韩国专利KR19990077308A Quinolin-2- (1H) -one

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The present invention relates to quinolin-2- (1H) -one derivatives of formula (I) and their possible enantiomers and salts and solvates thereof. Formula I [Wherein, R 1 , R 2 and R 3 are each independently H, Hal, A or OA, R 4 is H,-(CH 2 ) m -NR 6 R 7 , R 5 is H,-(CH 2 ) n -NR 6 R 7 , R 6 is H, A or is — (CH 2 ) 4 — or — (CH 2 ) 5 — together with R 7 ; R 7 is H, A or — (CH 2 ) m — bonded to the same ring or adjacent ring B or D, or — (CH 2 ) 4 — or — (CH 2 ) 5 — together with R 6 , X is -CHR 5- , -NR 5- , -O-, -S-, A is alkyl having 1-6 carbons, Hal is F, Cl, Br or I, m is 1-3, n is 0-3, Wherein at least one of the two radicals R 4 or R 5 is — (CH 2 ) m —NR 6 R 7 or — (CH 2 ) n —NR 6 R 7. ] The invention also relates to the use of these compounds and their physiologically acceptable salts thereof for the treatment of neurodegenerative changes in CNS function.
公开号:KR19990077308A
申请号:KR1019980705454
申请日:1997-01-10
公开日:1999-10-25
发明作者:크리스토프 제이프리트；칼아우구스트 악커만；루돌프 고트슐리히；귄터 횔제만；요하킴 라이브록크；빌프리트 라우텐베르그
申请人:플레믹 크리스티안；메르크 파텐트 게엠베하；
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专利说明:

