DE4223164A1 - New 9-carbamoyl-beta-carboline derivs. - used as benzodiazepine antagonists, inverse agonists and agonists for treating neuro:degenerative and psychiatric disorders - Google Patents

Abstract

9-carbamoyl-beta-carboline derivs. of formula (I) and their isomers and acid addn. salts are new. In (I), RA is H, halo, CHR1R2, opt. halo-, 1-4C alkoxy or amino-substd. Ph, hetaryl or OR5, and can be present once or twice; R1 is H or 1-4C alkyl; R2 is H, 1-4C alkyl, O-(1-4C) alkyl or opt. substd. Ph, benzyl or PhO; R5 is H, 1-6 alkyl, 3-7C cyclo alkyl or opt. substd. Ph, benzyl, hetaryl, or benzo-condensed hetaryl; R4 is H, 1-4C alkyl or 1-4C alkoxy (1-2C) alkyl; R3 = CO2(1-4C)alkyl, COR6, COOH or a gp. formula (a) or (b); X is N or CH; R6 is 1-4C alkyl, 3-7C cycloalkyl or opt. 1-4C-alkyl-, 1-4C alkoxy- or amino-substd. mono- or bicyclic 6-12C aryl; R7 is H, 1-4C alkyl or 1-4C alkoxy (1-2C) alkyl; R8 and R9 are each H, 1-6C alkyl, phenyl (1-2C) alkyl, or an opt. mono-, di- or tri-substd. mono- or bicyclic 6-12C aryl gp. USE/ADVANTAGE - (I) have good affinity for benzodiazepin receptors and have an antagonistic, inverse agonistic and agonistic effect on the properties of benzodiazepins. The reduction of the cramp thresholds for quisqualate shows that (I) have non competitive glutamate antagonistic properties and can be used in the prophylaxis and therapy of neurodegenerative and psychiatric diseases. Suitable daily doses are 0.1-1000 (esp. 1-30) mg/day.

Description

The invention relates to new 9-carbamoyl-β-carbolines, their preparation and use in drugs.

It is known from numerous publications that β-carbolines are due to the central nervous system due to its good affinity for benzodiazepine receptors influence and be used as a medicine. Are β-carbolines in Position 9 substituted with an alkyl, aryl or alkanoyl radical, so the binding to the benzodiazepine receptor is much worse than with β-carbolines unsubstituted in the 9-position (A. Huth et al. Arch. d. Pharmaz. 321, 1988, 297). It was therefore expected that at launch of the carbamoyl residue the binding affinity to benzodiazepine receptors decreases. Surprisingly, it was found that 9-carbamoyl-β-car bolin derivatives have good affinity for the benzodiazepine receptors and are therefore suitable for the production of very effective drugs and additionally those induced by a competitive quisqualate agonist Eliminates cramps in mice.

The compounds of the invention have the formula

wherein
R ^{A is} hydrogen, halogen, -CHR ¹ -R ² , optionally substituted with halogen, C _1-4 -alkoxy or amino-substituted phenyl, hetaryl or OR ⁵ and can be one to two times and
R ^{1 is} hydrogen or C _1-4 alkyl,
R ^{2 is} hydrogen, C _1-4 alkyl, -OC _1-4 alkyl or an optionally substituted phenyl, benzyl or phenoxy radical and
R ^{5 represents} hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl or an optionally substituted phenyl, benzyl, hetaryl or benzo-fused hetaryl radical,
R ^{4 is} hydrogen, C _1-4 alkyl or C _1-4 alkoxy-C _1-2 alkyl and
R ³ -CO ₂ -C _1-4 alkyl, -CO-R ⁶ , COOH,
means where

X = N or CH,
R ^{6 is} C _1-4 alkyl, C _3-7 cycloalkyl or a mono- or bicyclic C _6-12 aryl radical which is optionally substituted by C _1-4 alkyl, C _1-4 alkoxy or amino and
R ^{7 is} hydrogen, C _1-4 alkyl or C _1-4 alkoxy-C _1-2 alkyl and
R ⁸ and R ^{9 are the} same or different, each represents hydrogen, C _1-6 alkyl, phenyl-C _1-2 alkyl or an optionally mono- to tri-substituted mono- or bicyclic C _6-12 aryl radical and their Isomers and acid addition salts.

The substituent R ^A can be in the A ring in the 5-8 position, preferably in the 5-, 6- or 7-position.

Alkyl contains both straight and branched chain residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl and hexyl.  

