JPS6081181A - Tetrahydrocarbazole 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 the general formula 1 [wherein The is N- or di-alkyl, 0-alkyl, S-alkyl, SO-alkyl, SO-alkyl, OH, F, Cl, Br, CF3 and (only in size) CN] 1,2,3,4-tetrahydro-3, optionally substituted with yoshi, or methylene oxide/group
-carbazolyl group; the two groups Y are each H or straddled to represent a C-C bond; one of the groups Z is Ar, and the other of the group Z is H And;
A is CH2- or -CH,CH2-; and Ar is unsubstituted or alkyl, 〇-alkyl, S-argyl,
O-alkyl+ So,. -alkyl, OH, F, CA, Br, CF3 and/or cN is a phenyl substituted by a methylene oxide group or a 3-chenyl group; Each of the γ-alkyl groups has an elementary atom in 1 of 1 to 71 blocks. Ra's life 111! A scientifically acceptable acid addition should be carried out overnight. The object of the present invention was to discover new compounds that can be used for the construction of medical helicopters. This objective was achieved by making available a compound of formula I. Compounds of formula l and sled. It has been found that the biologically acceptable acid addition salts of J114, et al., have useful chemical properties. That is, these compounds have a particularly central nervous system action and a tonoyamine-stimulating (anti-Parkinesia) action. Specifically, the compound of formula I induces the anti-I111 activity of hemisokinosis in rats [
This is the method of Mr. Ungerstedt et al. (Brain
Red. (1970), pp. 485-493)], and these compounds also contain tritiated dolphins that bind A1 to the ilil-like receptor. Impairing the binding of pEmin agonists and antagonists [method of SChWarCz et al. (J, Neurochemistr 7, 3'l,
(1980), 772-778 edition) and Cr00
80 et al.'s method (B; europeanJ, Phar
maCOl, 46, (1977), 377~
This can be proven by p. 381). Furthermore, these compounds inhibit the lingual-mandibular reflex in anesthetized rats.
nJ, pharmacol. 21, (1973), pp. 178-182 and Ilhan et al.
pean J. Pharmacol, 33, (1
975), pp. 61-64. Furthermore, they have shown antihypertensive and antihypertensive effects, and after intragastric administration of these compounds, catheterized conscious spontaneously hypertensive rats (SHR
/N]',,H-MO/CHB-EMD species) to lower the arterial surface pressure (Proc, Soc, Exptl of WeekS and Tones).
. Biol, Med, IO'l, (1!16 (1 year)
, pp. 646-6118]. The compounds of formula I and their physiologically acceptable compounds can therefore be used as active compounds in medicaments and as intermediate products for the production of other compounds which are useless medicines. The present invention relates to tetrahydrocarbazole derivatives of formula I and their physiologically acceptable acid additions J:'Ai. In the groups Thc and ArJ, alkyl is preferably methyl, but also ethyl, n-propyl, isopropyl,
It may be n-butyl, inbutyl, sec-butyl or tertiary-butyl. O-alkyl is preferably methoxy, but also includes ethoxy, n-propoxy, imbutoxy, n-
Butoxy, imbutoxy, sec-butoxy or tertiary-butoxy may be used. The S-alkylthio is preferably methylthio, but may also be ethylthio, 11-propylthio, inzolopylthio, n-butylthio, inbutylthio, sec-butylthio or tertiary-butylthio. SO-alkyl is preferably methylsulfinyl, but also ethylsulfinyl, n--f propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, inobutylsulfinyl, sec-butylsulfinyl or tertiary-butylsulfinyl. It may be. 502-Alkyl is preferably methylsulfonyl, but 4
7”tethylsulfonyl r+ -fropylsulfonyl, isopropylsulfonyl, n--fflsulfonyl,
Inftylsulfonyl, sec-butylsulfonyl tda84
M3 butyl sulfonylte. The group The is a specifically unsubstituted 1,2.3.4-tetrahydro-3-carbazolyl group. However, when The is a substituted 1,2,3,4-tetrahydro:3-carbazolyl group, mono-substitution, especially mono-substitution at the 7-position 1d is preferred. 12-1: 3-14-15-18- or 9-position i
May be substituted with i″j. Preferred di-substitution 1 +
2 +: U, 4-tetrahydro-; 3-carbazolyl group is substituted at 6,7-position, but di-substitution is 1.1-11.2-11,3-11,4 -1
■, 5-1 ■, 6-11, 7-1J, 8-11, 9-1
2, 2-12, 3-12. 4-12, 5-12, 6-1
2,7-52.8-12.9-13.4'-13,5-
13,6-13,7-13,8-13,9-14,4-
14,5-1lI, 6-1ll, 7-14,8~.
4.4-1-15.6-15,7-1518-15+5
It can also be i6 at the l-16,8-16,9-17,8-17,9-position or at the 8,9-position. In all cases, the substituents can be the same or different. In detail, the preferred substitution b of the benzene ring of Tbc&
u methyl, ethyl, methoxy, ethoxy, methylthio,
Ethylthio, OH, F, Ct. Br, CF3 and CN. Therefore, g Th
Some preferred meanings of e are l, 2,
3.・1-tetrahydro-3-carbazolyl, size ξl
-12-13-1lI-15-1O-17-18-Madaha 9)-Methyl-1,2,3,4-tetrahydro:Urbazolyl,■-12-1;3-111-15-1
(i-17-18- or 9-ethyl-1+ 21
:') 14-tetrahydro-3-carbazolyl, 5-
10-17- or 8-methquine-1,2,3,4-tetrahydro-3-carbazolyl, 5-10-17- or 8-ethoxy to 1.2. : L.1-TeI.Lahydro-3-carbazolyl, 5-10-17- or 8-methylthio-1,2,3,1I-tetrahydro-3-carbazolyl, 5-16-17- or 8-ethylthio -1,2
,3,4-tetrahydro-3-carbazolyl, 5-16
-17-4 or 8-methylsulfinyl-1,2,3,
4-tetrahydro:3-carbazolyl, 5-16-1
7-4 or 8-methylsulfonyl-1,2,3,4-tetrahydro-3-cartuxizolyl, 5-16-17- or 8-hydroxy-1,2,3,4-tetrahydro-
3-lupazolyl, 5-16-17-metaba 8-fluoro-1,2,3,4-tetrahydro-3-carbazolyl, 5-16-17-dilupazolyl, 8-chloro-1,2,3 ，
4-tetrahydro-; 3-carbazolyl, 5-10-1
7-1 Dani 18-bromo-1,2,3,4-te!・Rahydro 3-carbazolyl, 5-16-17-sun or 8-
Trifluoromethyl-1,2゜3.4-tetrahydro:3-carbazolyl, 5-16-17-oxdah8-diano-1,2,3,4-tetrahydro-3-carbazolyl, 1,2-1 [,4-11,5-11,6-11,7-
11,8-11,9-52,4-12,5-12,6-
12,7-12,8-12,9-14,5-14,6-
14,7-1lI, 8-14,9-15,6-15,7
-15,8-15,9-1617-16,8-16.9
-17,8-17,9-size or 8,9-dimethyl-1,
2,: U,4-tetrahydro-3-carbazolyl, 5-
16-17-size or 8-methoxy7-9-methyl-1,2
,3,4-tetrahydro-;3-carbazolyl,5-1
6-17-Madaha 8-methylthio-9-methyl-1,2
, co-3,4-tetrahydro-3-carbazolyl, 5-
16-17- or 8-fluoro-9-methyl-1,2
,3,・t-tetrahydro:3-carbazolyl,5-
16-17-o or 8-chloro-9-methyl-1,2,
: U, ll-tetrahydro-3-carbazolyl, 5-1
(u-17- or 8-bromo-9-methyl-1,2,
:U,・1-te)・Rahydro 3-carbazolyl, 5-
16-17-t or 8-trifluoromethyl-9-methyl-1,2,:(,4-tetrahydro:u-carbazolyl, 5-10-17-or 8-diano-9-methyl-1 , 2,3,4-tetrahydro: u-carbazolyl, l- or 2-methyl-5-1-(u-, ~7- or -8-methquine-1,2,3,4-tetrahydro-3
-carbazolyl, 1-madaha 2-methyl-5-1-6=
, -7-1fd-8-methylthio-1,2,3,4-
Tetrahydro: 3-carbazolyl, ■- or 2-methyl-5-1-(5-1-7- or -8-fluoro-
1,2,3,4-tetodo-3-carbazolyl, 1
-4 or 2-methyl-5-1-6-1-7- or -8
-Chloro-1,2,: U,4-tetoh,hydro-;3-