Quinolin-2- (1H) -one
Patent applications WO 93/11115 A1 and EP 0 481 676 A1 describe quinoline- (1H) -one derivatives which act as antagonists of glutamate receptors, in particular NMDA receptors. Because of this property, the compound can cause stroke or hypoglycemia, cerebral palsy, transient cerebral ischemic attack, cerebral ischemia during surgical cardiopulmonary intervention or cardiac arrest, asphyxiation at delivery, epilepsy, Huntington's chorea, Alzheimer's disease, muscular dystrophy Suitable for the treatment of acute neurodegenerative diseases caused by poisoning by exogenous and endogenous NMDA receptor agonists or neurotoxins, including Parkinson's disease, cerebellar atrophy, drowning, oxygen deficiency due to bone marrow and head damage, and those in the natural environment It is described.
In addition, suitable compounds are suitable for the prevention of related neurodegenerative diseases and, due to NMDA receptor-antagonistic action, can be used as antispasmodic, analgesic, antiemetic, or to prevent or alleviate the dependence of anesthetics.
However, when applied to certain indication fields, it has not been possible to detect the desirable activity of quinolin-2- (1H) -one in which the 3-position is substituted with various phenyl groups. This is especially true when using such agents in liquid form; This is particularly true when administered as infusions. Such dosage forms are necessary if the patient to be treated is unconscious.
Accordingly, it is an object of the present invention to provide compounds with improved neuroprotective action.
It is also an object of the present invention to provide a process which can be used in such a way that a suitable compound can be prepared in the highest possible yield and high purity.
The present invention relates to quinolin-2- (1H) -one derivatives of formula (I) and salts and solvates thereof.
Where
R ¹ , R ² and R ³ are each independently H, Hal, A or OA,
R ⁴ is H,-(CH ₂ ) _m -NR ⁶ R ⁷ ,
R ⁵ is H,-(CH ₂ ) _n -NR ⁶ R ⁷ ,
R ⁶ is H, A or is — (CH ₂ ) ₄ — or — (CH ₂ ) ₅ — together with R ⁷ ;
R ⁷ is H, A or — (CH ₂ ) _m — bonded to the same ring or adjacent ring B or D, or — (CH ₂ ) ₄ — or — (CH ₂ ) ₅ — together with R ⁶ ,
X is -CHR ^5- , -NR ^5- , -O-, -S-,
A is alkyl having 1-6 carbons,
Hal is F, Cl, Br or I,
m is 1-3,
n is 0-3,
Wherein at least one of the two radicals R ⁴ or R ⁵ is — (CH ₂ ) _m —NR ⁶ R ⁷ or — (CH ₂ ) _n —NR ⁶ R ⁷ .
The invention also relates to the use of these compounds and their physiologically acceptable salts for the treatment of neurodegenerative changes in CNS function.
This object is achieved by the present invention.
It has been found that the compounds of formula (I) wherein the radicals R ¹ to R ⁷ , A, Hal, X, m and n are as described above, and their physiologically acceptable salts, have useful pharmacological properties. In particular, such compounds are selective antagonists of N-methyl-D-aspartate receptors (NMDA receptor antagonists). The compounds according to the invention have proved to be in particular selective ligands of the strkinin-insensitive glycine receptor which modulates the NMDA receptor. Therefore, the present compounds are suitable for the treatment of neurodegenerative diseases including cerebrovascular diseases. The compounds are particularly useful for stroke or hypoglycemia, cerebral palsy, transient cerebral ischemic attacks, cerebral ischemia during surgical cardiopulmonary intervention or cardiac arrest, asphyxiation at delivery, oxygen starvation, drowning, bone marrow and head injury, exogenous and endogenous NMDA receptors. It is caused by poisoning by agonists or neurotoxins and is well suited for the treatment of acute neurodegenerative diseases caused by epileptic seizures or Huntington chorea.
Experiments show that the compounds according to the invention are particularly effective in the case of infarction. Therefore, these compounds can be administered, for example, in the form of infusions to patients in an unconscious state.
However, the compounds according to the invention are also suitable for the prevention of appropriate neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, cerebellar atrophy, amyotrophic lateral sclerosis or poisoning by environmental toxins. It is also suitable for the treatment of psychosis due to excessively high amino acid levels.
Because of the NMDA receptor-antagonistic properties, suitable compounds according to the invention are valuable as analgesics, antidepressants or anxiolytics, especially for migraines, or to prevent or lessen the potential for dependence on anesthetics.
In general, this means that the compounds according to the invention can be effectively used for all indications associated with an abnormal increase in extracellular glutamate concentrations in the brain, with an increase in both NMDA and AMPA receptor activity. Therefore, it is particularly desirable to use in situations where an immediate effect on the NMDA receptor is required, for example in brain dysfunction due to vascular damage or occlusion or due to oxygen deficiency associated with lack of energy in the brain. The compounds according to the invention are particularly advantageous in this situation as they can be administered by injection and / or infusion. In this case, the treatment must be treated in a very short time, so the faster the active compound reaches the site of action, the better the anticipated treatment for the patient and the avoidance of sustained damage to the patient.
M.B. Tests for glycine binding sites of NMDA receptors according to Baron et al. Are described in Eur. J. Pharmacol. (1991) 206 149-154. In vitro amino acid release can be detected according to the methods of D. Lobner and P. Lipton (Neurossci. Lett. (1990) 117, 169-174). The action on Parkinson's disease, ie, in Hemi-Parkinson rats, synergism of L-dopa-induced contralateral rotation is described by U. Ungerstedt and G. W. Arbuthnott [Brain Res. (1970) 24, 485.].
The above actions can additionally be detected or identified by the methods described in the following references.
J.W. McDonald, F.S. Silverstein and M.V. Johnston, Eur. J. Pharmacol. (1987) 140, 359; R. Gill, A.C. Foster and G.N. Woodruff, J. Neurosci. (1987) 7, 3343, S.M. Rothmann, J.H. Thurston, R. E. Hauhart, G.D. Clark and J.S. Solomon, Neurosci. (1987) 21, 73 or M.P. Goldbert, P.-C. Pham and D.W. Choi, Neurosci. Lett. (1987) 80, 11.
Therefore, these compounds can be used as pharmaceutically active compounds in human and veterinary medicines. It is also suitable for use as an intermediate in the preparation of other compounds having useful properties.
The present invention therefore relates to compounds of formula (I), salts thereof and uses thereof, and to processes suitable for the preparation of compounds according to the invention.
In formula (I), group A is alkyl having 1,2,3,4,5 or 6 carbon atoms, especially methyl or ethyl, and also propyl, isopropyl, butyl, isobutyl, secondary-butyl and tert-butyl to be. Group OA is preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary-butoxy or tert-butoxy, group -NA- is N-methyl-di, group- NHA is preferably NH-methyl.
R ¹ is preferably H, Hal or alkyl, with H or Hal being particularly preferred.
R ² is preferably a halogen or alkoxy group OA, with fluorine or chlorine being particularly preferred.
R ³ is preferably H or A.
R ⁴ is preferably H or-(CH ₂ ) _m -NR ⁶ R ⁷ . Wherein R ⁶ is H, A, or together with R ⁷ ,-(CH ₂ ) ₄ -or-(CH ₂ ) ₅ -is preferred, wherein R ⁷ is H, A, in the same ring or in an adjacent ring Or-(CH ₂ ) _m -or-(CH ₂ ) ₄ -or-(CH ₂ ) ₅ -together with R ⁶ .
R ⁵ is H or-(CH ₂ ) _n -NR ⁶ R ⁷ and R ⁶ is H, A or together with R ⁷ is-(CH ₂ ) ₄ -or-(CH ₂ ) ₅ -and R ⁷ Is H, A, or-(CH ₂ ) _m -which is bonded to the same ring or adjacent ring, or-(CH ₂ ) ₄ -or-(CH ₂ ) ₅ -together with R ⁶ .
X is preferably -CHR ^5- , O or -NR ^5- , where R ⁵ is preferably H when R ⁴ is-(CH ₂ ) _m -NR ⁶ R ⁷ .
The present invention therefore relates in particular to compounds of the formula (I) in which at least one of the foregoing radicals is one of the above preferred definitions. Some preferred groups of compounds may also be represented by the following formulas corresponding to formula (I). Here, radicals which are not described in more detail are as defined in formula (I).
In la, R ¹ is H or Hal, R ² is Hal, X is -CHR ^5- , wherein R ⁵ is-(CH ₂ ) _m -N ⁶ R ⁷ , R ⁶ is methyl, R ⁷ is-(CH ₂ ) _m -attached to ring B.
In Ib R ¹ is H or Hal, R ² is Hal, X is -CHR ^5- , wherein R ⁵ is-(CH ₂ ) _m -N ⁶ R ⁷ , R ⁶ is methyl, R ⁷ is-(CH ₂ ) _m -attached to ring D.
In Ic R ¹ is H or Hal, R ² is Hal, X is -CHR ^5- , where R ⁵ is H, R ⁴ is-(CH ₂ ) _m -N ⁶ R ⁷ , and R ⁶ is methyl and R ⁷ is-(CH ₂ ) _m -attached to ring B.
In Id R ¹ is H or Hal, R ² is Hal, X is -CHR ^5- , where R ⁵ is H, R ⁴ is-(CH ₂ ) _m -N ⁶ R ⁷ , and R ⁶ is methyl and R ⁷ is-(CH ₂ ) _m -bonded to ring D.
In Ie, R ¹ is H or Hal, R ² is Hal, X is -CHR ^5- , where R ⁵ is H, R ⁴ is-(CH ₂ ) _m -N ⁶ R ⁷ , and R ⁶ is methyl and R ⁷ is-(CH ₂ ) _m -bonded to ring D.
In If, R ¹ is H or Hal, R ² is Hal, X is -CHR ^5- , where R ⁵ is H, R ⁴ is-(CH ₂ ) _m -N ⁶ R ⁷ , and R ⁶ and R ⁷ together are — (CH ₂ ) _m — to form a heterocycle with the nitrogen connected.
In Ig, X is -CHR ^5- , wherein R ⁵ is-(CH ₂ ) _m -N ⁶ R ⁷ , and R ⁶ and R ⁷ together are-(CH ₂ ) _m- , the nitrogen and heterocycle linked To form.
Preference is also given to compounds of the formulas 2a to 2d which correspond to formulas I and Ic to If, wherein X is O.
When using the compound of formula (I) as a pharmaceutically active ingredient, both the compound itself and its physiologically acceptable salts can be used. Other salts may be used to release the compounds of formula (I). However, these salts can be converted in part to pharmaceutically acceptable salts or used as intermediates in the preparation of other active compounds. Suitable salts of the compounds of formula (I) which can be used pharmaceutically are alkali metal salts such as lithium salts, sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts or otherwise salts formed with quaternary ammonium compounds. . However, in the present invention, compound I may also exist as a salt of a physiologically acceptable acid. In particular, it may be present as a salt of hydrochloric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, malic acid, formic acid or phosphoric acid.
