DE3801479A1 - Pilocarpine derivatives - Google Patents

Abstract

Pilocarpine derivatives of the formula I <IMAGE> in which R1 to R5 are as defined in the description, their preparation and use as therapeutics.

Description

The present invention relates to new pilocarpine derivatives, their manufacture and use in therapeutic Treatment.

Pilocarpine is the generic name of (3S-cis) -3-ethyldihydro- 4- [1-methyl-1H-imidazol-5-yl) methyl] -2 (3H) -furanone. These Compound and its cholinergic effects are from the literature known.

The applicant has now surprisingly found that obtained by replacing the furan ring with a thiophene ring Compound as well as derivatives of this compound distinguish a new, particularly interesting therapeutic effect.

These pilocarpine derivatives, hereinafter referred to as new compounds include the compounds of formula I.

wherein

R₁ represents alkyl with 1 to 4 carbon atoms, R₂ and R₃ independently of one another are hydrogen or alkyl 1 to 4 carbon atoms mean  R₄ and R₅ together for = O, = S or = NR, where R is mono- or di-alkyl (1 to 4 carbon atoms) carbamoyloxy means to stand or R₄hydrogen means and R₅ for hydrogen, hydroxy or -OR ', where R' alkyl with 1 to 4 carbon atoms or mono- or di-alkyl (with 1 to 4 carbon atoms) means carbamoyl,

in the form of free bases or acid addition salts.

The new compounds can, depending on the existing substituents asymmetric carbon atoms in positions 2, 3 and 4 have. The invention includes all resulting from it cis / trans isomers and more generally all stereomers and theirs Mixtures, for example the racemates of the enantiomers.

Those contained in the compounds of formula I above defined alkyl groups preferably contain 1 or 2 carbon atoms.

R₁ is preferably methyl.

Preferably one of the substituents R₂ and R₃ is hydrogen and the other for ethyl.

R₄ and R₅ are preferably together = O.

The invention includes e.g. B. a group of compounds of Formula I, wherein R₁ has the above meaning, R₂ is hydrogen and R₃ Mean ethyl and R₄ and R₅ together represent = O or = S, in the form of free bases or acid addition salts.  

In particular, those compounds of formula I are included wherein R₁ is methyl, those in which one of the substituents R₂ and R₃ for hydrogen and the other for alkyl defined above (preferably ethyl), and those in which R₄ and R₅ together = O or = S (preferably = O), in the form of the free bases or of acid addition salts.

According to the present invention, the compounds are obtained of the formula I and its acid addition salts via a process, containing the step that compounds of formula II

wherein R₁, R₂ and R₃ have the above meaning, with a phosphorus sulfide converts the compounds of formula I obtained, wherein R₄ and R₅ together represent = O or = S, optionally in transferred further compounds of formula I and the so obtained Compounds of formula I in the form of the free bases or Acid addition salts wins.

The reaction of the compound of formula II with the phosphorus sulfide can be carried out in a manner known per se, using as phosphorus sulfide e.g. B. P₄S₁₀ can use, but preferably the Lawesson's reagent of the formula

The reaction mixture can be worked up in a manner known per se Methods are carried out. A mixture is obtained a compound of formula I, wherein R₄ and R₅ together for Are oxygen, and a compound of formula I, wherein R₄ and R₅ together represent sulfur. The separation can e.g. B. done chromatographically.

Compounds of formula I, wherein R₄ and R₅ together for oxygen can also be made by making connections of formula II with thioacetic acid potassium salt on itself implements known manner, e.g. B. as described in Example 2 below.

The transfer of the compounds of formula I, wherein R₄ and R₅ together represent oxygen or sulfur, in further compounds of the formula I can by known methods, for. B. as follows:

For the preparation of compounds of formula I, wherein R₄ is hydrogen means and R₅ is hydroxy, you can compounds of the formula I, in which R₄ and R₅ together represent = O, e.g. B. with diisobutylaluminium hydride, as in the following Example 4 described. The compounds thus obtained can by reaction with a compound of the formula R′OH (if R ′ represents alkyl defined above) or by reaction with a Compound of the formula R′Cl (if R ′ is defined above Alkylcarbamoyl) in compounds of formula I, wherein R₄ Means hydrogen and R₅ is -OR ′, be transferred, such as described in Examples 5 and 6 below.

