HK1088009B - Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use - Google Patents

Description

Phenylethylamines and fused ring variants as prodrugs of catecholamines and uses thereof

The invention is a divisional application of Chinese patent application 01808285.8 with the application date of 2001, 4, 17, and the name of the original application is 'phenylethylamine and condensed ring variant as catecholamine prodrug and application thereof'.

Technical Field

The present invention relates to novel chemical compounds as novel prodrug ingredients for the production of catecholamines, especially catecholamines, to processes for their preparation, to pharmaceutical compositions containing them and to their therapeutic use.

Background

Neurodegenerative diseases are increasingly prevalent in the elderly population. One particular neurodegenerative disease that commonly occurs between the ages of 50 and 80 is parkinson's disease. Parkinson's disease is a brain disease characterized by tremor and difficulty with walking, movement, and coordination.

Parkinson's disease appears to be caused by progressive degeneration of dopamine-containing neurons in the substantia nigra pars compacta of the brain. Dopamine is a neurotransmitter used by brain cells to transmit impulses to control or regulate peripheral muscle movement. Loss of dopamine-containing neurons results in a decrease in the amount of dopamine available to the body. The deficiency of dopamine is thought to disturb the balance between dopamine and other neurotransmitters, such as acetylcholine. When dopamine levels fall, nerve cells are unable to properly transmit impulses, resulting in loss of muscle control and function.

At present, parkinson's disease is incurable. The general therapy aims to control the symptoms of parkinson's disease, mainly by replacing dopamine with L-DOPA, which can be metabolized to dopamine, or by methods of administering chemical agents that can promote dopamine receptors. Current therapies that slow the progression of the disease include compounds such as the selective monoamine oxidase inhibitor deprenyl (selegiline) and the compound amantadine that appears to increase dopamine uptake into presynaptic neurons.

Some hydroxylated (mono-phenolic or catechols) phenylethylamines (e.g. forming part of a semi-rigid/rigid ring system) are known to have useful dopaminergic activity. However, their clinical use is limited by their low or no bioavailability (high first pass effect).

(+ -) -5-keto-2-N, N-bis-N-propyl-amino-tetralin ((+ -) -5-keto-DPATT (formula A)) has been reported to have dopaminergic activity in rats. However, in vitro binding of this compound did not occur, i.e., (. + -.) -5-keto-DPATT itself had no affinity for the DA receptor. It must therefore be activated before its action is manifested. This has been published by Steven Johnson in 1994 on the poster of the local pharmaceutical chemistry conference of Ann Arbor, MI, usa. There is no mention of catecholamine formation on this poster. However, this is only a presumption that the active drug was not shown to be (. + -.) -5-OH-DPTA (see formula B below). The invention therefore additionally encompasses the compounds of the formula II included in the overall claimed structure of the formula I.

In recent years, a large body of pharmacological, biochemical and electrophysiological evidence has provided considerable support in favor of the existence of a specific group of central autoregulatory dopamine (DA receptors) located in dopaminergic neurons and in the D2 receptors belonging to the DA receptor subgroup. These receptors are part of the homeostatic mechanism that regulates nerve impulse flow and transmitter synthesis and regulates the amount of DA released from nerve endings. Recently, Sokoloff et al in Nature, 347146-51(1990) have proposed the existence of a novel dopamine receptor known as D3. Among the series of screening categories and non-standard antipsychotic drugs, the preferred dopamine autoreceptor antagonists (±) -AJ76 and (±) -UH232 have the greatest preference for the D3 site. The D3 receptor appears to occupy both pre-and post-synaptic and its regional distribution (highly preferred limb brain regions) is different from that of the D1 and D2 receptors.

Clinically, drugs that act as agonists or antagonists of central DA transport are effective in treating various central nervous system disorders such as parkinson's disease, neuropathy, huntington's disease, and other cognitive dysfunctions.

For example, in parkinson's disease, hypofunction of the substantia nigra-neostriata can be restored by increased stimulation of postsynaptic DA receptors (see above). In schizophrenia, the condition is normalized by achieving a reduction in postsynaptic DA receptor stimulation. Typical antipsychotic drugs are capable of directly blocking postsynaptic DA receptors. The same effect can also be achieved by inhibiting the presynaptic agent in the neuron that is necessary to maintain adequate neurotransmission, transport mechanisms and transmitter synthesis.

Direct DA receptor agonists such as apomorphine (mixed DA D1/D2 agonists) are capable of activating both the DA autoreceptors as well as the postsynaptic DA receptors. The stimulation of autoreceptors appears to predominate when apomorphine is administered at low doses, whereas at higher doses, the relief of DA transmission is outweighed by the increased postsynaptic receptor stimulation. The anti-psychotic and dyskinetic effects of low doses of apomorphine in humans may be due to the autoreceptor-stimulator properties of this DA receptor agonist. These facts suggest that DA receptor stimulators with high selectivity for central nerve DA autoreceptors would be of value in the treatment of psychiatric disorders.

Compounds have been developed which have a preferential antagonistic effect on DA autoreceptors, Johansson et al, j.med.chem., 28, 1049 (1985). Examples of such compounds are (. + -.) -cis-1S, 2R-5-methoxy-1-methyl-2- (N-N-propylamino) tetralin ((. + -.) -1S, 2R-AJ76) and (. + -.) -cis-1S, 2R-5-methoxy-1-methyl-2- (N, N-di-N-propylamino) tetralin ((. + -.) -1S, 2R-UH 232). These compounds act biochemically as typical DA antagonists, such as haloperidol. Therefore, they are able to increase dopamine accumulation in normal animals after blocking of the aromatic amino acid decarboxylase by NSD1015 and they are also able to increase the levels of the DA metabolites DOPAC and HVA (without NSD1015 treatment). Nevertheless, functionally, in behavioral tests (light cell motility meters), they exhibit stimulating properties, for example they are able to increase the motor activity. In addition, gross behavioral observations show that these compounds, at certain doses, can induce weak traditional dopaminergic stereotypy in chewy animals such as nasal inhalation and hind limb stance.