Cal/Mizolyl, 1- or 2-methyl-5-1-6-
1-7-sun/koha-8-bromo 1.2. :Uh, 11-
Tetrahydro; 3-tunorbazolyl, 1-1 dani],
2-Methyl-5-1-6-1-7-Madaha-8-1 Lifluoromethyl-1,2,:(,lI-tetrahydro-3
-Rubazolyl, 1-" or 2-methyl-5-1-1;
-1, -7-ma/ζ is -8-n ano-1, 2, 3, 11
-TetrahydroT:I-:', -carbazolyl, 6-methyl-7-fluoro-1,2,:U,4-tetrahydro:3-carbazolyl,6-norreolof-
9-methyl-1,2,:3. lI Tetrahi 1 + Rho:
3-carbazolyl, [i-methyl-7-chloro-],
2゜3.4-Tetrahydro: U-carbazolyl, 6-
Chloro-7-methyl-1,2,3,4-tetrahydro-
Co-3-carbazolyl, 5-chloro-6-sundani-7-methyl-1,2,3,4-tetrahythro:3-tunorbazolyl, 5.6-15,7-15,8-16,7-,
6,8--1: Puko &:i 7,8-ji
Methoki/-t, 2.3.4-tetrahydro-3
-carbazolyl, 5.6-15.7-15.8-16,
7-1b, 8-' or 7,8-dichloro-1,2,
3,lI-tetra, 3-carbazolyl, 5-
Trifluoromethyl 0-17-18-chloro-
1+21: L・1-detrahyde Ilow: another carbazolyl, 5. (i, fi, 7-'' or 7.8-methyledioxy/-1,2,: U, .1-tetrahydro-3-carbazolyl is 2) The group A is -CH2-, which is much larger than that of -CH2-. is fξ, phenyl without lt is ↓ new 1, Ar is jr (4 parts), phenylno ((teλ
"Riru", I7°17mV, 7] 1 direct conversion is very small. Sara l/(size A-ji 1 white ゛) Disaster 61) is also possible. iI = 4 Negative group is I-1 (・[can be I-, θ of phenyl group]' large substituent i, t-i
Tatri p -i lomonoenyl Q-, -1 ■ t
Fuco kl: p-tolyl, 0-1I11-suntani1
p-methoxyphenyl, o-1m-4, p-trifluoromethylphenyl, 0-1n1-p-ethylphenyl, 0-1m-i or p-n-f lobylphenyl, 0- 1m-4k is p-isopropylphenyl, 0-lm-size or p-n-butylphenyl, 0-
lm--4tabap-earj-f-ruphenyl, 0-1
m-4 is p-iodophenyl, dihalogenophenyl (
Tato Kaba 2.3-12. /1-12,5-12,6-1
3,4- or 3,5-difluorophenyl, 2,3
-12,4-12.5-12.6-13,4-Madada 3
, 5-dichlorophenyl, 2,3-12, 4-12,
5-12.6-13.4 4 kl'J: 3.5-
Cyfuromophenyl, 2-fluoro-4,-chlorophenyl, z-bromo-4-chlorophenyl), )) tylphenyl (for example 2.3-12.4-12.5-1216
-13,4- or 3,5-1 methylphenyl), methylcumylphenyl (e.g. 2-methyl-4-chlorophenyl), dimethoxyphenyl (e.g. 2.3-12
．． lI~, 2,5-12.6-13,4-size or 3,5
-dimethoxyphenyl), 2,3-dimethoxyphenyl, and 3,4-methylenedioxyphenyl are preferred. The invention therefore provides compounds of the formula l in which at least one of the radicals mentioned in the line t(1,1) has one of the abovementioned meanings, in particular one of the abovementioned preferred meanings. Some preferred groups can be represented by the following sub-formulas 1a-1g. Formulas 1a-it) correspond to 4F1 in formula Meaning 'a: I Jl, and in la, Th
e is 1, 2, 3. ll-tetrahydro-3-carbazolyl, methyl-1,2,3,ll-detrahydro-3-carbazolyl, methoxy-1,2,3,4-tetrahydro-3-carbazolyl, dimethoxy-1,2,3,4-tetrahydro -3-carbazolyl, hydroxy-1,2,
3,4-tetrahydro:u-carbazolyl, dihydroxy-J, 2. :L4--j trachtrow: u-carbazolyl, fluoro-1゜2.3.4-tetrahydro-3
-carbazolyl, chlor-1,2,3,4-tetrahydro-3-carbazolyl, dichloro-1,2,3,4-tetrahydro-3-carbazolyl, bromo 1.2. : U, 4-tetrahydro-3-carnomazolyl, cyano-1
, 2,3,4-tetrahydro: (-carbazolyl or methylene dioxidoxy Jr 2 + 3, lI-tetrahydro-3-carbazolyl, these 11゛ conversion) Il, if: [i- and ( Sundaha) 7th place (1
It is preferable that: In 1b, The ii
l, 2. %l-Tetrahydro-3-carbazolyl, 6-'4 or 7-methyl-1,2,:U,ll-tetrahydro-;U-carbazolyl,6,7-dimethyl-1
．． 2. :(,4-tetrahydro-3-carbazolyl, 6
-Sumita1d7-Medkin-J. 2, 3, lI-tetrahuman

[J-: U-carbazolyl, 6,7-dimethogine-1.2,3.・I-tetrahydro-3-rubazolyl, 〇-sunda+17-chloro-
1,2,: U, 1-TeI Lahydro: 3-carbazolyl, (5- or 7-hydroxy-1,2.: U, /
1-tetrahydro-3-carbazolyl, (i,7-cyhydroxo1.2゜3.4-tetrahydro1.:I -:
(carbazolyl size 6.7-methylenedione-1+
2 + 3 + 4-tetrahydro-3-carbanolyl: in IC, A is -CH2-; in 1d,
Ar is phenyl, tolyl, methquinophenyl, fluoronoenyl, RI:I ruphenyl, 1'linololomethylphenyl or chlorotrifluoromethylphenyl; in 1e, Ar is halenoenyl. If, ThCt:+: l, 2. :3. ．． 1
-Tetrahydro: Uriki Lubazolyl, 6-1 G1
7-7 Tokizo L2. : U, ll-tetrahydro-11
Carbazolyl, 6-1, 7-hydrokiller 1 r 2
+ 'U, 1-tetrahydro-; 3-carbazolyl, 6,7-simethoxy J, 2,3. /l-tetrahydro: 3-carbazolyl, 6-1 or 7-chloro-1
,2+knee1. 'I-atrahydro rj:, ', -carbazolyl 1, 7-hydroxyl, 2. :cormorant,
11-tetrahydro, 1-carbazolyl, and Ar is phenyl.
, 2, 3. ll-ketolahydro: U~carbazolyl,
(3-sunpuko(-17-hydroxy-1,2,3,4-
Tetrahydro: 3-tunorbazolyl, Arl-CH2-, and Ar is phenyl. The compound of formula (1) has an asymmetric carbon atom at the 3-position of the tetrahydrocarbazole ring. These compounds can still contain additional asymmetric carbon atoms. Therefore, these compounds can exist as racemates and, if several asymmetric carbon atoms are present, they can exist in mixtures of several racemates and in various optically active forms. . The present invention also relates to a process for the preparation of compounds of formula 1 and their physiologically acceptable acid salts, which process comprises compounds of the general formula II B,' NH2f
A' I), Soshite Xke Ct, Br, Engineering, OH still O
reactive derivatives of the H group, and The and A have the meanings given above) of the general formula 111, in which X2 and X3 can be the same or different,
and if Xl is NH2, then both are X, otherwise together represent NH, and Y and Z are t'nl :41. ', has the meaning)
Let's react with the 11th compound, or it's ox! fi one or more reducible groups in place of one or more hydrogen atoms and/or one or more, two additional C-C and (t or) C Compounds corresponding to formula l except for having a -N bond may be treated with a reducing agent or one or more hydrogen atoms replaced with one or more hydrogen atoms. Compounds corresponding to formula 1, except containing J's that can be eliminated by decomposition, are treated with solvate iIJ cutting, or the two groups Y together form C-C
When preparing compound 11 of the formula (IV) without expressing a bond, one of the groups E is i, l:X, CN or NH2, and the other group is EidH, and Thc,
A, X and Z have the meanings given above)
and, optionally, the thioether group and SO, I, in the compound of formula 1.
jj It is still oxidized to SO2 group, or the SO group is still oxidized to 80
J-engineering of formula I which oxidizes to 2 groups and (yet) splits the alkogia group with the formation of an OH group and/or hydrogenates the C-C double bond and (almost) produces By treating the M group in one step, the 41 physical properties of 1. This method is characterized by converting acid into 1 volume of acid and τ1 salt. The preparation of compounds of formula I is otherwise described in the literature (e.g. by Georg-Thieme of Schl-71□Gart).