Compounds of formula I, wherein R₄ and R₅ together for = NR can be made by connecting the Formula I, wherein R₄ and R₅ together represent = S, as in the following Example 7 reacted with hydroxylamine hydrochloride and  the compounds obtained analogously to Example 6 with a mono- or reacting di-alkylaminocarboxylic acid chloride.

The compounds of formula I can be in free form or in form their addition salts can be isolated with acids. From the free Bases can be prepared in a known manner by acid addition salts and vice versa.

The starting compounds of formula II are known or according to known methods can be produced. So z. B. the (3S-cis) - 3-ethyl-dihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2 (3H) - furanon [(+) - pilocarpine] described as a pharmaceutical in the literature and commercially available.

The 4 - [(1H-imidazol-5-yl) methyl] tetrahydrothiophenes and their physiologically acceptable acid addition salts, hereinafter referred to as Designated compounds according to the invention have in animal experiments interesting pharmacological properties and can therefore can be used as a remedy.

In particular, the compounds according to the invention effect one Increase in cholinergic effects in the following experiments:

Electrically induced H-acetylcholine release in hippocampal sections on the rat

In the range of 10 ^-6 -10 ^-4 M, the compounds antagonize the inhibitory effects of muscarinic agonists such as oxotremorine on presynaptic, muscarinic receptors, it being possible to conclude that the compounds are presynaptic, muscarinic antagonists. In addition, the compounds antagonize the inhibitory effect of endogenous acetylcholine, which accumulates after release from nerve endings in the presence of the acetylcholinesterase inhibitor physostigmine.

Effect on the electrical activity of cultured hippocampus pyramidal cells

In the range of 10 ^-6 -10 ^-4 M, the compounds in an experimental situation characterized by the absence of cholinergic cells have no effect on the activity of pyramidal cells, while the compounds in co-cultures (from septum and hippocampus) initiate excitatory effects with functional cholinergic linkages. This proves that the presence of cholinergic cells is necessary for the excitatory effects to be exerted. The data are compatible with the view that the compounds induce the release of acetylcholine from cholinergic nerve endings without blocking postsynaptic muscarinic receptors.

Effect on the acetylcholine concentration in the rat brain

After oral administration of approx. 1-10 mg / kg, the effects Compounds a dose-dependent, long-lasting decrease in the Acetylcholine content in the striatum, hippocampus and cortex. With the (+) - (3S-cis) -3-ethyl-dihydro-4 - [(1-methyl-1H-imidazol-5-yl) - methyl] -2 (3H) thiophenone, e.g. B., will have a significant effect after 3 mg / kg p. o. in the cortex and after 1 mg / kg p. o. in the hippocampus and striatum found. This effect is similar, but 10 times weaker than the effect with scopolamine, a pre- and post-synaptic muscarinic antagonists. The simultaneous administration of the compounds and an acetylcholinesterase Hemmers clearly shows different effects the acetylcholine level in combination with the classic Antagonists scopolamine. It can be seen that the Compounds of the invention selective, presynaptic Antagonists without post-synaptic antagonistic properties are.  

In addition to the previously described presynaptic antagonism the compounds according to the invention act with cis- Configuration in C 3 / C 4 as muscarinic agonists on postsynaptic Receptors. This was based on the classic pharmacological tests:

• a) Isolated guinea pig ileum: It becomes the influence of the substance measured isotonic on the contraction of the muscle and compared to the effects of muscarin.
• b) Isolated cervical ganglion of the rat: Muscarinic Agonists call depolarization of the cervical ganglion the extent becomes apparent with the effect of muscarin compared.

[Methods described in: J.M. Palacios et al., Europ. J. Pharmacol. 125, 45-62 (1986)].

The compounds mentioned show pD2 values between 5 and 6.5 in these tests and can act as full or partial agonists occur.

