JPS59116265A - Improvement on organic compound - 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 novel heterocyclic compounds.

The present invention provides novel compounds of formula (1) and acid addition salts thereof. The compounds also include, by definition, the optical antipodes and racemic mixtures of optical antipodes of compounds of formula (II), where k is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, or Alkynyl (the multiple bond is not in the α-position relative to the nitrogen atom to which it is attached), alkyl of 1 to 4 carbon atoms substituted by cycloalkyl of 3 to 6 carbon atoms, 2 to 5 carbon atoms hydroxyalkyl, 7 carbon atoms
~11 phenylalkyl/Iz, phenyl group or halogen, alkoxy of 1 to 4 carbon atoms or 1 to 4 carbon atoms
phenylalkyl of 7 to 11 carbon atoms monosubstituted with alkyl of Mono fj2 with alkyl, phenyl, halogen
tL taphenylte), k□ and R2
are the same or different, each is hydrogen, halogen, or alkyl having 1 to 4 carbon atoms, and rings B and C are connected by a cis bond] groups k and R3 have 1 to 5 carbon atoms; is lower alkyl of 1 to 4 carbon atoms, preferably 1 to 4 carbon atoms, preferably 1 to 4 carbon atoms.
Contains 3 pieces.

When k is an alkyl group of 1 to 4 carbon atoms substituted by a cycloalkyl group of 3 to 6 carbon atoms, the alkyl group especially contains 1 to 2 carbon atoms, and the cycloalkyl group In particular, it contains 3 carbon atoms. This kind of preference 1
The - substituent is a cyclopropylmethyl group.

If the radical is a hydro, xyalkyl group of 2 to 5 carbon atoms, it especially contains 2 to 4 carbon atoms, preferably 2 to 3 carbon atoms.

MR is a phenylalkyl group having 7 to 11 carbon atoms, or 7 to 11 carbon atoms monosubstituted with halogen, alkoxy having 1 to 4 carbon atoms, or alkyl having 1 to 4 carbon atoms;
phenylalkyl group, the phenylalkyl group has in particular 7 to 9 carbon atoms, preferably 7 to 8 carbon atoms.
Including. Halogen substituents which may be present in this radical mean in particular fluorine, chlorine or bromine, preferably fluorine or chlorine. 1 to 4 carbon atoms that may be present in this group
alkoxy or alkyl substituents in particular 1 to 1 carbon atoms
3 pieces, preferably 1 to 2 pieces.

If the group A is a group A-GO-R and is not phenyl or phenyl monosubstituted with halogen, the alkylene group A has especially 1 to 3 carbon atoms, preferably 1 to 2 carbon atoms. including.

In the case of phenyl substituted with 3 or halogen,
Halogen substituents especially represent fluorine, chlorine or bromine, preferably fluorine or chlorine.

If the radicals R1 and/or R2 are halogen, these represent in particular fluorine, chlorine or bromine, preferably fluorine or chlorine.

If the radicals R1 and/or 2 are alkyl radicals of 1 to 4 carbon atoms, they in particular contain 1 to 2 carbon atoms, preferably 1 carbon atom.

Particularly preferred compounds of formula 1 are compounds of formula 1w and their acid addition salts, which according to the definition also include the optical antipodes and racemic mixtures of the optical antipodes of compounds of formula 1w, and where Ra is hydrogen, carbon atom 1
~3 alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms (the multiple bond is not in the alpha position to the nitrogen atom to which Ra is attached), cyclopropylmethyl 1.
Hydroxyethyl, phenylalkyl of 7 to 8 carbon atoms, phenylalkyl of 7 to 8 carbon atoms monosubstituted with fluorine, chlorine, methyl or methoxy, acetonyl, 3
-oxobutyl, phenacyl, P-fluorophenacyl, 4-(P-fluorophenyl)-4-oxobutyl, Rb and Rc are the same or different, and each is hydrogen, chlorine, fluorine or methyl.

Furthermore, according to the invention, compounds of formula (1) and their salts include a) formula (1f) (the compounds according to the definition also include the optical antipodes of the compounds of formula (1f) and racemic mixtures of these optical antipodes; (1, R2 and K are as defined above) into a compound of formula (1), b) formula IV, (this compound is the optical enantiomer of the compound of formula (1) according to the definition and the optical enantiomers thereof It also includes racemic mixtures of enantiomers, where R1 and R2 are as defined above, and 1) is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, 3 1 to 3 carbon atoms substituted with ~6 cycloalkyl (1) 7 /l/ , =l-l, hydroxyalkyl of 1 to 4 carbon atoms, phenyl,
phenylalkynobehalogen of 7 to 10 carbon atoms, saletaphenyl monosubstituted with alkoxy of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, or phenyl group is halogen, alkoxy of 1 to 4 carbon atoms or carbon atom 1
7 to 1 carbon atoms monosubstituted with ~3 lower alkyl
0 phenylalkyl) with a metal hydride to form a compound of formula 1m, which by definition also includes the optical antipodes of compounds of formula 1m and racemic mixtures of these enantiomers; (wherein R1, k2 and D are as defined above) and isolating the resulting compound of formula (1) as it is or as a salt.

Salts can be purified from the free base or acid by well known methods, and vice versa.

Separation of any resulting racemates of the formula ■ into their optical antipodes may be carried out by well-known methods, for example by fractional crystallization of salts of these racemates with optically active acids. good.

Next, details of the technical method considered in the preparation of the compound of formula (1) will be described.

a) Conversion of the compound of formula 1 to the compound of formula 1 is carried out under strongly alkaline conditions, for example potassium hydroxide or potassium tertiary
It is carried out using a strong base such as butyrate and/or at elevated temperatures, e.g. about 100-200<0>C, and/or at long reaction times, e.g. 1-7 days.

Particularly suitable reaction media for this conversion are a saturated solution of potassium hydroxide (approx. ℃ for 1 to 7 days).

b) Reduction of amides of formula IV with metal hydrides may be carried out analogously to known methods. Suitable metal hydrides are, for example, aluminum hydrides and dialkylaluminum hydrides and compounds of the formula (II) or, if they have no chlorine, bromine or iodine substituents, also lithium aluminum hydride or lithium aluminum hydride/aluminum chloride. It is. Suitable solvents are inert solvents, for example cyclic or linear ethers such as tetrahydrofuran.