The compounds of the formula (I) according to the invention may have asymmetric centers due to their molecular structure and therefore may have several enantiomers or diastereomers. Due to one or more chiral centers, they may exist in racemic or optically active form. All such optically active forms and mixtures thereof are included in Formula (I). Since the pharmaceutical activity differs for each optically active form, it may be desirable to use pure isomers or enantiomers. In this particular case, the final product can be partitioned into pure enantiomeric compounds by chemical methods known to those skilled in the art, or, if separated, by mechanical methods. Preference is given to using the optically active splitting agent to form diastereomers from the racemic mixture. The splitting agent is suitably suitable for optically active acids such as various optically active camphorsulfonic acids such as, for example, D- and L-type tartaric acid, diacetyl tartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or β-camphorsulfonic acid. Do. It is also advantageous to split the enantiomers using a column packed with an optically active splitting agent (eg dinitrobenzoylphenylglycine). As eluent for this purpose, for example, a mixture of hexane / isopropanol / acetonitrile (for example, a ratio of 82: 15: 3) is suitable.
However, in special cases, suitable pure enantiomeric intermediates may be used during synthesis. Accordingly, all enantiomers or diastereomers of the intermediates described below are also included in the following general formula.
The invention also relates to quinolin-2- (1H) -one derivatives of formula (I) and salts thereof according to claim 1. According to one preparation process, the compound of formula I can be prepared by a cyclization reaction in which a suitable compound of formula II is reacted in the presence of a base such as sodium hydroxide or potassium hexamethyldisilazide to obtain a compound of formula I.
(Wherein R ¹ , R ² , R ³ and R ⁴ and X are as defined above and G is a cyano group or a reactive carboxylate group.)
The reactive carboxylate group may be an ester group, with alkyl ester groups having 1 to 4 carbon atoms or mixed anhydrides (eg, anhydrides of acids having 1 to 4 carbon atoms) being preferred; For example, it may be an acid halide group such as an acid chloride group, an ortho ester group, or a primary, secondary or tertiary amide group.
The reactive carboxylate group is preferably a methoxycarbonyl or ethoxycarbonyl group.
The cyclization reaction can be carried out by known methods, for example under mild conditions in the presence of sodium hydroxide or potassium hexamethyldisilazide (J. Heterocycl. Chem. (1975) 12, 351). The reaction finish is carried out under mild weak acid conditions.
Cyclization reactions of suitable compounds wherein G is a cyano group can yield quinolin-2- (1H) -one derivatives of formula (I), but the 4-position is substituted with an amino group. This amino group can be substituted with a preferable hydroxyl group by a well-known method, if it protects the other amino groups contained in a compound by a protecting group, and will not participate in reaction.
According to the general formula, up to two -identical or different-protecting groups can be present in the molecule of the starting material. If the protecting groups present are different from one another, most of them can be removed selectively.
The term "amino protecting group" means a known group which is generally suitable for protecting (blocking) an amino group from a chemical reaction and is easy to remove after carrying out the desired chemical reaction in another part of the molecule. Typical examples of such groups include unsubstituted or substituted acyl, aryl [eg dinitrophenyl (DNP)], aralkoxymethyl [eg benzoxymethyl (BOM)] or aralkyl groups (eg Benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protecting group is removed after the desired reaction (or series of reactions), its nature and size are not critical; However, it is preferable that they are C1-C20, especially C1-C8.
The term "acyl group" may be interpreted in the broadest sense with respect to the method of the invention. Acyl groups include acyl groups derived from aliphatic, aromatic aliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, in particular alkoxycarbonyl groups, aryloxycarbonyl groups and especially aralkoxycarbonyl groups. Examples of this type of acyl group include alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenacetyl; Aroyl such as benzoyl or tolyl; Aryloxyalkanoyl such as phenoxyacetyl; Such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodo-ethoxycarbonyl Alkoxycarbonyl; Aralkyloxycarbonyl such as benzyl-oxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC). Preferred amino protecting groups are BOC, DNP and BOM, with CBZ, benzyl and acetyl being preferred.
Compounds of formula (II) can be prepared from known compounds of formula (III) by known methods.
Wherein G is as described above.
Wherein R ³ , R ⁴ and X are as defined above and Q is a reactive carboxylate group as described above. Q is preferably an acid halide group, and precisely an acid chloride group. Compounds of formula IV wherein Q is an acid chloride group can be prepared simply by treating compounds with Q corresponding to the appropriate acid group —COOH with thionyl chloride or oxalyl chloride by methods known to those skilled in the art.
This reaction is carried out under an appropriate condition in an inert solvent such as, for example, dichloromethane or 1,2-dichloroethane. For this purpose, the reaction mixture is heated with stirring. It is preferable to perform reaction by setting to the boiling point of the solvent using temperature under reflux conditions.
Compounds of formulas (III) and (IV) which are required as intermediates in the preparation of compounds of formula (I) according to the invention, if not commercially available, are prepared by methods known to those skilled in the art or by modifications to the corresponding compounds. can do. Methods of preparation are described, for example, in EP-A1-0 481 676 or in J. Pat. Heterocycl. Chem. (1975) 12, 351 and ibid (1988) 25, 857. Corresponding compounds can be prepared by the methods described in the Examples below or by analogous methods.
Compounds of formula (I) can also be prepared by cyclization of the compounds of formula (V) and optionally hydrolysis to convert them into preferred compounds of formula (I).
Wherein R ¹ , R ² , R ³ and R ⁴ and X are as described above and Q ¹ is a reactive carboxylate group as described above, preferably for example methoxycarbonyl or ethoxy Alkyl, such as carbonyl, is a C1-C4 alkyl ester group.
Compound V, obtained as an intermediate, wherein Q ¹ is an alkyl ester group, can be obtained from the compounds of formulas III and IV by the Claisen ester condensation reaction wherein both substituents G and Q are each alkyl ester groups having 1-4 alkyl atoms . The reaction can be carried out at elevated temperature in the presence of a strong base such as, for example, potassium hexamethyldisilazide. It is preferable to carry out under reflux conditions so that the temperature is set close to the boiling temperature of the solvent. The cyclization reaction of the compound of formula V to the compound of formula I can be carried out under conditions known to those skilled in the art or under slightly modified conditions. This reaction is preferably carried out in the presence of an acid. The cyclization reaction can be carried out directly in the same reaction solution without separating the previously prepared compound.
In addition, compounds of formula (I) may be prepared from compounds of formula (VI).
Wherein R ¹ to R ⁴ and X are as described above. Compounds of formula (VI) can be prepared by reacting the malonic acid derivative of formula (VII) with a suitable compound of formula (VIII) under appropriate conditions under appropriate conditions.
Wherein R ³ , R ⁴ and X are as defined above and R is alkyl of 1-6 carbon atoms)
(Wherein R ¹ and R ² are as defined above).
J. Heterocycl. Chem. (1988), 25, 857] are particularly preferred. The reaction conditions can be easily modified depending on the substituents. The compounds of formulas (VII) and (VIII) are preferably heated together for about 15 to 20 hours in a suitable solvent. The reaction is carried out under reflux conditions, and the reaction temperature is preferably set to the boiling temperature of the solvent used.
The cyclization of the compounds of Formula VI to Formula I is described in J. Chem. Heterocycl. Chem. (1988), 25, 857, it is preferable to carry out in the presence of phosphorus pentoxide in methanesulfonic acid as a solvent.
The compounds of the formulas III, IV, VI, VII and VIII and the precursors used for this can be prepared by the methods described in the following examples or by modifications known to those skilled in the art, if not commercially available. have.
In addition, compounds of formula (I) prepared by one of the methods described above may be converted to other compounds of formula (I) by known methods, if necessary. In particular, it is often necessary to remove previously introduced protecting groups in a suitable manner after the cyclization reaction.
If the compound of formula (I) is prepared as a stereoisomer mixture, the corresponding isomers can be separated by conventional methods known to those skilled in the art. Separation of the isomeric compounds is preferably carried out by chromatography. The compounds are formed as racemic mixtures, as described above, or specifically synthesized as individual enantiomers, and then divided into pure enantiomers using different solubility of salts in certain solvents. For this purpose, by means known to those skilled in the art, starting from the enantiomers and suitable optically active acids according to the invention, the corresponding salts which can be divided into fractional crystals are prepared. For this purpose it is preferred to use optically active natural substituents or derivatives thereof. Suitable optically active acids are, for example, (-)-di-p-toluoyl- (D) -tartaric acid and / or (+)-D-p-toluoyl- (D) -tartaric acid. Preferred bases can then be liberated again in a simple manner. The formation of diastereomeric esters or amides that can be separated by chromatography is suitable for the separation of enantiomers. After completion of the cleavage, the isomerically pure compound may again be advantageous.
Therefore, the compounds of formula (I) and their physiologically acceptable salts can be used in the production of pharmaceutical preparations by preparing in suitable dosage forms together with at least one excipient or adjuvant and, if necessary, one or more other active compounds. The formulation thus obtained can be used as a medicament in human medicine or veterinary medicine. Possible excipients are organic or inorganic substances that are suitable for enteral (eg oral or rectal) or parenteral administration and do not react with the novel compounds, for example, water, vegetable oil, benzyl alcohol, polyethylene glycol, Carbohydrates such as glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, lactose or starch, magnesium stearate, talc or cellulose.