The above results indicate that the compounds predominantly as presynaptic muscarinic antagonists and z. T. act as post-synaptic muscarinic agonists. Because of your Ability to memory functions degraded by scopolamine They can improve in the treatment of senile mental disorders such as senile dementia and Alzheimer's disease application find, especially in the early stages, when a number is still undamaged by cholinergic nerve endings. Moreover they can be used to treat confusion in older people People, myasthenia gravis, schizophrenia and mania, further to Treatment for glaucoma can be used.  

A suitable daily dose is in the range of about 1 to 250 mg the substance, suitable dosage forms for e.g. B. oral applications generally contain about 0.25 to 125 mg active substance in addition to solid or liquid carrier substances or diluents.

The compounds according to the invention alone can be used as medicines or in a suitable pharmaceutical form with pharmacologically indifferent Substances are administered.

The invention also relates to pharmaceutical compositions, the compounds of the invention as active ingredients contain. Those used in pharmacy can be used for their manufacture Auxiliaries and carriers are used. Suitable galenic forms are e.g. B. tablets, capsules and drip solutions.

The following examples illustrate the invention. Temperatures are in degrees Celsius and are uncorrected.

Example 1 (+) - (3R-trans) -3-ethyl-dihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] - 2 (3H) -thiophenone and (-) - (3R-trans) -3-ethyldihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] - 2 (3H) -thiophene-thione

10 g (+) - Pilocapin hydrochloride together with 24.8 g Lawesson's reagent suspended in 600 ml of xylene and at 7 hours 135 ° under nitrogen in a 1.5 liter sulfonation flask with gas inlet tube and stirred reflux condenser. After cooling down The xylene is decanted off at room temperature and the resinous, brownish residue in 400 ml methylene chloride / methanol (95: 5) dissolved and extracted twice with 150 ml of 2 N sodium carbonate solution. To Drying the organic phase with sodium sulfate is filtered and evaporated.

The residue is chromatographed with 100 times the amount Silica gel with methylene chloride / methanol / ammonia (93: 7: 0.7) as an eluent.

The (+) - (3R-trans) -3-ethyldihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2 (3H) -thiophenone dihydrogenphosphate (from ethanol) melts at 189- 192 °. [ α ] = + 20.2 ° ( c = 1.0 in water).

The hydrochloride of (-) - (3R-trans) -3-ethyl-dihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2 (3H) -thiophene-thione (from methanol / ether) melts at 158-161 °. [ α ] = - 23.6 ° ( c = 0.5 in ethanol).

Example 2 (+) - (3S-cis) -3-ethyldihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2 (-3H) thiophenone

39.7 g of thioacetic acid potassium salt together with 42.5 g (+) - Pilocarpine in 500 ml of dimethylformamide stirred at 150 ° for 6 hours. After cooling and evaporation of the solvent  brown residue dissolved in 1.5 liters of 95% methylene chloride / methanol and with twice 200 ml of saturated sodium bicarbonate and washed once 200 ml of water. After drying the organic Phase with sodium sulfate is filtered and evaporated.

The residue is chromatographed with 100 times the amount Silica gel and methylene chloride / methanol / ammonia (97.5: 2.5: 0.3) as an eluent.

The oil consists of a mixture 80:20 trans: cis.

26.3 ml of butyllithium (1.6 N in hexane) become a solution of 6.55 ml of diisopropylamine in 250 ml of absolute tetrahydrofuran Dripped 0 ° under argon. Then you drip onto it -70 ° cooled lithium diisopropylamide 7.0 g of the trans / cis Mixture, dissolved in 60 ml of absolute tetrahydrofuran. You stir ½ hour at -70 ° and then drips 15.6 g Di-t-butylhydroxytoluene, dissolved in 70 ml of tetrahydrofuran. The cold solution is poured into 300 ml of 2N HCl and extracted aqueous phase twice more with 500 ml of methylene chloride. With 2 N Sodium carbonate solution, the aqueous phase is adjusted to pH 8 and extracted three times with 250 ml of methylene chloride. The organic Phase is dried with sodium sulfate, filtered and evaporated.

By recrystallization of the D (+) - toluic tartaric acid salt Ethanol is obtained stereoisomerically pure cis.