Metho by publisher Houben-Weyj
den derOrganiacl+en C1〕em
J o and J Ohn V, of New York City, '1
1 eyl [; S 0118 company Organic R
The reactions are carried out according to methods known per se, such as those described in US Pat. Variants of these methods, which are known per se and are not described in detail here, can still be used. If desired, the raw materials can also be produced in situ by a method such as direct reaction of these compounds from the reaction mixture to produce the compound of formula I. , tetrahydrocarbazole ii:r: ;;j of formula 11
In the body 1f, xl is preferably X. Therefore, formula 111
If X2 and X3 of the compound are NH together, θ is undesirable. 3r is preferred, OH4 or reactive derivatives of OH groups, especially 1-G
Alkylsulfonyloxy having 1 to 1 carbon atoms (such as methanesulfonyloxy), arylsulfonyloxy having 1 or 6 to IO carbon atoms (such as benzenesulfonyloxy, p-toluenesulfonyloxy, 1- Therefore, the tetrahydrocarbazole compound of formula 1 can be particularly represented by the formula Thc-A-Ctt or 'rilc-A- Br
can be obtained by reacting a compound of formula +U with a piperidine derivative of formula +U (wherein X2 and X3 together represent an NH group; this compound will be hereinafter represented by formula 111a). Some compounds of formula H and in particular of formula 111 are known. Unknown compounds of formulas 11 and 111 can be easily prepared by the same methods as known compounds. Therefore, compounds of formula II (A=-CH2-) can be prepared by, for example, carboxylic acids of formula Tbc-COOH ( This compound is generally known and can be prepared by Fischer's indole synthesis from phenylhydrazine 411 and the corresponding fuclohexanone-4-carboxylic acid ester) to form the corresponding carbinol of formula -C The-CH20H. Once produced, this carbinol, for example 5
By OCt2, the corresponding value of the formula The-CH,,Cz is changed to the formula Tb, for example, by PBr3.
c -CH2Br can be converted into the corresponding bromide. nf, I E What is the size of the chloride? When bromide and KCN are reacted, acetonitrile of the formula The-CH2CN is obtained? L ヲ7J11 Moisture M, formula Thc
-CH2C0OH monoacetic acid can be produced. Reduction and subsequent analogous reactions give the formula Thc -CH2CH20H
, Thc-CH2CH20H and Thc-CH2C
Compounds of H2Br are iodine compounds of the formula The-A-, for example 3-
Iodomethyl-1,2,3,4-tetrahydrocarbazole is, for example: I commercially available p-toluenesulfone [・d
By acting potassium iodide on the ester, A4
I can. Amines of the formula The-A-Nl2 can be obtained, for example, from halides by reduction of the corresponding di-IJ compound, using, of course, phthalimide. Most of the 74 piperidine t/'i compounds of the formula Illa are known (West German published patent application m2, 060).
, No. 816), for example, 3-piperitono is converted to 4-piperitono with the formula 1vl-Ar (where M is the L1 atom and u:
MgHaA) and then hydrolyzed to form the corresponding 3-Ar-3-4 or 4-
Ar-4-hydroxypiveridine is produced and then optionally dehydrated to form 3-Ar- or 4-Ar-3,4
-dehydropiperidine and optionally hydrogenated to produce 3-Ar- or 4-Ar-piperidine. Formula 111 (in the formula, X2 and X3 are each h X)
Compounds include, for example, 2-Ar-glutaric acid ester, and 2-Al-Ar-2-penteno-1+ 57-ionic acid ester, 2-Al-Ar-2-Ar-glutaric acid ester, and 2-Al-Ar-2-Ar-glutarate.
Ar 1 , 5-bentanediol and 2-Ar-2-penteno-1,5-diol, respectively, and then optionally 5OCL2 and P
It can be produced by reacting with Br3. The reaction of compound 11 with compound 111 is carried out in a manner known from the literature on alkylation of amines. Both components are melted together in the absence of a solvent, if desired, in an autoclave or an autoclave. ＋I can do it. However, it is also possible to react both compounds zl/I in the presence of an inert solvent. Examples of legitimate m-agents include
hydrocarbons, such as benzene, toluene or xylene;
Ketones such as acetone or butanone, methanol,
Alcohols such as ethanol, isozolo/ξnor and n-butanol; tetrahydronolane (THF)
ethers such as dioxane; dimethylformamide (DMF); amides such as methylpyrrolidone; and nitriles such as acetonitrile, optionally also in mixtures with water. Acid binders, such as alkali metal or alkaline earth metals
d) Addition of water (changes, carbonates, carbonates or bicarbonates or other salts of alkali metals or alkaline earth metals, preferably salts with weak acids of potassium, sodium or calcium, still nucleated) j'111, and the compound is triethylamine, dimethylaniline, pyridine or quinoline, or the 7'mine compound Tbc-A-
It is often advantageous to add an excess amount of Nl2-yet the pynamic lysine derivative of formula 111a. Depending on the conditions of use,
The reaction time is from several minutes to 1.1 days, and the reaction temperature is about 0 to 15σ, usually 20 to 13σ. Even more, it has one or more reducible groups instead of a hydrogen atom and one or more (yet) additional C-C and (as yet) C-N bonds. Compounds of formula (1) can also be obtained by treating the precursor with a reducing agent, preferably in the presence of at least 11 inert solvents at temperatures between -8() and +250°. Groups (groups which can be substituted by hydrogen) include, in particular, oxygen in carbonyl groups, hydroxyl, arylsulfonyloxy (!=tech&"jrp-1+ruenesulfonyloxy), N-benzenesulfonyl, N-benzyl or O-benzyl In principle, a compound that cures only the 111M of the additional bond in the above groups, or the 21M of the additional bond in the above mentioned group.
1 or more can be converted to compounds of formula 1 by reduction. Although it is preferred to use generator hydrogen or Ii':Ji:metal hydrides for this purpose, the Wolf-Kishner method can also be used. Suitable starting compounds for this reduction have the formula: The'-L-Q-hr'M (where The' is 1 or 2 alkyl, 0-argyl, S-alkyl, SO-argyl, SO2-argyl, OHS1!'', CtlBr 1CF'3, CN and/or 0-benzyl, methylenodioxy, 11 (and (size ii) substituted in the 9-position by an arylsulfonyl group 71-benzyl group) 1,2,3,4-tetrahydro-
3-Carbazolyl;! 1 (; L is -CH2-1-
CH2CH2-1-CO-, -CH2CO-1-COC
H2-1 is an anion of a strong acid, and Ar' is unsubstituted or not yet 11/Q; ↓21 solid alkyl, 0-alkyl, S-alkyl, SO-alkyl, SO □-Alkyl, OH, FlCt, Br,
CF3, a phenyl group substituted by CN and/or 0-benzyl or by a methylenedioxy group, or a 2- or 3-chenyl group, provided that at the same time The' is The, L is A and Ar ' is A
It corresponds to [cannot] be r. L in the compound of formula V is -co--4 (preferably -CH2Co-). The compound of formula
r'-PyR-lysine, -1,2,:3,6-titrahydrobiridine or monopyridino and the formula ~TI The'-L-x" (v+) (wherein Ar', Tbc', Amides of the formula V (L --, co- still can be prepared, for example, by reacting compounds of the formula V (L --, co-
hc-COOH is still Thc-CH2-COOH from the free carboxylic acid and the piperidine of formula IIIa, in the presence of a dehydrating agent (e.g. carbonyldiimidazole 1 dicyclohexylcarbodiimide) in one of the above inert solvents, each J Alternatively, it can be prepared in THF. This can be produced, for example, by treating a metal with a group A, using hydrogen as a reducing agent. Thus, for example, zinc and alkali metal hydroxides Mixture with or +N'f:
111) can be used in mixtures with 2. It is suitable to use sodium or other alkali metals in alcohols or phenols such as ethanol, inozolominol, butanol, 7811 alcohol or inamyl alcohol. It is also possible to use aluminum/nickel alloys in aqueous alkaline solutions, optionally with addition of ethanol. Hydrogen can also be produced using sodium amalgam or aluminum amalgam in hydro-alcoholic or aqueous solutions. The reaction can still be carried out in the unconfined U phase; preference is given to using an aqueous phase and benzene or toluene. Another 1, LiA as reducing agent, /=H4, NaBH
4, diisobutylaluminum hydride or NaA,
A lead metal hydride such as g(OCH2CH20CH3)2H2 and diborane are optionally added to B, F'3, A
The addition of catalysts such as lCl2 or LiBr can be used with particular advantage. Solvents suitable for this purpose are ethyl ether, di-n-butyl ether, THF. dioxane, diglyme, ethers such as 2-dimethoxyethane, and hydrocarbons such as benzene. In the case of reduction with NaBH, water and aqueous alcohols are primarily suitable as solvents, although alcohols such as methanol and ethanol are primarily suitable as solvents. The reduction by these methods is 18
It is preferred to carry out at a temperature of 0 to +15 tf, especially about 0 to about 1 tf. To reduce -Co-', r4M in the amide, THF
Particularly when the CH2 group is generated using L i AAH, in the range of about 0 to 6 (I), during this treatment, the 1,2,3,1-tetrahydrocarbazole ring is The arylsulfonyl protecting group located at position 9 can be removed reductively at the same time.
The methanol extract can be reduced using NaBH4 with a crystallinity of about 0 to 80' in ethanol or a mixture of other solvents, optionally with the addition of a base such as NaOH, and can be reduced using NaBH4 of formula I. The N-benzyl group can be reductively eliminated using sodium in ammonia. In addition, the N-benzyl group can be removed reductively using sodium in ammonia. from about 150 to 25σ, for example, by anhydrous hydrazine in absolute ethanol.
