TWI459946B - Processes for preparing piperazinium salts of kmup and use thereof - Google Patents

Description

Preparation and medical use of KMUP quaternary ammonium piperazine salt

The present invention relates to a process for the piperazine group complex salt of the formula (I) or the formula (II), and the complex salt of the KMUP type or the piperazine quaternary ammonium piperazine group formed can exhibit a prodrug (Pro- Drug) and polymorphic medical functions.

The structure of Statin drugs belongs to formula (III) X _b represents the structure of the rest of the statin drug, and is a highly effective drug for reducing the concentration of low-density lipoprotein (LDL) particles in patients with cardiovascular disease. Therefore, Statin drugs can treat hypercholesterolemia, hyperlipoprotein disease and atherosclerosis. Goodman and Gilman (The pharmacological basis of therapeutics page, 879, 9th Ed. 1996; pharmacological drug base for treatment) means that high levels of low-density lipoprotein in the blood are associated with the formation of coronary artery damage, which can impede blood flow and cause thrombosis. .

U.S. Patent No. 7,390,504 discloses the formulation of a water-soluble salt of statin and fibric acid comprising a dihydroxy ring-opening acid. However, Evans M et al. found that the Statin drug may exhibit adverse effects of muscle toxicity and rhabdomyolysis, especially in combination. The fibric acid drug rhabdomyolysis increases the crisis of rhabdomyolysis (Drug Saf. 2002). Although Jacobson, T A believes that the above-mentioned crisis caused by the combination of statin and fibric acid drugs, there is no large experimental data to support. However, recent studies by Jacobson and T A cannot overcome the above crisis (Nat Rev Endocrinol. 2009).

In view of the incompleteness of the prior art, the inventors have carefully conceived the "KMUP quaternary ammonium piperazine salt for preparation and medical use" in a spirit of perseverance and research, which can overcome the prior art. Insufficient, the following is a brief description of the case.

The present invention provides a piperazine group complex salt of the formula (I) or formula (II), wherein R ₁ may be a hydrogen group or a halogen, an amine group, a nitro group, or an alkyl group having 1 to 5 carbon atoms. a benzene ring having a substituent such as an alkoxy group having 1 to 5 carbon atoms. R _a may be a hydrogen group or a xanthine group having a substituent such as a halogen, an amine group, a nitro group, or an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. The RX group may be a mineral acid, an organic acid, a Statin drug containing a carboxylic acid group derivative, a fibric acid derivative of a hypolipidemic, an anti-inflammatory drug containing a carboxylic acid group, and an anti-diabetes containing a carboxylic acid group. and other drugs, anti-asthma drugs containing the carboxylic acid groups, RX ^- negatively chargeable anionic groups of the above.

The above halogen means a group such as fluorine, chlorine, bromine or iodine. An anti-inflammatory drug containing a carboxylic acid group, if necessary, a non-steroidal anti-inflammatory (NSAIDs) drug having a structural group containing a carboxylic acid group, and an anti-asthmatic drug or the like for inhibiting the human immune system.

According to the above concept, the formula (I) in which both R ₁ and R _a are hydrogen represents a complex salt of piperazine, and the formula (I) may be represented by the amount of the reaction acid and the steric bond. Or a dimeric carboxylic acid group . Wherein Xa represents an organic acid, a Statin-like drug containing a carboxylic acid group derivative, a fibric acid derivative of a hypolipidemic, an anti-inflammatory drug containing a carboxylic acid group, an anti-diabetic drug containing a carboxylic acid group, A partial structure other than a carboxylic acid group of a compound such as an anti-asthmatic drug containing a carboxylic acid group. Formula (I) can also be represented by formula (II), and formula (IA) can be represented as a composite salt.

According to the above concept, the formula (I) or formula (II) in which both R ₁ and R _{a are} not hydrogen represents a complex salt of KMUP type, belonging to the chlorophenyl piperazine structure (7-2-4-(2) -Chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethyl-xanthine) derivative , abbreviated as KMUP-1 is a KMUP derivative of xanthine structure, which can be transferred to 7-ethylchloro-theophylline and 1-(2-chlorophenyl) piperazine (7-ethylchloro-theophylline). 1-(2-chlorophenyl)piperazine). After many years of research, it was confirmed that KMUP-1 can inhibit phosphodiphosphate cyclase (sGC), inhibit phosphodiesterase (PDE), Increase intracellular cyclic adenosine monophosphate (cAMP) and cyclized guanosine monophosphate (cGMP), increase protein kinase G (Protein kinase G, PKG), resulting in potassium ions The opening of the channel and the relaxation of the aorta (Wu et al., 2001), Corporeal carvenosa, and tracheal smooth muscle (Wu et al., 2004).

KMUP-1 also inhibits Phenylephrine-induced contraction, effectively inhibits β _A /β _1D -adenoreceptor binding activity, increases cAMP/cGMP content, and inhibits phenylephrine-induced Rho kinase 2 (Rho) Kinase, ROCK2) performance. Therefore, KMUP-1 can act as an inhibitor of phosphodiesterase 5A (PDE5A)/ROCK2 to inhibit the growth of human normal prostate cell line PZ-HPV-7, leaving the cell cycle stationary at G ₀ /G ₁ Period, increased p21 protein expression (Liu et al., 2007).

In addition, KMUP-1 has also been shown to stimulate calcium-activated potassium (Ca ²⁺ -activiated potassium, BK _Ca ) currents by enhancing cGMP-dependent protein kinase activity, which leads to physiological The closure of a voltage-dependent calcium channel and cerebral artery relaxation (Wu et al., 2005). Therefore, KMUP-1 has the benefit of treating hypertension. In rat tracheal smooth muscle cells (TSMCs), KMUP-1 inhibits Tumor necrosis factor-a (TNF-a) inducible nitric-oxide synthase (iNOS). Performance, including the sGC/cGMP/PKG pathway but excluding the expression pathway of cyclooxygenase-2 (COX-2) (Wu et al., 2006).

KMUP-1 compounds have a Pleitropic activity and are shown in this patent, for example, reducing lipid activity and inhibiting Rho-kinase expression. U.S. Patent No. 7,550,468 discloses the activation of endothelial nitric oxide synthase (eNOS), U.S. Patent No. 6,979,687, which discloses the activation of cyclic guanosine monophosphate (cGMP), lowering plasma glucose and anti-pulmonary hypertension (PAH). Such as the activity of statin, and the activity of cGMP enhancement (Wu et al., 2006). Therefore, KMUP-1, KMUP-2, KMUP-3, etc. disclosed in the above-mentioned U.S. Patent Nos. 6,979,687 and 7,550,468 are KMUP compounds, and piperazine is a derivative of the 1,4 disubstituted piperazine structure. The present invention provides a process for the preparation of the above KMUP-1 or piperazine quaternary ammonium piperazine complex salt.

In order to overcome some adverse effects of the currently marketed Statin drugs, the present invention utilizes KMUP-1 and Statin drugs to form an ionic complex, which is beneficial to hypercholesterolemia, hyperlipoproteinosis and atherosclerosis, pulmonary hypertension, The treatment of diabetes and influenza confirmed that KMUP-1 and statin piperazine group complex salts are commonly known as "KMUP-1-Statins complex salt (KMUP-1-statins)", which can present prodrugs and polymorphisms. The medical function reduces the risk of these side effects. Therefore, the present invention may also provide a salt comprising KMUP-1 or piperazine and a mineral acid or an organic acid, for example, KMUP-1 hydrochloride (1) or the first figure of the first figure (a) ( b) KMUP-1 citrate (2), adding Statin drugs and excipients into a pharmaceutical composition, and simultaneously administered to mammals, can present prodrugs and multi-modal medical functions to reduce the risk of these side effects Sex.