The (+) - (3S-cis) -3-ethyldihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2 (3H) -thiophenone dihydrogenphosphate (from ethanol) melts at 193- 196 ° (dec.); [ α ] = + 37.4 ° ( c = 0.65 in water).

Example 3

Analogously to Example 1 or 2, the following compounds are the Formula I made:

• 3a. (-) - Dihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2 (3H) thiophenone
  M.p .: 142-145 ° (dec.). [ α ] = - 20.8 ° ( c = 0.73 in H₂O).
• 3b. (+) - 3-Ethyldihydro-3-methyl-4 - [(1-methyl-1H-imidazol-5-yl) - methyl] -2 (3H) thiophenone
  M.p .: 195-196 ° (dec.).

Example 4 (+) - (3R-trans) -3-ethyl-2-hydroxy-4 - [(1-methyl-1H-imidazol-5-yl) methyl-1] tetrahydrothio phen

17 ml (17 mmol) diisobutylaluminum hydride (1.0 M in hexane) become a solution of 2.7 g (12 mmol) of trans-thiopilocarpine added in 30 ml dichloromethane at -70 ° C under argon. You leave warm the solution to 0 ° and give 2 ml of saturated sodium sulfate solution to whereupon a white precipitate turns out. The The solution is filtered off with suction and concentrated to an orange oil. The oil is washed over a 50-fold amount of silica gel with methylene chloride / Chromatographed methanol / ammonia (89: 10: 1) as eluent. The product comes with one equivalent of fumaric acid implemented and the fumarate obtained recrystallized from ethanol-ether. The 360 MHz 1 H NMR spectrum shows that the product as 2: 1 mixture of diastereomers is present at the C2 site.

The (+) - (3R-trans) -3-ethyl-2-hydroxy-4 - [(1-methyl-1H-imidazol-5-yl) methyl] tetrahydrothiophene fumarate melts at 125-127 °. [ α ] = + 85.2 ° ( c = 0.43 in H₂O).

Example 4a (+) - (3S-cis) -3-ethyl-2-hydroxy-4 - [(1-methyl-1H-imidazol-5-yl) methyl] - tetrahydrothiophene

The procedure is analogous to Example 4, using cis-thiopilocarpine. The hydrogen fumarate of the title compound melts at 110-112 ° (dec.). [ α ] = + 38.3 ° ( c = 0.35 in H₂O).

Example 5 (+) - (3S-cis) -3-ethyl-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2-methoxy-tetrahydrothiophene

1.1 ml of methanol become a solution of 3.0 g (13.3 mmol) cis-thiopilocarpine lactol in 40 ml dichloromethane at 60 ° given. 3.4 ml (27 mmol) of boron trifluoroetherate solution are added and let warm to room temperature. The reaction mixture is Stirred overnight, then 2 N soda is added and extracted with dichloromethane. The entire organic phases are over Dried sodium sulfate and concentrated to a yellow resin. The resin is poured over silica gel with dichloromethane: methanol: ammonia (90: 9: 1) chromatographed as eluent. The received Product (2.8 g; 11.6 mmol) comes with one equivalent Oxalic acid reacted and the salt obtained from ethanol ether recrystallized. NMR analysis shows that the product is 90: 10- Diastereomer mixture at C2 is present.

The (+) - (3R-cis) -3-ethyl-4 - [(1-methyl-1H-imidazol-5-yl) methyl] - 2-methoxy-tetrahydrothiophene hydrogen oxalate (from ethanol ether) melts at 144 -148 °. [ α ] = + 112 ° ( c = 0.47 in ethanol).

Example 5a (+) - (3R-trans) -3-ethyl-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2-methoxy-tetrahydrothio phen

The procedure is analogous to Example 5 using trans-thiopilocarpine lactol. The hydrogen oxalate of the title compound melts at 87-89 °. [ α ] = + 19.7 ° ( c = 0.33 in ethanol).