A disease in which an increase in dopaminergic turnover is beneficial may be geriatric, which is used to prevent mental and physical retardation and depression and to improve mental functioning (e.g. recognition). It has effects on depression patients. It can be used as an anorectic for obesity. It can also improve the very mild symptoms of brain dysfunction (MBD), narcolepsy and schizophrenia, in addition to impotence, erectile dysfunction and restless legs. Thus, improving sexual function is another indication (available for both men and women).

Summary of The Invention

It is an object of the present invention to provide novel prodrugs of catecholamine derivatives which are uniquely metabolised in vivo to strong dopamine receptor ligands with agonistic, partial agonistic, inverse agonistic and/or antagonistic action.

According to the present invention there is now provided novel compounds having the general formula (I):

wherein rings B, C, D and E may or may not be present and, if present, are bound to A in a manner A + C, A + E, A + B + C, A + B + D, A + B + E, A + C + E, A + B + C + D or A + B + C + D + E, rings B, C and E are aliphatic rings and ring D may be aliphatic or aromatic/heteroaromatic, and wherein X is- (CH) forming ring E₂)_m-, where m is an integer from 1 to 3, or, when the ring E is absent, the radical R₁Bound to a nitrogen atom, wherein R₁Selected from the group consisting of hydrogen atoms, alkyl groups or haloalkyl groups of 1 to 3 carbon atoms, cycloalkyl (alkyl) groups of 3 to 5 carbon atoms (i.e., including cyclopropyl, cyclopropylmethyl, cyclobutyl and cyclobutylmethyl), and Y is- (CH) forming a ring C₂)_n-, where n is an integer from 1 to 3, or, when the ring C is absent, the radical R₂Bound to a nitrogen atom, wherein R₂Selected from hydrogen, alkyl or haloalkyl of 1 to 7 carbon atoms, cycloalkyl (alkyl) of 3 to 7 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms, aralkyl, heteroaralkyl of 1 to 3 carbon atoms in the alkyl moiety, when the aryl/heteroaryl nucleus may be substituted, if rings B, C, D and E are absent, NR₁R₂Other than dimethylamino, N-methyl-N-ethylamino, N-methyl-N-propynylamino, N-methyl-N-propylamino and N-hydroxypropyl-N-methylamino, and salts thereof with pharmaceutically acceptable acids or bases.

Such excluded compounds are known per se, but their therapeutic use has not been previously disclosed.

The invention thus provides the following classes of compounds based on differential binding of rings a to E:

wherein R is₁、R₂M and n are as defined above.

Preferred combinations of rings A to E are A + B + C (formula Ie), A + B + C + D (formula Ig), A + B + E (formula If), A + E (formula Ib) and A + C + E (formula Id), the most preferred combination being A + B + C (formula Ie).

R₁And R₂The preferred meaning of (A) is n-propyl.

It will be apparent to those of ordinary skill in the art that the compounds of the present invention contain one or more chiral centers. The compounds of formula I contain an asymmetric carbon atom in the part of the aliphatic ring. The scope of the present invention includes all (theoretically possible) R/S-combinations of the compounds of the formula I in purified form. In general, the flatter the molecule of formula I the more effective it is as a dopaminergic agonist, provided that it has appropriate n-alkyl substituents. Planar molecules of the general formula I are those having trans-fused ring systems.

Since the pharmaceutical activity of the racemates or the different R/S combinations at the chiral carbon atoms of the molecules of the present invention may vary, it is desirable to use as pure a "chiral" form as possible (e.g., the examples given below). In these cases, the final product or even other intermediates can be resolved into enantiomeric compounds by chemical or physical methods known to those of ordinary skill in the art or even be available for synthesis as such.

Preferred absolute configurations of the compounds of formulae Ia-h:

wherein R is₁、R₂M and n are as defined above.

The prodrugs of the invention show useful therapeutic effects for the treatment of: for example (in central nervous system diseases (CNS)) parkinson's disease, psychosis (schizophrenia), huntington's disease, impotence; (at the periphery): renal failure, heart failure and hypertension. Other areas of therapeutically active catechins are adrenergic, anti-adrenergic compounds.

Some compounds of the invention have presynaptic and postsynaptic antagonism. Compounds with more postsynaptic effects can be used to alleviate symptoms of schizophrenia (both positive and negative) and to restore drug addiction. Other diseases studied herein are "jet lag", sleep disorders and early stages of parkinson. Other indications for the compounds of the invention are diseases associated with the recognition of disorders such as huntington's disease and alzheimer's disease.

Other diseases/conditions than Parkinson's disease that can be treated with suitable formulations of the compounds of the invention are Restless Legs Syndrome (RLS), erectile dysfunction (impotence in men) and sexual stimulation in for example menopausal women (stimulation of vaginal lubrication and clitoral erection). Corresponding low plasma and striatal tissue concentrations of the compounds of the invention in the autoreceptor dose range can also be used for the treatment of psychotic disorders (e.g. schizophrenia; see above).

The diseases mentioned here are not limiting for the present invention, so that other disease states including DA-ergic systems may also be suitable for treatment with the compounds of the present invention.

In the CNS and/or periphery in vivo, compounds of formula I can be converted to their corresponding "built-in" 3, 4-di-OH-phenylethylamines (formula II):

x, Y, R therein₁、R₂M and n are as defined above in relation to formula I.