According to the above concept, a sufficient amount of a piperazine group of KMUP or piperazine can be reacted with a Statin-like drug containing a carboxylic acid group derivative to form a complex salt of a KMUP quaternary ammonium piperazine drug carboxylic acid group. Further, the "RX" group can be used to prepare the above-mentioned KMUP or piperazine quaternary ammonium compound according to the statin drug containing a carboxylic acid group derivative, and the piperazine group of KMUP or piperazine. The method of salt. The synthesized piperazine group quaternary ammonium complex salt exhibits prodrug and multi-modal medical function by chemical or enzymatic hydrolysis in the living body.

According to the above concept, the KMUP-1 and Statin drugs are charted together as an example for describing the above-mentioned KMUP-type or piperazine quaternary ammonium complex salt. Thus, KMUP-1 is a KMUP class or a piperazine representing KMUP-1, KMUP-2 or KMUP-3, if necessary, and the Statin drug, if necessary, represents the above-mentioned "RX" group involved in the preparation of the quaternary ammonium complex salt in the present invention. Mission or "RX ^- ".

According to the above concept, the Statin-like drug, the hypolipidemic fibric acid derivative, the anti-inflammatory drug, the anti-asthmatic drug, the anti-diabetic drug, the prostacyclin and the like have a derivative of a carboxylic acid group, including the above The drug structure uses a lactone ring, an ester, and a protecting group to mask the carboxylic acid group of the drug. When the carboxylic acid group can be visualized by pretreatment, the lactone ring derivative and ester derivative of the drug are derived. The present invention, as well as derivatives with protecting groups, and the like, are suitable for use in the present invention to provide a method for preparing the above-mentioned KMUP and piperazine quaternary ammonium complex salts.

The invention discloses that the "RX" group is a mineral acid, and the organic acid is selected from the group consisting of citric acid, fumaric acid, maleic acid, nicotinic acid, isonicotinic acid, tartaric acid, succinic acid, and hexanic acid. Acid, fatty acid, methanesulfonic acid, phenoxyvaleric acid and other organic acid groups, or hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid (H ₃ PO ₄ ), sodium dihydrogen phosphate (NaH ₂ PO ₄ ), disodium hydrogen phosphate (Na ₂ HPO ₄ ), and the like. It reacts with KMUP or piperazine to form a quaternary ammonium complex salt. These salts are a prodrug that exhibits the medical function of KMUP or piperazine by chemical or enzymatic hydrolysis in the organism.

The process for preparing the KMUP-1 quaternary ammonium piperazine salt disclosed in the present invention is to link the 2-chlorobenzene group (R1) and the Ethyl-1,3-dimethyl-xanthine group with the KMUP-1 piperazin group structure. (Ra), the structure of the Statin drug is linked to the remaining part structure (R1) by a carboxylic acid group, as shown in the first figure (c). Specifically, KMUP-1 is dissolved in a mineral acid solution such as an alcohol of C ₁ to C ₄ such as methanol or ethanol and hydrochloric acid, and reacted at a temperature of 40 ° C to 70 ° C or lower, and an alcohol solution is added at room temperature to crystallize. The KMUP-1 salt was obtained by filtration. Further, the Statin drug is dissolved in an alcohol solution and poured into a flask in which a stirring magnet is placed, and an aqueous solution of sodium, potassium, calcium metal hydroxide or ammonium hydroxide is added at room temperature, and the alcohol reaction filtrate of the above KMUP-1 salt is added. Stirring is continued. After rapid filtration and crystallization, KMUP-1 quaternary ammonium piperazine complex salt was obtained. It is chemically or enzymatically hydrolyzed in living organisms to present the medical functions of KMUP-1 and Statin drugs. Thus, the KMUP-1-Statinic acids complex salt belongs to a drug that has a polymorphic medical effect.

KMUP-1 quaternary ammonium complex formed by the carboxylic acid group-containing anti-inflammatory drug, because KMUP-1 has the effect of enhancing cGMP (Wu et al., 2006) and increasing the anti-platelet aggregation activity of non-steroidal anti-inflammatory drugs. Prodrugs and multi-modal medical functions are exhibited by chemical or enzymatic hydrolysis in living organisms. For example, the combination of KMUP-1 in place of Statin and the carboxylic acid group of the cellulose acid derivative can reduce the dose of Statin, which is another combination that reduces muscle toxicity. Methotrexate dicarboxylic acid structure and KMUP-1 form a complex of quaternary ammonium, which can be used for rheumatoid arthritis and chemotherapy for cancer. The carboxylic acid structure of prostacyclin (PGI ₂ ) forms a complex of quaternary ammonium with KMUP-1 and can be used for the treatment of pulmonary hypertension. The triterpenoid compound of the Antrodia camphorata complex, Zhankuic acid A, B, C carboxylic acid structure and KMUP-1 form a quaternary ammonium complex, which can be used for anticancer.

Both KMUP-1 and Statin have a diversified action in addition to reducing lipid activity, and combined with a specific carboxylic acid structure that reduces lipid, anti-inflammatory, anti-asthmatic, anti-diabetic compounds to form a quaternary ammonium bond complex salt, Intensified by its intensification.

In the synthesis pathway of cholesterol in human body, Statin drugs and 3-hydroxy-3-methylpentadienyl-CoA (HMG-CoA) inhibit the synthesis of cholesterol through competitive inhibition. The HMG-CoA reductase catalyzes the conversion of HMG to mevalonate, which is the rate determining step for cholesterol synthesis. Decreased cholesterol production leads to an increase in the number of low-density lipoprotein receptors and a decrease in the concentration of corresponding blood-low-density lipoprotein particles. Therefore, clinical studies have shown that lowering the LDL content in the blood can reduce the risk of coronary heart disease (Lipid Research Clinics Program. 1984).

Currently marketed Statin drugs, including atorvastatin, cerivastatin, fluvastatin, lovastatin, and mevastatin , Pravastatin, Rosuvastatin, and Simvastatin, the structure of Statins is represented by formula (III), and its chemical names are listed in Table 1. Lovastatin, U.S. Patent No. 4,231,938, and Simvastatin, U.S. Patent No. 4,444,784, which are incorporated herein by reference. After absorption, the lactone ring is chemically or enzymatically hydrolyzed in the liver to produce an active hydroxy acid. Pravastatin is disclosed in U.S. Patent No. 4,346,227, which is incorporated herein by reference. The cerivastatin disclosed in U.S. Patent No. 4,739,073, U.S. Patent Nos. 5,006,530 and 5,177,080, also to the medicinal use of sodium salts, is a fully synthesized compound having a structure and a hexahydronaphthalene comprising a fungal derivative. These drugs are different in the ring. Rosuvastatin and Pitavastatin are two new lipid-lowering drugs known as Superstatins. Atorvastatin is used in combination with calcium salts.