It can be reduced to CH2 group under pressure at a temperature of . As a catalyst,
Preference is given to using sodium alcoholate. This reduction also allows this reaction to occur with highly water-miscible substances such as diethylene glycol or triethylene glycol! Ilj
By using hydrazine hydrate-1 in the presence of an alkali such as sthorium hydroxide in a point solvent, Huang-Minlon
It is also possible to change hb by the following method. Generally, the reaction mixture is boiled for about 13 to 11 hours. The water is then distilled off and the hydrazone formed is decomposed at a temperature of up to about 20σ. The Worno-Kosschner reduction can also be carried out with hydrazine in dimethyl sulfoxide at room temperature. 1 or 2 instead of 1 or 2 or more 11 atoms
Part 1! A compound having a group which can be removed by i'l: and otherwise corresponding to formula I can be treated with a solvate of 1 The raw material for this solvolysis is, for example, a compound of 111a corresponding to 2I (xl-X), or one or two or more H atoms instead of one or two or more H atoms. It can be obtained by reacting with a compound having a group that can be eliminated by solvolysis. Therefore, 1-acyl-1,2,3,4-tetrahydrocarnomizole has an acyl group, preferably t t, < lql: 7L1 (
1i'. Alkanoyl having 41 carbon atoms in I dimension,
Alkylsurun-11yl or arylsulfonyl group,
For example, methane, benzene, p-toluene, and sulfonyl molecules are hydrolyzed in a neutral or alkaline medium at a temperature of 0 to 20σ to produce 1,2,3. /I-corresponding l which is not substituted at the 1-position of the tetrahydrocarbazole ring
, 2,3,4-tetrahydrocarnomizole dicenter. As salt-loving tactile, sodium, potassium and calcium water! It is preferable to use sodium or potassium carbonate, sodium or potassium charcoal, or ammonia. Favorable solvents are water: methanol, lower alcohols such as ethanol, THF, ethers such as dioxane; sulfurs such as tetramethylene sulfone;
Katsuta is a mixture of these. Hydrolysis 19i is achieved through a process that uses only water! You can even do it at the boiling point in the agency. Furthermore, a compound r1 of formula 1 in which two groups Y together represent a C--C bond, and a compound r1 of formula 1 in which two groups Y together represent a C--C bond, and a double bond formed by removing HE from the compound r1 of formula 1 Depending on the definition of E, this can be, for example, the removal of hydrogen halides, water (dehydration), carboxylic acids or acids, ammonia or HCH.The starting materials of formula tV are: For example, a compound of formula H (x”=x) and a compound of formula I
X): can be obtained by reaction with a compound of the formula (E and 2 have the meanings given above). When one of the ends E is Hat, this substituent is easily eliminated under basic reaction conditions. In this case, the following bases can be used as bases: alkali metal hydroxides, alkali metal carbonates, alcoholates (for example potassium tertiary
butyrate), amines (e.g. dimethylanilino, pyridine, collidine or quinoline):
Toehabenzene, toluene, cyclohexane, methanol, nooxane, THF-4 and tert-butanol are used. When one of the groups E is an OH group, monoacid,
It is preferred to use vinegar or a mixture of these 24-fold compounds as a water desorbing agent (7). Addition of a solvent (e.g. water or ethanol) is advantageous. 'il
can be carried out under similar conditions. Elimination of sulfonic acid groups, e.g. mesylate or tosylate, can be carried out by dimethyl sulfoxide or alkali metal carbonate salts (e.g. L
i2C03) or by r! It is carried out under mild conditions by boiling with potassium acid. Ammonia can be removed simply by heating the salt of the corresponding amine compound (especially 4-amine derivative). In a similar manner, HCN can be eliminated from compound 2 (in which one of the groups E is CN) by heating. Desorption of HE from 1.sup.1 is generally carried out at a temperature g of from about 0 to about 25.sigma., preferably from 50 to 20 cj'. Furthermore, the thioether group in the thioether of formula (1) can be oxidized to an s'o group or to an SO2 group, and the SO group in the sulfoxide of formula 1 can be oxidized to an SO2 group. l! A thioether or sulfoxide group which undergoes conversion can be present as a substituent in the group Thc and (in the case of sulfur) in the group Ar. When it is desired to prepare a sulfoxide, 1'1 conversion can be performed using, for example, hydrogen peroxide, peracids (e.g. m-chloroperbenzoate), cr(Vl) compounds (e.g. chromic acid), KMnO,... 1-chlorobensitol) azole,
ce(1y) compound [for example (NH4)2 Ce(N
O3)6 ], negative! 5j: Use aromatic diazonium salts (e.g. o-4 or p-nitrophenyldiazonium chloride) or use relatively mild conditions and relatively low temperatures. (approximately -80 to +10σ). If curved edges, sulfones are to be obtained (from thioethers or sulfoxides), the same oxidizing agent is used under stronger conditions and (still) in excess, generally at higher f' crystallinity. These reaction cores can be carried out in the presence or absence of readily available non-i&iiC solvents. Examples of suitable inert solvents include water, aqueous mineral acids, aqueous alkali metal hydroxides,
liquid, lower alcohol (e.g. methanol or ethanol), ester (e.g. vinegar 1:2 ethyl), ketone (e.g. acetone), low-grade carbon 1-2 (e.g. 1'...), nitrile ( acetonitrile), carbonaceous arsenides (e.g. benzene), chlorinated hydrocarbons (e.g. chloroform and CC6).A preferred sunburning agent is a 30% aqueous solution of hydrogen peroxide. sulfoxide, acetone, methanol, ethanol or sulfoxide (in the combined solution, a total of 14:11.1% of 120 to 11.1 oof) of sulfoxide. obtained, preferably at higher temperatures, with acetic acid Iki or r 11λ and anhydrous tq'+: When used in excess in a mixture with acid, sulfonate is obtained. The groups The and/or Ar are one or 2 O-
Ether compounds of formula I substituted by alkyl can be cleaved by methods known from the literature to produce the corresponding hydroxy derivatives. For example, these ethers can be prepared by treating an aqueous or deoxyacid solution with HBr or HI, or by heating with a Lewis acid such as AtCt3 or boron trihalide.
or pyridine or aniline hydrohalide, preferably pyridine hydrochloride, at about 150 to 25σ. i!
l! It can be cleaved by I+'t. Genuine cleavage using diisobutylaluminum hydride (see, for example, Synthesis, 3975-1617) is particularly mild. Optionally, unsaturated compounds of formula I in which the two radicals Y together represent a C--C bond can be prepared using an alcohol (e.g. methanol solution), preferably in the presence of a heavy metal catalyst such as platinum, noradium solution or Raney nickel. or ethanol)
at a temperature of about 0 to 15σ in an inert solvent such as
Hydrogenation under pressure of about 1 to 200 bar can produce the corresponding saturated compounds of formula 1 in which the two groups Y are each H. The resulting base of formula 1 can be converted into the corresponding acid addition salt using 1-1 salt. Acids that provide physiologically acceptable salts are suitable for this reaction. Thus, inorganic acids such as sulfuric acid, hydrohalic acids (such as hydrochloric acid, hydrobromic acid), phosphoric acid (such as orthophosphoric acid), nitric acid (sulfamino acid) can be used, and organic acids, especially fatty acids, can be used. group, alicyclic, aromatic-aliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic acids, sulfones 1.Iβ or sulfonic acids, such as Gi 1, 1 □Sakui !β, propion,
Pivarinales 2, Diethylphylum I: i:il, malonic acid, succinic acid, himelic acid, fural 1, maleic acid,
Lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-
Phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methano-ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfone The acids naphthalene monosulfonic acid, naphthalene disulfonic acid and lauryl sulfate can be used. If desired, the free base of formula I can be liberated from these acids by treatment with a strong base such as sodium or potassium hydroxide or strium or potassium carbonate. The present invention relates to the use of compounds of formula 1 and their physiologically acceptable salts for the manufacture of pharmaceutical preparations, in particular by non-chemical means. For this purpose, they can be converted into suitable dosage forms together with at least one vehicle or auxiliary and, optionally, in combination with one or more other active compounds. The present invention relates to formulations, in particular pharmaceutical formulations, containing at least one compound of formula I and (yet) a physiologically acceptable salt thereof. These preparations can be used as medicaments in human or veterinary medicine. Suitable vehicles include enteral (e.g.
]), suitable for parenteral administration or parenteral topical administration, and does not react with the new compound, yet contains inorganic substances such as water, 411
(oil, benol alcohol, ro +) ethylene tallycol, seratin, carbohydrates (such as milk or starch), stearin] finished magnesium, Merck and petrolatum. In particular, for enteral administration, tablets, coated tablets, capsules, syrups, liquids, and 1 liter tablets are recommended.
For parenteral administration, solutions, especially oily or aqueous solutions, are used, but suspensions, emulsions and injectables can also be used. For topical application, cartilage, creams or powders are used. The novel compounds of the invention can be lyophilized and the lyophilizates obtained are used, for example, for the production of injectable preparations. The preparations can be sterilized and/or contain auxiliary agents, such as lubricants, preservatives, stabilizers and wetting agents, emulsifiers, salts that change the osmotic pressure, buffer substances, colorants, flavoring agents and ( or) may contain aromatic substances. As desired,
These can still contain one or more other active compounds, for example vitamins of one size or more. The present invention provides compounds of the formula I and their physiologically acceptable salts for the therapeutic treatment of the human or animal body or for the treatment of diseases such as Bamboo-Ginson disease, extrapyramidal disorders (in this case neuroleptic therapy). combination), depression and (sundaha) first
"Relates to the use in the management of side effects of occlusion and blood pressure lowering treatment 1(5) (e.g. due to α-methyldo-ξ)." The compounds are also used in the internal and gynecological systems, such as acromegaly, sexual dysfunction, secondary amenorrhea, premenstrual syndrome, undesirable childbirth, lactation, and prolactin in general. As a deterrent it can also be used as well as an ergot alkaloid in brain disorders (eg migraines) and especially in geriatrics. For these purposes, the substances according to the invention are generally used in amounts analogous to known commercially available preparations (e.g. promonoliftin and dihydroergocornine), preferably in amounts of about 0.2 to 500 n1 g, especially 0.2 to 5 Q IIJ.