Cycloalkyl can be used for cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl, cycloheptyl, and 2-methyl-cyclopropyl, with 3-5 carbons atoms are preferred.

If R ⁵ or R ^{A is} a hetaryl radical, this is 5- or 6-membered and contains 1-3 heteroatoms such as nitrogen, oxygen and / or sulfur. For example, the following 5- and 6-ring heteroaromatics may be mentioned: pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, thiazole, imidazole, triazine.

If R ^{5 is} a benzo-condensed hetaryl radical, it contains 1-2 nitrogen atoms such as quinoline, isoquinoline, quinoxaline or benzimidazole before.

The substituent of the phenyl, benzyl, hetaryl and benzo-fused hetaryl radical R ⁵ can be one to three times in any position. Suitable substituents are halogens, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy, amino, C _1-4 alkoxycarbonyl, C _1-4 alkylthio and trifluoromethyl, the phenyl and benzyl radical being the one to two times substitution with halogens is preferred.

Halogens are to be understood as fluorine, chlorine, bromine or iodine.

Preferred hetaryl radicals and benzo-fused hetaryl radicals R ⁵ are nitrogen-containing heterocycles which are substituted one to two times with halogen, C _1-4 -alkyl, C _1-4 -alkoxy or trifluoromethyl, in particular with halogen.

Suitable substituents for the phenyl, benzyl and phenoxy radical R ² are the aromatic substituents mentioned for R ⁵ , in particular halogen such as chlorine and bromine.

The aryl radical R ⁶ can be present as a mono- or bicyclic radical, such as phenyl, biphenylyl, naphthyl, indenyl and mono- to triple, preferably monosubstituted.

If R ⁸ or R ^{9 are} an aryl radical, the meanings mentioned for the aryl radical R ^{6 are} preferred, preferably phenyl, biphenyl and naphthyl, where halogens, C _1-4 alkyl, C _1-4 - Alk oxy, trifluoromethyl are preferred and in particular mono- or di-substitution is present.

As phenyl C _1-2 alkyl, for example, benzyl, phenethyl and α-methyl-benzyl are mentioned.

Preferred embodiments are hydrogen and OR ⁵ for R ^A and R ^{3 is} -CO ₂ -C _1-4 -alkyl, -CO-R ⁶ with R ^{6 is} C _1-4 -alkyl, C _{3- 7-} cycloalkyl or phenyl, and the 3-alkyl-1,2-4-oxadiazol-5-yl radical.

If there is a chiral center, the connections of the Formula I is in the form of the stereoisomers or mixtures thereof.

The physiologically acceptable acid addition salts are derived from the known inorganic and organic acids such as Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, ants acid, acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, Tartaric acid, citric acid, oxalic acid, glyoxylic acid and alkanesulfone acids and arylsulfonic acids such as methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid u. a.

The compounds of formula I and their acid addition salts are on Because of their affinity for benzodiazepine receptors as drugs ver reversible and practice on the properties known from the benzodiazepines antagonistic, inverse agonistic and agonistic properties. The lowering of the cramp threshold for quisqualate shows that the verb of formula I non-competitive glutamate antagonistic effect own and therefore for the manufacture of medicinal products for symptoma table and preventive treatment of neurodegenerative and psychiatric Diseases.  

The invention also encompasses pharmaceutical agents which include the aforementioned Contain compounds, their preparation and the use of the inventions compounds according to the invention for the manufacture of medicaments which are used for Treatment and prophylaxis of the above diseases used will. The pharmaceuticals are produced by methods known per se provides by the active ingredient with suitable carrier, auxiliary and / or Brings additives into the form of a pharmaceutical preparation that is suitable for enteral or parenteral administration. The applica tion can be taken orally or sublingually as a solid in the form of capsules or Tablets or as a liquid in the form of solutions, suspensions, Elixirs or emulsions or rectally in the form of suppositories or in Form of injection solutions, which may also be used subcutaneously respectively. As auxiliaries for the desired pharmaceutical formulation are the inert organic and inorganic known to those skilled in the art Suitable carrier materials such as water, gelatin, rubber arabicum, milk sugar, starch, magnesium stearate, talc, vegetable oils, Polyalkylene glycols, etc. If necessary, conservie agents, stabilizers, wetting agents, emulsifiers or salts for change tion of the osmotic pressure or buffer may be included.

