DE19624282A1 - Use of 5-(omega-amino-alkylamino)-isoxazole derivatives as 5-HT receptor antagonists - Google Patents

Abstract

Use of 5-(w-aminoalkylamino)-isoxazole derivatives of formula (I), as well as their salts or esters, to treat diseases which respond to 5-HT receptor ligands: R1,R2 = H, alkyl, cycloalkyl, aryl or heteroaryl (optionally 1-3 fold substituted by alkyl, alkoxy, alkylthio, alkylsulphonyl, aryl, aryloxy, arylthio, arylsulphonyl, aralkyl, halo, CN, nitro, haloalkyl, alkoxycarbonyl, acyl, OH, COOH or NR7R8); R7,R8 = alkyl, aryl, arylsulphonyl, aralkyl, acyl or alkylsulphonyl; R3-R5 = H, alkyl, aryl, arylsulphonyl, heteroaryl, acyl or alkylsulphonyl (optionally 1-3 fold substituted as above); R6 = alkylene residue.

Description

The present invention relates to the use of 5- (ω-amino alkylamino) isoxazoles for the treatment of diseases which respond to ligands for 5-HT receptors.

5- (ω-Aminoalkylamino) isoxazoles are especially for their pronounced hypertensive activity known. For example describe Dannhardt et al in Arch. Pharm. 324, 141-148 (1991), that the blood pressure increasing effect of such compounds in Depends on the rigidity of the side chain in 5 position of the isoxazole varies. Process for making this Connections are for example in the above Publication or by Dannhardt et al in Synthesis 1989, 12 described.

5-hydroxytryptamine, also called serotonin or 5-HT for short, plays on a variety of physiological and pharmacological effects usually play a role binding of serotonin to a serotonin receptor is conveyed. Accordingly, one has been around for a long time suitable serotonin antagonists endeavor to prevent the serotonin-dependent Can influence processes. Known substances can be found for example, among the Ergot alkaloids, for example Methysergide, or a series of indole compounds that are considered Bind antagonist to 5-HT receptors, for example those on smooth muscles. However, there are no active substances that selectively respond to serotonin receptors. The above Show methysergide or for example cyproheptadine, though classified as 5-HT antagonist, other significant pharmacological effects on. This limits their use as a pharmaceutical for the treatment of certain diseases, because when used with significant side effects too to calculate.

Surprisingly, it has now been found that certain 5- (ω-amino alkylamino) isoxazoles in a suitable manner on 5-HT recipe bind gates and therefore for the treatment of diseases can be used in which serotonin receptors a Role-play.

The object of the present invention is therefore the use at least one 5- (ω-aminoalkylamino) isoxazole of the formula I.

wherein
R₁ and R₂, which may be the same or different, represent hydrogen or alkyl, cycloalkyl, aryl or heteroaryl, which may have one, two or three substituents which are independently selected from alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy , Arylthio, arylsulfonyl, aralkyl, halogen, CN, NO₂, alkylhalogen, alkoxycarbonyl, acyl, OH, COOH or a group of the formula -NR₇R₈, wherein R₇ and R₈, which may be the same or different, for alkyl, aryl, aralkyl, acyl , Alkylsulfonyl or arylsulfonyl,
R₃, R₄ and R₅, which may be the same or different, represent hydrogen or alkyl, aryl, heteroaryl, acyl, alkylsulfonyl or arylsulfonyl, which may have one, two or three substituents as defined above, and
R⁶ represents a linear or branched alkylene radical,
as well as pharmacologically acceptable salts or esters thereof
for the treatment of diseases that respond to ligands for 5-HT receptors.

The pharmaceutically acceptable salts can in the present Case be acid addition or base addition salts. For Acid addition salts use inorganic acids, for example like hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids, such as tartaric acid, Lactic acid, citric acid, malic acid, mandelic acid, Ascorbic acid, maleic acid, fumaric acid or gluconic acid.

Base addition salts include salts of the compounds of Formula I with inorganic bases, for example sodium or Potassium hydroxide or with organic bases, for example Mono-, di- or triethanolamine.

The esters of the compounds of the formula I include in particular physiologically easily hydrolyzable esters, for example Alkyl, pivaloyloximethyl, acetoxymethyl, phthalidyl, Indanyl and methoxymethyl esters.

The term "alkyl, alkoxy, alkylthio or alkylsulfonyl" includes straight-chain or branched alkyl groups, such as methyl, Ethyl, n- and i-propyl, n-, i- or t-butyl, n-pentyl, Neopentyl or n-hexyl.