'J/dose unit. -El administration゛'r1
j(cLL12 or about 0, 0 f month to l(l m(j
/k! 7 weight. In this regard, when used as an analgesic, a low dosage of 11'r (approximately 0.
2 to Img/f of doses, approximately 0.0 (11 to 0.005
n,! A 77 kg body vehicle) is being sold at the temple, and in other cases, a dosage of about dIO ~ 5t) wg 7 doses is preferable. Suitable dosage ranges in particular cases are as follows.・ξ-Ginson disease: 1-200
, preferably if 110~] 0(l mg/dose unit: dyskinesia, 40~1001 IILj/dose unit;
Administration 1) Oshikiri (e.g., schizophrenia): 2 to 20 mg
/dose (li position; acromegaly, 2-50 mq /dose unit. However, the specific dosage for each particular patient will vary widely depending on factors such as the potency of the particular compound used, age, body weight, general The state of health, sex, diet, time and mode of administration, rate of excretion and the drugs used in combination and also the severity of the particular disorder being treated will vary. Oral administration is preferred. For finishing, add water as needed, extract the mixture with organic solvents such as tolueno, chloroborum or dichloromethane, separate the phases, dry the organic phase over sodium sulfate and filtrate. 411j by evaporation, product r chromatography and (-1 nib) crystallization. Temperatures are given in degrees Celsius. Rf values are measurements on silica gel (not otherwise specified). /H2C-29
5:5). , / \'7・'' / 7/ 1++11 3-chloromethyl-1,2,3,I-tetrahydrocarbazole 2.1'LF (also 3-promonothyl-1
,2,3,4-tetrahydrocarbazole 2.639
)(1,2,:L4-tetrahydrocarbachylu:3
-Carbo71.1': is reduced with LiAl-H4 to produce 3
-Hydroquinemethyl-1,2,3,4-tetrahydrocaraxole is produced, and then 5ocz2-4 or P
1.62 of 1-phenyl-1,2,3,6-titrahydrobilinone in acetonitrile] (12 3-(lI-phenyl-1,,2,3,6
-tetrahydro-1-bilinormethyl)-1,2,3,
4-tetrahydrocarbazole (hereinafter referred to as "P")
is obtained. "I', , a, 163-165°0 (child, 3-chloroalkyl or Iri
3-bromoalkyl-1,2,3,4-tetrahydrocarbazole, for example 3-chloromethyl-6-medquin-1,2,3,4-tetrahydrocarbazole, 3-chloromethyl-7-medquin/-L2+:L4-tetrahydro Carbazole, 3-chloromethyl-6-hydroxy-1.2.3°4-
Tetrahydrocarbazole, 3-chloromethyl-7-hydroxy-1,2,3°4-
Tetrahydro-3-chloromethyl-(逼,7-nometquin-l,2.3,4-tetrahydrocar/guzole,3-(2-chloroethyl)-1,2,3.4-tetrahydrocarbazole,3-(2-chloroethyl) )-6-Medoxy 1
, 2, 3, , I-tetrahydrocarbazole,
3-(2-chloroethyl)-7-medoxy 1, 2,:
(, 4-tetrahydrocarbazole, 3-(2-10 ethyl)-6-hydroxy- 1.2,3.4-tetrahydrocarbazole, 3-(2-chloroethyl)-7-
Hydroxy-1.2.3.4-tetrahydrocarbazole, 3-(2-chloroethyl)-7-chloro-]. 2, 3,4-tetrahydrocarbazole, or 3-(
2-chloroethyl)-6,7-nomethoxy J, 2
, 3,4-tetrahydrocarbazole and 5-corresponding 4-aryl-1.2.3.6-tetrahydrobirinones give the following compounds. 3-(4-phenyl-1.2.3.6-tetrahydro-1-pyridylmethyl)-6-methyl-1,2. 314-f) Lahydrolupasol, 3-(4-phenyl-1.2.3.6-tetrahydro-1-pyridylmethyl)-7-methyl-1,2. 3,4-tetrahydrocarbazole, 3-(4-phenyl-1.2,:6-tetrahydro-1-biriturmethyl)-9-methyl-1.2. 3,4-Tetrahydrocarbazole, 3-(4-phenyl-1.2,3.6-tetrahythro-1-pyridylmethyl)-6-7toxyl. 2, 3, 4-tetrahydrocarbazole: melting point 161-16.3°, 3-(4-phenyl-1.2.3.6-tetrahydro-1-bilinormethyl)-7-medoxy 1. 2,3.4-Tetrahydrocarbazole: e! point 164
~166°, 3-(4-phenyl-1.2,3.6-titrahydro-1-bilinormethyl)-8-methoxy-1. 2,3.4-Tetrahydrocarbazole, 3-(4-phenyl-1.2.3.6-tetrahythro-1-pyrinolmethyl)-6-nitoki/-1. 2,3.4-Tetrahydrocarbazole, 3-(4-phenyl-1.,2,3.6-te,trahydro-1-pyrinolmethyl)-6-methylthio-1,2.3
．． 4-tetrahydrocarbazole, 3-(4-phenyl-1.2,3.6-tetrahydro-1-biridylmedyl)-7-methylthio-1,2,3.4-tetrahydrocarbazole, 3-(4-phenyl-1. 2,3.6-tetrahydro]-h!' IJ normethyl)
-6-methylsulfinyl-1.2,3. lI-tetrahydrocarbazole, 3-(4-phenyl-1,2
, 3. 6-tetrahydro1-hyIJylmethyl)-7-methylsulfinyl-1, 2, 3
, 4-tetrahydrocarbazole, 3-(4-phenyl-1.2,3.6-tetrahydro1-t=linolmethyl)-6-methylsulfo=1+2,:L4
-f-hydrocarbazole, 3-(4-phenyl-1.2,3.6-tetrahydro-1-hyIJ)-7-methylsulfonyl-1 12
+3°, 4-tetrahydrocarbazole, 3-(4-phenyl-I + 2 + 3 1 6-titrahydro-1-pyrinolmethyl)-5-hydroxy-1, 2.3.
4-tetrahydrocarbazole, 3-(4-phenyl-1 +2+3+6-tetrahydro-1-bilinormethyl)-6-hydroxy-1,2.3.4-tetrahydrocarbazole; 2 (toluene/triethylamine 9.1) 3-(4-phenyl-1, 2, 3
, 6-tetrahydro-1-bilinormethyl)-7-hydroxy-1,2.3',4-tetrahydrocarbazole; Rf (1.28( CH2Ct2/H2C-2
9:1), 3-(4-phenyl-i,2,3,-tetrahydro-1-bilinormethyl)-8-hydroxy-1
, 2,3.4-tetrahydrocarbazole, 3-(4-
Phenyl-1,2,3,6-tetrahydro-1-pyridylmethyl)-6-fluoro-1゜2,3.4
-tetrahydrocarbazole, 3-(4-phenyl-1
, 2,3,6-tetrahydro-1-Hil)) Lumether)-7-fluoro-1゜2.3.4-Tetrahydrocarbazole, 3-(4-phenyl-1,2, :No., 6-
titrahydro-1-pyridylmethyl)-6-chloro-1
,2゜3.4-tetrahydrocarbazole, 3-(4-phenyl-1+2+3.6-tetrahy-120-1-pyridylmethyl)-7-chloro-1,2゜3.4-tetrahydrocarbazole, 3 -(4-phenyl-], ]2,3.6-titrahydro34-tetrahydrocarbasol, 3-(4-phenyl-1,2,:6-tetrahydro-1-pyrinornotel)-7-promo1, 2゜3.4
-tetrahydrocarbazole, 3-(4-phenyl-1,2,3,6-tetrahydro-
1-pyridylmethyl)-6-1-lifluoromethyl-1
, 2,3,4-tetrahydrocarbazole, 3-(4-
Phenyl-1,2,:3,6-tetrahydro r+ -1
-H+) Normethyl)7Trifluoromethyl-1.2
, 3.4-tetrahydrocarbazole, 3-(4-phenyl-1,2,3,6-titrahydro-1-pyridylmethyl)-6-/ano 1,2°3, = 1-fl-lahydrocaireba sol, 3-(4-phenyl-], ]
2,3,6-titrahydro-1pyridylmethyl)-7-
/ano], 2゜3.4-tetrahydrocarbazole, 3-(4-phenyl-1,2,3,6-tetrahydro-
1-pyridylmethyl)-8-anor], 2゜3.1-
Tetrahydrocarbazole, 3-(4-phenyl-1,2,3,6-tetrahydro-
1-pyridylmethyl)-6,7-simethoxy 1.
2,3.4-tetrahydrocarbazole; melting point 178~
180°, 3-(4-phenyl-1,2,3,6-tetrahydro-
1-pyridylmethyl)-6,7-methylenethioxy7]
r 2 + 3+ 4-tetrahydrocarbazole,
3-(4-o"tolyl-1',2,3.6-tetrahydro-1-pyridylmethyl)-1,2,3,4-tetrahydrocarbazole, 3-(4-In-tolyl-1.2. 3.6-titrahydro-1-bilinormethyl)-1,2,3,4-tetrahydrocarbazole, 3-(ll-IJ-,)lylu 1,2,3,6-
titrahydro]-pyridylmethyl) -1,2,3,
4-tetrahydrocarbazole, 3-(4-o-methogynephenyl-1,2,3,6-
Tetrahydro-1-pyridylmethyl)-1,2°3.4
-tetrahydrocarbazole, -3-(lI-m-mel-ginovx,=-ru 1.