Atorvastatin, U.S. Patent No. 4,681,893, and U.S. Patent No. 5,273,995, the disclosure of which is incorporated herein by reference. The water and alcohol mixed solvent system allows KMUP-1 hydrochloric acid to undergo a metathesis exchange reaction with Atorvastatin calcium salt and release sodium chloride, potassium chloride, calcium chloride or ammonium chloride. Such statins, whether calcium or sodium, are contacted with the hydrochloride salt of KMUP-1 to form water-soluble sodium chloride or calcium chloride. The non-salt type free state carboxylic acid statin forms a "KMUP-1-statins complex salt" with the KMUP-1 piperazin group.

(4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl] is disclosed in U.S. Patent No. 5,298,627 Ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide is dissolved in methanol and reacted with hydrochloric acid to form [R-(R*,R*) ]-5-(4-fluorophenyl)-β,d-dihydroxy-2-(1-methylethyl)-N,N,4-triphenyl- 3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide Mixed with methanol and sodium hydroxide. After filtration, it is washed with tert-butyl methyl ester, and the aqueous layer is acidified with hydrochloric acid and extracted with tert-butyl methyl ester to obtain [R-(R*,R*)]-2-(4-fluorophenyl)-β,d-dihydroxy- Sodium salt of 5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid. An equimolar amount of KMUP hydrochloride can be converted to convert the KMUP-Statinic acid to the KMUP quaternary ammonium piperazine group.

A similar amine salt structure of Atorvastatin can be converted into a complex salt of KMUP quaternary ammonium piperazine group; for example (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N- Bis(phenylmethyl)-1,3-dioxane-4-acetamide can be converted to [R-(R*,R*)]-5-(4-fluorophenyl)-β,d-dihydroxy-2-(1-methyl -ethyl)-4-phenyl-3-[(phenylamino)carbonyl]-N,N-bis(phenylmethyl)-1H-pyrrole-1-heptanamide, which can be converted to the KMUP quaternary ammonium piperazine group via the reaction. Acid complex salt. And (4R-cis)-6-(2-aminoethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide is converted into [R-(R*,R*)]- N,N-diethyl-5-(4-fluorophenyl)-β,d-dihydroxy-2-(1-methyl-ethyl)-4-phenyl-3-[(phenylamino)-carbonyl]-1H-pyrrole-1- Heptanamide can form a complex salt of KMUP-statinic acid, and similarly reacts (4R-cis)-6-(2-aminoethy1)-N-butyl-N,2,2-trimethyl-1,3-dioxane- 4-acetamide is converted to [R-(R*,R*)]-N-butyl-5-(4-fluorophenyl)-β,d-dihydroxy-N-methyl-2-(1-methylethyl)-4- Phenyl-3-[(phenyl-amino)carbonyl]-1H-pyrrole-1-heptanamide is further reacted to form a complex salt of KMUP-Statinic acid, and (4R-cis)-6-(2-aminoethyl)-N -(1,1-dimethylethyl)-2,2-dimethyl-N-(phenylmethyl)-1,3-dioxane-4-acetamide is converted to [R-(R*,R*)]-N-(1,1 -(dimethylethyl)-5-(4-fluorophenyl)-β,d-Dihydroxy-2-(1-methylethyl)-4-phenyl-3-[(phenyl-amino)carbonyl]-N-(phenylmethyl)-1H- Pyrrole-1-heptanamide is further reacted to form a complex salt of KMUP-Statinic acid. Even (4R-cis)-1-[[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan- 4-yl]-acetyl]piperidin e, can also be converted to [R-(R*,R*)]-1-[3,5-dihydroxy-7-oxo-7-(1-piperidinyl)-heptyl]-5-(4-fluorophenyl-2 -(1-methylethyl)-N-4-diphenyl-1H-pyrrole-3-carboxamide, which further forms a KMUP-1-Statinic acid complex salt of KMUP-1 quaternary ammonium ammonium piperazine group.

Commercially available Statin calcium salt drugs are two molecules of Statin combined with one molecule of calcium, so the so-called hemi-calcium salt (Hemicalcium) means that both statin and calcium molecules are one molecule. Rosuvastatin calcium salt and the lactone, disclosed in U.S. Patent No. 5,260,440, which is related to the process via the return line, NaBH ₄ reduction reaction Rosuvastatin methyl ester compound is obtained. After further hydrolysis at room temperature, the alcohol solution of sodium hydroxide was dehydrated, and the sodium salt of Rosuvastatin was obtained by adding diethyl ether. Also disclosed in U.S. Patent No. 6,316,460 is a Rosuvastatin composition comprising a polyvalent phosphate of Rosuvastatin. The process according to the present invention dissolves the Rosuvastatin sodium salt in water under nitrogen, and after KMUP is added, a KMUP-Rosuvastatinic acid complex salt of KMUP quaternary ammonium ammonium piperazine group is formed by precipitation and crystallization steps.

In the past, the work of Green, T.W. et al., did not mark the release of ester groups and the protection of carboxylic acids. Statin can be prepared via an intermediate which is a ring-opening or a hydroxyl group of a cyclic structure; for example, a diol structure of a valeric acid group or a lactone, a hydrolyzable protecting group or an ester derivative is used to protect the carboxylic acid. The preparation of simvastatin is disclosed in U.S. Patent No. 5,260,440, the disclosure of which is incorporated herein by reference to U.S. Patent Nos. 6, 002, 021 and 4, 444, 784, the disclosure of which is incorporated herein by reference. Or an anthracene compound such as t-butyl-dimethyl-silyl to give an anthracene protecting group. U.S. Patent No. 6,294,680 discloses the preparation of Simvastatin by using a cyclic protecting group such as dioxane, cyclic sulfate, cyclic phosphate, or boronylidene to replace alkyl or aromatic in a timely manner. base. Further, WO 95/13283 discloses boric acid as a protecting group. U.S. Patent No. 5,159,104 discloses the esterification reaction with acetic anhydride, and some protecting groups are also disclosed in U.S. Patent No. 6,100,407.

The present invention utilizes a piperazine group of KMUP to react with a carboxylic acid of a Statin drug, and although Atorvastatin is protected by an ester group, it can be directly converted into an Atorvastatin hemi-calcium salt. The process for preparing the KMUP quaternary ammonium piperazine group Statin salt according to the invention is also applicable to the ester derivative of Statin and the derivative of the statin protected group. It is a metal hydroxide such as sodium, potassium or calcium, an amine hydroxide, an ester derivative of a statin drug, a mixed solution of KMUP, water and a C ₁ to C ₄ alcohol, and is heated at a slight temperature to prevent Decomposition of statin and its prodrugs.

The preferred Statin drugs are Atorvastatin, Lovastatin, Pitavastatin, Rosuvastatin and Simvastatin. The Statin structure of this drug is catalyzed by sodium, potassium, calcium hydroxide or other metal hydroxides with ammonia or other acids to make Statin The ester group of the drug is hydrolyzed.

The amount of KMUP-1 hydrochloride piperazine group can be easily controlled when reacting with sodium hydroxide. For example, sodium ion is equimolar with hydrochloric acid in KMUP-1 hydrochloride as the sodium hydroxide hydrolyzes the amount of Statin derivative. The neutralization reaction produces NaCl and is dissolved in an aqueous alcohol solution. Statin can be in an ionic state or a free state in a mixed solution of a C1-C4 lower alcohol such as ethanol or isopropanol and water, or a mixture of other unreacted Statin ester derivatives. As the amount of sodium hydroxide hydrolyzed with the Statin derivative, the so-called "sufficient piperazine group" is about equal molar amount.