Alkylene stands for linear or branched alkylene groups preferably 1 to 6 and in particular 1 to 4 carbon atoms.

"Cycloalkyl" includes cyclic alkyl groups such as cyclopropyl, Cyclopentyl or cyclohexyl.

Unless otherwise stated, "alkyl" is used in the above radicals mentioned preferably for C₁-C₈-alkyl, in particular for C₁-C₆-alkyl and particularly preferably for C₁-C₄-alkyl.

The term "halogen" includes a fluorine, chlorine, bromine or Iodine atom and especially a fluorine or chlorine atom.  

The term "haloalkyl" includes alkyl radicals, preferably Methyl radicals that are replaced by one or more halogen atoms may be the same or different, are substituted and preferably represents trifluoromethyl.

The term "aryl, aryloxy, arylthio or arylsulfonyl" includes aromatic radicals, preferably naphthyl and in particular Phenyl.

"Acyl" stands for RCO, where R preferably the above for "alkyl" and "aryl" has the meanings given. Is acetyl particularly preferred.

"Alkoxycarbonyl" stands for ROCO, where R is preferably the above has meanings given for "alkyl". Methoxycarbonyl is particularly preferred.

The term "aralkyl" preferably stands for benzyl.

The term "heteroaryl" includes aromatic radicals that at least one heteroatom selected from O, N or S. contain. It is preferably a 5- or 6- membered heterocyclic ring, one, two or three Contains heteroatoms. Preferred examples are thiophene, Pyrrole, imidazole, thiazole, thiadiazole, furan, oxazole, isoxazole, Pyridine, pyrimidine, benzofuran or quinoline.

In a preferred embodiment, compounds are used of formula I, wherein R¹ and R² are the same or different can, for hydrogen or optionally substituted Alkyl, aryl or heteroaryl. R 1 and R 2 are preferably for hydrogen or optionally substituted aryl, in particular Phenyl.

Preferred substituents of alkyl, aryl or Heteroaryl radicals are selected from halogen, in particular Fluorine and chlorine, haloalkyl, especially trifluoromethyl, CN,  NO₂, and for the aryl and / or heteroaryl radicals also alkyl or Alkoxy. Phenyl substituents are preferably in o- and / or p position.

In a further preferred embodiment, one uses Compounds of formula I, wherein aryl and also Heteroaryl substituents under halogen, alkoxy or alkyl, in particular chlorine, methoxy or t-butyl are selected.

In particularly preferred compounds according to the invention R² for hydrogen.

The radicals R³, R⁴ and R⁵, which may be the same or different can preferably represent hydrogen or alkyl, Aryl or heteroaryl, optionally the above-mentioned substituents can wear. Used in a special embodiment compounds of formula I wherein R³ is hydrogen or Aryl stands, which in particular by the above preferably used substituents can be substituted. Particularly interesting are compounds in which R³ for Is hydrogen or phenyl.

The radicals R⁴ and R⁵, which can be the same or different, preferably represent hydrogen or alkyl, which in particular by the preferred substituents mentioned above can be substituted. The alkyl radical is preferably not substituted.

In a further special embodiment, one uses Compounds of formula I, wherein R⁴ and R⁵ are hydrogen stand.

Compounds of formula I, wherein R⁶ is ethylene particularly preferred.

5- (2-Aminoethylanilino) is very particularly preferably used. 3- (4-chlorophenyl) isoxazole used to treat diseases that  respond to ligands for 5-HT receptors.

The compounds of the invention can be synthesized in a known manner. According to Dannhardt and Laufer, Synthesis 1989, 12, substituted 4,5-dihydro-imidazoles are converted to substituted acyl ketene-N, N-acetals, also called enaminones. Subsequent ring transformation of the enaminones leads to the isoxazoles according to the invention (method A, FIG. 1).

An alternative method, in particular for compounds according to the invention in which R 1 and / or R 2 represent optionally substituted alkyl, is described in Laufer, dissertation, University of Regensburg (1989). The substituted 5-chloroisoxazole is reacted with the lithium salt of the N, N, N-tri substituted ethylenediamide and the main product is the isoxazole according to the invention (method B, FIG. 2).

The compounds of the invention have proven to be potent Ligands of serotonin receptors have been proven and are therefore used Treatment of diseases in which serotonin Receptors and in particular the binding of ligands to them Receptors are important.