Tablets, coated tablets, capsules, syrups, juices or drops are especially used for oral administration. Of particular interest are lacquered tablets and capsules with a shell or capsule shell. Suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions and suspensions, emulsions or implants for parenteral administration.
The active compounds claimed according to the invention can also be lyophilized and the lyophilisate obtained can be used, for example, in the production of injections or infusions.
The formulation may be sterilized and / or may contain auxiliaries such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants and / or flavoring agents. It may also contain one or more further active compounds, if desired, for example one or more vitamins, diuretics or anti-inflammatory agents.
Infusions containing one or more compounds of formula (I) and / or physiologically acceptable salts thereof are prepared by conventional conventional methods. However, immediately before use, one or more compounds according to the invention can be added as an active ingredient to a suitable infusion solution which is commercially available.
The compounds of formula (I) according to the invention are generally administered similarly to other known commercially available formulations for the claimed indications, preferably in the range of about 0.1 mg to 500 mg, especially 5 to 300 mg per dosage unit. Do. The daily dose is preferably in the range of about 0.01 to 250 mg per kg of body weight, particularly in the range of 0.02 to 100 mg.
However, the specific dosage of each patient may vary depending on a variety of factors, such as activity, age, weight, general health, sex, diet, time and route of administration, and rate of excretion, concomitant medications and the specific disease to be treated. Depends on the severity Administration in the form of injections or infusions is preferred.
In the following examples, "normal or general reaction finishing" means: if necessary, water is added, extracted with an organic solvent such as dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered and evaporated Concentration and purification of the residue by chromatography and / or crystallization. In the above and below examples, all temperatures are in degrees Celsius (uncorrected) and all parts and percentages are by weight.
In the following, the examples are used to explain the present invention, and the present invention is not limited to the given examples.
Example 1
7-chloro-1,2-dihydro-4-hydroxy-3- [3- (R, S) -1,2,3,4-tetrahydro-2-methyl-4-isoquinolyl) phenyl] Quinolin-2-one
Starting material:
a) 2.7 g of methyl 3- (2-bromoacetyl) phenylacetate [obtainable by radical bromination of methyl 3-acetylphenylacetate] is dissolved in 30 ml of acetonitrile and 2.8 g of N-methyl To the solution containing benzylamine and 20 ml of acetonitrile was added dropwise with stirring. The mixture was stirred at rt for 2 h. The solvent was distilled off and the residue was treated with ether. The solution was finished with general reaction to give 3-methoxycarbonylmethyl-alpha-benzylmethylamino-acetophenone as an oil.
aa) similarly using dichloromethane as solvent,
From ethyl 4- (2-bromoacetyl) phenylacetate and N-methylbenzylamine
4-Ethoxycarbonylmethyl-alpha-benzylmethylamino-acetophenone was prepared.
b) 2-benzylmethylamino-1- (3-methoxycarbonylmethylphenyl) ethanol
3.2 g of 3-methoxycarbonylmethyl-alpha-benzylmethyl-aminoacetophenone was dissolved in 15 ml of methanol. 0.39 g of NaBH ₄ was added to the reaction mixture with stirring and cooling. After stirring the reaction solution for about 1 hour, the solvent was removed. The residue was treated with ether and shaken with water and extracted three times. The organic phase was dried. The ether was removed by distillation to give 2-benzylmethylamino-1- (3-methoxy-carbonylmethylphenyl) ethanol.
bb) similarly,
From 4-ethoxycarbonylmethyl-alpha-benzylmethylamino-acetophenone,
2-benzylmethylamino-1- (4-ethoxycarbonylmethylphenyl) ethanol was obtained.
c) methyl 3- (2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl acetate
1.5 g of 2-benzylmethylamino-1- (3-methoxycarbonylmethylphenyl) ethanol was dissolved in 13 ml of dichloromethane. To this solution was added dropwise 3.7 ml of concentrated sulfuric acid with cooling and stirring. Stir at room temperature for 3 hours. The reaction solution was diluted with dichloromethane and treated with ice. Then this solution was adjusted to the pH of the alkali using a NaOH solution. The precipitated organic phase was separated off and the aqueous phase was extracted two more times with dichloromethane. The combined organic phases were dried and the solvent was removed. The residue was dissolved in ether and the solution was filtered. The solvent was removed by distillation to give methyl 3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl acetate.
cc) similarly,
From 2-benzylmethylamino-1- (4-ethoxycarbonylmethylphenyl) ethanol,
Ethyl 4- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl acetate was obtained.
It was dissolved in 4- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl acetate in ether and treated with hydrochloric acid to give HCl-salts.
d) 3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl acetate
3.6 g of the ester obtained in the previous reaction was slowly treated with 36 ml of concentrated hydrochloric acid while stirring and cooling. The mixture was then stirred again at reflux for 3 hours. The reaction solution was cooled, diluted with water, and reaction-finished in the usual manner to obtain an acid.
dd) similarly,
From ethyl 4- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenylacetate,
4- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenylacetic acid x HCl (m. P .: 275-280 °) was obtained.
e) 3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenylacetyl chloride
3.4 g of 3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenylacetate were treated with 17.6 ml of thionyl chloride with stirring. The mixture was heated to reflux and stirred for 1 hour while maintaining this temperature. The supernatant was then distilled and dried to afford 3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenylacetyl chloride.
ee) similarly,
From 4- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenylacetic acid,
4- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenylacetyl chloride was obtained.
f) methyl 2- {3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl} acetamido-4-chlorobenzoate
2 g of methyl 2-amino-4-chlorobenzoate was dissolved in 30 ml of dichloroethane and 4.0 g of 3- [2-methyl-1,2,3,4-tetrahydro-4- (R , S) -isoquinolinyl] phenylacetyl chloride was added to a solution of about 20 ml of dichloroethane, and then the mixture was heated with stirring for 3 hours. The residue obtained by distilling off the solvent was dissolved in dichloromethane, and the solution was reacted to completion in a conventional manner. The residue was separated by chromatography (dichloromethane containing silica gel / 1-2% methanol). Methyl-2- {3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl} acetamido-4-chlorobenzoate as oil Got it.
ff) similarly,
From 4- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenylacetyl chloride and methyl 2-amino-4-chlorobenzoate
Methyl-2- {4- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl} acetamido-4-chlorobenzoate was obtained.
g) methyl-2- {3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl} acetamido-4-chlorobenzoate
Segmentation of Enantiomers:
500 mg of methyl-2- {3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl} acetamido-4- from the previous reaction Chlorobenzoate was added to a column (25 cm x 5 cm) packed with a support for enantiomeric splitting based on cellulose derivatives (Kiracel-OD) (25 cm x 5 cm), consisting of hexane and i-propanol (ratio 9: 1), with a flow rate of 40 ml. Segmentation was performed using an eluent set to / min (detection: UV220). Fractions already containing high purity of two enantiomers were chromatographed again.
Purity of Enantiomers:
(-)-Methyl-2- {3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl} acetamido-4-chlorobenzo 8-100%
(+)-Methyl-2- {3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl} acetamido-4-chlorobenzo 8%-98%
h) 7-chloro-1,2-dihydro-4-hydroxy-3- [3-((R, S) -1,2,3,4-tetrahydro-2-methyl-4-isoquinoli Yl) phenyl] quinolin-2-one hydrate
1.2 g of methyl-2- {3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl} acetamido-4-chlorobenzoate Was dissolved in anhydrous THF and cooled to about 5 ° C. 6 ml of a 1 molar KN [Si (CH ₃ ) ₃ ] ₂ solution in THF was added dropwise at room temperature with stirring under argon as a protective gas. The mixture was stirred for an additional hour. Then the reaction mixture was treated with water and extracted with ether. Acidification of the aqueous alkaline phase with 25% HCl resulted in the formation of a viscous precipitate. This precipitate was opened with water, filtered off by suction, washed again with water and dried. The resulting mixture was separated by chromatography on a silica gel column using a solvent mixture consisting of 70-80% THF and 20-30% methanol as eluent. 7-chloro-1,2-dihydro-4-hydroxy-3- [3-((R, S)-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl) Phenyl] quinolin-2-one hydrate (amorphous) was obtained.
Similarly,
From methyl-2- {4- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl} acetamido-4-chlorobenzoate,
7-chloro-1,2-dihydro-4-hydroxy-3- [4-((R, S) -1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl) Phenyl] quinolin-2-one was obtained.
Precipitating the product dissolved in water with hydrochloric acid gives crystalline HCl salt from this product.
i) 7-chloro-1,2-dihydro-4-hydroxy-3- [3-((R, S) -1,2,3,4-tetrahydro-2-methyl-4-isoquinoli Yl) phenyl] quinolin-2-one methanesulfonate
40 mg of 7-chloro-1,2-dihydro-4-hydroxy-3- [3-((R, S) -1,2,3,4-tetrahydro-2-methyl-4-isoquinoli Nil) phenyl] quinolin-2-one was boiled with 1 ml of ethanol and 0.02 ml of methanesulfonic acid. The reaction mixture was diluted dilute with ether to precipitate the product as a precipitate. The precipitate was separated, washed with ether and dried to give 7-chloro-1,2-dihydro-4-hydroxy-3- [3-((R, S) -1,2,3,4-tetra Hydro-2-methyl-4-isoquinolinyl) phenyl] quinolin-2-one methanesulfonate (amorphous) was obtained.
Similarly,
7-chloro-1,2-dihydro-4-hydroxy-3- [3-((R, S) -1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl) Phenyl] quinolin-2-one methanesulfonate
5,7-dichloro-1,2-dihydro-4-hydroxy-3- [3-((R, S) -1,2,3,4-tetrahydro-2-methyl-4-isoquinoli Nil) phenyl] quinolin-2-one
5,7-dichloro-1,2-dihydro-4-hydroxy-3- [4-((R, S) -1,2,3,4-tetrahydro-2-methyl-4-isoquinoli Nil) phenyl] quinolin-2-one