When reacting with calcium hydroxide, it needs to have the dual function of having a basic catalyst for hydrolyzing esters and providing calcium ions into a hemi-calcium salt, and performing equimolar neutralization with hydrochloric acid in KMUP-1 hydrochloride, respectively. The reaction produces a one or two molecules of KMUP-1-Statinic acid precipitate. The incompletely reacted Statin derivative is dissolved in an aqueous alcohol solution. In the process of the present invention, the progress of the reaction is controlled by thin layer chromatography (TLC), and the developing solvent used is MeOH: Ethyl acetate = 1:9.

Reaction with sodium alginate, polyglycolic acid, sodium polyglutamate, calcium polyglutamate, requires an excess of KMUP-1 hydrochloride to fully react to synthesize sodium. The product, the excess KMUP-1 hydrochloride, is dissolved in the aqueous alcohol filtrate after filtering the precipitated product.

The synthesis reaction of the quaternary ammonium piperazine group complex salt is carried out in a mixed solution of a C1-C4 low alcohol and water, and the amount thereof is considered to be sufficient for the reaction product of the "RX" group such as Statin in the mixed solution. Acid derivatives, ester derivatives of Statin, derivatives of the protective group statin, sodium alginate, polyglutamic acid, sodium polyglutamate, calcium polyglutamate cross-linked sodium alginate, Repaglinide It is dissolved with a carboxylic acid group-containing reactant such as Nateglinide, Montelukast, Cromolyn sodium, Nedocromil, Gemfibrozil, Bezafibrate, etc., and C1-C4 is selected depending on factors such as the nature of the water, the reaction temperature, and the specific gravity of the reactant such as the Statin ester derivative. Low alcohols and adjust the amount of mixed solution, the preferred choice is ethanol, isopropanol with 5% ~ 30% moisture, 10% moisture with 90% ethanol or isopropanol. In the reaction of the alkaline catalyst to hydrolyze the ester derivative of Statin, the amount of the ester derivative of Statin is added to the mixed solution, and is about 10 mmol to 1 mol per liter. In order to accelerate the reaction solution for the reflux mixed solution, the temperature of the mixed solution should be raised to about 40 ° C ~ 70 ° C. The complex salt forming the KMUP-1 quaternary ammonium piperazine group is re-dissolved in the mixed solution after filtration, preferably at room temperature.

The trialkyl hydrazine is preferably a hydrazine protecting group which is hydrolyzed by calcium hydroxide. The dioxane system is formed into a ring by acetone to protect the dimethyl group. For example, the Atorvastatin intermediate L-1 (Intermediates L-1) can be hydrolyzed by a mineral acid to dihydrogenation. Methyl hydrazine is protected. Further, an aqueous solution of sodium hydroxide having a pH of 8.3 is added to hydrolyze the ester group, so that the enthalstatin intermediates L-1 protected by the ester derivative can be converted into Atorvastatin sodium salt by a continuous heating reaction. The guanidine group reacts with calcium hydroxide to exhibit hydrolysis and elimination. Therefore, under the action of the calcium salt, the protection of the oxime group can be released and converted into an ester structure. The above-mentioned mineral acid catalysis may utilize an acid hydrolysis protecting group, and suitable acids include acetic acid, trifluoroacetic acid, p- Toluenesulfonic acid, zinc bromide and zinc bromide. Hydrochloric acid or other hydrohalides, preferred for acetic acid and hydrochloric acid.

The invention relates to related drugs for human immune system, and refers to anti-inflammatory drugs containing carboxylic acid groups, prostacyclin, triterpenoid compounds of Antrodia camphorata, Zhankuic acid A, B, C and anti-asthmatic drugs. . These carboxylic acid group-containing anti-inflammatory drugs may be commercially available non-steroidal anti-inflammatory drugs, usually having a carboxylic acid group such as aspirin or salicylic acid. , Indomethacin, Diclofenac, Meclofenamic acid, Tolmetin, Ketoprofen, Methotrexate, Flubbiol Flurbiprofen, Fenoprofen, Tiaprofen, Diflunisal, Etodolac, Ibuprofen, Prostacyclin, Antrodia The triterpenoid compound of the fruiting body, Zhankuic acid A, B, C. For anti-asthmatic drugs, commercially available products such as Montelukast, Cromolyn sodium, and Nedocromil are used. The above-mentioned drugs directly react with a compound such as KMUP or a piperazine structure to form a KMUP or piperazine quaternary ammonium piperazine group complex salt. Can also use sodium hydroxide, potassium hydroxide, calcium hydroxide or other metal hydroxides and ammonium hydroxide, so that non-steroidal anti-inflammatory drugs first form salts, and then formed with KMUP hydrochloride or piperazine hydrochloride Compound salt. Commercially available anti-asthmatic or anti-allergic drugs, such as montelukast, Cromolyn sodium, and Nedocromil. The antiallergic drug can exhibit an antiallergic effect via antagonism of the Leucotriene-D4 (LT-D4) receptor or other routes. The fibric acid derivative of hypolipidemic, including the fibric acid group of Gemfibrozil and Fenofibrate, and the fibric acid can be combined with KMUP to form a complex salt with the carboxylic acid group. class. In addition, alginate sodium, polyglutamic acid, sodium polyglutamate, calcium polyglutamate-alginate sodium, which is used in the treatment of diabetes, contains a carboxylic acid group. The antidiabetic drugs Repaglinide and Nateglinide can be as shown above, comparing the "RX" group of Statin drugs or their derivatives with a sufficient amount of KMUP or piperazine piperazine group. The reaction forms a complex salt of KMUP or piperazine quaternary ammonium piperazine. The reactants of the "RX" group or its derivative and the like which can react with KMUP are as shown in the second figure, and form a 1 or 4 single-bonded KMUP or a quaternary ammonium salt of a piperazine group depending on the reactants. Piperazine complex salts, while prodrugs and multi-modal medical functions.

Based on the present invention, a mineral acid or an organic acid salt of KMUP-1 or piperazine can be provided, and a Statin drug and an excipient are added to form a pharmaceutical composition, and are administered to a mammal to exhibit a prodrug and a multi-modal medical function. And reduce the risk of the above side effects. Therefore, commercial products of the "RX" group such as Statin drugs, atorvastatin, cerivastatin, fluvastatin, lovastatin, and mevastatin ( Mevastatin, Pravastatin, Rosuvastatin, Simvastatin, and non-steroidal anti-inflammatory (NSAIDs) drugs, Aspirin, Salicylic acid ), Indomethacin, Diclofenac, Meclofenamic acid, Tolmetin, Ketoprofen, Methotrexate, Fluorine Flufuriprofen, Fenoprofen, Tiaprofen, Diflunisal, Etodolac, Ibuprofen, or Prostacyclin, Triterpenoids Zhankuic acid A, B, C, or anti-asthmatic Montelukast, Cromolyn sodium, Nedocromil, or hypolipidemic Gemfibrozil , Fenofibrate, or anti-diabetic drugs Alginate sodium, polyglutamic acid, sodium polyglutamate, calcium polyglutamate-alginate sodium, and Repaglinide and nateglinide (repaglinide) Nateglinide) may be added with a mineral acid of KMUP or piperazine, a salt formed by an organic acid, and a combination thereof to form a pharmaceutical composition. The above sodium alginate is a natural compound of brown algae, and its molecular chain contains L-guluronic acid of a-1,4 structure and D-mannuronic acid of β-1,4 structure. (D-mannuronic acid) two structural units. Γ-polyglutamic acid is abbreviated as γ-PGA (1, 2).