The pharmaceutical preparations can be in solid form, for example as Tablets, dragees, suppositories, capsules or in liquid form for Example as solutions, suspensions or emulsions. Given they also contain auxiliary substances such as preservatives, Stabilizing, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffer.  

In particular, injection solutions or are for parenteral use Suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, suitable.

Surface-active auxiliaries such as salts can also be used as carrier systems of bile acids or animal or vegetable phospholipids, but also Mixtures thereof as well as liposomes or their components are used.

Tablets, coated tablets or capsules are particularly suitable for oral use with talc and / or hydrocarbon carrier or binder, such as Example lactose, corn or potato starch, suitable. The application can also be in liquid form, such as juice, the optionally a sweetener is added.

The compounds of the invention are in a dose unit of 0.05 up to 500 mg of active substance in a physiologically compatible carrier brought in.

The compounds of the invention are used in a dose of 0.1 to 1000 mg / day, preferably 1-30 mg / day.

The compounds according to the invention are prepared per se known methods. For example, the connections of Formula I in that

• a) a compound of formula I. wherein
  R ^A , R³ and R⁴ have the above meaning, with an isocyanate of the formula IIIO = C = NX (III) in which X is R⁸ or -CO-Cl, or with carbamic acid halides of the formula IVHal-CO-NR⁸R⁹ (IV) in which R⁸ and R⁹ is the same meaning and Hal is halogen, in the presence of bases or
• b) a compound of formula V wherein R ^A , R ⁴ and R ^{3 have} the above meaning and is RC _1-6 alkyl or phenyl, substituted with amines R ⁸ R ⁹ -NH and, if desired, subsequently saponifying the β-carboline-3-carboxylic acid ester or separating the isomers or forms the acid addition salts.

The reaction of the compounds of formula II with isocyanates takes place in aprotic solvents such as hydrocarbons, halogenated Hydrocarbons and for example in toluene, xylene, benzene, Methylene chloride u. a.

In general, at elevated temperature, up to the boiling point of Reaction mixture worked. However, implementation is also possible to be carried out at room temperature, as is particularly the case during introduction the 9-carbamoyl group happens with chlorocarbonyl cyanate.

Are the compounds of formula I by reaction with carbamic acid halides, especially chlorides or bromides, is produced the reaction in the presence of bases such as potassium carbonate, sodium hydroxide u. a. preferably metal hydrides such as sodium hydride, generally at Room temperature.

The compounds of formula V are substituted with amines elevated temperature to the boiling point of the reaction mixture in polar solvents such as acyclic and cyclic ethers such as ethylene glycol monomethyl ether.

The isomer mixtures can be prepared using the customary methods, such as, for example Crystallization, chromatography or salt formation in the diastereomers or enantiomers are separated.

The saponification of the ester group can take place after acidic or alkaline the usual methods.

To form the physiologically acceptable acid addition salts, a Compound of formula I, for example, dissolved in a little alcohol and with a concentrated solution of the desired acid.  

If the preparation of the starting compounds is not described, are these known or analogous to known compounds or be here described methods can be produced.

The compounds of the formula V are prepared by converting 9H-β-carbolines with chloroformate ester derivatives in the presence of Sodium hydride at room temperature in polar solvents such as dimethyl formamide.

The preparation of the compounds of formula II is, for example, in EP-A-2 99 667, EP-A-2 34 137, EP-A-2 22 693 and EP-A-2 37 467.

The following examples are intended to explain the process according to the invention tern.

example 1 6-benzyloxy-4-methoxymethyl-9- (1-naphthylcarbamoyl) -β-carboline-3-carbon acid isopropyl ester

0.404 g of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester are mixed in 30 ml of toluene with 0.72 ml of α-naphthyl isocyanate and Heated at reflux for 16 hours. After the concentration is obtained Solid product over silica gel with methylene chloride: isopropanol = 10: 1 chromatographed. After recrystallization, 0.170 g is obtained 6-benzyloxy-4-methoxymethyl-9- (1-naphthylcarbamoyl) -β-carboline-3- carboxylic acid isopropyl ester with a melting point of 103-105 ° C.