Preferred are compounds according to the invention which are selective Bind serotonin receptors. Under selectivity is in this Connects the preferred binding to 5-HT receptors understand while affinities for other receptors are relative are low. As a result, they practice the present invention Compounds have a targeted pharmacological effect.

Compounds according to the invention which are particularly suitable are: act as 5-HT antagonists. Such connections are in the Able to 5-HT agonists from the receptor binding site displace and consequently the action of the agonist belittling. The action of the agonist is preferably variable inhibit even with low concentrations of the antagonist. Furthermore, the compounds of the invention can also be used  other antagonists compete for receptor binding and such influence their effect.

In a special embodiment, one uses compounds according to the invention which are linked to 5-HT₃ receptors, preferably bind as an antagonist. With such Connections can have very targeted effects.

Due to the above properties, the Compounds for prevention and treatment according to the invention a variety of diseases. In particular diseases that on changes in smooth muscle muscle tone are to be mentioned here. This effect affects both cardiovascular as well as respiratory or gastrointestinal Systems. The compounds according to the invention preferably practice stimulating or relaxing effect on the smooth Muscles of respiratory or gastrointestinal systems out. Relaxing effects are of particular interest. For example, with the invention Compounds treat diseases with symptoms such as Headache, especially migraines, depressive conditions or Vomiting. Of particular interest is the Treatment or prevention of cytostatic-induced vomiting in cancer treatment.

The present invention also relates to the use of the bonds according to the invention for the production of pharmaceutical agents for the treatment of those described above Diseases.

The compounds of the invention can either individually or in combination as therapeutic agents or as Mixtures with other therapeutic agents administered will. They can be administered as such in the in general, however, they are in the form of pharmaceuticals Formulations administered, that is, as mixtures of Active substances with suitable pharmaceutical carriers or Thinners. The compounds or agents can be oral  or parenterally (intramuscularly, subcutaneously, intravenously etc.) administered, but preferably they are in oral Dosage forms given.

The type of pharmaceutical and pharmaceutical Carrier or diluent depends on the desired one Type of administration. Oral agents can be used, for example, as Tablets or capsules are present and can be conventional excipients contain, such as binders (e.g. syrup, acacia, gelatin, Sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g. Lactose, sugar, corn starch, calcium phosphate, sorbitol or Glycine), lubricants (e.g. magnesium stearate, talc, Polyethylene glycol or silicon dioxide), disintegrating agents (e.g. starch) or wetting agents (e.g. sodium lauryl sulfate). Oral liquid preparations can be in the form of aqueous or oily Suspensions, solutions, emulsions, syrups, elixirs or Sprays, etc. are available or can be used as dry powder Reconstitution with water or other suitable vehicle available. Such liquid preparations can be conventional Additives, for example suspending agents, flavorings, Contain diluents or emulsifiers. For the parenteral administration can be solutions or suspensions use with common pharmaceutical carriers.

The compounds or agents according to the invention can be one Mammals (humans and animals) in doses of about 0.5 mg to about 1000 mg per kg body weight per day.

The following examples describe the invention without restricting it. It describes a general procedure of method A shown schematically in Fig. 1, according to which the substances defined in FIG. 2 and FIG. 3 have been prepared.

example 1 General procedure for the synthesis of acyl ketene-N, N-ace tale 2 (enaminones)

The 2-alkyl-1-phenyl-4,5-dihydroimidazole 1 (1 mmol) is added N₂ dissolved in dry THF (50 ml). At -78 ° C you let slowly a solution of n-BuLi (20% in hexane, 21 mmol) while stirring well dropwise and then stirred for a further 1 h at -78 ° C (yellow-orange color). Then you leave a solution of Carboxylic acid methyl ester (20 mmol) in dry THF (40 ml) slowly add dropwise at -78 ° C and stir for a further 2 h at -78 ° C. The solution is then hydrolyzed with water (2 ml) and brought to RT brought. The precipitated LiOH is filtered off and that Filtrate rotated in a water jet vacuum. Takes the backlog in 200 ml of CH₂Cl₂, dried over Na₂SO₄ and concentrated to a residual volume of 20-30 ml. Isolation and cleaning is carried out by column chromatography on silica gel (63-200 µm) a suitable eluent.