2, 3. C. -tetrahydro-1-bilinormethyl) -1,2゜3
．． 4-tetrahydrocarbazole, 3-(4-p-7toxyphenyl-1.2.3.6-
Tetrahydro-1-bilinormethyl) -1,2゜3.
4-tetrahydrocarbasol, 3-(ll-o-hydroxyphenyl-1,2,3゜6-tetrahydro-1-pyridylmethyl)-1゜2.3
．． 4-tetrahydrocarbazole, 3-(4-m-hydroxyphenyl-1,2,3゜6-titrahydro-1-
Bilinolmethyl) -1゜2, ;U, ・1-tetrahydrocarbazole,: < -(lI -p-hydroxyphenyl-1,2,3゜6-tetrahydro'-1-bilinormethyl)-1゜2,:'J , 4--'-r trahydrocarbazole, :(-(4-0-fluorophenyl-
1,2,3,6-tetrahydro=1-pyrinolmethyl)
-1,2゜3,4-tetrahydrocarbazole, 3
-(4-m-fluorophenyl-1,2,3,6-teI
・Dihydro-1-pyridylmethyl) -1,2゜3,
ll-tetrahydrocarbazole, 3 (4p-fluorophenyl-1,2,3,6-titrahydro-1-bilinormethyl)-1,2°:'3 + 4-tetrahydrocarbazole, 3- (lI -0-riolua x
, =-/l/-1+2+3+6-titrahydrol-
pyridylmethyl) -1,2,3゜4-tetrahydrocarbazole, 3-(4-m-ri Ofiv= Roux 1 +2+3
+6-tetrahydro-1-bilinormethyl) -1,2
,3゜4-tetrahydrocarbazole, 3-(4-1)-chlorophenyl-1,2,3,6-tetra-hydro-1-pyridylmethyl) 1,2,3゜4
-Tetrahydrocarbazole, 3-(4-p-bromophenyl-1,2,3,6-tetrahydro-1-bilinormethyl) -1,2,3゜4-
Tetrahydrocarbazole, 3-<4- m −+-lifluoromethylphenyl-
1,2,3,'6-titrahydro-1-bilinormethyl)-1,2,3,4-tetrahydrocarbazole, 3
-'(4-p-cyanophenyl-i, 2,3.6-tetrahydro-1-pyridylmethyl) -1,2,3゜4-
Tetrahydrocarbazole, 3-[4-(3,4-nomethoxy/phenyl)-1,2
,3;6-tetrahydro-l-bilinormethyl]-'1
, 2,3.4-tetrahydrocarbazole, 3- [4
-(3,4-methylenedioki7phenyl) -1,2,
3,6-tetrahydro-1-pyridylmer) -
1,21314-tetrahydrocarbazole, 3-[4-(4-chloro-3-trifluoromethylphenyl)-L2,3.6-titrahydro-1-pyridylmethyl)-1,2,3,4-tetrahydrocarbazole, 3 -(2-(4-phenyl-1,2,3,(3-tetrahydropyrinol)ethyl) -1,2,3,4-ti・
Lahydro Rubazole; hydrochloride, melting point 263-265°
, 3-1:2-(4-phenyl-1,2,3,6-tetrahydropyrinol)ethyl-6-mether] ,2,3
．． 1-tetrahydrocarbazole, 3-(2-(4-phenyl-1,2,3,6-tetrahydropyrinol)ethylcou 6-medquin-1.2.3.4-tetrahydrocarbazole: hydrochloride, melting point 214-216° , 3-(:2-(4-phenyl-1,2,3,6-tetrahydropyrinol)ethyl]-7-medok7-1.2,3
．． 4=tetrahydrocarbazole; hydrochloride, melting point 258
~260°, 3-42-(4-phenyl-],2,3.6-titrahydrobiridyl)ethylcy6~methylthio~J,2
, 3.4-tetrahydrocarbazole 3-12- (l
I-phenyl-1+ 2 , J , ('-tetrahydropyrinol)ethyl]-7~methylthio~1,2,3.
tI-tetrahydronocarpanol 3- [2-(+-
Phenyl-1,2,3,6-tetrahydropyrinol)ethyl-5-hydro-1,2,3,,1-tetrahydrocarbazole 3-[2-(・1-phenyl-1+
2 + 316-tetrahydropyrinol)ethyl-6-hydroxy-1,2,3,4-teI lahydrocarpasol, hydrochloride, melting point 290-292°, 3-[2-(,1-phenyl-1 ,2,:3,6-tetrahydropyrinol)ether]-7-hy-1-1,2,3,,i-tetrahydrocarbazole, 11
Point 20 (i~208°, 3-(2-(1-phenyl-1,2,3,6-tetrahydropyrinol)ethylcy8-hydroxy-'1,2,
3.4-tetrahuman 80 carbazole 3-(2-(4-
Phenyl-1,2,3,6-tetrahydropyrinol)ethyl]-6-fluoro-1,2,3,ll-tetrahydrocarbazole, 3-[2-(4-phenyl-1,2,
: U, 6-tetrahyF lobilinol)ethyl]-7-fluoro-1,2,3,lI-tetrahydrocal3-[2-(4-phenyl-l+21316-tei)
lahydrobilinor)ethyl 1-(i-chloro-
I. 2,3,4-tetrahydrocarbazole, '3-42-
('1-phenyl-1.2,3.6-titrahydrobiridyl)ethyl]-7-chloro-I+2, 3, 7
1-tetrahydrocarbazole; );,',i! Point 1
82-18i, 3-42-(4-phenyl-1 + 2 + 3 +
6-titrahydrobirisol) ethylcou 6-promo 1
. 2,3.4-tetrahydrocarbazole, 3-[2-(
4-phenyl-1.2,3.6-tetrahy-1-'rohyridyl)ethyl]-7-bromo-1+2,3.4-tetrahydrocarbazole, 3-42-(4-phenyl-1.
2,3.6-tetrahydropyridyl)ethyl]-6-trifluoromethyl-1,2,3,4-tetrahydrocarbasol, 3-C2-(lI-phenyl-1,2,3,6-titrahydrobyridyl) nor)ethyl E -7-'l-lifluoromethyl-1,2,3,/1-detrahydrorubazole, 3-42-(i-phenyl-1,2,3,6-titrahydrobinol)ethyl ]-6-Jiatu 1゜2.3.4
-Tetrahydrocarbazole, 3["2(4-phenyl-1,2,3,6-titrahydrobilinol)ethyl]-
7-/ano-1゜2, , 3, 4-tetrahydrocarbazole, 3-[2-, (=1-1-phael-L2,
3.6-titrahydropyrinol)ethyl]-8-aneano-1゜2,3,-1-tetrahydrocarbazole, 3
-['2-(4-phenyl~l,2,3,6-tetrahydrobilinor)ethyl]-6,7-dimethquine-1,2.3.4-tetrahydrocarbazole; hydrochloric acid group 1
,7! Points 172 to 174°, 7゛hi is 3-(2-(ll-phenyl-1,2,3,'6-te]-lahydropyridyl)ethyl:] -]6.7-methylenedioxy-1 , 23,11-tetrahydrocarbazole. Example 2 3-p-)luenesulfonyloxymethyl = 1.2.3
．． A mixture of 3.18 f of 4-tetrahydrocarbazole 4,4'+47 and 4-phenyl-1+2+3+6-tetrahydropyridine is heated at 13o. Mix this after the exothermic reaction has finished! Cooling of the snout followed by conventional finishing results in a (-P') of 163-165° to the melt.