The above excipients, or "pharmaceutically acceptable carriers or excipients", "bioavailable carriers or excipients", include solvents, dispersing agents, coatings, antibacterial or antifungal agents, or Any suitable compound suitable for the preparation of a dosage form such as an absorbent is delayed. Usually such carriers or excipients do not themselves have the activity of treating diseases, and the derivatives disclosed in the present invention, together with pharmaceutically acceptable carriers or excipients, are prepared for administration to animals or humans. Causes adverse reactions, allergies or other inappropriate reactions. Thus, the derivatives disclosed herein, in combination with pharmaceutically acceptable carriers or excipients, are suitable for use in clinical and human applications. The therapeutic effect can be achieved by administering the dosage form of the compound of the present invention intravenously, orally, by inhalation or by local or sublingual administration such as nasal, rectal, vaginal or the like. For patients with different conditions, about 0.1 mg to 100 mg of active ingredient is administered daily.

The carrier will vary with each dosage form, and the sterile injectable compositions may be solution or suspended in a non-toxic intravenous diluent or solvent such as 1,3-butanediol. A carrier acceptable therebetween may be Mannitol or water. In addition, fixed oils or synthetic single or diglyceride suspension media are common solvents. Fatty acids, such as oleic acid, olive oil or castor oil, and their glyceride derivatives, especially in the form of polyoxyethylation, are useful as injections and are natural pharmaceutically acceptable oils. These oil solutions or suspensions may contain long chain alcohol diluents or dispersants, carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as Tween, Spans or other similar emulsifiers or generally used in the pharmaceutical industry are commercially available solid, liquid or other bioavailable enhancers which are useful in the development of dosage forms.

The composition for oral administration is in any orally acceptable dosage form, and the form thereof includes a capsule, a tablet, a tablet, an emulsifier, a liquid suspension, a dispersing agent, and a solvent. Oral dosage forms are generally used as carriers, and in the case of tablets, lactose, corn starch, and a lubricant such as magnesium stearate are basic additives. The diluent used in the capsules includes lactose and dried corn starch. The liquid suspension or emulsifier dosage form is prepared by suspending or dissolving the active substance in an oily interface combined with an emulsifier or a suspending agent, and adding a moderate sweetener, flavor or pigment as needed.

Nasal gasifying sprays or inhalant compositions can be prepared according to known formulation techniques. For example, the composition is dissolved in physiological saline, benzyl alcohol or other suitable preservative, or an absorbent is added to enhance bioavailability. The compositions of the compounds of the invention may also be formulated as a suppository for rectal or vaginal administration.

The compounds of the present invention may also be administered "intravenous administration", including subcutaneous, intraperitoneal, intravenous, intramuscular, or intra-articular, intracranial, intra-articular, intraspinal injection, aortic injection, intrathoracic injection, intralesional injection. , or other suitable drug delivery technology.

A 1 or 4 single-bonded KMUP or piperazine quaternary ammonium piperazine complex salt is prepared according to an embodiment of the present invention, as shown in the schematic diagrams of the second and third figures. These complex salts are shown in the following activity experiments to reduce lipids (Table 2), treat diabetes (Table 3 to Table 5), antiplatelet aggregation (Table 6), reduce pulmonary hypertension (Tables 7-8), and inhibit the treatment. Glandular hypertrophy (Table 9), inhibition of H1N1 virus growth (Table 10), inhibition of cancer cell growth (Table 11), inhibition of asthma in animals (Table 12), showing the above-mentioned KMUP or piperazine group of quaternary ammonium piperazine The compound salt can present a multi-modal medical function of a commercially available product of the "RX" group such as a statin drug, an anti-inflammatory drug, an anti-diabetic, an anti-asthmatic drug, a prostacyclin or a hypolipidemic drug.

Therefore, the present invention is a rare and innovative invention, which has profound industrial value and is submitted in accordance with the law. In addition, the invention may be modified by those skilled in the art without departing from the scope of the appended claims.

The preparation and medical use of the KMUP quaternary ammonium piperazine salt as set forth in the present application will be fully understood by the following examples, so that those skilled in the art can do so. However, the implementation of the present invention is not limited to the following. The embodiments are intended to be limited to the embodiments, and those skilled in the art can devise other embodiments in accordance with the spirit of the embodiments disclosed herein.

Experimental materials and methods:

Activity experiment: 1. Lipid reduction in C57BL/6J mice

The 8-cycle C57BL/6J mice were divided into standard diet (STD) and high-fat diet (HFD) experimental groups. In the high fat diet group, oral KMUP-1 hydrochloride (1,2.5,5 mg/kg), Simvastatin (5 mg/kg), KMUP-1-nicotinic acid (1,5 mg/kg), and KMUP- 1-Simvastatinic Acid (1,5 mg/kg), KMUP-1-Gemfibrozil (2.5 mg/kg), KMUP-1-Fibric acid (2.5 mg/kg), KMUP-1- -polyglutamic acid (2.5 mg/kg) With KMUP-1-citric acid (2.5 mg/kg), the mice were tested for 21 days, Triglyceride (TG), total cholesterol (tot.-C), high density High Density Lipoprotein Cholesterol (HDL-C), Low Density Lipoprotein cholesterol (LDL-C) and other plasma fat content mg/100 ml (mg/dl), 6 mice in each group . Serum glucose content mg/100 ml (mg/dl) is shown in Table 2.

2. KMUP-1 promotes the reduction of serum glucose content in streptozotocin-induced diabetic rats (Streptozosin (STZ)-induced diabetic rats)

Intravenous Streptozosin streptozotocin 60 mg/kg to induce diabetic rats (Streptozosin-induced diabetic rats STZ), oral KMUP-1 hydrochloride (0.5, 1.5, 2.5, 5 mg/kg) and KMUP-1-Simvastatinic Acid (5 mg/kg), serum glucose levels (mg/L), serum insulin levels (mg/L), body weight (g), and body weight changes after 21 days of testing.

3. Post-meal administration of KMUP-1 and complex salts have synergistic effects on serum glucose and insulin levels.

Nateglinide, Repaglinide (1, 2, 3, 4 mg/kg) or placebo 1 hour before breakfast on the first day, orally take KMUP-1/KMUP-1 at 1, 2, 3, 4, 5, 6 hours - Nateglinide/KMUP-1-Repaglinide, determination of serum glucose content (mg/L), serum insulin content (mg/L), body weight (g), and body weight change.

4. Rabbit plasma exhibits anti-platelet aggregation activity

Rabbit marginal ear vein blood was collected and mixed with Ethylene diamine-N (N-tertraacetic acid, EDTA) to form a final concentration of 6 mmol/L, and centrifuged at 90 s for 10 minutes at room temperature. The supernatant was cleared to platelet-rich plasma (PRP). The platelet suspension was obtained by EDTA-anticoagulated PRP (EDTA-anticoagulated PRP), and the platelet particles were finally suspended in the solution of T. Each liter of Tyrode's solution contains the following ingredients in millimoles: sodium chloride (136.8), potassium chloride (2.8), sodium bicarbonate (1.1), magnesium chloride (2.1), sodium dihydrogen phosphate (0.33). Calcium chloride (1.0) and glucose (1.2) and bovine serum albumin (0.35%). The turbidity was measured at 37 ° C as an agglutination phenomenon, and was measured by a two-channel recorder connected by a Lumi-aggregometer. The platelets were stirred at 1200 rpm to remove the influence of the solvent on the agglutination, and the final concentration was fixed at 0.5% (vol/vol) with Dimethyl sulfoxide (DMSO). Compound salts such as Indomethacin and KMUP-1 hydrochloride were tested to inhibit U46619-induced platelet aggregation activity (n=8).