7-chloro-1,2-dihydro-4-hydroxy-3-((R, S) -2-methyl-1,2,3,4-tetrahydro-4-phenylisoquinolin-6-yl) Quinolin-2-one
5,7-dichloro-1,2-dihydro-4-hydroxy-3-((R, S) -2-methyl-1,2,3,4-tetrahydro-4-phenylisoquinoline-6- (1) quinolin-2-one
7-chloro-1,2-dihydro-4-hydroxy-3-((R, S) -2-methyl-1,2,3,4-tetrahydro-4-phenylisoquinolin-8-yl) Quinolin-2-one
5,7-dichloro-1,2-dihydro-4-hydroxy-3-((R, S) -2-methyl-1,2,3,4-tetrahydro-4-phenylisoquinoline-8- (1) quinolin-2-one was obtained.
j) (-)-7-chloro-1,2-dihydro-4-hydroxy-3- [3-((R, S) -1,2,3,4-tetrahydro-2-methyl-4 -Isoquinolinyl) phenyl] quinolin-2-one methanesulfonate
67.7 mg (-)-2- {3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) isoquinolinyl] phenyl} acetamido-4-chlorobenzo The acid was dissolved in 3 ml of dry THF. 0.3 ml of a 1 mol solution consisting of KN [Si (CH ₃ ) ₃ ] ₂ and THF was added dropwise with stirring under an argon atmosphere at a temperature of <10 ° C. The product formed as a reaction precipitate in crystalline form. The reaction solution was left for about 12 hours. The solvent was then distilled off in a vacuum rotary vaporizer. The residue was dissolved in water. The aqueous solution was extracted with ether, acidified with hydrochloric acid and the aqueous solution was distilled off. The residue was briefly boiled with 2 ml of absolute ethanol and 0.03 ml of methanesulfonic acid. The reaction mixture was treated with ether to precipitate the product. (-)-7-chloro-1,2-dihydro-4-hydroxy-3- [3-((R, S) -1,2,3,4-tetrahydro-2-methyl-4-iso Quinolinyl) phenyl] quinolin-2-one methanesulfonate (amorphous) was obtained. [a] _D ² ° = -7.6 °.
k) (+)-7-chloro-1,2-dihydro-4-hydroxy-3- [3-((R, S) -1,2,3,4-tetrahydro-2-methyl-4 -Isoquinolinyl) phenyl] quinolin-2-one methanesulfonate
32 mg of (+)-methyl-2- {3- [2-methyl-1,2,3,4-tetrahydro-4- (R, S) -isoquinolinyl] phenyl} acetamido-4- Chlorobenzoate was dissolved in 2.5 ml of THF. 0.14 ml of a 1 molar solution of KN [Si (CH ₃ ) ₃ ] _{2 in} THF was added dropwise with stirring at a temperature of <10 ° C. The product formed by the reaction precipitated in crystalline form. The reaction solution was left for about 12 hours. The aqueous solution was then distilled off. The residue was dissolved in water. The aqueous solution was extracted with ether, acidified with hydrochloric acid and the solvent was distilled off. The residue was briefly boiled with 2 ml of anhydrous ethanol and 0.02 ml of methanesulfonic acid. The reaction mixture was treated with a large amount of ether to precipitate the product. (+)-7-chloro-1,2-dihydro-4-hydroxy-3- [3-((R, S) -1,2,3,4-tetrahydro-2-methyl-4-iso Quinolinyl) phenyl] quinolin-2-one methanesulfonate was obtained. [a] _D ² ° = +11 degrees.
Example 2
7-chloro-3- [3- (2-dimethylaminomethylphenoxy) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
a) ethyl 3- (2-cyanophenoxy) phenylacetate
4.23 g (35 mmol) of 2-fluorobenzonitrile, 6.3 g (35 mmol) of ethyl 3-hydroxyphenylacetate and 4.84 g of potassium carbonate (anhydrous) are dissolved in 40 ml of dimethylformamide and stirred at 160 ° C. The reaction was carried out to obtain ethyl 3- (2-cyanophenoxy) phenylacetate by heating. The mixture was stirred for 3 hours while maintaining this temperature. The cooled reaction solution was treated with 150 ml of water and extracted with methyl t-butyl ether. The organic phase was separated off, washed with water and NaCl solution and dried. After distilling off the solvent, the product was obtained as an oil.
b) ethyl 3- (2-aminomethylphenoxy) phenylacetate
8 g of the obtained ethyl 3- (2-cyanophenoxy) phenyl acetate was dissolved in 200 ml of methanol and hydrogenated in the presence of 3.5 g of Pd-C 5% catalyst. After the reaction was completed, the catalyst was removed by filtration. Then, the solvent was distilled off. The residue was dissolved in ether. The solution was filtered and the ether was distilled off again to give ethyl 3- (2-aminomethylphenoxy) phenylacetate in the oil phase.
c) ethyl 3- (2-dimethylaminomethylphenoxy) phenyl acetate
7.3 g of ethyl 3- (2-aminomethylphenoxy) phenyl acetate obtained as a residue was dissolved in 5.7 ml of 95% formic acid (150 mmol). The reaction solution was heated to 80 ° C. 5.6 ml of 37% formaldehyde solution was added dropwise with stirring over 30 minutes, after which the mixture was boiled for about 12 hours. The solvent was distilled off. The residue was adjusted to basic pH using bicarbonate solution and then extracted with methyl t-butyl ether. The organic phase was then washed with water, washed with NaCl solution and dried. The ether was distilled off. The product was obtained in oil phase. As eluent, the product was separated by chromatography using a solvent mixture consisting of methyl t-butyl ether and methanol (5%) in which 0.3% NH ₄ OH was dissolved.
d) 3- (2-dimethylaminomethylphenoxy) phenylacetic acid
3- (2-dimethylaminomethylphenoxy) phenylacetic acid obtained in the previous reaction was dissolved in 20 ml of 25% hydrochloric acid and heated for 5 hours with stirring under reflux. Then, the solvent was distilled off. The residue was dissolved in toluene. The residue obtained by distilling off the solvent again was opened in acetone to obtain the product in crystalline form. The crystals were suction filtered, washed with acetone and dried to give 3- (2-dimethylaminomethylphenoxy) phenylacetic acid (m. P. 205-208 °).
e) 3- (2-dimethylaminomethylphenoxy) phenylacetyl chloride
2 g (6 mmol) of 3- (2-dimethylaminomethylphenoxy) phenylacetic acid were treated with 20 ml of thionyl chloride and heated with stirring for 30 minutes under reflux. Then, the solvent was distilled off, the residue was dissolved in toluene, and the solvent was distilled off again.
f) methyl 2- [3- (2-dimethylaminomethylphenoxy) phenylacetamido] -4-chlorobenzoate
3- (2-dimethylaminomethylphenoxy) phenylacetyl chloride obtained as a residue in the reaction was dissolved in 30 ml of dichloroethane, 1.1 g of methyl 2-amino-4-chlorobenzoate was added thereto, and then, under reflux conditions, 1 Heated for hours. The solvent was distilled off. The obtained residue was dissolved in dichloromethane, and the mixture was washed with sodium carbonate solution and water, followed by NaCl solution. The organic phase is separated and the solvent is distilled off. The residue was separated by chromatography using methyl t-butyl ether / methanol (5%) / NH ₄ OH (0-0.3%) as eluent.
g) 7-chloro-3- [3- (2-dimethylaminomethylphenoxy) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
1.2 g of methyl 2- [3- (2-dimethylaminomethylphenoxy) phenylacetamido] -4-chlorobenzoate was dissolved in 45 ml of THF. 5.5 ml of a 1 molar solution of KN [Si (CH ₃ ) ₃ ] _{2 in} THF was added dropwise while stirring at a temperature of 10 ° C. or lower. The mixture was stirred for an additional 12 hours at room temperature to give a precipitate. Some methanol was added. The solvent was removed by distillation in a vacuum rotary vaporizer. The residue was dissolved in water and extracted with ether. The alkaline aqueous solution was then adjusted to pH 6 with 25% hydrochloric acid to precipitate the product. After water was separated, the product was washed again with water and dried. The product gave 7-chloro-3- [3- (2-dimethylaminomethylphenoxy) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one (crude product).
Similar to that described in Example 1, from 7-chloro-3- [3- (2-dimethylaminomethylphenoxy) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one, The methanesulfonic acid salt was prepared.
Similarly,
5,7-dichloro-3- [3- (2-dimethylaminomethylphenoxy) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one,
7-chloro-3- [3- (3-dimethylaminomethylphenoxy) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one,
5,7-dichloro-3- [3- (3-dimethylaminomethylphenoxy) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one,
7-chloro-3- [3- (4-dimethylaminomethylphenoxy) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one,
5,7-dichloro-3- [3- (4-dimethylaminomethylphenoxy) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one was obtained.
Example 3
7-chloro-3 [3- (dimethylaminophenylmethyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
a) 3- (hydroxyphenylmethyl) phenylacetonitrile
3- (hydroxyphenylmethyl) phenylacetonitrile is described in Eur. J.M.C. 9, 381 (1974), prepared from commercially available 3-methyl-benzophenone.
b) 3- (chlorophenylmethyl) phenylacetonitrile
9 g of 3- (hydroxyphenylmethyl) phenylacetonitrile were dissolved in 150 ml of toluene and treated with 5.8 ml of thionyl chloride with stirring. The reaction mixture was heated to reflux and stirred for 1 hour under reflux. In this process, about 50 ml of toluene was initially removed in a water separator, and after the reaction was completed, the solvent was removed. The residue was 3- (chlorophenylmethyl) phenylacetonitrile.
c) 3- (dimethylaminophenylmethyl) phenylacetonitrile
Without further reaction finishing, the residue obtained in the previous reaction was treated with 80 ml of a 20% dimethylamine solution in methanol. The reaction solution was left at room temperature for about 12 hours. The solvent was distilled off. The residue was dissolved in ether and the ether phase was washed with water. Then, the ether phase was washed again with 2N HCl. The ether phase still containing unreacted 3- (chlorophenylmethyl) phenylacetonitrile was decanted and the hydrochloric acid containing aqueous phase was made alkaline using concentrated NaOH solution. Extract with ether and after drying, ether phase is filtered off. The ether was distilled off to obtain 3- (dimethylaminophenylmethyl) phenylacetonitrile (oil).
d) 3- (dimethylaminophenylmethyl) phenylacetic acid
3.3 g of 3- (dimethylaminophenylmethyl) phenylacetonitrile was dissolved in a mixture of 25 ml of concentrated sulfuric acid and 25 ml of glacial acetic acid and 25 ml of water and heated for 20 hours with stirring under reflux conditions. The solvent mixture was distilled off and the residue was dissolved in water. The solution was then treated with a sufficient amount of BaCl ₂ solution (about 80 g of BaCl ₂ ) until no more BaSO ₄ precipitation was obtained in the filtrate of the precipitate that was suction filtered through diatomaceous earth. The filtrate was distilled off in a vacuum rotary vaporizer, the residue was suspended in ethanol and the insoluble component was filtered off. The filtrate was distilled off again, the residue was treated with water and made alkaline with concentrated ammonia solution. This solution was extracted with dichloromethane and the dichloromethane phase was dried. After drying, dichloromethane was removed by distillation. 1.8 g of oil corresponding to ethyl ester was obtained. 1.7 g of this oil was heated in 20 ml of 25% hydrochloric acid under reflux conditions for 3 hours. This solution was then distilled off to obtain 3- (dimethylaminophenylmethyl) phenylacetic acid as an amorphous product.