is obtained. Similarly, the following compounds are obtained from the corresponding tosylates. 3-(4-phenyl-1,2,3,6-tetrahydro-
1-pyridylmethyl)-1-methyl-1,2゜3.4-
Tetrahydrocarbazole, 3-(4-phenyl-1,2,3,6-tetrahydro-
1-pyridylmethyl)-2-methyl-1,2゜3.4-
Detrahydrocarbazole, : U-(4-phenyl-112+ 31 G-tetrahydro-1-biridylmethyl)-3-methyl-1,2°3.4-tetrahydrocarbazole, 3-(4-phenyl-1,2 ,3,6-titrahydro-1-pyrinolmethyl)-4-methyl-1,2゜3.4-
Tetrahydrocarbazole, 3-(4-phenyl-1,2,3,6-titrahydro]-pyridylmethyl)-6-butyl-1,2°3.4-
Tetrahydrocarbazole, 3-(4-phenyl-1,2,3,6-tetrahydro-
1-pyridylmethyl)-6-butoxy-1゜2.3.4
-tetrahydrocarbazole, and 3-(4-phenyl-1,2,3,6-titrahydro-1-pyridylmethyl)-6-butylthio-1,2,3,
4-Tetrahydropnorhasol. Example 3 3-iodomethyl-1,2,3,4-tetrahydrocarbazole: 17.11-phenyl-1,2,3,f
1.59f of i-tetrahydropyridine and anhydrous potassium carbonate 1. ',)7n-bi'/Ay'','+
Yong in NE! l! Z 2] 1911 November 4th 10th day group) Tosaze, Ia left 11th day, then customary work L
If you do this, 1≠1j 1. '16:3 to 165° 1-P' is exhausted. The same % ic and the corresponding -1-Ar -1,2,3
, G-tetrahydropyridine to fjP the following compound. 3-(4-p-butoxyphenyl-1,2,3,6-titrahydro-1-pyridylmethyl)]+2+3.4-
Tetrahydrocarbazole, 3 (4p-methylthiophenyl-L2+3+6-tetrahydro-1-pyridylmethyl)-1゜2.3.4-tetrahydrocarbazole, 3-(4-p-butylthiophenyl-1,2,3゜6- titrahydro-1-bilinormethyl)-1゜2.314 7 doorhydrocarbazole, 3-(4-I)-methylsulfinylphenyl-1
,2,3,6-tetrahydro-1-pyridylmethyl)
-1,2,3,4-tetrahydrocarbazole and 3- (51-II, -methylsulfonylphenyl-
1,2,3,6-titrahydro-1-pyridylmethyl)
-1,2,3,-1-tetrahydrocarbazole. Example 11 7 cells and 40 ml of water! 3-aminomethyl-1,2,3,4-fl・lahydrotunorpazole (3-bromomethyl-1,2,3,,1
2.02 and 1,5-dichloro-3-phenyl-2-1ξnteno (diethyl-3-phenyl-2 A mixture of 2157 (obtained by reducing J+5-n-oate with 1.jAlI]4 and then reacting with 5oca2! The snout is boiled for 211 hours and then conventionally worked up. "P" with melting point 103-165°
is obtained. In a similar manner, other compounds of formula I listed in Examples 1.2 and 3 can be prepared from the corresponding amine and the corresponding 1,5-dichloro-3-Ar-2-pentene. Example 5 Water2Fl int Nr inside, +B) i41 f f I
N N;ull15()m(1-(1,2,3
,・■-tetrahydro; u-carbanolyl) 5-l)-・1-phenylhyricinium bromide (obtained from 3-bromomethyl-1,2,3,I-detrahydrocarpazole and 4-phenylhyricinium bromide) )4. ．． To 19 g of solution, add 4 t with stirring and add l of the mixture (stir at 50° for 31 minutes. After the customary addition, melting point 16
3 to 165°]r P J Ka4') f'L Ru In the same manner, other compounds of the formula Example 6 'l'1lfi' 3-(4-]x in 1Ornl =
/L, -1+2+3 +6-tetrahydrobiridylcarbonyl) -1,2,3,4-tetrahydrocarbazole (di1f0.9 il, '2,3,4-tetrahydrocarbazole-3-carboxylic acid and 4-phenyl-1 , 2,3,6-tetrahydrobiridine in the presence of caracarponyldiimidazole (2I)°) in the presence of THF, LiAAll, (1-: 8g) 1 yen! 'Add dropwise to the cloudy solution while stirring. When Pukomi finished her reaction,
Add 5 me of ethyl acetate and prepare the mixture as (l't J, I?i!I!ge, (1(i:3-16
5° 1-P” is done. Similarly, examples 1-
Compounds of formula 1 listed in 3 are 1). 3-(4-phenyl-1,2,3,6-titrahydropyricylcarbonyl)-(i-methoxy1,2°3+4
-Tet lahydrocarbasol (to 1llt: 210
~212°), - 3-(lI-phenyl-+,z,:Lt5-tetrahydrobi'lysylnonol+l?nyl)-7-medquin-1,
2゜3+4-tetrahydrocarbazole (Rf: 0
．． 2:C■(,7Ct2/methanol 8:2
), 3-(4-phenyl-1,2,3,(i-tetrahydrobinolcal,j?nyl)-6-hydroxyl゜2.3.4-tetrahydrocarbazole (melting a: 21
0-212°), 3-(4-phenyl-1,2,3,6-tetrahydropyridylcarbonyl) 6.7-nomethquine-1.2,3
．．・1-tetrahydrocarpanol 143-145°)
, 3-(,i-phenyl-L2+3.6-detocyhydropyridylcarponylmether)-1.2,:L・
1-tetrahydrocarbazole ((': 0.8
; l.Luene IC+-1301-1 / +.diethylamine 7:2:]), 3-(1-phenyl-1,
2,:U,6-tetrahydropyridylcarbonylmethyl)-6-medogiso J. 2,3.4-tetrahydrocarbazole (r<ro, 85), 3-(4-phenyl-1.2,3.6-titrahydropyridylcarbonylmethyl)-7-medquin-1.2,
3.4-tetrahydrocarbazole (Rf': (1.6
), 3-(4-phenyl-1 +2+3+6-titrahydropyridylcarbonylmethyl)-6-hydroxy- L2
+: L4-tetrahydrocarbasol (rtr: 0, 8
5), 3-(4-phenyl-1.2,3.6-tetrahydrohylycylcar7'?nylmethyl)-'7-chloro1.2
, 3.4-detrahydrorubazole (Rf: 0.9
;
: o, ss). Example 7 9-benzenesulfonyl-3-(,1-phenyl-1,
2,3,(5-tetrahydropyridylmethyl)-1,2
,3,4-tetrahydrocarbazole (9-ben7bensulfonyl 3,-chloromethyl-3,4-tetrahydrocarbazole and 4-phenyl-1,2
, 3, >4.82y-t-water obtained from G-tetrahydrobiridine 7me and ethanol 14j
boiled for 16 hours with 1 g of KOH in ml, concentrated the mixture and worked up as usual to give a mp of 163~
1-P of IG5' is inputted. Example 8 3-(1-hydroxy-,1-phenyl-1-bisnormeter)-9-methyl-1.2,3.1-tetrahydrocarbazole (:3-bromomethyl-9-methyl-I
H 2 1 J l-1-tetrahydrocarbazole is reacted with ■-piperidone, then C 6H 5
By reacting with L j , 3.74f (obtained by hydrolysis at ) was converted to 11·■''. (acid IU mt
and the mixture was worked up as usual for 3-(4-phenyl-1+2+3+6-titrahydro1.J-1-pyridylmethyl)-1)-methyl-1,2,3.4- Tetrahydrocarbasolka format)
) can be done. 1ri1''9 30% H2O2 6ml f xri/-/l/
50 me L7) 3-(4=phenyl-1
, 2,3,6-titrahydro-1-pyridylmethyl)
-7-Meteltheo 1.2,3.4-detrahydrocarpazole 3.81' is added to the boiling solution and the mixture is then boiled for 3 hours. 4 more oxidizer
ml of this mixture f: Boiled for 9 hours, cooled and worked up to give 3-(, 1-
Phenyl-1.2,3.6-tetrahydro-1-pyridylmethyl)-7-methylsulfinyl-1.2,3.4
- Tetrahydrocarbasol fj. 1. Example IO 30% 11202 9 m(!N'n k 2(l
III (! (1) 3-(4-7xnyl-1,2,3.6-titrahydro-1-pyridylmethyl)-7-methylthi-1.2,3.1-tetrahydrocarbazole: 3.88!i 1 volume of water and boil the mixture for 0 minutes. After conventional finishing, 3-
(*1-phenyl-1 1 2 + 3) 6-titrahydro 1-hili';rumethyl)-7-methylsulfonyl-1,2,3,4-tetrahydrocarbazole is 747 produced. Example Jl 3-(4-phenyl-1.2,3.6-tetrahydroJ-pyridylmethyl)-6-medki/-1. 2,3.4-tetrahydrocarbazole hydrochloride 1.19
1 and pyridine hydrochloride 3.57. Stir for 3 hours. After conventional work-up, 3-(4-phenyl-L2+3+6-titrahydro-I-pyridylmethyl)-6-hydrogi/I+2r:4+.I
-Tetrahydrocarbazole 1). 1(f:
0,2 (toluene/triethylamine 9.1). Example j2 Analogously to Example 6, the following compound is obtained from the corresponding amide. 3-[・l-(2-chenyl) 1,2,3.6-titrahydro-1-pyridylmethyl) - L2,3.4-
Tetrahydrocarbasol, 3-(4-phenyl dinomethyl) - 1+2,
3.4-tetrahydrocarbazole, 3-(4-
Phenyl e - < IJ Schiffle) - 6-hydrokyl 1.2.3.4-tetrahydrocarbano
-ru, 3-(4-phenylpisodinomethyl)-7-hydroxy-1,2,3.4-tetoxyhydrocarpaso
- Le, 3 - (4. - m-Methoquinphenylpibasdinomethel) - X. 2,3,<-Tetrahydro Rubazole, 3-(・i-m-Hydroxyphenylpiperidinomethyl)-1,2,3,・1-Detrahydro Rubazole, 3-(3-phenyl-1+2.5+6 -tetrahydro-1-pyridylmethyl) -L2,3.4-detrahydronolpasol, 3-(3-phenyl-1,2,5,6-titrahydro-1-pyridylmethyl)-6-hydroxy-1,2,3,
4-tetrahydrocarbazole, 3-(3-phenyl-1,2,5,6-titrahydro-1-pyridylmethyl)-7-hydroxy-1,2,3,S-tetrahydrocarbazole, 3-(3-m-methoxy /phenyl-1,
2,5,6-tetrahydro-1-pyridylmethyl) -
1,2゜3 + 4-tetrahydrocarbasol, 3-
(3-+lowhydroquinephenyl-1.2+5.6-titrahydro-1-pyridylmethyl) -1,2°3.4
-tetrahydrocarbazole, 3-(3-phenylpiperitunomethyl) -1゜2+3