Reduction may be carried out at room temperature and is usually complete after about 1.5 to 5 hours.

The compounds of formula (1) obtained according to each of the above methods are isolated and purified according to well-known methods.

Further, according to the present invention, formula (b) R'M (wherein R7 is hydrogen and 2 is halogen or 1 to 1 carbon atoms)
4 alkyl or kq is halogen or alkinogel of 1 to 4 carbon atoms (/ is hydrogen) compounds of the formula VlR'1 2 (the compounds have the formula A method C characterized in that the group R9 is removed from the compound (2), which also includes an optical antipode of the compound (2) and a racemic mixture of the optical antipodes (in which 9 is an electron-withdrawing group)
The resulting compound ii)b is isolated as a base or as an acid addition salt.

Acid addition salts are prepared from the free base and vice versa by well known methods.

Details of the technical process considered in the preparation of the compounds of the formula Il) are given below.

Examples of suitable electron-withdrawing groups in 9 are trifluoroacetyl groups,
Acyl groups such as benzoyl, aliphatic or aromatic sulfonyl groups such as tosyl, methoxy- or ethoxy-
It is a lower alkoxycarbonyl group such as a carbonyl group or a phenoxycarbonyl group.

Removal of the group R9 according to the invention may be carried out, for example, by hydrolysis with a 1 to about 5N solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in a lower alcohol, preferably methanol or ethanol. .

If R9 is an easily separable acyl group, for example a trifluoroacetyl group, the hydrolysis may be carried out at room temperature or slightly elevated temperature. In this case, hydrolysis is complete after about 0.5 to 3 hours.

When 1(9) is an acyl group that is difficult to separate, such as a phenoxycarbonyl group, the reaction is conveniently carried out with heating, preferably at the reflux temperature of the reaction mixture. Lasts 20 hours.

When kg is an aliphatic or aromatic sulfonyl group,
This group may be separated by methods analogous to known methods, for example under reducing conditions with phenol in sodium/ammonia or 40% hydrobromic acid.

Hydrolysis of the compound of formula (II) may also be carried out under acidic conditions, for example with 2N hydrochloric acid, conveniently at elevated temperature, preferably at the reflux temperature of the reaction mixture.

Compounds of formulas f, ■ and VI are also new.

Compounds of formula If may be combined, for example, with compounds of formula X (wherein kl and R2 are as defined above) and compounds of formula Alkyl of 1 to 4 carbon atoms substituted with ~6 cycloalkyl, hydroxyalkyl of 2 to 5 carbon atoms, phenylalkyl of 7 to 11 carbon atoms, phenyl radical, 1 to 4 carbon atoms (a phenylalkyl having 7 to 11 carbon atoms monosubstituted with 2 alkoxy) is condensed with a compound of the formula (including racemic mixtures, in which RR and 8 are as defined above) 1 2 and removing water from the resulting compound of formula (1).

The condensation of compounds of formula The reaction lasts approximately 20-200 hours.

Compounds of formula (1) may be dehydrated with organic or inorganic acids according to known methods. Examples of suitable organic acids are aliphatic or aromatic sulfonic acids, trifluoroacetic acid, trichloroacetic acid and formic acid; examples of suitable inorganic acids are sulfuric acid, hydrochloric acid, perchloric acid and phosphoric acid.

The reaction lasts about 1 to 15 hours depending on the acid used and its concentration.

If concentrated strong acids such as sulfuric acid or trifluoroacetic acid are used, water removal may proceed smoothly at room temperature, or if dilute or weak acids are used, it may be advisable to heat the reaction mixture.

This is accomplished, for example, by dissolving the compound of formula (1) in an organic acid such as trifluoroacetic acid and stirring the reaction mixture at about 20-40°C for about 2-5 hours.

The formula obtained in this way■ By reducing a compound of formula Iu with a metal hydride, into a compound.

Reduction of compounds of formula (1) with metal hydrides may be carried out in a manner analogous to well known methods for the reduction of amides.

This can be done, for example, by adding a solution of an aluminum hydride or dialkylaluminum hydride in an inert organic solvent, preferably a cyclic or linear ether such as tetrahydrofuran, to a solution of the compound of formula (1) in the same inert organic solvent. , by stirring at room temperature or higher temperature for about 20 to 30 hours. For example, reduction may also be carried out using a lithium aluminum hydride/aluminum chloride mixture. If the compound of formula (II) does not have chlorine, bromine or iodine substituents, reduction can also be carried out using complex hydrides, e.g. complex aluminum hydrides such as lithium aluminum hydride, or complex lithium aluminum hydride-aluminum chloride. You can also do it by This process may be carried out analogously to that described for reduction with aluminum hydride.

The compound of formula Iu thus obtained can be further prepared by hydriodic acid/red phosphorus or catalytic reduction to form a compound of formula If (wherein k is 8
(with the meaning defined as ).

Formula If of a compound of formula 1u using hydroiodic acid/red phosphorus
The hydrogenation to the compounds may be carried out analogously to known methods. This is carried out by adding dropwise an aqueous solution of hydriodic acid to a solution or suspension of a mixture of a compound of formula If and red phosphorus in a suitable solvent or suspending agent, such as glacial acetic acid. The resulting reaction mixture is then conveniently heated to 80-120<0>C. Approximately 2 under the above conditions
Continue stirring for ~5 hours.

The thus obtained formula If (where k is hydrogen)
Compounds of can be further alkylated (eg, by direct or reductive alkylation) to other compounds of formula If.

Compounds of formula (1) can be prepared by preparing the corresponding compounds of formula (1) (wherein k is hydrogen), for example with the corresponding acid halide, preferably with the corresponding chloride or bromide, or with the corresponding acid anhydride, according to well-known methods. It may be produced by acylation with Optional N-formylation is also carried out according to well known methods. Compounds of formula If may be directly synthesized, especially as described below.

a■) Formula ■a (This compound also includes the optical antipodes and racemic mixtures of optical antipodes of the compound of formula ■a according to the definition, in which R□, R
2 and 9 are as defined above) can be obtained by thermally cyclizing a compound of formula xm (wherein R0, R2 and R9 are as defined above).