e) 3- (dimethylaminophenylmethyl) phenylacetyl chloride
1.5 g of 3- (dimethylaminophenylmethyl) phenylacetic acid was heated in 15 ml of thionyl chloride while stirring at reflux for 30 minutes. Thionyl chloride not consumed in the reaction was distilled off. The residue was dissolved in toluene and the solvent was distilled off again.
f) methyl 3- (dimethylaminophenylmethyl) phenyl-2-acetamido-4-chlorobenzoate
3- (dimethylaminophenylmethyl) phenylacetyl chloride was dissolved in 30 ml of dichloroethane. 0.9 g of methyl 2-amino-4-chlorobenzoate was added and the mixture was boiled for about 30 minutes. Then, the solvent was distilled off. The residue was dissolved in dichloromethane and washed with water, sodium carbonate solution and NaCl solution. The organic phase is dried, the solvent is distilled off and the residue oil is separated by chromatography (silica gel / dichloromethane, 1-2% methanol and 0.1-0.2% NH ₄ OH). Methyl 3- (dimethylaminophenylmethyl) phenyl-2-acetamido-4-chlorobenzoate (oil) was obtained.
g) 7-chloro-3- [dimethylaminophenylmethyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
2.0 g of methyl 3- (dimethylaminophenylmethyl) phenyl-2-acetamido-4-chlorobenzoate was dissolved in 15 ml of THF. While cooling slowly, 15 ml of a 1 molar solution of KN [Si (CH ₃ ) ₃ ] _{2 in} THF was added with stirring. The mixture was stirred again for 1 hour 30 minutes at room temperature. The solvent was distilled off and the residue was treated with water. The solution thus obtained was washed with dichloromethane and the organic phase was decanted. The aqueous phase was adjusted to acidic pH with hydrochloric acid and extracted again with dichloromethane. The separated organic phase was dried. The solvent was distilled off. To further purify the obtained brown oil, the product is dissolved in ethanol, acidified with etheric hydrochloric acid and opened in ether to give 7-chloro-3- [dimethylaminophenylmethyl) phenyl] -1,2-dihydro-4 Hydroxyquinolin-2-one hydrochloride (dihydrate, mp-230 °) was inhaled filtered.
Similarly,
5,7-dichloro-3- [3- (dimethylaminophenylmethyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
7-chloro-3- [3- (methylaminophenylmethyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
5,7-dichloro-3- [3- (methylaminophenylmethyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
7-chloro-3- [3- (isopropylaminophenylmethyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
And
5,7-dichloro-3- [3- (isopropylaminophenylmethyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one was prepared.
Example 4
7-chloro-3- [4- (2-dimethylaminomethylbenzyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
a) ethyl 2- (4-formylphenyl) acetate
25.7 g of ethyl 4-bromomethylphenylacetate and 28 g of hexamethylenetetraamine were dissolved in 200 ml of 20% acetic acid and heated to 100 ° C. with stirring. The reaction solution was stirred for 4 hours, allowed to cool, and then sufficient amount of sodium carbonate was added until a saturated solution was obtained. The solution thus obtained was extracted with ether. After drying the ether phase, the ether was distilled off in a vacuum rotary vaporizer. The residue was purified by chromatography using methyl t-butyl ether / ether mixture as eluent on a column packed with silica gel.
b) ethyl (2- (N, N-dimethylaminomethyl) phenyl) hydroxymethyl-4-phenylacetate
3 ml (20 mmol) of N, N-dimethylbenzylamine was dissolved in 20 ml of diethyl ether, and 25 ml of 6 mol n-butyllithium solution (40 mmol) was added slowly with stirring at room temperature. The mixture was further stirred at rt for 24 h, resulting in a precipitate. To the obtained solution, 3.84 g of ethyl 2- (4-formylphenyl) acetate dissolved in 20 ml of diethyl ether was added dropwise at about 0 deg. Then, the mixture was stirred at room temperature for 4 hours. The solution was reaction-finished by the conventional method, and ethyl (2- (N, N-dimethylaminomethyl) phenyl) hydroxymethyl-4-phenylacetate (oil) was obtained.
c) ethyl (2- (N, N-dimethylaminomethyl) phenyl) methyl-4-phenylacetate
40 ml of trifluoroacetic acid was cooled to 0-5 ° C. 2 g of NaBH ₄ were introduced with stirring. After raising the temperature to about 15 ° C., 3.8 g of ethyl (2- (N, N-dimethylaminomethyl) phenyl) hydroxymethyl-4-phenylacetate dissolved in 30 ml of dichloromethane was added dropwise. The reaction mixture was stirred for an additional 24 h at room temperature, added to ice and adjusted to alkaline pH using concentrated NaOH solution. The resulting solution was extracted with dichloromethane. The separated organic phase was washed with NaCl solution and dried. The solvent was distilled off and the residue thus obtained was dissolved in methyl tert-butyl ether and filtered. After distilling off the solvent, a yellowish oil was obtained which was purified by chromatography (silica gel / methyl tert-butyl ether and diethyl ether 1: 1). Ethyl (2- (N, N-dimethylaminomethyl) phenyl) methyl-4-phenylacetate was obtained.
d) (2- (N, N-dimethylaminomethyl) phenyl) methyl-4-phenylacetic acid
600 mg of ethyl (2- (N, N-dimethylaminomethyl) phenyl) methyl-4-phenylacetate was dissolved in 15 ml of 25% hydrochloric acid and stirred at reflux for 5 hours. The acid was distilled off, the residue was dissolved in toluene, and the solvent was distilled off again to obtain (2- (N, N-dimethylaminomethyl) phenyl) methyl-4-phenylacetic acid hydrochloride.
e) methyl (2- (N, N-dimethylaminomethylbenzyl) -4-phenylacetamido-2- (4-chlorobenzoate)
600 mg of (2- (N, N-dimethylaminomethyl) phenyl) methyl-4-phenylacetic acid (hydrochloride) was heated for 30 minutes under reflux with 10 ml of thionyl chloride. The residue obtained by concentrating this solution was dissolved in toluene, and toluene was distilled off again. The acid chloride thus obtained was dissolved in 10 ml of dichloromethane. 353 mg of methyl 2-amino-4-chlorobenzoate was added and the mixture was heated under reflux for 1 hour. The solvent was removed by distillation in a vacuum rotary vaporizer. The residue was dissolved in dichloromethane and then washed with sodium carbonate solution, water and NaCl solution. The organic phase is separated and the solvent is distilled off. The residue was dissolved in methyl tert-butyl ether. Undissolved components were filtered off. The filtrate was evaporated to dryness and the resulting product was purified by chromatography (silica gel / methyl tert-butyl ether, ether 1: 1 and about 1% methanol) to afford methyl (2-N, N-dimethylaminomethylbenzyl). 4-phenylacetamido-2- (4-chlorobenzoate) (oil) was obtained.
f) 7-chloro-3- [4- (2-dimethylaminomethylbenzyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one dimethanesulfonate
500 mg of methyl (2-N, N-dimethylaminomethylbenzyl) -4-phenylacetamido-2- (4-chlorobenzoate) was dissolved in 20 ml of THF. 2.5 ml of a 1 molar solution of KN [Si (CH ₃ ) ₃ ] _{2 in} THF was added with stirring at a temperature of <10 ° C. The mixture was further stirred at room temperature for about 12 hours. Methanol was added to the finely formed precipitates to form a solution again. The residue obtained by distilling the reaction solution was dissolved in water, and the obtained solution was washed with ether. The aqueous alkali solution was adjusted to pH 6 with 25% HCl to precipitate the product. The supernatant water was decanted and the product was opened several times with water. The product was then suction filtered and air dried. The resulting product was dissolved in 3 ml of methanol and treated with 0.13 ml of methanesulfonic acid. This solution was stirred with 400 ml of diethyl ether to precipitate the product 7-chloro-3- [4- (2-dimethylaminomethylbenzyl) phenyl] -1,2-dihydro-4-hydroxyquinoline-2- On dimethanesulfonate (mp 100 °).
Similarly,
5,7-dichloro-3- [4- (2-dimethylaminomethylbenzyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
7-chloro-3- [3- (2-dimethylaminomethylbenzyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
5,7-dichloro-3- [3- (2-dimethylaminomethylbenzyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
7-chloro-3- [3- (3-dimethylaminomethylbenzyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
5,7-dichloro-3- [3- (3-dimethylaminomethylbenzyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
7-chloro-3- [3- (4-dimethylaminomethylbenzyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
5,7-dichloro-3- [3- (4-dimethylaminomethylbenzyl) phenyl] -1,2-dihydro-4-hydroxyquinolin-2-one
7-chloro-3- (4-dimethylaminomethyl-3-phenoxyphenyl] -1,2-dihydro-4-hydroxyquinolin-2-one was prepared.
The following example relates to pharmaceutical preparations.
Example A: Vials for Injection
A solution of 100 g of the active compound of formula (I) and 5 g of sodium diphosphate dissolved in 3 l of secondary distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, sterilized by filtration, filled into an injection vial, lyophilized and sealed under sterile conditions. . Injectable vials containing 5 mg of the active compound were obtained.
Example B: Suppositories
A mixture of 20 g of the active compound of formula I and 100 g of soya lecithin and 1400 g of cocoa butter was poured into the mold and cooled. Suppositories containing 20 mg of the active compound were obtained.
Example C: Liquid
A solution was prepared by dissolving 1 g of the active compound of Formula I, 9.38 g of NaH ₂ PO ₄ · 2H ₂ O, 28.48 g of Na ₂ HPO ₄ · 12H ₂ O, and 0.1 g of benzalkonium chloride in 940 mL of secondary distilled water. The solution was adjusted to pH 6.8, adjusted to 1 L, and sterilized by radiation to prepare a solution that can be used in the form of eye drops.
Example D: Ointment
An ointment was prepared by mixing 500 mg of the active compound of formula I with 99.5 g of petrolatum under aseptic conditions.
Example E: Tablets
A mixture of 1 kg of active compound of formula (I), 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate was compressed in a conventional manner to prepare a tablet in which each tablet contains 10 mg of the active compound.
Example F: Tablets
Similar to Example E, tablets were compressed and then coated in a conventional manner using a coating consisting of sucrose, potato starch, talc, tragacanth and a colorant to prepare a tablet.
Example G: Capsule
2 kg of active compound of formula (I) were filled in hard gelatin capsules in a conventional manner such that each capsule contained 20 mg of active compound.
Example H: Ampoules
A solution of 1 kg of the active compound of formula (I) in 60 liters of secondary distilled water was sterilized by filtration and filled in an ampoule, lyophilized under sterile conditions, and aseptically sealed. An ampoule containing 10 mg of the active compound was obtained.

