekoxy group in the 6- and 7-positions), for example formula (■): 3 [In the formula, B is a trans bond to the ring. R1'# and R, '' are each individually hydrogen, hydroxy or methoxy (however, at least one of Rr and R is methoxy), R3 and R4 have the same meaning as in Section 3.] ether cleavage; (f) 6 and/or 7-oxy-trans-1.2; 8,4,4a,5,10,10a-octahydro-benzo[g]quinoline (with its 3-position amidated 6- and/or 7-oxy-trans-
1, 2. 8, 4. 6 and/or V to produce physiologically hydrolyzed and physiologically acceptable esters of Ma7-oxy-[rans-1
．． 2,8. 4,4a,5,10,10a-octahyto o-benzo[
g] Amidating quinoline (a compound in which the 3-position is substituted with a carboxyl group) or a reactive derivative thereof, or 6- and/or 7-oxy-Lr described in item 1.
anS - 1.2, 8, 4, 4a, 5, 10, 1
Acylation or esterification of 01-octahydro-benzo[g]quinoline (e.g. a compound having one or more hydroxy and/or carboxyl groups in the 3-, 6- and/or 7-position) or a reactive derivative thereof For example, the benzo[glquinoline (compound (I) in which R4 is a carboxyl group) described in Section 3 or a reactive derivative thereof and an amine: HN(R6)R7 (R6 and R7 have the same meanings as in Section 3.) or benzo[g]quinoline according to item 3 (at least one of R1, R2 and R4 is hydroxy (in the case of R1 and R2) or hydroxymethyl (in the case of R4)) ■)) or the benzo [gllquinone R] described in item 3.
React a compound (■) in which 4 is carboxy or a reactive derivative thereof with a suitable acid or a reactive derivative thereof or a suitable alcohol; 9. A method for producing the compound according to item 1, particularly the free form and salt form of the compound according to item 8, which is recovered as a free form or a salt form. 14. A pharmacological composition comprising the free or pharmacologically acceptable salt compound according to any one of Items 1 to 12, combined with a pharmacologically acceptable diluent or carrier. thing. 15. The composition according to claim 14, which is used to suppress prolactin secretion. 16. For use in the treatment of galactorrhea, premenstrual disorders, hyperprolactinaemic sexual dysfunction, prolactin tumors, or for milk suppression 17. Patent for use in the treatment of Parkinson's disease The composition according to claim 15. 18. The composition according to claim 15 for use in the treatment of coronary artery disease, hypertension or acidic renal failure. 19, Formula (■): [In the formula, R1 and R2 are each individually hydrogen or methoxy (however, both of R1 and R2 may not be hydrogen), Y is each C1-4 alkyl or aryl (especially C
(1-4 alkyl or phenyl) or Y together represents C324 alkylene. ] A compound represented by Or formula (■): B' [wherein R1 and width have the same meanings as above. D and E together represent oxo or -N-OX
(X is benzyl or C1-4 alkyl), or D is hydrogen, E is -NtI-0X (X has the same meaning as above)'c, A' and B' are each hydrogen, or When D and E are combined to represent oxo, 'A'
and B' are each a group represented by A-8-y (Y has the same meaning as above), and R11 represents ClN4 alkyl (particularly methyl, i-propyl or [-butyl)]. ] Compound represented by 2 or formula (X): [wherein R1 and R2 have the same meanings as above. F is 10X (X has the same meaning as 01), G is (il-C
OOR1, (R1 has the same meaning as above). (fil -RQ (Ri is -CH20R5, -CI(
A pharmacologically acceptable and pharmacologically hydrated compound selected from 2CN, -CON(R6)R7, -CH2SR8, or esterified 1000H or esterified 1CI-12ott. Ester group (R5,
R6, R7p and R8 have the same meaning as in Section 3) or +n++ -cs20802C13 or the above (11)
ter-C0OH'fr, or F is -R3 (R3 is hydrogen or C1-4 arg), G is -NH2 or esterified other than as described in (11) above. ] or its reactive derivative (for example, the acid wide or acid anhydride of compound (X) (where F
is -Rs (Ra is hydrogen or 01-4 alkyl), G
represents 1000)l. )). 20. The compound according to claim 19, wherein rings A and B are in the trans configuration. 21. The compound according to claim 20, which is a racemic compound.