The thermal cyclization of the compound of formula X■ may preferably be carried out in an inert organic solvent with a high boiling point, such as dichlorobenzene. The reaction is conveniently carried out in the absence of oxygen and the reaction mixture is heated to about 160-190°C for about 1-6 hours.

The resulting compound of formula (a) is as described above (the corresponding NH
- deacylated to compounds and catalytically hydrogenated.

It should be noted that in the latter case any chlorine, bromine or iodine substituents that may be present will also be partially reduced.

b) Formula ylb (According to the definition, the present compound also includes the optical enantiomer and racemic mixture of the optical enantiomers of the compound of formula (b), where □ and R2 are as defined above, and R12 alkyl or phenyl group), for example, the compounds of the formula (r) (the present compounds also include the optical antipodes and racemic mixtures of the optical antipodes of the compounds of the formula (r) according to the definition; 2 is as defined above) is reduced with hydriodic acid/red phosphorus according to well-known methods, followed by the resulting compound of the formula It is produced by substituting the benzyl group in a compound (R and R2 are as defined above), including racemic compounds of the isomer and its optical enantiomer.

The substitution of benzyl groups in compounds of formula IS is also carried out according to well-known methods, for example by reacting compounds of formula Is with the corresponding chlorocarbonate esters.

The resulting compound of formula ylb is the corresponding tetrahydride compound of formula If (R=
H).

Compounds of formula VI can be obtained by thermal cyclization of compounds of formula XIV, where 0, k2 and 9 are as defined above.

Thermal cyclization of compounds of formula XiV may be carried out under the conditions described in Method 3. However, the reaction usually lasts for a somewhat longer time (16-30 hours).

Compounds produced by each of the above methods are isolated in conventional manner and purified according to well-known procedures.

The preparation of starting materials, unless otherwise stated, are well known or are prepared according to well known methods or by method sequences analogous to those described herein or to well known methods.

Compounds of Formula (1) and Their Pharmacology - The acceptable acid addition salts exhibit interesting pharmacological properties and have low toxicity, so they can be used as medicines.

In animal studies, the compound showed pharmacological effects that are particularly typical of antidepressants. That is, approximately 2 mf/
/K! At dosages of i' to about 30 my/Ky, the compounds of the invention eliminate the infarct syndrome induced in mice by administration of tetrabenazine (tetrabenazine antagonism). Due to its antidepressant effects, this compound can be used in the treatment of depression.

The dosage to be administered for the above uses will, of course, depend on the compound used, the mode of administration and the condition to be treated. However, satisfactory results are usually around 1-30
It is obtained by administering a compound of formula (1) or a physiologically acceptable acid addition salt thereof at a dosage of 7nfl equivalent to animal weight. For large mammals, the required daily dosage is about 50-500++v. This daily dosage may be divided into smaller portions, for example 2 to 4 doses per day.
It may be administered in batches or as a delayed form. A unit dosage, e.g. a tablet suitable for oral administration, may contain from about 12.5 to 250 mf of active compound together with suitable pharmaceutically active excipients.

Furthermore, the compounds of the present invention have been tested in the tail pinch test in rats, in rats I
(tail fl
They are useful as analgesics as shown by their properties in the hot plaid test (hoLl)laLe Lest) in mice and yet in suppressing phenylbenzoquinone syndrome in mice.

The new compounds of the general formula (III) or their physiologically acceptable acid addition salts are used as medicaments on their own or in the form of pharmaceutical preparations suitable for parenteral administration, such as tablets, dragees, suppositories, injection solutions. may be done. These preparations may contain useful inorganic or organic pharmaceutically inert excipients, such as lactose, starch, talc, stearic acid, water, alcohol, natural or hydrogenated oils and waxes, as well as suitable preservatives. ,
It may also contain stabilizers, wetting agents, solubilizing agents, sweetening substances, coloring substances and flavoring agents.

They form stable salts with acids such as hydrogen chloride, hydrogen bromide, fumaric acid, maleic acid, tartaric acid, naphthalene-1,5-disulfonic acid, which are usually soluble in water.

The invention further comprises a process for the preparation of novel medicaments containing compounds of formula (1) by methods known per se and the use of compounds of formula (1) as medicines in the treatment of depression or pain.

The above characteristics are particularly expressed by the formula ■z ■1 (where Ra is hydrogen, methyl, 2-propynyl, cyclopropylmethyl, acetonyl, and kb and 1 are hydrogen,
(methyl or chlorine) compounds.

The embodiments of the present invention are as follows.

(3aR8,4SR,9aSR)-6-chloro-3a,
A process according to claim 1, characterized in that it is a method for producing 4,9,9a-tetrahydro-2-methyl-4-phenyl-benz[f]isoindoline or an acid addition salt thereof.

Example 1: (3aR5, 4SR, 9aSR) -3a, 4°9.9
a-tetrahydro-4-phenyl-benz (f) isoindoline [Method C)] 22,:l of (3aR5,4SR,9aSR)-31,
4,9,9a-tetrahydro74-phenyl-benz [
f) Isoindoline-2-trifluoroacetamide is dissolved in a 3N caustic potash solution in methanol with heating. The mixture is stirred at room temperature for 30 minutes, then poured into water and extracted with methylene chloride. 136~ by drying the extract over sodium sulfate, concentrating the solution by evaporation, and crystallizing the residue from methylene chloride/pentane.
The title compound is obtained with a melting point of 138°C.

Required as starting material (3a RS, 4S R19a
SR)-3a,4,9.9a-tetrahydro-4-phenyl-benz[f) isoindoline-2-trifluoroacetamide can be obtained, for example, as follows: 6A? 3107 N in 0-dichlorobenzene.

A solution of N-bis-(trans-cinnamyl)trifluoroacetamide is heated to reflux under an argon atmosphere for 16 hours and then concentrated by evaporation. 150-15 by crystallizing the residue from methylene chloride/pentane.
Has a melting point of 8°C (3aR8, 48R19aSR)
-3a, 4. g.