5. Rats treated with monocrotaline (MCT) showed reduced pulmonary hypertension

Intraperitoneal injection of wild lily (60 mg/kg) rats caused pulmonary hypertension after 21 days. Oral daily KMUP-1 hydrochloride (2.5 mg/kg), Simvastatin (2.5 mg/kg), KMUP-1-nicotinic acid (2.5 mg/kg), KMUP-1-citric acid (2.5 mg/kg) , KMUP-1-Simvastatinic Acid (2.5 mg / kg), and KMUP-1-γ-polyglutamic acid (2.5 mg / kg), or inhaled KMUP-1-PGI ₂ (0.1 mM) can inhibit the treatment of males treated with monocrotaline Wistar rats have the effect of reducing pulmonary artery blood pressure (PABP).

6. Bleomycin induces pulmonary fibrosis in mice via transforming growth factor (TGF)-β expression in lung tissue, inhibited by KMUP-1 salts

The increase in collagen synthesis and the production of alveolar macrophages promote the production of transforming growth factor (TGF)-β, and the expression of TGF-beta is considered a biomarker of pulmonary fibrosis. Oral administration of KMUP-1 hydrochloride (1,2.5,5 mg/kg), Simvastatin (5 mg/kg), KMUP-1-Nicotinic acid (2.5 mg/kg), KMUP-1-Simvastatinic Acid (2.5 mg) /kg), KMUP-1-γ-polyglutamic acid (2.5 mg/kg) to induce pulmonary fiber induced by inhalation of 60 mg/kg bleomycin (BM) in mouse tracheal lavage fluid (Table 7). The expression state of the transforming growth factor of the lavage fluid was determined according to Enzyme immunoassay (EIA).

7. KMUP-1 Salt Inhibits Mouse Prostate Hypertrophy Induced by Indolinone

Testosterone (TS, 3 mg/kg/day) was administered for 4 weeks to induce mouse Prostate hypertrophy (BPH), and then KMUP-1 hydrochloride (2.5 mg/kg), KMUP- 1-Citric acid (2.5 mg/kg), KMUP-1-Nicotinic acid (2.5 mg/kg) was measured on the 28th day for the ratio of the mass (grams) to the body weight (grams) (n=6).

8. Inhibit H1N1 virus growth

In the culture medium of Mardin Darby Canine Kidney (MDCK), after infecting H1N1 virus, a glucose solution (5%) of KMUP-1 hydrochloride or KMUP-1-Simvastatinic acid was administered and found to inhibit the growth of the virus ( n=6).

9. inhibit cancer cell growth

In this experiment, the cytotoxic activity of L1210 leukemia cell line was tested by MTT (diphenyltetrazolium bromide) chromogenic assay, KMUP-1 hydrochloride, KMUP-1-Methotrexate (KMUP-1-MTX) glucose solution (5%). n=6). Methotrexate (MTX) was used as a positive control group. Briefly, cancer cells (5000 to 10000 cells/ml) were added to each well of a 96-well cell culture dish together with the test compound, and cultured for 3 days, and the attached cells were cultured in MTT (0.5 mg/ml). In 1 hour, the formazan crystals were dissolved in dimethyl air. The absorbance at a wavelength of 550 nm was measured by an enzyme-linked immunosorbent colorimeter. The IC ₅₀ is the concentration at which the test compound inhibits 50% of cell growth under the experimental conditions.

10. Suppress the asthma of animals

Male BALB/c mice (20~23g) were intraperitoneally injected with ovalbumin (OVA; 5mM; 30min), and on day 1 and day 8 were intraperitoneally injected with ovalbumin to induce asthmatic animals, and then adsorbed 10μg of egg white. The protein was sprayed with aluminum hydroxide (2 mg). A spray of 5 mM / 30 mins / day KMUP-1 hydrochloride or related complex salts was administered from day 21 to day 27. The asthmatic animals were divided into 5 groups. The control group was only given saline spray. The other experimental groups were first sprayed with 1% ovalbumin, and then sprayed with relevant compound salts as shown in Table 12 to determine the inhibition of ovalbumin. The expression of matrix metalloproteinase (MMP)-9 in lung tissue of BALB/c mice was induced.

Example 1 Preparation of KMUP-1 Hydrochloride (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethyl xanthine HCl,1)

KMUP-1 (8 g) was dissolved in a solution of ethanol (10 mL) and 1N hydrochloric acid (60 mL), and reacted at 50 ° C for 20 minutes, and methanol was added overnight at room temperature to carry out crystallization, and KMUP-1 hydrochloride was obtained by filtration. (7.4g).

Example 2 Preparation of KMUP-1 Citrate (KMUP-1-Citric acid, 2)

Take KMUP-1 (8g) dissolved in a solution of ethanol (10mL) and citric acid (4g), react at 50 ° C for 20 minutes, add methanol overnight at room temperature to crystallize, filter to obtain KMUP-1 citrate (10.5g).

Example 3 Preparation of KMUP-1 Nicotinate (KMUP-1-Nicotinic acid, 3)

Take KMUP-1 (8g) dissolved in a solution of ethanol (10mL) and nicotinic acid (2.4g), react at 50 ° C for 20 minutes, add methanol at room temperature overnight to crystallize, filter to obtain KMUP-1 smoke Basic acid salt (8.3 g).

Example 4 Preparation of KMUP-1-Simvastatinic acid (4) Complex

KMUP-1 (8g) was dissolved in a solution of ethanol (10 mL) and 1N hydrochloric acid (60 mL), and reacted at 50 ° C for 10 minutes. At room temperature, methanol was added overnight to carry out crystallization, and KMUP-1 hydrochloride was obtained by filtration. (7.4g). KMUP-1 hydrochloride (4.4 g) was weighed and dissolved in ethanol (150 mL) for use.

The Simvastatin (4.2 g) was dissolved in ethanol (50 mL) and poured into a flask placed with a stirring magnet, and an aqueous sodium hydroxide solution (4 g/60 ml) was added at room temperature, and the ethanol reaction filtrate of the above KMUP-1 hydrochloride was used at 50 The reaction was carried out at ° C for 20 minutes. After rapid filtration, the crystal was allowed to stand for 1 hour to obtain a KMUP-1-Simvastatinic acid complex.

Example 5 Preparation of KMUP-1-Lovastatinic acid (5) Complex

KMUP-1 (8g) was dissolved in a solution of ethanol (10 mL) and 1N hydrochloric acid (60 mL), and reacted at 50 ° C for 10 minutes. At room temperature, methanol was added overnight to carry out crystallization, and KMUP-1 hydrochloride was obtained by filtration. (7.4g). KMUP-1 hydrochloride (4.4 g) was weighed and dissolved in ethanol (150 mL) for use.

Lovastatin (4.2 g) was dissolved in ethanol (50 mL) and poured into a flask placed with a stirring magnet, and an aqueous sodium hydroxide solution (4 g/60 ml) was added at room temperature, and the ethanol reaction filtrate of the above KMUP-1 hydrochloride was used at 50 The reaction was carried out at ° C for 20 minutes. After rapid filtration, the crystals were allowed to stand for 1 hour to obtain a KMUP-1-Lovastatinic acid complex.