After oral and parenteral administration of the compounds of formula I, the compounds of formula II may be present in brain cells of animals. Thus, in accordance with the present invention, applicants have surprisingly found that cyclohexanone-ethylamine having the structure of formula I above, may be bioactivated in vivo, possibly corresponding to 3, 4-di-OH-phenylethylamine (formula II).

The compounds of formula II may also have catechol-O-methyl-transferase (COMT) inhibitory properties, a dopaminergic effect which synergistically increases the production of catechols.

The compounds of the present invention may be administered to a patient alone or as part of a pharmaceutical composition.

The term "patient" as used herein refers to all animals including humans. Examples of patients include humans, chew animals, and monkeys.

Thus, according to other aspects of the present invention, there is provided a composition comprising a compound as defined above but having no disclaimer of NR when rings B, C, D and E are absent₁R₂A compound of the general formula I as defined in (1) or a pharmaceutically acceptable salt thereof as active ingredient in combination with a pharmaceutically acceptable carrier, diluent or excipient.

The pharmaceutical compositions of the present invention may be administered to a patient orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, topically (powders, ointments or drops) or as a buccal or nasal spray.

The preferred route of administration is oral, although parenteral and transdermal administration are also contemplated. Especially, the preparation controlled to release by skin patch is especially suitable for treating the elderly patients.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluent solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil, sesame oil, and sulfurized oil (viscoleo)), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

These compounds also contain adjuvants such as preservatives, emulsifiers and dispersants. The action of microorganisms can be prevented by adding various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Delayed absorption of the injectable pharmaceutical form may be brought about by the use of agents which delay absorption such as aluminum monostearate and gelatin.

Oral delivery of the compounds of the invention is preferred when administered to a patient population of general age and to treat the condition. Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert excipient (or carrier) commonly used, such as sodium citrate or dibasic calcium phosphate or:

(a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid,

(b) binding agents, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia,

(c) the amount of humectant, such as glycerin,

(d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate,

(e) solution retarders, such as paraffin wax,

(f) absorption accelerators, such as quaternary ammonium compounds,

(g) wetting agents, such as cetyl alcohol and glyceryl monostearate,

(h) adsorbents, such as kaolin and bentonite, and

(i) lubricants, for example talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In capsules, tablets and pills, the dosage forms may also contain buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and others well known in the art. They contain a masking agent and are also capable of releasing the active compound or compounds in a delayed manner in a certain part of the intestinal tract. Examples of embedding compositions which can be used are polymers and waxes. The active compounds can also be used in the form of microcapsules, if desired, containing one or more of the above-mentioned excipients. Sustained release formulations are also preferred, including osmotic pumps and layered delivery systems.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils such as, in particular, cottonseed, groundnut, corn germ, olive, sulfurized oil (viscoleo), castor and sesame oils, glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

In addition to inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide (metahydroxide), bentonite agar-agar, and tragacanth, or mixtures of these materials.

Compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore melt in the rectum or vagina and release the active ingredient.

Dosage forms for topical administration of the compounds of the invention include ointments, powders, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and a preservative, buffer or propellant as required. Ophthalmic formulations, eye ointments, powders, and solutions are also included within the scope of the present invention.

The term "pharmaceutically acceptable salts" as used herein refers to those amino acid addition salts of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use and the zwitterionic forms of the compounds of the present invention, if possible. The term "salts" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of formula I. These salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting the purified compound in free form with a suitable organic or inorganic acid and isolating the salt thus obtained. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, sstarate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, lauroyl sulfate and the like. These salts may include cations based on alkali and alkaline earth metals such as sodium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like (see, e.g., s.m. berge et al, "pharmaceutically acceptable salts", j.pharm. sci., 1977; 66: 1-19, which is incorporated herein by reference). In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms are generally considered equivalent to unsolvated forms for the purposes of the present invention.

According to a further aspect of the invention there is provided a method of treating parkinson's disease in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of any one of formulae Ie, If and Ig as defined above, or a pharmaceutically acceptable salt thereof.

By "therapeutically effective amount" is meant an amount of a compound of formula I that, when administered to a patient, is capable of alleviating the symptoms of Parkinson's disease.

One of ordinary skill in the art will readily identify patients suffering from Parkinson's disease. For example, symptoms of the patient include, but are not limited to, tremors and/or shaking and difficulty with walking, other movements, and coordination.

According to a further aspect of the invention there is provided a method of treating schizophrenia in a patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of any one of formulae Ib and Id, or a pharmaceutically acceptable salt thereof, as hereinbefore defined.

The compounds of the present invention can be administered to a patient at dosage levels ranging from about 0.01 to about 1,000mg per day. For an adult weighing about 70 kg, a dosage in the range of about 0.001 to about 100mg per kg of body weight per day is preferred. The particular dosage employed may vary. For example, the dosage may be determined by a variety of factors including the requirements of the patient, the severity of the condition being treated and the pharmacological activity of the compound being used. Determination of the appropriate dosage for a particular patient is well known to those of ordinary skill in the art.

In addition, the present invention encompasses compounds prepared using standard organic synthesis techniques, including combinatorial chemistry or by biological methods, such as by metabolism. The following examples are presented for the purpose of illustrating particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any way.

The compounds of formula I used in the process of the present invention are ideally suited for several reasons. First, these compounds are stable and may be excellent candidates for oral administration. Secondly, these compounds are long acting and therefore can be effectively treated with fewer dosing intervals, which is very important for elderly patients. Third, the compounds of the present invention have excellent oral bioavailability.

According to a further aspect of the present invention there is provided a compound of formula I as described above without giving up NR in the absence of ring B, C, D and E₁R₂A compound of the meanings of (a) and pharmaceutically acceptable salts thereof for therapeutic use.