2- (1-phenylimidazolidin-2-ylidene) acetone 2a:

SC (SiO2 / THF, R = 0.4); Recrystallization from ethyl acetate / ether gives white crystals. Yield 60%, mp. 148 ° C
C₁₂H₁₄N₂O (202.3):
Ber. C 71.3; H 6.98; N 13.85.
Found C 71.0; H 6.93; N 13.61.
IR: 3290 (NH), 1615 (CO) cm ^-1
H-NMR (300 MHz): δ (ppm) = 1.69 (s, 3H, CH₃); 3.73-3.79 (m, 2H, CH₂-NH); 3.86-3.92 (m, 2H, CH₂-N-Ph); 4.83 (s, 1H, CH); 7.21-7.44 (m, 5H, aroma)
MS (90 eV): m / z = 202 (52, M⁺), 185 (4), 187 (100), 160 (8), 159 (12), 146 (22), 144 (13), 106 ( 22), 91 (18), 77 (42)

2- (1-phenylimidazolidin-2-ylidene) acetophenone 2c:

SC (SiO2 / ethyl acetate, R = 0.35; recrystallization from ethyl acetate gives white crystals. Yield 55%, mp. 161 ° C.
C₁₇H₁₆N₂O (264.3):
Ber. C 77.3; H 6.10; N, 10.60.
Found C 77.0; H 6.18; N 10.41.
IR: 3270 (NH), 1605 (CO) cm ^-1
H-NMR: δ (ppm) = 3.78-4.00 (m, 4H, CH₂); 5.50 (s, 1H, CH); 7.22-7.50 (m, 8H, aroma); 7.61-7.87 (m, 2H, aroma); 10.12 (s, 1H, interchangeable, NH)

p-Chloro-2- (1-phenylimidazolin-2-ylidene) acetophenone 2e:

SC (SiO2 / ethyl acetate, R = 0.4); Recrystallization from ethanol / water gives yellow needles. Yield 60%, mp. 155 ° C.
C₁₇H₁₅N₂O (298.8):
Ber. C 68.3; H 5.06; N 9.37.
Found C 68.0; H 5.15; N 9.31.
IR: 3280 (NH), 1610 (CO) cm ^-1
H-NMR: δ (ppm) = 3.80-4.00 (m, 4H, CH₂); 5.44 (s, 1H, CH); 7.20-7.60 (m, 5H and BB ′); 7.70 (AA ′, 2H, J = 8Hz); 10.20 (s, 1H, interchangeable, NH).

General procedure for the synthesis of 5- (2-amino ethylanilino) isoxazole 3 by ring transformation

The solution of the acyl ketene-N, N-acetal 2 (5 mmol) in 60 ml NH₃OH⁺Cl⁻ (50 mmol) is added to ethanol, 25 ml are added aqueous acetate buffer (0.2 molar) and after all NH₃OH⁺Cl⁻ has dissolved, with acetic acid to pH = 3.5-4.0 a. The solution is under N₂ until the educt disappears (DC control) refluxed (5-15 h). After cooling, give 30 ml of water and 100 ml of CH₂Cl₂, shake well, separate the organic phase and shake it four more times with each 30 ml of water. The organic phase contains Fission products. The aqueous phase contains in addition to the searched product further basic cleavage products. The combined aqueous phases are adjusted to pH = 10-11 with NaOH adjusted and extracted four times with 50 ml of CH₂Cl₂. After  drying over Na₂SO₄ one rotates in and cleans the oily Residue by SC on silica gel with MeOH / conc. aq. NH₃ (99: 1) as eluent (R = 0.4-0.5).

The 5- (2-aminoethylanilino) isoxazoles are colorless to weak yellowish, highly viscous oils, which in little abs. Ethanol dissolved and with ethereal HCl in the hydrochloride (hygroscopic, white powdery solids) can be transferred. The Hydrochlorides change color after standing for a while in the light Room temperature brownish red.

5- (2-Aminoethylanilino) -3-methylisoxazole (3a):

Yield 60%, colorless, highly viscous oil
Mp from 150 ° C dec. (Hydrochloride)
C₁₂H₁₅N₃O (217.3):
Ber. C 66.3; H 6.96; N 19.34.
Found: C 66.7; H 7.11; N 19.03.
IR (film): 3380, 3300 (NH₂), 1615 (C = N) cm ^-1
H-NMR (300 MHz): δ (ppm) = 1.25 (s, 2H, exchangeable, NH₂); 2.15 (s, 3H, CH₃); 2.96 (t, 2H, J = 6.5 Hz, Ch₂-NH₂); 3.84 (t, 2H, J = 6.5 Hz, CH₂-N-Ph); 4.9 (s, 1H, CH); 7.19-7.41 (m. 5H, aroma.)
MS (90 eV): m / z = 217 (33, M⁺), 188 (30), 187 (38), 106 (43), 105 (100), 104 (27), 84 (44), 82 ( 74), 77 (26), 56 (20), 54 (24)