9a-tetrahydro-4-phenyl-benzCf, ll
Isoindoline-2-trifluoroacetamide is obtained.

m-1 i R(CH2Cl2) 1690.950-990
No absorption band.

The N,N-bis-(trans-cinnamyl)trifluoroacetamide required as starting material is obtained as follows: 275 in hexamethylphosphoric triamide of 6QQcc
7 of N-cinnamyl-trifluoroacetamide in 540 cc of hexamethylphosphoric triamide.
．． Add dropwise to a suspension of :1 of sodium hydride while cooling and stirring. After the gas generation has finished, 540CC
A solution of 248.5P cinnamyl bromide in hexamethyl phosphate triamide was added dropwise and the mixture was heated at 25°C.
Stir for 16 hours. The reaction mixture is then poured into water and extracted with ether. The ether solution, dried over sodium sulfate, was concentrated by evaporation to give an oily residue of 1.5K
Chromatograph on Si' silica gel with toluene.

The filtrate is concentrated by evaporation to give N,N- as an oily residue.
Bis-(trans-cinnamyl)trifluoroacetamide is obtained.

Ding■((CI-12CI!2)1690,968C+1
-1 title compound under normal conditions (3aR5,4SR
19aSk) 3 ar 4 + 9 + 9 a
7 toyhydro-4-phenylubenz ([3 Also obtained by reducing isoindoline-2-p-1-luenesulfonic acid amide.
aR5,4SR,9aSR)-3a,4°9.9a-tetrahydro-4-phenyl-benzCf)isoindoline-2-p-)luenesulfonamide is obtained, for example, as follows: 120 cc of O - 2 g of N in dichlorobenzene.

A solution of N-bis-(trans-cinnamyl)-P-1-luenesulfonic acid amide was heated to reflux in an argon atmosphere for 48 hours and then concentrated by evaporation to yield (3aR5,4SR19aSR)-33,4, 9,9a
-Tetrahydro-4-phenyl-benz[f]isoindoline-2-p,-toluenesulfonic acid amide is obtained.

Melting point 185-187°C (after crystallization from ether/pentane).

The following compound of formula I+) is also obtained by a method analogous to that described in Example 1 using the corresponding starting materials and Method C: (3aR8,4SIL,9aSR)-6-chloro-4-
(4-Chlorphenyl)-31,4,9,93-tetrahydro-benz[11-in isodrine, 133-1
34°C; (3aR5,4SR,9aSR)-6-fluoro-1-
(p-fluorophe=7m)-31,4,c+.

(3aR5
,4SR,9asR)-7-chloro-4-(m-chlorophenyl)-38,4,9,9a-tetrahydro-benz[f]isoindoline, melting point of 7-leic acid hydrogen salt 16
6-168°C; (3aR5, 4SR, 9aSR)-3
a, 4,9゜9a-tetrahydro-6-methyl-4-(
P-tolyl)benz[f]isoindoline, melting point 12
9-132°C; (3aR5,4SR,9aSR)-3a, 4,9°9a
-tetrahydro-6-methyl-4-phenyl-benz [
1] Melting point of isoindoline, hydrochloride 174-176°C; (3aR5,4SR,9aSR)-33,4,9°9a
-tetrahydro-7-methyl-4-phenyl-benz[
flIisoindoline, hydrochloride melting point 225-227℃
; (3aR8,4SR,9aSR)-6-chloro-3a,
4,9,9a-tetravitro-4-phenyl benz(
Melting point of fl isoindoline, hydrochloride 205-207°C; Example 2: (3aR8-4SR,9aSR)-3a, 4°9.9a
--Tetrahydro-6-methyl-4-phenyl-benz (t1 Isoindoline C Method "1 20 in 50 Qcc of n-butanol saturated with solid potassium hydroxide
．． 21 (3aR5, 4R5, 9aSR)-3a, 4,
9.9a-tetrahydro-6-methyl-4-phenyl-
The solution of benz[f]isoindoline is heated to reflux under an argon atmosphere for 70 hours and then concentrated by evaporation. The residue is partitioned between water/methylene chloride, the organic phase is dried and concentrated by evaporation, the residue is taken up in excess hydrochloric acid in methanol, the solution is concentrated by evaporation and the residue is dissolved in methanol/- 174-176℃ after crystallization from L/ether
The hydrochloride salt of the title compound is obtained with a melting point of (decomposition).

Example 3: (3aR5,4SR,9aSR)-6-riOru3a,
4. 9. 9a-tetrahydro-4-phenyl-
Benz[f]isoindo IJ [method a]] 6.47 (3aR5,4R5,9aSR)-6-chloro-31
, 4,9,9a-tetrahydro-2-phenoxycarbonyl-4-phenyl-benz (f'lisoindoline) in a saturated solution of potassium hydroxide in n-butanol at 320 cc
The mixture is heated under reflux for 70 hours in a nitrogen atmosphere. The reaction mixture is then concentrated, the residue taken up in water and extracted with methylene chloride. The title compound is obtained by concentrating the washed and dried methylene chloride solution by evaporation. The melting point of hydrochloride is 205-207℃ (methylene chloride/
after crystallization from ether).

The following compounds are obtained from the corresponding starting materials in a manner analogous to that described in Example 2 or 3 using Method 3: (3aR5,4SR,9aSR)-3a,4,9°9a
-tetrahydro-4-phenyl-benz(f) isoindoline, melting point 136-138°C; (3aR5,4SR
,9aSR) -6-chloro-4-(4-chlorophenyl)-31,4,9,9a-tetrahydro-benz[f
゛11 Indoline point 133-134°C; (3aR5,4SR,9aSR)-6-fluoro-4-
(+)-fluorophenyl)-33,4,9゜9a-tetrahydro-benz[f) isoindoline, 7-oleic acid hydrogen salt melting point 134-136℃; (3aR5,4SR,
9aSR)-7-chloro-4-(m-chlorophenyl)
-31,4,9,9a-tetrahydro-benz[f]isoindoline, hydrogen maleate salt melting point 166-168
℃; (3aR814SR, 9aSR)-3a, 4,9゜9a-tetrahydro-6-methyl-4-(P-tolyl)-benz(f) isoindoline, melting point 129-132
8C; (3aR814SR, 9aSR)-3a, 4,9°9a
-tetrahydro-7-methyl-4-phenyl-benz[
f) Isoindoline, hydrochloride melting point 225-227°C.