Example 6 (+) - (3R-trans) -3-ethyl-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2- (N, N - dimethylcarbamoyloxy) tetrahy drothiophene

2.7 ml of N, N-dimethylcarbamoyl chloride become a solution of 2.7 g (12 mmol) of the compound of Example 4, 0.4 ml (30 mmol) Triethylamine and 270 mg dimethylaminopyridine in 25 ml dichloromethane dropped at room temperature. The solution will be overnight stirred and extracted with sodium bicarbonate. The organic Phase is separated off, dried over sodium sulfate and up to an oil is concentrated. The oil is poured over silica gel with methylene chloride / Chromatographed methanol (97: 3) as the eluent. The The product obtained (1.4 g; 4.7 mmol) is as according to NMR analysis 70:30 diastereomer mixture on C2 before.

The (+) - (3R-trans) -3-ethyl-4 - [(1-methyl-1H-imidazol-5-yl) methyl] - 2- (N, N-dimethylcarbamoyloxy) tetrahydrothiophene hydrogen fumarate (from ethanol Vinegar ester) melts at 134-137 °. [ α ] = + 43 ° ( c = 0.5 in H₂O).

Example 7 (-) - (3R-trans) -3-ethyldihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] - 2- (N, N-dimethylcarbamoyl-oximi no) -3H-thiophene

• a) To a solution of 1.0 g (4.2 mmol) of (+) - (3R-trans) -3-ethyldihydro- 4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2 (3H) thiophenthione and 420 mg (6.0 mmol) hydroxylamine hydrochloride in 13 ml of methanol are added to 5 ml of 2N sodium hydroxide solution. You leave that Stir mixture overnight and add dichloromethane and Sodium bicarbonate. The organic phase is over sodium sulfate dried and concentrated. The oil obtained is over Silica gel with dichloromethane / methanol / ammonia (90: 9: 1) chromatographed as eluent.
• b) The (+) - (3R-trans) -3-ethyl-dihydro-4 - [(1-methyl-1H-imidazol-5-yl) methyl] -2-oximino-3H-thiophene obtained under a) is analogous converted to Example 6 in the title compound. The hydrogen fumarate melts at 123-127 ° (dec.). [ α ] = -3.0 ° ( c = 1.0 in H₂O).

Claims (8)

1. A compound of formula I whereinR₁ is alkyl with 1 to 4 carbon atoms, R₂ and R₃ independently of one another are hydrogen or alkyl with 1 to 4 carbon atoms, R₄ and R₅ together for = O, = S or = NR, where R is mono- or di-alkyl (with 1 to 4 carbon atoms ) carbamoyloxy means, or R₄ means hydrogen and R₅ is hydrogen, hydroxy or -OR ', where R' is alkyl with 1 to 4 carbon atoms or mono- or di-alkyl (with 1 to 4 carbon atoms) carbamoyl, in the form of the free Base or an acid addition salt. 2. A compound according to claim 1, wherein R₁ represents alkyl with 1 to 4 carbon atoms, R₂ means hydrogen R₃Ethyl means and R₄ and R₅ together stand for = O or = S. 3. The (+) - (3S-cis) -3-ethyl-dihydro-4 - [(1-methyl-1H-imidazole- 5-yl) methyl] -2 (3H) -thiophenone in the form of the free base or an acid addition salt. 4. The (+) - (3R-trans) -3-ethyl-dihydro-4 - [(1-methyl-1H-imidazole- 5-yl) methyl] -2 (3H) -thiophenone in the form of the free base or an acid addition salt. 5. A process for the preparation of a compound according to claim 1, comprising the step that compounds of formula II wherein R₁, R₂ and R₃ are as defined in claim 1, reacted with a phosphorus sulfide, the compounds of formula I obtained, wherein R₄ and R₅ together represent = O or = S, optionally converted into further compounds of formula I and the so obtained Compounds of formula I in the form of free bases or acid addition salts. 6. A compound according to any one of claims 1 to 4 in free or pharmacologically acceptable acid addition salt form for use as a pharmaceutical.   7. A compound according to any one of claims 1 to 4 in free or pharmacologically acceptable acid addition salt form for the treatment of senile mental disorders such as senile dementia and Alzheimer's disease, confusion in older people, myasthenia gravis, schizophrenia and mania and to treat glaucoma. 8. A pharmaceutical composition containing one Compound according to one of claims 1 to 4 in free or pharmaceutically acceptable acid addition salt form.