According to another aspect of the present invention there is provided a compound of formula I as described above without giving up NR in the absence of ring B, C, D and E₁R₂The use of a compound of the meanings of (a) and pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment of parkinson's disease, neuropathy, huntington's disease, impotence, renal failure, heart failure or hypertension.

The following detailed examples detail general synthetic techniques for preparing compounds and some of the bioassays used to determine the efficacy of the compounds of the invention.

Example (b): (alkylated) dopamine prodrugs

Scheme 1) (alkylation) prodrugs of dopamine:

reagent: (a) CH-2 ═ CHMgBr; (b) R1R2NH, Cs2C03(C) CH ≡ CMgBr; (d) NaBH3CN

The following procedure represents the Birch reduction.

Example 1.3- (2-dipropylamino-ethyl) -cyclohex-2-enone (GMC6598)

3-vinyl-cyclohex-2-enone (0.75g, 6.1mmol) (prepared according to the method of Nasarow) was dissolved in acetonitrile (1mL) and dissolved in Cs₂CO₃After (50mg), dipropylamine (1.5g, 16mmol) was added. After the mixture was stirred at room temperature for 3 hours, it was diluted with diethylamine (100mL), filtered and evaporated to dryness. The residue was distilled under vacuum (175 ℃, 0.01mm Hg) to give a pale yellow oil which was then converted to the hydrochloride salt. Recrystallization from isopropyl ether/isopropyl alcohol gave: 1.2g, 4.6mmol (75%),

mp 95-97℃.IR(KBr)2962，2613，1667；¹H-NMR(CDCl₃)δ5.84(d，1H)，2.65(m，2H)，2.27-2.60(m，9H)，1.99(m，2H)，1.39-1.51(m，5H)，0.86(t，6H)ppm；¹³C-NMR(CDCl₃)δ198.2，163.5，124.9，54.2，50.1，35.7，33.7，28.4，21.2，18.5，10.4ppm；MS(EI)m/z 223(M⁺).

example 2.3- (2-diethylamino-ethyl) -cyclohex-2-enone (GMC6608)

The same procedure as in example 1 was used but diethylamine was used. Distillation at 120 ℃ C/0.01 mm Hg gave a colorless oil which was converted to the hydrochloride salt. Recrystallization from isopropyl ether/isopropyl alcohol gave:

1.3g，5.6mmol(91％)，mp 148-149℃.IR(KBr)2948，2851，1661；¹H-NMR(CDCl₃)δ5.86(d，1H)，2.48-2.67(m，6H)，2.27-2.39(m，6H)，1.96(m，2H)，1.02(t，6H)ppm；¹³C-NMR(CDCl₃)δ198.3，163.5，124.8，48.9，45.2，35.7，33.7，28.4，21.2，10.1ppm；MS(EI)m/z 195(M⁺).

example 3.3- (2-dibutylamino-ethyl) -cyclohex-2-enone (GMC6623)

The same procedure as in example 1 was used but dibutylamine was used. Purification by column chromatography (silica gel, ethyl acetate) gave a colorless oil which was converted to the hydrochloride salt. Recrystallization from isopropyl ether/isopropyl alcohol gave 1.3g, 5.6mmol (91%), mp 115-.

IR(KBr)2959，2494，1661；¹H-NMR(CDCl₃)δ5.84(d，1H)，2.60(q，2H)，2.26-2.44(m，8H)，1.96(m，3H)，1.21-1.46(m，8H)，0.87(t，6H)ppm；¹³C-NMR(CDCl₃)δ198.2，163.6，124.9，52.0，50.2，35.7，33.8，28.4，27.5，21.2，19.1，12.5ppm；MS(CI)m/z 252(M+1).

Example 4.3- (2- ((2-phenyl) ethyl-propylamino) -ethyl) -cyclohex-2-enone (GMC6624)

The same procedure as in example 1 was used but with N-propyl-2-phenylethylamine. Purification by column chromatography (silica gel, ethyl acetate) gave a colorless oil which was converted to the hydrochloride salt. Recrystallization from ether/ethanol gave 1.8g, 5.6mmol (91%), mp 110-.

IR(KBr)2937，2538，2442，1667；¹H-NMR(CDCl₃)δ7.15-7.83(m，5H)，5.95(s，1H)，3.07(t，2H)，2.83，(q，2H)，2.27-2.50(m，6H)，2.04(p，4H)，1.47-1.64(m，4H)，0.86(t，3H)ppm；¹³C-NMR(CDCl₃)δ198.2，163.5，136.4，127.2，127.0，126.7，119.2，48.1，42.7，42.4，36.2，34.0，32.2，22.8，20.7，20.3，9.4ppm；MS(CI)m/z 286(M+1).

N-N-propyl-3- (3, 4-di-hydroxyphenyl) pyridine prodrugs

Scheme 2) prodrugs of 3-APC (alkylpyridineocatechols)

Reagent: (a) chloropropyl-alkylamine; (b) NaBH3CN

For dopamine prodrugs, the same possibility of Birch reduction exists:

example 5

a) 3-ethynyl-2-cyclohexen-1-one (GMC6573)

In N₂And to a 0.5N solution of ethynylmagnesium bromide in tetrahydrofuran (100mL) was added, with stirring, a solution of 3-ethoxy-2-cyclohexen-1-one (3.75g, 26.8mmol) in tetrahydrofuran (12.5 mL). The mixture was stirred at room temperature for 20 hours and acidified with 1N HCl (200 mL). After stirring for 15 min, the acid phase was extracted with dichloromethane (5X 50 mL). The combined organic extracts were washed with water (2X 50mL) and dried (MgSO₄). Evaporation of the solvent gave an oil which was purified by column chromatography (silica gel, ethyl acetate/hexane 1: 9) to give a yellow oil, 2.71g, 22.6mmol, 84%). The analytical data are identical to the literature data.