The following compounds are obtained from the corresponding starting materials in a manner analogous to that described in Example 2 using method a: (3aR5,4SR,9aSR)-3a,4,9°9a
-tetrahydro-2-methyl-4-phenyl-benz [
f] Melting point of isoindoline hydrochloride 207-209°C
(3aR5,4SR1QaSR)-2-cyclopropylmethyl-33,4,9,9a-tetrahydro-4-phenyl-ben, ((flisoindoline, mp 65-68
°C; (3aR5,4SR,9aSR)-3a,4,9°9a
-Tetrahydro-2-isopropyl-4-phenyl-benz[f]isoindoline, melting point of hydrogen maleate 1
50-158°C; Melting point of (3aR5,4SR,9aSR)-2-(0-chlorophenyl)-3a,4,9.9a-tetrahydro-4-phenyl-benz[f]isoindoline, hydrogen maleate 178 ~179°C; (3ai(s, 4si<,
gaSR)-2-(3a.

4, 9. 9a-tetrahydro-4-phenyl-benz(f)isoindolin-2-yl)acetophenone,
Melting point 120-130'C; (3aR5,4SR,9aSR)-P-fluoro-4-
(3al 4.9,9a-tetrahydro-4-phenyl-benz[f]isoindolin-2-yl)butyrophenone, melting point 81-84°C; (3aR8,4SR,9a
SR)-6-chloro-4-(4-chlorophenyl)-3
1,4,9,9a-tetrahydro-2-methyl-benz[f]isoindoline, melting point 133-135°C; (3aR8,4'SR,9aSR) -6-rihane-4
-(41ylorphenyl)-2-cyclopropylmethyl-3a,4,9.9a-tetrahydro-benz(f) isoindoline, melting point 124-126°C: (3aR5,4SR,9aSR)-7-riO/lz -
4-(tn-chloro/L/phenyl)-3a,4,9,9
a-Tetrahydro-2-methyl-benz[f]isoindoline, bis(basic) naphthalene-1,5-disulfonate melting point 244-248°C; (3aR5,4SR,
9aSR)-7-chloro-4-(m-chlorophenyl)
-2-Cyclopropylmethyl-3a,4,9,9a-tetrahydro-benz[f]isoindoline, bis(base)naphthalene-1,5-disulfonate melting point 243~
247°C; (3aR5,4SR,9aSR)-3a, 4,9°9a
-Tetrahydro-2,6-simethyl-4-(P-tolyl)benz(f)isoindoline, bis(base)naphthalene-1,5-disulfonate melting point 195-198°
C; (3aR5,4SR,9aSR)-2-cyclopropylmethyl-3a,4,9.9a-tetrahydro6 methyl-4-(p-1-ruyl)benz macroisoindoline, melting point 98-1oo0c; (3a1 (S14SIL, 9
aSR)-2-(2-hydroxyethyl)-3a, 4,
9.9a-Tetrahydro-6-methyl-4-CP-)ruyl)-2-benz[f) Isoindoline, mp 128
~129°C; (3aR514SR, 9aSR) -3a,, 4,9° Melting point of 9a-tetrahydro-2,6-dimethyl-4-phenyl-benz (f) isoindoline, bis(base) naphthalene-1,5-disulfonate 280~283°C
(3aR5,4SR,9aSR)-5-chloro-2-cyclopropylmethyl-3a,4,9,9a-tetrahydro-4-phenyl-benz[f]isoindoline, (3aR8,4SR19aSl<)-2- -F-/l
/-6-chloro-3a, 4,9.9a-tetrahydro-4-phenyl-benz([)isoindoline, r3
aR8,4S R19a S R) -2-n-butyl-6-ri0/l/-3a, 4. 9. 9a-Tetrahydro-4-phenyl-benz(f) Isoindoline, (3aR5,4SR,9aSR)-6-chloro-2-
Isopropyl-31,4,9,9a-tetrahydro-4
-phenyl-ben, ([flisoindoline, (3aR5,4SR,9aSR)-2-cyclopropylmethyl-331419+ 9 a-tetrahydro-6
-Methyl-4-phenyl-benzCf) Indoline, hydrochloride, melting point 198-204°C; (3aR5,4S
R19aSR) -3a, 4,9゜9a-tetrahydro-2,7-dimethyl-4-phenyl-benz [f) isoin FIJn, his (base) naphthalene-1,5-disulfonate melting point 244-248°C; ( 3aR5,4SR19a S R) -2-cyclopropylmethyl-31,4,9,9a-tetrahydro-7
-Methyl-4-phenyrubens[f]isoindoline, melting point 79-82°C; 2-[(3aR5,4SR,9aSR)-3a.

4.9.9a--Tetrahydro-7-methyl-4-phenyl-benz[f)isoindolin-2-yl]-p-
Fluoroacetophenone, hydrogen maleate melting point 16
4-166°C; (3aR5,4SR,9aSR)-6-chloro-3a,
4,9,9a-tetrahydro-2-methyl points 231-2
to 3°C; (3aR5,4SR19aSR)-3a, 4,9°9a
-tetrahydro-2-(p-methylbenzyl)-4-phenyl-benz [fl isoindoline, mp 120-1
218C; (3aR5,4SR,9aSR)-32,4,9°9a
-tetrahydro-2-(p-methoxybenzyl)-4-
Phenyl-benz [f1 isoindoline, melting point 95-1
00℃.