The following are produced analogously:
6-Benzyloxy-4-methoxymethyl-9-phenylcarbamoyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 160-162 ° C
6-Benzyloxy-4-ethyl-9-phenylcarbamoyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 138-140 ° C
6-Benzyloxy-4-methyl-9-phenylcarbamoyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 139-141 ° C
Isopropyl 5- (4-chlorophenoxy) -4-methoxymethyl-9- (2-naphthylcarbamoyl) -β-carboline-3-carboxylic acid, melting point 141-142 ° C
6,7-Dimethoxy-4-ethyl-9-phenylcarbamoyl-β-carboline-3-carboxylic acid methyl ester, melting point 141-143 ° C
Isopropyl 6-benzyloxy-9- (4-chlorophenylcarbamoyl) -4-methoxymethyl-β-carboline-3-carboxylate, melting point 132-135 ° C
6,7-Dimethoxy-4-ethyl-9-tert-butylcarbamoyl-β-carboline-3-carboxylic acid methyl ester, melting point 155-158 ° C
Isopropyl 6-benzyloxy-4-ethyl-9-tert-butylcarbamoyl-β-carboline-3-carboxylate, melting point 133-135 ° C
6-Benzyloxy-4-methoxymethyl-9-methylcarbamoyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 110-112 ° C
6-Benzyloxy-4-ethyl-9-methylcarbamoyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 174-175 ° C
Isopropyl 6-benzyloxy-4-methoxymethyl-9-tert-butylcarbamoyl-β-carboline-3-carbonate, melting point 133-135 ° C
6,7-Dimethoxy-4-ethyl-9-methylcarbamoyl-β-carboline-3-carboxylic acid methyl ester, melting point 185-188 ° C
6-Benzyloxy-3- (3-ethyl-1,2,4-oxadiazol-5-yl) -4-methoxymethyl-9-pheny-1 carbamoyl-β-carboline, melting point 156-158 ° C
5- (4-Chlorophenoxy) -3- (3-ethyl-1,2,4-oxadiazol-5-yl) -4-methoxymethyl-9-phenylcarbamoyl-β-carboline, melting point 244-246 ° C
6-Benzyloxy-4-methoxymethyl-9- (4-phenyl-phenylcarbamoyl) -β-carboline-3-carboxylic acid isopropyl ester, melting point 156-158 ° C
3-acetyl-6-benzyloxy-4-methoxymethyl-9-phenylcarbamoyl-β-carboline, melting point 160-161 ° C
9-phenylcarbamoyl-β-carboline-3-carboxylic acid ethyl ester, melting point 174-176 ° C.
4-methoxymethyl-9-phenylcarbamoyl-β-carboline-3-carboxylic acid ethyl ester, melting point 125-128 ° C
6-Benzyloxy-4-methoxymethyl-9- (4-trifluoromethyl-phenyl-carbamoyl) -β-carboline-3-carboxylic acid isopropyl ester, melting point 166-168 ° C
5- (4-Chlorophenoxy) -3- (5-methoxymethyl-3-isoxazolyl) -4-methoxymethyl - 9-phenylcarbamoyl-β-carboline, melting point 169-171 ° C
6-Benzyloxy-4-methoxymethyl-9- (4-methoxyphenylcarbamoyl) -β-carboline-3-carboxylic acid isopropyl ester, melting point 115-118 ° C
6-Benzyloxy-9- (3,4-dichlorophenylcarbamoyl) -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 155-157 ° C.

Example 2 6-Benzyloxy-9-carbamoyl-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester

0.404 g of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl are ester in 20 ml of methylene chloride with 0.8 ml of chlorocarbonyl isocyanate stirred overnight at room temperature. After concentration, the resul The resulting residue is stirred with water and filtered off. The solid product is chromato over silica gel with methylene chloride: ethanol = 10: 1 graphed. 0.230 g of 6-benzyloxy-9-carbamoyl-4-methoxymethyl β-carboline-3-carboxylic acid isopropyl ester, melting point 152-155 ° C.

Example 3 6-benzyloxy-9-diphenylcarbamoyl-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester

1.2 g of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester in 40 ml abs. Dissolved dimethylformamide, mixed with 0.108 g of sodium hydride (80%) and stirred for 1 hour at room temperature. 0.834 g of diphenylcarbamic acid chloride are added to the reaction mixture and the mixture is stirred for 16 hours at room temperature under an N ₂ atmosphere. After concentration, the residue is chromatographed on silica gel using cyclohexane: ethyl acetate = 1: 1. 1.33 g of 6-benzyloxy-9-diphenylcarbamoyl-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester of melting point 146-149 ° C.