b)3- (1-propyl-1, 4, 5, 6-tetrahydro-pyridin-3-yl) -cyclohex-2-enone (GMC6602)

3-ethynyl-cyclohex-2-enone (3.20g, 26.8mmol) (from a above) and (3-chloro-propyl) -propylamine (4.50g, 33.2mmol) were mixed in acetonitrile (50 mL). Adding Cs₂CO₃(100mg) and KI (200mg) and the mixture was kept in N₂Reflux for 10 hours. After cooling, the mixture was diluted with water (50mL) and extracted with dichloromethane (3X 50 mL). The combined organic layers were washed with brine and dried (MgSO)₄) And evaporated. The dark oil obtained was purified by column chromatography (silica gel, ethyl acetate) to give a yellowish red oil. Yield 5.1g, 23.3mmol (87%). IR (neat)2932, 2871, 1589, 1538 and 1157cm^-1；¹H-NMR(CDCl₃)δ6.84(s，1H)，5.69(s，1H)，3.04-3.12(m，4H)，2.44(t，2H)，2.33(t，2H)，2.18(t，2H)，1.83-2.03(m，4H)，1.49-1.64(m，2H)，0.87(t，3H)ppm；¹³C-NMR(CDCl₃)δ197.0，158.5，140.1，112.1，102.4，56.6，44.3，35.6，23.6，21.4，20.2，20.1，19.7，9.6ppm；MS(CI)m/z 220(M+1).

c)3- (1-propyl-pyridin-3-yl) -cyclohex-2-enone (GMC6606)

3- (1-propyl-1, 4, 5, 6-tetrahydro-pyridin-3-yl) -cyclohex-2-enone (5.0g, 22.8mmol) (from b above)) was dissolved in THF (100 mL). Introduction of NaBH in small portions at 0 deg.C₃After CN (1.9g, 30.0mmol), acetic acid (1.38mL, 22.8mol) was added while maintaining the same temperature. After the addition was complete, the mixture was stirred at this temperature for 1 hour and at room temperature overnight. Water (50mL) and saturated NaHCO were added completely₃The aqueous solution (50mL) was then extracted with dichloromethane (5X 50 mL). The combined organic layers were dried (MgSO)₄) And evaporated. The residue was purified by column chromatography (silica gel, dichloromethane/ethanol 20: 1) to give a colorless oil which was converted to the hydrochloride salt. Recrystallization from isopropyl ether gave 4.2g, 17.5mmol (77%), mp184-185 ℃.

IR(KBr)3396，2941，2469，1667，1455cm^-1；¹H-NMR(CDCl₃)δ5.83(s，1H)，3.85(d，2H)，2.29-2.56(m，7H)，1.23-2.17(m，10H)，0.88(t，3H)ppm；¹³C-NMR(CDCl₃)δ198.4，165.1，123.4，59.0，55.6，51.9，41.6，36.0，27.3，26.9，22.8，21.2，17.6，10.2ppm；MS(EI)m/z 221(M+).

Benzo [ g ] quinoline prodrugs

Scheme 3) benzene [ g ] quinoline prodrugs:

reagent: (a) h₂，Pd/C；(b)SOCl₂，RNH₂；(c)LiAlH₄；(d)Li，NH₃；(e)EtO₂C(CH₂)₃P(Ph)₃Br，K^tOBu；(f)PPA。

Or a different approach:

example 6

a)3- (4-methoxyphenyl) -propionic acid n-propionamide (GMC6632)

3- (4-methoxyphenyl) -propionic acid (8.8g, 49mmol) was refluxed in dichloromethane (200mL) containing thionyl chloride (6.6mL, 90mmol) for 1 h. The volatiles were evaporated and the resulting oil was dissolved in dichloromethane (100 ml). This was added to a vigorously stirred mixture of 5% aqueous NaOH (200ml), dichloromethane (100ml) and n-propylamine (3.0ml, 71 mmol). After stirring for 1 hour, the layers were separated, and the aqueous layer was extracted with dichloromethane (3 in a large amount)50ml) was extracted. The combined organic layers were washed with water (50ml) and brine (50ml), MgSO₄And (5) drying. Evaporation of the solvent gave the amide quantitatively (10.7g, 49mmol, 100%). IR

(neat)cm^-1 3300，2961；1734，1642；MS(EI)m/z 221(M+).

The analytical data is the same as the literature data.

b) N- (3- (4-methoxyphenyl) -propyl) -N-propionamide (GMC6633)

To the stirred LiAlH₄(8.0g, 200mmol) of tetrahydrofuran (100mL) to a mixture was added dropwise a solution of 3- (4-methoxyphenyl) -propionic acid n-butylamide (10.7g, 49mmol) (from step a) above) in tetrahydrofuran (100 mL). After 12 hours of reflux, the mixture was cooled to 50 ℃ and excess hydride was destroyed by careful addition of water (10mL), 5% aqueous NaOH (40mL), and water (20mL) while maintaining reflux. The hot slurry was filtered and the white precipitate was washed thoroughly with ethanol. The volatiles were evaporated and the resulting oil was dissolved in ethyl acetate (50mL) and extracted with 0.5N aqueous HCl (4X 50 mL). To the acid phase was added a 30% aqueous NaOH solution to make it basic (pH 9) and extracted with ethyl acetate (4 × 50 mL). The organic layers were combined, washed with brine, dried (MgSO)₄) And evaporated to dryness to give an oil which was crystallized stepwise in diethyl ether as the hydrochloride. Recrystallization from acetone/diethyl ether gave a white flaky (flacky) crystalline material. Total yield (based on free base): 9.9g, 48mmol, 98%, mp 176-. IR