．． 4--Tetrahydrocarbasol, 3-(3-phenyl el < lysine methyl)-6-hydroxy J + 2
+ 3 +, 4-tetrahydrocarbazole, 3-(3-phenyl<Ritz methyl)-7-hydroxy:,y-L2,3,4-tetrahydrocarbazole, 3'(3-m-methoquinophenylpi peridinomethyl)
-J, 2,3.4-tetrahydrocarbazole; Rf:
0165 (CH2Cl2/methanol 9:1), 3-
(3=m-methquinphenylpiperidinomethyl)-6
-Medquin-1,2,3,4-tetrahydrocarbazole; Rf: 0.7 (cn2c12/)tanol91), 3-(3-m-hydroxyphenolhyOIJ,)tumethyl)-1,2,3,4- Tetrahydrocarbazole; melting point 128 ~] 30°, 3 (3m-hydroxyphenylpiperidinomethyl)-
6-Hydroxy-1,2,3,4-tetrahydrocarbazole; melting point 123-125°. A bath solution of 1 g of :(-(3-m-hydroxyphenol-1+2+51G-tetoxyhydro-1-pyridylmethyl)-J,2,3.4-tetrahydrocarbanol) in 15rrre of methanol was added to 5 parts. Pd-C] f at 1 bar and 20° C. The mixture is filtered and evaporated to give 3-(3-II+-hydroxyphenylpiperidinomethyl)-L2,3.!-tetrahydrocarbazole as described by fiJ et al. Melting point: J28 ~] 30°. The following relates to pharmaceutical colors containing the amines of formula 1 or one of them. 1-Phenyl-L2,3.6-tetrahydro-1-hyperidylmethyl)-1,2,3,.I-tetrahydrocarbasol IK, milk 4'j44 Kg, potato starch 1,21 (g, talc 0 , 2K
g:F;
Form tablets containing mg. Example B Tablet legs are formed using a pressure of λ16 in the same manner as in Summer Tablet Example Δ, and then the cans are broken in a conventional manner with a covering material consisting of /Yo311+, potato starch, talc, gum tragacanth, and a coloring agent. . Shiori C Capsules 3-(4-phenyl-1,2,3,6-titrahydro-1-biridylmethyl)-6-hiISloki/-1,2,
3,4-DeI Lahydrocarpasol 21 (ri in hard gelatin capsules, each capsule contains active compound!)
Example D Ampoule Double-distilled water: 3U (3-(4-phenyl=
1.2. : U, 6-tetrahydro-1--lysylmethyl)-7-hydroxy-1,2,3,.I-tetrahydrocarbasol hydrochloride 11 (sterilize the number of baths by filtration, and put the P solution into an ampoule. Each a/sol contains 10 mg of the active compound. Similarly, other active compounds of formula I and ) 1ftI+ of their physiologically acceptable acid addition salts
Tablets, tablets, capsules and ampoules containing only one or more of the two can be obtained. For pharmacological testing, the method of Reese et al.
pharmcol. In the Gantt binding test with tritium tritium chloride in the rat striatum body test, published by J. F. (1977), p. 377-: p. 81, the compound's proboscis of formula
It was effective at doses of -7 mg/l<p body weight. The test results are summarized in the table below. The effectiveness coefficient value is 100t on the opposite shore.
I) indicates the bonding relationship of the test compound. / Flagellated object η1. Formula l Effect 'H2A4'i combination 1-c6FI,,, I(CH
2) 2” 7:3 7-M8゜ 72 1;-) 1025 6.7-Di-MeO--(CH,,)-II 176
．． 7-Di-MeC+---(CH2)2- 82
6-MeO-CH2-Otsu6-HO8 -MeO7 7-HO6 -H,1(3-m-H0C6H,63 6-HOH,H54

Claims (1)

[Claims] (1) General formula I [wherein 'rhc is 1- or 2-alkyl, 〇-alkyl, S-alkyl, SO-alkyl, SO3-alkyl, OH, F, C/= is a 1,2,3,4-tetrahydro-:u-carbazolyl group which may be substituted by , Br, C1i'3 and (Kadada)CN or by a methylene/dioxy group; Each of the 11 divination Y is; h H, or together they are C-
represents a C bond; one of the groups Z is Ar, and J.
The other side of εZ is J(; A is -CH2- or -
CH2CH2- and Ar is 1-: unspecified or 1 or 2 alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH. F, cL rrr, CF3 and 1 dimension or) CN, still id methylene oxide/group 11'T, J
+7'l: is a phenyl group, - or 2- or 3-thenyl; the alkyl group 1
Each tetrahydrocarbazole B' has 1 to 4 atoms and their physiologically acceptable acid 1τ1 additives. (21a) 3-(4-phenyl-1,7,:L(i
-tetrahydro-1-bilinormethyl) -1,2,3
, 4-tetrahydrocarbazole. 1)) 3-(4-phenyl-1,2,3,6-titrahydro-1-bilinormethyl)-6-hydroxy-1,
2,3,4-Te) lahydroruhasol; and C) 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridylmethyl)-7-hydroxyl
．． 2,3.4-Tetrahydrocarbazole; 2,3.4-Tetrahydrocarbazole; (3) General formula 1 [In the formula, The is 1 or 2 alkyl, 〇-alkyl, S-alkyl, SO-alkyl, 502-argyl, OH, F, cA, Br, CF3 and/or C
N is a 1,2,3,4-tetrahydro-3-carbazolyl group which may be substituted by a methylenedioxy group; Together, they represent a C-C bond; one side of a certain Z is Ar, and the other side of the group Z is H;
A is -CH2-t or -CH2CH2- and Ar is unsubstituted or 1 or 2 alkyl, 0-alkyl, S-alkyl, SO-alkyl, 5o2-alkyl, 0H1F, cL, Br, C
is a phenyl group substituted by F3 and/or CN or by a Z ethylene dioxy group, or is a 2- or 3-chenyl group, said alkyl group each having 1 to 4 carbon atoms. 11! A method for producing an acid salt having a chemically 1:'1 degree capacity, which has the general formula 11% formula% () (wherein X1 is NH2 up to X, and X is C/-
, Br, ■, OH group or reactive derivative of OH group,
and Thc and A have the pre-jjF consonance) compound of the general formula 111 (wherein X2 and X3 can be the same or different,
when Xl is NH2, both are
Or 1 or /'i 1/'i in place of 2 or more hydrogen atoms 21 or more;
ro and (suntake) one or more additional C-C
and (straddle) Formula 1 except that it has a c −p+ bond
A compound corresponding to 11 is treated with an element 1, or 1 or more hydrogen atoms are removed by adding 1 or more solvates instead of F. Formula 1 has the phase l! except that it has a group that can 1 with a solvolysis agent
(Studying compounds of formula l in which fB(H or two Y together represent a C-C bond.) To Shimadai,
Formula 1v (where one of the groups E is X, CN- is IvH2, and the other group E is IJ''c, and T
hC1A, Amase is SO2 group ``, 2f Shishi, and (suntake) 7'
The rukoki/group is cleaved 1JIj to form OHノ・:・, and (bite) ξ is) hydrogenated with C-C double #:i'i 17'r, and (simply) produced By converting the 347 well of formula I with r12 /7JL, 111j, the raw
Compound 11 of formula I and its physiologically acceptable acid are added with I (;1' Method for producing 5!f□! of g. (4) General formula l [In the formula, ThC is 1 - still 2 alkyl, 〇-argyl, S-alkyl, SO-alkyl, OH-F to 5O2-alkyno , C/-, Br-CF, and/or CN is a 1,2,3,4-tetrahydro-3-cal-guzolyl group optionally substituted with a methylenedioxy group; The groups Y are each H or - together represent a C-C bond: one of the groups Z is IdAr, and the other of A, z is H, and A is -CH2- or -CH2CH,, with -te: and Ar is not substituted, but the size is 1 - or 2
alkyl, 0-alkyno v-B-furkyl-1So
-Alkinope 5o2-alkyl, OH, F, CL-
a phenyl group substituted by Br, CF'3 and (or) CN, or by a methylene oxide group, or a 2- or 3-chenyl group; each of the alkyl groups (1) containing at least one of the tetrahydrocarbazole derivatives and/or physiologically acceptable acid addition salts thereof having 4 carbon atoms; Tadasei kiss. (5) General formula Va (in the formula, -co-"ilJ is -CH2Co-te, The is 1 or 2f alkyl, S-alkyl, so-alkyl, So2-alkyl, O
H, F, C/=, Br, CF3 and (not yet)
1,2,3.7+-tetrahydro-3-, which may be substituted with 1 by CN or by methylene oxy/group
is a carbazolyl group; each of the Y's in 21 is H or taken together represents a C-C bond; the group 2
One of the groups is Ar, and the other of the group 2 is H.] A tetrahydrocarbazole derivative represented by the following.