5- (2-Aminoethylanilino) -3-phenylisoxazole (3c):

Yield 70%, mp. From 150 ° C dec. (Hydrochloride)
C₁₇H₁₇N₃O (279.3):
Ber. C 73.1; H 6.13; N 15.04.
Found C 72.7; H 5.98; N 14.71.
IR (film): 3370, 3300 (NH₂), 1615 (C = N) cm ^-1
H-NMR: δ (ppm) = 1.33 (s, 2H, exchangeable, NH₂); 2.99 (t, 2H, J = 6 Hz, Ch₂-N-Ph); 5.36 (s, 1H, CH); 7.17-7.49 (m, 8H, aroma); 7.6-7.8 (m, 2H, aroma).

Claims (17)

1. Use of at least one 5- (ω-aminoalkylamino) isoxazole of the formula I. wherein
R₁ and R₂, which may be the same or different, represent hydrogen or alkyl, cycloalkyl, aryl or heteroaryl, which may have one, two or three substituents which are independently selected from alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy , Arylthio, arylsulfonyl, aralkyl, halogen, CN, NO₂, alkylhalogen, alkoxycarbonyl, acyl, OH, COOH or a group of the formula -NR₇R₈, wherein R₇ and R₈, which may be the same or different, for alkyl, aryl, aralkyl, acyl , Alkylsulfonyl or arylsulfonyl,
R₃, R₄ and R₅, which may be the same or different, represent hydrogen or alkyl, aryl, heteroaryl, acyl, alkylsulfonyl or arylsulfonyl, which may have one, two or three substituents as defined above, and
R⁶ represents a linear or branched alkylene radical,
as well as pharmacologically acceptable salts or esters thereof
for the treatment of diseases that respond to ligands for 5-HT receptors. 2. Use of a compound according to claim 1 of the formula I, wherein R₁ and R₂, which may be the same or different, for hydrogen or optionally substituted alkyl, preferably methyl, aryl or heteroaryl. 3. Use of a connection according to one of claims 1 or 2 of formula I, wherein R₁ and R₂ are the same or can be different, for hydrogen or optionally substituted aryl, preferably phenyl. 4. Use of a connection according to one of claims 2 or 3 of formula I, wherein the substituent (s) is selected from halogen, in particular fluorine and chlorine, haloalkyl, CN, NO₂, and, if R₁ and / or R₂ stand for aryl and / or heteroaryl, also alkyl or Alkoxy. 5. Use of a compound according to any one of claims 1 to 4 of formula I, wherein the substituent (s) if R₁ and / or R₂ is phenyl, in the o- and / or p-position stands (stand). 6. Use of a compound according to claim 5 of the formula I, wherein the substituent (s) is selected from Halogen, alkoxy or alkyl, especially chlorine, methoxy or t-butyl. 7. Use of a connection according to one of the preceding Claims of formula I, wherein R₁ is optionally substituted phenyl and R₂ are hydrogen. 8. Use of a connection according to one of the preceding Claims of formula I, wherein R₃, R₄ and R₅ are the same or can be different, for hydrogen or optionally substituted alkyl, aryl or heteroaryl stand.   9. Use of a compound according to claim 8 of the formula I, wherein R₃ is hydrogen or aryl, preferably phenyl, stands, optionally by those mentioned in claim 4 Substituents can be substituted. 10. Use of a connection according to one of the preceding Claims of formula I wherein R₄ and R₅ are the same or can be different, for hydrogen or alkyl stand, if necessary by those mentioned in claim 4 Substituents can be substituted. 11. Use of a connection according to one of the preceding Claims of formula I, wherein R₄ and R₅ are hydrogen stand. 12. Use according to claim 1 of the compound 5- (2-amino ethylanilino) -3- (4-chlorophenyl) isoxazole. 13. Use according to one of the preceding claims Treatment of diseases based on 5-HT antagonists speak to. 14. Use according to claim 13 for the treatment of Diseases based on ligands for 5-HT₃ receptors speak to. 15. Use according to one of the preceding claims Treatment of diseases due to changes in the Muscle tone the smooth muscle in cardiovascular, respiratory or gastrointestinal systems speak to. 16. Use according to claim 15 for the treatment of migraines, depressive states and vomiting. 17. Use according to claim 16 for the treatment of vomiting, especially of cytostatic-induced vomiting.