(neat)cm^-1 2960，2772，1611，1514；¹H-NMR(CDCl₃)δ9.46(br s，1H)，7.16(d，2H)，6.90(d，2H)，3.72(s，3H)，2.82(br s，4H)，2.59(t，2H)，2.15(p，2H)，1.83(h，2H)，0.89(t，3H)ppm；¹³C-NMR(CDCl₃)δ156.6，130.3，127.7，112.4，53.7，47.9，45.66，30.3，25.9，17.8，9.7ppm；MS(EI)m/z207(M+).

c) trans-N-propyl-7-keto-1, 2, 3, 4, 4a, 5, 8, 8 a-octahydro- [6H ] -quinoline (GMC6638)

N- (3- (4-methoxyphenyl) -propyl) -N-propylamine (6.15g, 31.45mmol) (from step b)) was dissolved in THF (60mL) and t-BuOH (4.65g, 5.93mL, 62.89 mmol). The mixture was cooled to-60 ℃ and introduced into liquid nitrogen (60 mL). Li metal (1.70g, 0.24mol) was then added gradually in small portions and the blue mixture was stirred at-60 ℃ for 4 hours. MeOH/NH was added₄After a saturated aqueous solution of Cl (1: 1, 20mL) the color faded and the cooling bath was removed. Evaporating NH₃Thereafter, concentrated hydrochloric acid was added to adjust the pH of the slurry to 1 and stirred for 24 hours. The mixture was then basified to pH10 (30% NaOH, T < 15 ℃) and solid NaCl was added until the organic layer separated. The aqueous solution was extracted with dichloromethane (8X 50mL) and the combined organic layers were washed with brine, over MgSO₄And drying. Evaporation gave a red oil which was purified by column chromatography (silica gel, dichloromethane/ethanol, 20: 1) to give a colorless oil (4.69g, 24.05mmol, 76%). The sample was converted to the hydrochloride salt for analysis, mp148-150 ℃.

IR(KBr)2950，2384，1711，1464cm^-1；¹H-NMR(CDCl₃)δ3.10(dt，1H，J＝3.91Hz，9.52Hz)，1.23-1.80(m，7H)，1.93-2.72(m，10H)，0.84(t，3H)ppm；¹³C-NMR(CDCl₃)δ210.4，59.5，54.3，46.3，36.6，36.0，33.7，26.8，23.6，22.7，18.0，10.3ppm；MS(EI)m/z 195(M+).

d) 1-propyl-trans-2, 3, 4, 4a, 5, 7, 8, 9, 10, 10 a-decahydrobenzo [ g ] quinolin-6-one (GMC6650) and 1-propyl-cis-2, 3, 4, 4a, 5, 7, 8, 9, 10, 10 a-decahydrobenzo [ g ] quinolin-6-one (GMC6651)

To a cooled (0 ℃ C.) KO^tBu (2.5g, 25.6mmol) in dry N₂To a washed suspension of dimethylformamide (4mL) was added dropwise (3-ethoxycarbonylpropyl) triphenylphosphine bromide (12.9g, 28.2mmol) dried over N₂Washed dimethylformamide (25 mL). After the addition was complete, the mixture was stirred at 0 ℃ for 30 minutes. Then adding trans-N-propyl-7-keto-1, 2, 3, 4, 4a, 5, 8, 8 a-octahydro- [6H ] dropwise at 0 DEG C]Dried N of quinoline (2.5g, 12.8mmol) (from step c) above)₂Washed dimethylformamide (4 mL). After stirring at 0 ℃ for 4 hours, the temperature was allowed to rise to room temperature and stirring was continued overnight. Water (50mL) was added and the mixture filtered through celite (2 g). The filtrate was extracted with hexane (5X 25 mL). The combined organic layers were dried (MgSO)₄) Filtered and evaporated to give a beige solid (9.1 g). The solid was dissolved in dichloromethane (10mL) and PPA (40g) was added with stirring at 100 ℃. After stirring at this temperature for 4 hours, crushed ice (50g) was added and the reaction mixture was cooled to about 80 ℃. Stirring was continued at this temperature for 1 hour, and then the solution was allowed to cool to room temperature. Concentrated aqueous ammonia was added until the pH was 8, and the solution was extracted with dichloromethane (6 × 100 mL). The combined organic layers were dried (MgSO)₄) Filtered and evaporated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol, gradient) and the product was subsequently converted to the hydrochloride salt and recrystallized from ether/ethanol. Cis-isomer: yield 0.07g, 0.3mmol (6%). IR (KBr)2928, 2592, 1668, 1457, 1394cm^-1；¹H-NMR 500MHz(CDCl₃)δ3.20(t，1H，J＝11Hz)，2.75(d，1H)，2.00-2.58(m，12H)1.82-2.00(m，2H)，1.52-1.79(m，4H)，1.38(d，1H)，1.22-1.29(dq，1H)，0.90(t，3H)ppm；¹³C-NMR(CDCl₃)δ197.3，151.1，128.7，54.8，53.5，45.1，36.3，31.0，29.7，26.3，24.0，23.3，22.6，20.9，18.0，10.3ppm；MS(EI)m/z 249(M⁺).

Trans isomer: yield 0.61g, 2.2mmol (67%), mp 235 ℃ IR (KBr)2928, 2592, 1668, 1457, 1394cm^-1；¹H-NMR 500MHz(CDCl₃)δ3.06(d，1H，J＝11.2Hz)，2.72-2.78(dt，1H)，2.15-2.55(m，10H)，1.51-1.99(m，9H)，1.01-1.10(dq，1H)，0.89(t，3H)ppm；¹³C-NMR 200MHz(CDCl₃)δ197.0，152.6，129.8，59.6，53.6，51.2，36.1，35.2，34.9，29.3，29.4，28.1，23.2，20.8，15.8，10.4ppm；MS (EI)m/z 249(M⁺).