Example 4: (3aR5,4R8,9aSR-) -3a, 4°9.
9a-Tetrahydro-6-methyl-4-phenyl-benz(fl) isoindoline (starting material for Example 2) A solution of 0.55P palladium-11 chloride and 0.39!ii! (7) 35.2! of (9aR5)-2-benzyl- in ethanol
Add to the solution of 9,9a-dihydro-6-methyl-4-phenyl-benz[11 isoindoline at 25°C. A solution of 2607 sodium borohydride in 25 cc of water was added dropwise to the mixture at 0 °C, stirred for 30 min at 25 °C, the pl-I of the solution was adjusted to 2 with concentrated aqueous hydrochloric acid, and finally at 60 °C. and hydrogenation for 18 hours at 4 atm. By filtering the reaction mixture, extracting the filtrate with hot ethanol and cooling the clear solution, the hydrochloride salt of the title compound with a melting point of 215-220° C. (from methanol/ether) crystallizes.

Example 5: (3aR514R8,9aSR)-2-benzyl-6-
Chlor-3a, 4. 9. 9a-tetrahydro-
4-Phenyl-benz[']isoindoline (starting material) 301 (9aR5)-2-benzyl-6-chloro-9,9a-dihydro-4-phenyl-benz [f) isoindoline in 400 CC of glacial acetic acid 46.8P red lint suspension GC190cc 57%
/\ Hydroiodic acid is added dropwise and the mixture is subsequently heated at 110° C. for 5.5 hours, then poured onto ice and made alkaline with caustic soda solution. After extraction with ethyl acetate, the organic phase was filtered through Celite and the filtrate was dried and concentrated by evaporation.
The title compound is obtained with a melting point (after crystallization from pentane) of 5-117°C.

The following compounds are obtained from the corresponding starting materials in a manner analogous to that described in Examples 4 and 5: (3aR5,
4R5,9aSR)-3a,4,9°9a-tetrahydro-2,6-dimethyl-4-phenyl-benz[f]isoisodrine, bis(base)naphthalene-1,5-sulfonate melting point 183-187°C; (3aR514R5,9aSR)-3a,4,9゜9a
-Tetrahydro-2,7-dimethyl-4-phenyl-benz[f]isoindoline, bis(base) naphthalene-1,5-disulfonate Q) Melting point 204-207°C
; (3aR514R5,9aSR) -3a, 4,9°9
a-tetrahydro-2-methyl-4-phenyl-benz[f]isoindoline, bis(base)naphthalene-1,
Melting point of 5-disulfonate 297-303°C.

The following compounds are obtained from the corresponding starting materials in a manner analogous to that described in Example 4: (3alLS, 4i
(3aR5,4Lts, 9aSR)-3a ,4,9゜9
a-Tetrahydro-4-phenyl-benz (f) isoindoline, hydrochloride melting point 256-258 °C; (3a
rt s, 4R5,9a S R) -2-7cetonyl-33r 4+ 9+ ” a-tetrahydro-
4-Phenyl-benz [f1 isoindoline, bis(basic)naphthalene-1,5-disulfonate melting point 265
~269℃. Example 6: (9aRS)-2-benzyl-9,9a-dihydro-6-methyl-4-phenyl-benz(filisoindoline (starting material of Example 4) of 27f! in 400 CC of tetrahydrofuran) To a 1 volume solution of lithium aluminum hydride, 35 cc of 100% sulfuric acid is added dropwise under nitrogen atmosphere with stirring at -5°C.The mixture is then stirred at room temperature for 30 minutes and then brought back to -5°C. Cool and (r)909-(9
aR,5)-2-benzyl-9,9a-dihydro-6-
A solution of methyl-4-phenyl-benz[f]-isoindoline-1°3-dione is added dropwise within 30 minutes.

After stirring for 26 hours at room temperature, the reaction mixture is decomposed by adding water and 12% caustic soda solution and the resulting precipitate is separated off. By concentrating the suspension by evaporation, taking up the residue in dense methylene, concentrating the filtered solution, and crystallizing the residue from ether/pentane, 139-
The title compound is obtained with a melting point of 143°C.

The (9aR8)-2-benzyl-9,9a-dihydro-6-methyl-4-phenyl-benz[f]isoindoline-1,3-dione used as starting material is prepared as follows: A solution of 351 2,5-dimethylbenzophenone and 31.57 N-benzylmaleimide in 500 CC of acetone or methylene chloride was passed through a pyrex filter under a mercury high-pressure lamp until all materials had reacted (20-130 hours). irradiation, followed by ρ filtration and concentration by evaporation. The residue was crystallized from ether to give 3 with a melting point of 162-164 °C.
5F of 2-benzyl-31,4゜9.9a-tetrahydro-6-methyl-4-phenyl-benz['']isoindoline-4-un-13-dione was obtained, which was converted to 17
Dissolve in 0 CC of trifluoroacetic acid. The solution is stirred at 25° C. for 3 hours and concentrated by evaporation. 30y-(7)(9aFLs)-2- with a melting point of 156-158°C after crystallization from methylene chloride/methanol
Hairzyl-9°9a-dihydro-6-methyl-4-phenyl-benzCf) isoindoline-1,3-dione is obtained.

The following compounds are obtained from the corresponding starting materials in a manner analogous to that described in Example 6: (gaR8)-2-
Benzyl-9,9a-dihydro-7-methyl-4-phenyl-benz(f)inindoline, mp 139-14
2°C (9aSR)-2-benzyl-6-chloro-9°9a-
Dihydro-4-phenyl-benz[']isoindoline, melting point 266-268°C.

(9aR5)-2-bendi/L/-9,9a-dihydro-4-phenyl-benzCD isoindoline, mp 11
3-115°C: (9aR5)-9,ga-dihydro-4-phenyl-benz[f) isoindoline, hydrochloride melting point 238-24
3°C (decomposition): (gaR5)-9,9a-dihydro-2-methyl-4-
Phenyl-benz[f]isoindoline, hydrogen maleate salt melting point 158-162°C (decomposition).