Example 6 Preparation of KMUP-1-Mevastatinic acid (6) Complex

KMUP-1 (8 g) was dissolved in a solution of ethanol (10 mL) and 1N hydrochloric acid (60 mL), and reacted at 50 ° C for 20 minutes, and methanol was added overnight at room temperature to carry out crystallization, and KMUP-1 hydrochloride was obtained by filtration. (7.4g). KMUP-1 hydrochloride (4.4 g) was weighed and dissolved in ethanol (150 mL) for use.

Mevastatin (4g) was dissolved in ethanol (50 mL), poured into a flask with a stirring magnet, and an aqueous sodium hydroxide solution (4 g / 60 ml) was added at room temperature. After 10 minutes, the above-mentioned KMUP-1 hydrochloride aqueous solution was added. , react at 50 ° C for 20 minutes. After rapid filtration, the crystal was allowed to stand for 1 hour to obtain a KMUP-1-Mevastatinic acid complex.

Example 7 Preparation of KMUP-1-Pravastatinic acid (7) Complex

KMUP-1 (8g) was dissolved in a solution of ethanol (10 mL) and 1N hydrochloric acid (60 mL), and reacted at 50 ° C for 20 minutes, allowed to cool to room temperature, added with ethanol, left to stand overnight for crystallization, and filtered to obtain KMUP- 1 hydrochloride (7.4 g). KMUP-1 hydrochloride (4.4 g) was weighed and dissolved in ethanol (150 mL) for use.

Pravastatin sodium (4.5 g) was dissolved in a solution of ethanol (50 mL) and 50 ml of water, poured into a flask in which a stirring magnet was placed, and an aqueous sodium hydroxide solution (4 g / 60 ml) was added at room temperature, and the above KMUP-1 salt was added. The ethanolic acid solution of the acid salt was reacted at 50 ° C for 20 minutes. After rapid filtration, the crystal was allowed to stand for 1 hour to obtain a KMUP-1-Pravastatinic acid complex.

Example 8 Preparation of KMUP-1-Rosuvastatinic acid (8) Complex

KMUP-1 hydrochloride was prepared in the same manner as in the fourth to seventh embodiments.

Rosuvastatin (10.5 g) was dissolved in ethanol (150 mL), poured into a flask placed with a stirring magnet, aqueous sodium hydroxide solution (4 g / 60 ml) was added at room temperature, and KMUP-1 hydrochloride dissolved in ethanol (150 mL) (4.4 g), stirring was continued at 50 ° C for 20 minutes. The mixture was concentrated under reduced pressure to 300 mL for rapid filtration and then cooled to obtain KMUP-1-Rosuvastatinic acid complex.

Example 9 Preparation of KMUP-1-Pitavastatinic acid (9) Complex

KMUP-1 hydrochloride was prepared in the same manner as in the fourth to seventh embodiments.

The pitavastatin (8.8 g) was dissolved in ethanol (100 mL) and poured into a flask in which a stirring magnet was placed, and an aqueous sodium hydroxide solution (4 g/60 ml) was added at room temperature, and KMUP-1 hydrochloride dissolved in ethanol (150 mL) ( 4.4 g), stirring was continued at 50 ° C for 20 minutes until the reaction was completed, and the mixture was quickly filtered and concentrated under reduced pressure. After cooling, water was added, and stirring was continued at room temperature for 20 minutes until the reaction was completed, and the precipitate was filtered to obtain a white KMUP-1-Pitavastatinic acid complex.

Example 10 Preparation of KMUP-1-Atorvastatinic acid (10) Complex

KMUP-1 hydrochloride was prepared in the same manner as in the fourth to seventh embodiments.

Atorvastatin (11.5 g) was dissolved in ethanol (100 mL) and poured into a flask placed with a stirring magnet, aqueous sodium hydroxide solution (4 g / 60 ml) and KMUP-1 hydrochloride dissolved in ethanol (150 mL) were added at room temperature ( 4.4 g), stirring was continued at 50 ° C for 15 minutes until the reaction was completed, and the mixture was quickly filtered and concentrated under reduced pressure. After cooling, water was added, and stirring was continued for 20 minutes at room temperature until the reaction was completed. After the precipitate was filtered, a white KMUP-1-Atorvastatinic acid complex was obtained.

Example 11 Preparation of KMUP-1-Atorvastatinic acid Complex

KMUP-1 hydrochloride was prepared in the same manner as in the fourth to seventh embodiments.

Atorvastatin hemi-calcium salt (13.6 g) was suspended in a solution of ethanol (100 mL) and water (30 mL), and poured into a flask in which a stirring magnet was placed, and KMUP-1 hydrochloride dissolved in ethanol (150 mL) was added at room temperature. A solution of (4.4 g) was stirred at 50 ° C for 20 minutes until the reaction was completed. After cooling, water was added, and stirring was continued for 20 minutes at room temperature until the reaction was completed. After the precipitate was filtered, a white KMUP-1-Atorvastatinic acid complex was obtained.

Example 12 Preparation of KMUP-1-Atorvastatinic acid Complex

KMUP-1 hydrochloride was prepared in the same manner as in the fourth to seventh embodiments.

Atorvastatin intermediates L-1 (6.6 g) was dissolved in ethanol (100 mL), poured into a flask containing a stirring magnet, 1N hydrochloric acid (30 mL) was added, and stirring was continued at 45 ° C, and a sodium hydroxide aqueous solution (pH 8.3) was added (6 g/ 60 mL) until the reaction is complete. While maintaining the temperature, a solution of KMUP-1 hydrochloride (4.4 g) dissolved in ethanol (150 mL) was added, and the reaction was continuously stirred at 50 ° C for 20 minutes. After rapid filtration, it was concentrated under reduced pressure. After the precipitation of the precipitate, the mixture was quickly filtered and stirred for 20 minutes to obtain a white KMUP-1-Atorvastatinic acid complex (9.8 g).

Example 13 Preparation of KMUP-1-Methotrexate (11) Complex

KMUP-1 (8g) was dissolved in a solution of ethanol (100 mL) and water (30 mL), and a solution of Methotrexate (MTX, 9.8 g) dissolved in ethanol (150 mL) was added and reacted at 50 ° C for 20 minutes. After cooling to room temperature, the resulting precipitate was dissolved in methanol, and left to stand for recrystallization. The KMUP-1-Methotrexate complex (15.3 g) was obtained by filtration.

Example 14 Preparation of KMUP-1-Indomethacin (12) Complex

KMUP-1 (8g) was dissolved in a solution of ethanol (100 mL) and water (30 mL), and a solution of Indomethacin (7 g) dissolved in ethanol (150 mL) was added and reacted at 50 ° C for 20 minutes, and the precipitate was filtered. Recrystallization was carried out by adding methanol overnight at room temperature, and filtration was carried out to obtain KMUP-1-Indomethacin complex (13.2 g).

Example 15 Preparation of KMUP-1-Repaglinide (13) Complex

KMUP-1 (8 g) was dissolved in a solution of ethanol (100 mL) and water (30 mL), and a solution of Repaglinide (9.1 g) dissolved in ethanol (150 mL) was added and reacted at 50 ° C for 20 minutes, and the precipitate was filtered. It was precipitated at room temperature, and methanol was added thereto at room temperature overnight to carry out recrystallization, and KMUP-1-Repaglinide complex (15.3 g) was obtained by filtration.