Example 7.1-propyl-trans-2, 3, 4, 4a, 5, 7, 8, 9, 10, 10 a-decahydrobenzo [ g ] quinolin-6-one (GMC6650) and 1-propyl-cis-2, 3, 4, 4a, 5, 7, 8, 9, 10, 10 a-decahydrobenzo [ g ] quinolin-6-one (GMC6651)

A solution of 3-ethynyl-2-cyclohexen-1-one (GMC6573) (example 5a) (1.80g, 15.0mmol) in 1, 2-dichlorobenzene (50mL) was added to a solution of 1-propylamine-4-pentene in 1, 2-dichlorobenzene (50 mL). The solution was stirred at room temperature for 30 minutes and then at 190 ℃ for 72 hours. After cooling, the mixture was poured into 4N HCl (400mL) and stirred at room temperature for 2 hours. The acidic layer was separated and extracted with ether (2X 50 mL). The aqueous layer was then made basic with concentrated aqueous ammonia (pH 8) and extracted with dichloromethane (5 × 50 mL). The combined organic layers were washed with brine (50mL) and dried (MgSO)₄). Evaporation gave a dark oil, which was purified by column chromatography (silica gel, dichloromethane/methanol, gradient) and the product was subsequently converted into the hydrochloride salt, isolated in 2% yield. Analytical data are as in example 6.

The above procedure was repeated, but without the 1, 2-dichlorobenzene solution, the reactants were reacted neat at 300 ℃. When carried out in this way, the yield is significantly increased.

Example 8.1-propyl-trans-2, 3, 4, 4a, 5, 7, 8, 9, 10, 10 a-decahydrobenzo [ g ] quinolin-6-one (GMC6650) resolution

5mg mL of^-1A solution of the racemate GMC6650 prepared in example 6 in hexane/isopropanol (4/1(v/v)) was injected into an HPLC system equipped with a Water 510HPLC pump and a Chiralpack AD semi-preparative column (250X 10mm) with a 500. mu.L cell. The mobile phase was a mixture produced by ISCOModel 2360Gradient Programmer and consisted of 98% hexane (containing 0.1% (w/w) triethylamine) and 2% isopropanol/hexane (1/1 (w/w)). The flow rate of the mobile phase was 4.0 mL/min. The separated enantiomers were determined with a Water 486Millipore Tunable absorption analyzer (. lamda. 254nm, AUFS. 2.0) and used by Kipp&Zonen planograph (recording paper speed 5 mm/min. alpha. 1.33; k)₁’＝2.16；k₂' -2.88) is recorded on paper. Fractions were collected manually. After evaporation of the mobile phase, the optical rotations of the two fractions were determined with a Perkin Elmer 241 Ploarimeter. First elution fraction: [ alpha ] to]_d ²⁰＝+185 ° (c 0.08, methanol). Second elution fraction: [ alpha ] to]_d ²⁰-214 ° (c ═ 0.07, methanol). The purity of both enantiomers was analyzed with the same HPLC system but now with a column (250 × 4.6mm) equipped with a Chiralpack AD assay and a 20 μ l cell (e.e. > 99.9% for both enantiomers). Both enantiomers were converted to the corresponding maleate salts and recrystallized from ethanol/diethyl ether. Melting point: (+) -GMC 6650. maleate mp: 186 ℃ and(-) -GMC6650 maleate mp: 192 ℃.

Scheme 4) prodrugs of benzo [ f ] quinolines:

reagent: (a) chloropropyl-alkylamine; (b) NaBH₃CN

Example 9N-propyl-benzo [ f ] quinoline prodrugs

N-propyl-8, 9-dihydro-10H-aporphine-11-one

a) The method comprises the following steps:

to a stirred solution of 3, 4, 7, 8-tetrahydro-2H, 5H-naphthalene-1, 6-dione (0.5g, 3.0mmol) in dry acetonitrile (15mL) was added 3-chloropropyl-propylamine (0.38g, 3.0 mmol). The mixture was heated to 80 ℃ under argon for 36 hours. The reaction mixture was then cooled to room temperature and diluted with ether (25 mL). Filtration and evaporation of the solvent gave an oil which was dissolved in tetrahydrofuran (15mL) and cooled to 0 ℃. Using NaBH under acidic conditions₃The crude product is reduced with CH. The procedure is carried out in the usual manner and the product is purified by column chromatography, followed by conversion of the separated cis-and trans-products into pharmaceutically acceptable salts and recrystallization to give the desired product.

b) The method 2 comprises the following steps:

mixing 1, 3-cyclohexanedione (0.2mol), paraformaldehyde (0.2mol), (3-chloropropyl) -propylamine (0.2mol) in tolueneAnd powderyAnd (3) a molecular sieve. The mixture was heated and acetone (0.2mol) was added and heating was continued. The reaction mixture was concentrated in vacuo and then washed with a silica gel column. The fractions containing the product were combined and concentrated. The material was further purified by column chromatography. Using NaBH under acidic conditions₃CN reduces the purified dienaminone (dienaminone). The product is purified by conventional procedures and column chromatography, followed by conversion of the isolated cis and trans products to pharmaceutically acceptable salts and recrystallization to give the desired product.

Scheme 5) synthesis of apomorphine prodrugs:

synthesis of main structural units:

keto-translocation and attachment to ring 4:

reagent: (a) NaBH₄；(b)6N HCl；(c)i)BrCH₂CONH₂，HCO₂H; ii) NaOH; (d) carrying out Wittig reaction; (e) PPA.