Example 7: (3aR5,4SR1gaSR)-2-cyclopropylmethyl-3a,4.9.9a-tetrahydro-4-7enylrubenzCf]isoindoline [Method! ])] 4.77 cyclopropylcarboxylic acid chloride to 7.
55' (7) (3aR5, 4SR, 9aSR)-31,
4,9,92-tetrahydro-4-phenyl-benz [
f) Isoindoline, 7.9F pyridine and 100c
Add dropwise to the methylene chloride mixture in c. at -5°C. The mixture was stirred at room temperature for 1 hour, then shaken well with 10% aqueous citric acid and sodium bicarbonate solution, dried over sodium silicate and concentrated by distillation to give a residue at 149-151°C. Melting point (after converting ether to %)
R19aSR)-32,4,9,9a-tetrahydro-
4-phenyl-benz([3isoindoline-2-cyclopropylcarboxylic acid amide is obtained.

8,6v (3a
R5,4SR,9aSR)-3a, 4.9°9a-Tetrahydro-4-phenyl-benz(f) Lithium aluminum hydride of 12 is added several times to a warm solution of isoindoline-2-cyclopropylcarboxylic acid amide. Add separately. The mixture was stirred at room temperature for 1 hour, then 2N
Digest with caustic soda solution and filter. By making the concentrated r-liquid into a paste with silica gel in benzene/ethyl acetate (1:1) and concentrating by filtration and evaporation, it has a melting point of 65-68°C (after crystallization from pentane). The title compound is obtained.

The following compounds of formula Tm are obtained from the corresponding starting materials in a manner analogous to that described in Example 7 using method b): (3aR514SR,9aSR)-3a,4,9°9a
-tetrahydro-2-methyl-4-phenyl-benz (
f) Isoindoline, melting point of hydrochloride 207-209°C: (3aR5,4SR19aSR)-6-chloro-2-cyclopropylmethyl-33,4,9,9a-tetrahydro-4-phenyl-benz[f]isoindoline : (3aR,S,4.SR,9aSR)-2-(Q-chlorophenyl)-3a,4.9,9a-tetrahydro-4
-Phenyl-benz [fl isoindoline, Malemono Shunsui X salt melting point 178-179°C.

(3aR5,4SJ 9aSR)-6-chloro-4-(
(3aR5,4SR,9aSR)-5-chloro-4-(
4-10ruphenyl)-2-cyclopropylmethyl-3
3,4,9,9a-tetrahydro-benz(f) isoindoline, melting point 124-126°C: (3aR514SR,9aSIR)-7-chloro-4-
(m-Chlorphenyl)-33,4,9,9a-tetrahydro-2-methyl-benz[f]isoindoline, bis(basic)naphthalene-1,5-disulfonate melting point 244-248°C: (3aR5, 4SR, 9aSR)
Melting point of -7-chloro-4-(m-chlorophenyl)-2-cyclopropylmethyl-31,4,9,91-tetrahydro-benz(f)isoindoline, bis(base)naphthalene-1,5-disulfonate 243~247°C
: (3aR514SR, 9aSR)-3a, 4,9°9
eA midpoint of a-tetrahydro-2,6-dimethyl-4-(p-tolyl)benz[f]isoindoline, bis(base)naphthalene-1,5-disulfonate 195-1
98°C: (3aR5,4SR,9aSR)-2-'y clopropylmethyl-31.4.9,9a-tetrahydro-6-methyl-4-(p-tolyl)benz[f]isoindoline, melting point 98~ 100℃: (3aR5, 4SR, gaS
R)-2-(2-hydroxyethyl)-3a, 4,9,
9a-tetrahydro-6-methyl-4-(p-tolyl)-2-benz(f) isoindoline, ML+a 12
8-129°C: (3aR514SR, 9aSR) -31,4,9°9a
-Tetrahydro-2,6-dimethyl-4-phenyl-benz(f)isoindoline, bis(base)naphthalene-
Melting point of 1,5-disulfonate 280-283°C: (3aR5,4SR19aSR)-2-cyclopropylmethyl-31,4,9,9a-tetrahydro-6-methyl-4-phenylrubens[f]isoindoline, hydrochloride Melting point of 198-204℃: (3aR5,4sa,9a
SR)-32,4,9゜9a-tetrahydro-2,7~
Dimethyl-4-phenyl-benz[f]isoindoline, bis(mi)naphthalene-1,5-disulfonate melting point 244-248°C: (3aR5,4SR,9aSR)-2-'i micropropylmethyl-3a, 9,9a-tetrahydro-7-methyl-4-7enylrubenz['fl isoindolinone, 1 point 79-82°C: (3aR8,4SR,9aSR)-2-ethyl-6-chloro-3a,4,9 ,9a-tetrahydro-4-phenyl-benz[f]isoindoline, (3a11S14S
R,9aSR)-2-n-butyl-6-chloro-3a,
4,9,9a-tetrahydro-4-phenyl-benz [
Lyisoindoline, (3aR8,4SR,9aSR)-
6-chloro-31,4,9,92-tetrahydro-2-
Methyl-4-phenyl-benz [fl isoindoline,
Melting point of salt 1 dredged salt 231-233°C9 (3aR5,4SR,9aSR)-3a, 4.9°9
a-tetrahydro-2-(p-methylbenzyl)-4-
Phenyl-benz[1]isoindoline, melting point 120~
121°C: (3aR5,4SR1gaSR) -3a, 4.9°9a-tetrahydro-2-(p-methoxybendi/l/
) -4-phenyl-benz[f]isoindoline,
Melting point 95-100°C: A specific example is now described to illustrate the above method of preparing the required starting materials: Example 8: (3aR8,4SR,gaSR)-6-ri-o-4-(
P-chlorophenyl)-31,4,9゜9a-tetrahydro-benz[f) indolicy 2-trifluoroacetamide 3(l N, N
The solution of -bis-(trans-I)-chlorcinnamyl)trifluoroacetamide is heated to reflux under an argon atmosphere for 16 hours and then concentrated by evaporation. 2 residues
Chromatograph with benzene on 50 g of silica gel. Concentrating the solution by evaporation yields the title compound as a distillate. Melting point: 107-112℃ (
after crystallization from ether/pentane).

N,N-bis-(trans-P-chlorcinnamyl)trifluoroacetamide used as starting material (6) was N-trans-P-chlorcinnamyl trifluoroacetamide in trans-p-chlorcinnamyl bromide. (method similar to Example 1).