The following are produced analogously:
6-Benzyloxy-9- (N-methyl-phenylcarbamoyl) -4-methoxymethyl-3-carboxylic acid isopropyl ester, melting point 87-90 ° C.
6-Benzyloxy-9-dimethylcarbamoyl-4-methoxymethyl-3-carboxylic acid isoprop-yl ester, oil.

Example 4 9-benzylcarbamoyl-6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester

A) 0.404 g of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isoprop ylesters are dissolved in 50 ml of dimethylformamide, with 0.036 g of sodium hydride (80%) and stirred at room temperature until no water substance development can be observed more. Then 0.25 ml Phenyl chloroformate was added to the reaction mixture and 1 hour stirred at room temperature. After concentration in a vacuum, the Residue taken up in ethyl acetate, with water and sat. Sodium chloride solution extracted the organ. Phase dried and concentrated in vacuo. The resulting residue is over silica gel with hexane: acetone 7: 3 chromatographed. 0.265 g of 6-benzyloxy-4-methoxymethyl 9-phenoxy-carbonyl-β-carboline-3-carboxylic acid isopropyl from the enamel point 139-140 ° C.

B) 0.150 g of 6-benzyloxy-4-methoxymethyl-9-phenoxycarbonyl-β-carboline-3- carboxylic acid isopropyl ester with 0.15 ml of benzylamine in 30 ml of ethyl boiled englykolmonomethylether 4 hours at reflux. After constriction the residue over silica gel with cyclohexane: ethyl acetate = 1: 1 chromatographed. 0.038 9-Benzylcarbamoyl-6-benzyloxy-4- is obtained. methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester melting at 131-132 ° C.

Claims (4)

1. Compound of formula I. wherein
R ^A denotes hydrogen, halogen, -CHR ¹ -R ² , optionally substituted with halogen, C ^1-4 alkoxy or amino, phenyl, hetaryl or OR ⁵ and can be one to two times and
R ^{1 is} hydrogen or C _1-4 alkyl,
R ^{2 is} hydrogen, C _1-4 alkyl, -OC _1-4 alkyl or an optionally substituted phenyl, benzyl or phenoxy radical and
R ^{5 represents} hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl or an optionally substituted phenyl, benzyl, hetaryl or benzo-condensed hetaryl radical,
R ^{4 is} hydrogen, C _1-4 alkyl or C _1-4 alkoxy-C _1-2 alkyl and
R ³ -CO ₂ -C _1-4 alkyl, -CO-R ⁶ , COOH means where
X = N or CH,
R ^{6 is} C _1-4 alkyl, C _3-7 cycloalkyl or a mono- or bicyclic C _6-12 aryl radical which is optionally substituted by C _1-4 alkyl, C _1-4 alkoxy or amino and
R ^{7 is} hydrogen, C _1-4 alkyl or C _1-4 alkoxy-C _1-2 alkyl and
R ⁸ and R ^{9 are the} same or different, each represents hydrogen, C ^1-6 -alkyl, phenyl-C ^1-2 -alkyl or an optionally mono- to trisubstituted mono- or bicyclic C _6-12 aryl radical and their Isomers and acid addition salts. 2. 6-Benzyloxy-4-methoxymethyl-9- (1-naphthylcarbamoyl) -β-carbolin-3-car isopropyl acid
Isopropyl 6-benzyloxy-4-methoxymethyl-9-phenylcarbamoyl-β-carboline-3-carbonate
6,7-Dimethoxy-4-ethyl-9-tert-butylcarbamoyl-β-carboline-3-carbonate, methyl ester
5- (4-Chlorophenoxy) -3- (3-ethyl-1,2,4-oxadiazol-5-yl) -4-methoxymethyl-9-phenylcarbamoyl-β-carboline according to claim 1. 3. Use of the compounds according to claim 1 and 2 in medicaments. 4. A process for the preparation of the compounds of formula I, characterized in that

• a) a compound of formula II wherein R ^A , R³ and R⁴ have the above meaning, with an isocyanate of the formula IIIO = C = NX (III) where X is R⁸ or -CO-Cl, or with carbamic acid halides of the formula IVHal-CO-NR⁸R⁹ (IV) in which R⁸ and R⁹ have the above meaning and Hal is halogen, in the presence of bases or
• b) a compound of formula V wherein R ^A , R ⁴ and R ^{3 have} the above meaning and is RC ^1-6 alkyl or phenyl, substituted with amines R ⁸ R ⁹ -NH and, if desired, then saponified to the β-carboline-3-carboxylic acid ester or separates the isomers or forms the acid addition salts.