Benzyne scheme:

n-propyl aporphine prodrugs

Example 10

a) 3-Aminophenylacetic acid ethyl ester (GMC6635)

To a cooled (-15 ℃ C.) solution of 3-aminophenylacetic acid (10.2, 67mmol) in ethanol (200mL) was added thionyl chloride (10mL, 0.14mol) dropwise. The reaction mixture was stirred for 24 hours and the temperature was slowly raised to room temperature. The volatiles were evaporated to give a beige solid which was stripped (strip) several times with dichloromethane. The solid was then treated with hot ether and filtered to remove diethyl sulfite. Recrystallization from ether gave 14.4g, 67mmol, 100% of the desired compound as pure white crystalline hydrochloride salt, mp 135 ℃. IR (KBr) cm^-1 2857，2614，1740。

b) N-propyl-2- (3-aminophenyl) ethylamine (GMC6636)

Ethyl 3-aminophenylacetate hydrochloride (2.7g, 13mmol) was added to n-propylamine (20mL) with stirring and cooled to 0 ℃. After stirring for 45 minutes, the reaction mixture was evaporated to give the amide product as a colorless solid. The amide was dissolved in tetrahydrofuran (20mL) and 2N BH was added at-10 deg.C₃·SMe₂Tetrahydrofuran (20 mL). After stirring at this temperature for 2 hours, the mixture was refluxed for 48 hours. The mixture was extracted to give an amine, which was converted to the hydrochloride salt. Recrystallization from acetone/diethyl ether gave 2.2g, 10mmol (77%) of product, mp 175 ℃. IR (KBr)2928, 2592, 1457, 1394cm^-1；MS(EI)m/z 178(M⁺)。

c) N-propyl-8, 9-dihydro-10H-11-oxo-aporphine (GMC6660)

A solution of 3-ethynyl-2-cyclohexen-1-one (GMC6573) (1.80g, 15.0mmol) in toluene (5mL) was added to a solution of N-propyl- (3-aminophenylethyl) amine (2.67g, 15.0mmol, free base) in toluene (5 mL). The solution was stirred for 30 minutes and then extracted with 6N HCl solution (2X 4 mL). The acidic solution was cooled to 0 ℃ and NaNO was slowly added while maintaining at 0 ℃₂(0.69g, 100mmol) in water (15 mL). After the addition was complete, the mixture was allowed to warm to room temperature and stirred until all starting material and diazotized intermediate were consumed. The acidic solution was made basic by extraction with ethyl acetate (2X 20mL)H ≈ 8), and extracted with dichloromethane (4 × 20 mL). The combined organic layers were washed with saturated Na₂CO₃The solution (50mL) was washed and dried (MgSO₄). Evaporation gave an oil which was purified by column chromatography (silica gel, dichloromethane/ethanol, 40: 1) and the purified product was subsequently converted into the hydrochloride to give 3.18g, 10mmol (67%) of product, mp 210-. Ir (kbr)2948, 2851, 1661;¹H-NMR(CDCl₃)δ5.86(d，1H)，2.48-2.67(m，6H)，2.27-2.39(m，6H)，1.96(m，2H)，1.02(t，6H)ppm；¹³C-NMR(CDCl₃)δ198.3，163.5，124.8，48.9，45.2，35.7，33.7，28.4，21.2，10.1ppm；MS(CI)m/z 282(M+1).

example 11

N-N-propyl-1, 3, 4, 4a, 5, 6, 8, 9, 10, 10 b-decahydro-2H-benzo [ f ] quinolin-7-one

1-propyl-7-oxo-2, 3, 7, 8, 9, 9 a-hexahydro-1H-benzo [ de ] quinoline is reduced to the corresponding alcohol, which is subsequently dehydrated. The exocyclic double bond is epoxidized after ring opening to form 1-propyl-6-oxo-2, 3, 6, 8, 9, 9 a-hexahydro-1H-benzo [ de ] quinoline. This keto group is subjected to wittig reaction with (3-ethoxycarbonyl-propyl) -triphenylphosphine bromide. After conventional operation, the crude product was dissolved in dichloromethane and added to PPA. After the cyclization is complete, the product is hydrolyzed under acidic conditions. After basification the crude final product is obtained by extraction. It is purified by column chromatography, then converted to a pharmaceutically acceptable salt and recrystallized.

Pharmacology of

Behavioral testing of the Compound GMC6650 (example 6) in rats

Rats weighing approximately 350g were injected subcutaneously with 1. mu. mol/kg of GMC6650 in the neck. Another rat weighing approximately 350g was given the same dose by oral injection. The drug (3.4mg) was initially dissolved in ethanol (50. mu.L), 1M acetic acid (2 drops) and water (1.4mL), corresponding to 15. mu. mol per 1.5mL, which means a concentration of 10. mu. mol/mL. The solution was first diluted 10 fold and injected with 0.35mL, giving a dose of 1. mu. mol/kg. Both rats were treated as such.

Both individuals showed the same form of biological activity, independent of the type of administration received by the rat: after the rats were gradually sedated for 10 minutes, their eyes were closed or partially closed. After 15 minutes a clear dopaminergic effect, i.e. chewing, sniffing, licking, combing the penis, combing, was seen, after 30 minutes both rats showed clear signs of stereotypy.

Engraving was severe and showed several hours with visual inspection. After 10 hours, both rats still showed signs of stereotypy. The next morning, the subcutaneously injected rats were still alive and the orally administered rats were calm. Therefore, the action time is more than or equal to 10 hours for subcutaneous injection and oral administration of 1 mu mol/kg.

Claims (4)

1. A compound of formula If:

wherein the content of the first and second substances,

m is 1;

R₂selected from hydrogen atoms, alkyl groups of 1 to 7 carbon atoms.

2. A compound according to claim 1, wherein R is₂Is n-propyl.

3. A pharmaceutical composition comprising a compound of general formula If as defined in claim 1 together with a pharmaceutically acceptable carrier, diluent or excipient.

4. Use of a compound of general formula If as defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of parkinson's disease.