Example 9゜(3ass, 4 S'R19a 5R)-6-fluoro-4-(P-fluorophenyl)-32,4゜9.9a
-Tetrahydro-benz[f]isoindoline-2-trifluoroacetamide The title compound with a melting point (after crystallization from ether) of 173-176°C is N,N-bis-(trans-P-fluorocinnamyl)trifluoro Prepared in a manner analogous to that described in Example 1 by thermal cyclization of acetamide.

As starting material the required N,N-bis-(trans-
(P-fluorocinnamyl) trifluoroacetamide may be produced from N-p-fluorocinnamyl-trifluoroacetamide and P-fluorocinnamyl bromide by the method described in Example 1 and the methods of Type 1 and above. .

Example 10: (3aR5,4SR,9aSR)-7-riD/lz-4
-(m-Chlorphenyl)-33,4,9°9a-tetrahydro-benz[f]isoindoline-2-trifluoroacetamide The title compound was prepared in a manner analogous to that described in Example 1 with N,N -bis-(trans-m-chlorcinnamyl)
It is obtained as an oil by thermal cyclization of trifluoroacetamide and purified by oxidation (benzene/ethyl acetate 19:1) on silica gel.

N, N-bis=(trans-m-
Chlorcinnamyl) trifluoroacetamide was prepared using I'J-m-
Chlorcinnamyl trifluoroacetamide and m-
It may be made from chlorcinnamyl promide.

Example 11゛(3aR8,4SR,9aSR)-3a, 4゜9.9a
-Tetrahydro-6-methyl-4-(p-)ruyl)benz(f)isoindoline-2-trifluoroacetamide The title compound having a melting point of 110-113°C (after crystallization from ether/pentane) was prepared in Example 1. It is obtained by thermal cyclization of N,N-bis-(trans-P-methylcinnamyl)trifluoroacetamide in a similar manner to that described in .

N,N-bis-(trans-P-) required as starting material
Methylcinnamyl trifluoroacetamide (oil) may be prepared from N-P-methylcinnamyl trifluoroacetamide and P-methylcinnamyl bromide in a manner similar to that described in Example 1.

Example 12: (9aR5)-1,c+a-dihydro-4-phenyl-
Benz['f)isoindoline-2-trifluoroacetamide 4.41 of 218F N-(
The solution of trans-cinnamyl)-N-(3-phenyl-2-propynyl)trifluoroacetamide is heated to reflux under an argon atmosphere for 5 hours and then concentrated by evaporation. After crystallization of the residue from ether/pentane, 195
The title compound is obtained with a melting point of ~197°C.

N-(1-lance-cinnamyl) required as starting material
-N-'(3-phenyl-2-propynyl)trifluoroacetamide is N-()lansucinnamyl)trifluoroacetamide, 1-bromo-3-phenyl-
It may also be produced by alkylation with 2-propyne.

Example 13 Tablet (3aR5, 4SR, 9aSR)-3a, 4.

9.9a-tetrahydro-2-methyl-4-phenyl-
Benz macro]isoindoline-hydrochloride 1"♂ 30m2 stearin 1(i) Magnenium 1"P polyvinyl pyrrolidone 4m1i + talc 5
”? Corn flour 10mV lactose
1187n! +'Dimethyl glycol oil 0.5 ''?Polyethylene glycol
6000], 5〃If707ng 6μ base 26.3'', corresponding to 9.

The active compound is synthesized according to well-known methods as pharmacologically inactive as above↑
Mixed with the η-adjuvant and carrier, the mixture is granulated and compressed in a manner known per se.

The active compound has the equivalent formula 1. Iw or Iz may be replaced by any other compound or acid addition salt thereof.

Patent applicant: Sandoz Akchengesellschaft, patent attorney Aoyama Aoyama, and 1 other person

Claims (1)

[Claims] ]) Formula Ja ■ [This compound also includes the optical antipodes of the compound of formula ■a and racemic mixtures of these optical antipodes according to the definition, where k and 2 are the same as - or different], each containing hydrogen, halogen, or 1 to 4 carbon atoms
Ring B and Ring C are connected by a cis bond, and k is alkenyl or alkynyl having 1 to 5 carbon atoms and 3 to 5 noanoalkyl atoms (the multiple bond is the nitrogen to which k is bonded). alkyl of 1 to 4 carbon atoms substituted with cycloalkyl of 3 to 6 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, 7 to 11 carbon atoms phenylalkyl of 7 to 11 carbon atoms monosubstituted with phenyl groups or halogens, alkoxy of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, or groups A-G
O-R3 (wherein A is alkylene of 1 to 4 carbon atoms and 3 is alkyl of 1 to 5 carbon atoms, phenyl, phenyl monosubstituted with halogen); and In the process for the preparation of salts thereof, a) compounds of the formula 1f 1 [the present compounds also include the optical antipodes of the compounds of the formula 1f according to the definition and racemic mixtures of these optical antipodes, in which R1, k2 and k are b) converting a compound of formula IV (as defined above) into a compound of formula IV; In the formula, k2 is as defined above, D is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, carbon atom, cyclo of 3 to 6 children. 1 to 3 carbon atoms substituted with alkyl (7) 7 /l/ + /l/
, hydroxyalkyl having 1 to 4 carbon atoms, phenyl,
Phenyl of 7 to 10 carbon atoms 7 ruki/lz, halogen, alkoxy of 1 to 4 carbon atoms or 1 to 4 carbon atoms
phenyl monosubstituted with alkyl of 7 to 10 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms monosubstituted with alkoxy of 1 to 4 carbon atoms or lower alkyl of 1 to 4 carbon atoms ) is reduced with a metal hydride to form a compound of formula 1m (which according to the definition also includes the optical antipodes of the compound of formula Im and racemic mixtures of these optical antipodes, where □, k2 and D are as defined above) or C) formula ■ (wherein R'/ is hydrogen and 5 is halogen or 1 carbon atom
~4 alkyl, or BH is a halogen or an alkyl having 1 to 4 carbon atoms, and B and 3 are hydrogen, and a method for producing compounds of formula (a) and salts thereof.