权利要求:
Claims (10)
[1" claim-type="Currently amended] Quinolin-2- (1H) -one derivative of formula (I), possible enantiomers thereof, and salts and solvates thereof.
Formula I

[Wherein,
R ¹ , R ² and R ³ are each independently H, Hal, A or OA,
R ⁴ is H,-(CH ₂ ) _m -NR ⁶ R ⁷ ,
R ⁵ is H,-(CH ₂ ) _n -NR ⁶ R ⁷ ,
R ⁶ is H, A or is — (CH ₂ ) ₄ — or — (CH ₂ ) ₅ — together with R ⁷ ;
R ⁷ is H, A or — (CH ₂ ) _m — bonded to the same ring or adjacent ring B or D, or — (CH ₂ ) ₄ — or — (CH ₂ ) ₅ — together with R ⁶ ,
X is -CHR ^5- , -NR ^5- , -O-, -S-,
A is alkyl having 1-6 carbons,
Hal is F, Cl, Br or I,
m is 1-3,
n is 0-3,
Wherein at least one of the two radicals R ⁴ or R ⁵ is — (CH ₂ ) _m —NR ⁶ R ⁷ or — (CH ₂ ) _n —NR ⁶ R ^7. ] [2" claim-type="Currently amended] Enantiomers or diastereomers of the compound of formula I according to claim 1.
[3" claim-type="Currently amended] The method according to claim 1 or 2,
7-chloro-1,2-dihydro-4-hydroxy-3- [3- (R, S) -1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl) phenyl ] Quinolin-2-one.
[4" claim-type="Currently amended] Reacting a compound of formula III with a compound of formula IV to give a compound of formula II, cyclizing a portion thereof in the presence of a base such as sodium hydroxide or potassium hexamethyldisilazide to obtain a compound of formula I,
Formula III

(Wherein
R ¹ and R ² are as defined in claim 1, G is a cyano group or a reactive carboxylate group)
Formula IV

(Wherein
R ³ , R ⁴ and X are as defined in claim 1 and Q is a reactive carboxylate group)
Formula II

(Wherein
R ¹ , R ² , R ³ and R ⁴ and X are as defined in claim 1, and G is a cyano group or a reactive carboxylate group)
or
To prepare one of the compounds of Formula I, a compound of Formula III wherein G is an alkyl ester group having 1 to 4 carbon atoms is reacted with a compound of Formula IV wherein Q is an alkyl ester group having 1 to 4 carbon atoms To obtain a compound of formula V, which is cyclized in the presence of an acid to obtain a compound of formula I,
Formula V

(Wherein
R ¹ , R ² , R ³ and R ⁴ and X are as defined in claim ¹ and Q ¹ is a reactive carboxylate group)
or
To prepare one of the compounds of formula (I), a compound of formula (VII) is reacted with a compound of formula (VIII) to obtain a compound of formula (VI), which is cyclized to obtain a compound of formula (I), which is another A process for the preparation of quinolin-2- (1H) -one derivatives of formula (I), characterized by conversion to
Formula VII

(Wherein
R ³ , R ⁴ and X are as defined in claim 1 and R is alkyl having 1-6 carbon atoms)
Formula VIII

(Wherein
R ¹ and R ² are as defined in claim 1)
Formula VI

(Wherein
R ¹ to R ⁴ and X are as defined above)
[5" claim-type="Currently amended] A physiologically acceptable salt or enantiomer or diastereomer of a compound of formula (I) according to claim 1 and / or a compound of formula (I) according to claim 1 together with one or more solid, liquid or semiliquid excipients or auxiliaries, A process for the preparation of a pharmaceutical preparation, characterized in that it is combined with one or more active compounds as necessary to form a suitable dosage form.
[6" claim-type="Currently amended] A pharmaceutical formulation characterized in that it contains at least one compound of formula I according to claim 1 and / or one of physiologically acceptable salts.
[7" claim-type="Currently amended] A compound of formula (I) or a physiologically acceptable salt thereof or an enantiomer or diastereomer thereof according to claim 1 for use in the manufacture of a medicament.
[8" claim-type="Currently amended] The method of claim 7, wherein
A compound of formula (I) or a physiologically acceptable salt thereof or an enantiomer or diastereomer thereof according to claim 1, which is used for the manufacture of a medicament for the treatment of diseases caused by dysfunction and disorders of the central nervous system.
[9" claim-type="Currently amended] The method of claim 7, wherein
A compound of formula (I) or a physiologically acceptable salt thereof or an enantiomer or diastereomer thereof according to claim 1, which is used for the manufacture of a medicament for the treatment of stroke or brain injury sequelae.
[10" claim-type="Currently amended] A compound of formula (I) or a physiologically acceptable salt thereof or an enantiomer or diastereomer thereof according to claim 1 for use in the control of a disease.

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同族专利:

公开号 | 公开日

JP2000503308A|2000-03-21|

HU9900563A2|1999-06-28|

PL327829A1|1999-01-04|

US6028080A|2000-02-22|

AU716230B2|2000-02-24|

EP0885196A1|1998-12-23|

AR005646A1|1999-07-14|

WO1997026244A1|1997-07-24|

NO983333D0|1998-07-17|

MX9805700A|1998-11-29|

CA2243474C|2009-10-27|

CN1211974A|1999-03-24|

HU9900563A3|2000-02-28|

AU1311297A|1997-08-11|

BR9707027A|1999-07-20|

CA2243474A1|1997-07-24|

CZ224098A3|1998-10-14|

SK93198A3|1999-01-11|

NO983333L|1998-09-18|

ZA9700364B|1997-07-22|

DE19601782A1|1997-07-24|

引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

法律状态:
1996-01-19|Priority to DE19601782.3

1996-01-19|Priority to DE19601782A

1997-01-10|Application filed by 플레믹 크리스티안, 메르크 파텐트 게엠베하

1999-10-25|Publication of KR19990077308A

优先权:

申请号 | 申请日 | 专利标题

DE19601782.3|1996-01-19|

DE19601782A|DE19601782A1|1996-01-19|1996-01-19|Quinoline-2-one|

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