Example 16 Preparation of KMUP-1-Nateglinide (14) Complex

KMUP-1 (8 g) was dissolved in a solution of ethanol (100 mL) and water (30 mL), and Nateglinide (9.1 g) dissolved in ethanol (150 mL) was added, and reacted at 50 ° C for 20 minutes, and allowed to cool to obtain a white precipitate. Methanol was added at room temperature, left to stand overnight for crystallization, and KMUP-1-Repaglinide complex (15.3 g) was obtained by filtration.

Example 17 Preparation of KMUP-1-Cromolyn (15) Complex

KMUP-1 hydrochloride (8.8 g) was dissolved in a solution of ethanol (100 mL) and water (30 mL), and a solution of Cromolyn sodium (10.2 g) dissolved in ethanol (300 mL) was added and reacted at 50 ° C for 20 minutes. The white precipitate was obtained by cooling, and methanol was added at room temperature, and left to stand for recrystallization. The crystals were filtered to obtain KMUP-1-Cromolyn complex (16.2 g).

Example 18 Preparation of KMUP-1-Montelukast (16) Complex

KMUP-1 hydrochloride (8.8 g) was dissolved in a solution of ethanol (100 mL) and water (30 mL), and a solution of Montelukast (11.7 g) in ethanol (300 mL) was added and reacted at 50 ° C for 20 minutes. The white precipitate was obtained by cooling, and methanol was added thereto at room temperature overnight to carry out crystallization, and the crystals were filtered to obtain KMUP-1-Montelukast complex (16.8 g).

Example 19 Preparation of KMUP-1-Gemfibrozil (17) Complex

Gemfibrozil (2.5 g) was dissolved in ethanol (100 mL), and aqueous sodium hydroxide solution (4 g / 60 mL) was added at room temperature to cause a solution of Gemfibrozil sodium for use.

KMUP-1 hydrochloride (4.4 g) was dissolved in ethanol (150 mL), and a solution of Gemfibrozil sodium was added and reacted at 50 ° C for 20 minutes. After cooling, a white precipitate was obtained, and after removing sodium citrate by filtration, methanol was added at room temperature, and it was left to stand for recrystallization, and the KMUP-1-Gemfibrozil complex (5.2 g) was obtained by filtration.

Example 20 Preparation of KMUP-1-Fibric acid (18) Complex

Fenofibrate (3.6 g) was dissolved in ethanol (100 mL), and aqueous sodium hydroxide solution (4 g / 60 mL) was added at room temperature to cause a Fenofibric acid sodium solution for use.

KMUP-1 hydrochloride (4.4 g) was dissolved in ethanol (150 mL), and a solution of Fenofibric acid sodium was added thereto, and the mixture was reacted at 50 ° C for 20 minutes. After cooling to obtain a white precipitate, after removing sodium citrate by filtration, methanol was added at room temperature, and it was allowed to stand overnight to recrystallize, and the KMUP-1-Fibric acid complex (5.6 g) was obtained by filtration.

Example 21 Preparation of Double Simvastatinic Acid Piperazine Salt (Di-Simvastatinic acid piperazinium salt, 19)

Simavaststin (8.4 g) was dissolved in ethanol (100 mL), and an aqueous solution of sodium hydroxide (4 g / 60 mL) was added at room temperature to give a solution of Simavaststinic acid sodium in ethanol.

Piperazine di-hydrochloride (1.6 g), dissolved in a solution of ethanol (100 mL) and water (30 mL), and added to a solution of aqueous solution of Simavisstinic acid sodium in water, and reacted at 50 ° C for 20 minutes. After cooling, a white precipitate was obtained. After removing sodium citrate by filtration, methanol was added at room temperature overnight to recrystallize, and the crystals were filtered to obtain a double Simvastatinic acid piperazine salt complex (8.8 g).

Example 22 Preparation of Double Rosuvastatinic Acid Piperazine Salt

(Di-Rosuvastatinic acid piperazinium salt, 20) Rosuvastatin (10.5 g) was dissolved in ethanol (100 mL), and an aqueous solution of sodium hydroxide (4 g / 60 mL) was added thereto at room temperature to cause a solution of Rosuvastatinic acid sodium in ethanol.

Piperazine dihydrochloride (1.6 g), dissolved in a solution of ethanol (100 mL) and water (30 mL), was added to a solution of Rosuvastatinic acid sodium dissolved in aqueous ethanol, and reacted at 50 ° C for 60 minutes. After cooling, a white precipitate was obtained, and after removing sodium citrate by filtration, methanol was added thereto at room temperature to carry out recrystallization, and the crystals were filtered to obtain a double Rosuvastatinic acid piperazine salt complex (9.8 g).

Example Twenty-three Preparation of Double Atorvastatinic Acid Piperazine Salt (Di-Atorvastatinic acid piperazinium salt, 21)

Atorvastatin hemi-calcium salt (13.6 g) was suspended in a solution of ethanol (100 mL) and water (30 mL), and poured into a flask placed with a stirring magnet, and piperazine dihydrochloride dissolved in ethanol (150 mL) was added at room temperature. A solution of (1.6 g) was stirred at 50 ° C for 60 minutes until the reaction was completed. After cooling, water was added, and stirring was continued at room temperature for 20 minutes until the reaction was completed. After the precipitate was filtered, a white bis-Atorvastatinic acid piperazine salt complex (20.2 g) was obtained.

Example Twenty-four Preparation of KMUP-1-Polyuric Acid (22) Complex

(A) 2 g of sodium glutamate (Sodium γ-polyglutamate) was dissolved in water to prepare a 5% viscous aqueous solution (40 mL), and KMUP-1 hydrochloride (2 g) powder was added. The reaction was stirred at 50 ° C for 1 hour to obtain a white precipitate. The aqueous solution was poured out, dehydrated by adding ethanol (100 mL), and then unreacted KMUP-1 was washed by adding ethanol (100 mL), and dried overnight (50 ° C). KMUP-1-polyglutamic acid complex (2.6 g) was obtained.

(B) 2 g of polyglutamate was dissolved in water to make a 5% viscous aqueous solution (40 mL), and KMUP-1 hydrochloride (2 g) powder was added. The reaction was stirred at 50 ° C for 1 hour to obtain a white precipitate. The aqueous solution was poured out, dehydrated by adding ethanol (100 mL), and then unreacted KMUP-1 was washed by adding ethanol (100 mL), and dried overnight (50 ° C). KMUP-1-polyglutamic acid complex (2.8 g) was obtained.

(C) 2 g of polyglutamic acid was dissolved in ethanol (50 mL), KMUP-1 (2 g) powder was added, and the reaction was stirred at 50 ° C for 1 hour, and allowed to stand at room temperature to obtain a white precipitate. After filtration, ethanol was added ( 100 mL) of unreacted KMUP-1 was washed out and dried overnight (50 ° C) to obtain KMUP-1-polyglutamic acid complex (3.1 g).

Example 25 Preparation of KMUP-1-polyglutamic acid cross-linked sodium alginate (23) complex

Calcium polyglutamate-alginate Sodium. 2g was dissolved in water to make a 5% viscous aqueous solution (40 mL), and KMUP-1 hydrochloride (2 g) powder was added. The reaction was stirred at 50 ° C for 1 hour to obtain a white precipitate. The aqueous solution was poured out, dehydrated by adding ethanol (100 mL), and then unreacted KMUP-1 was washed by adding ethanol (100 mL), and dried overnight (50 ° C). A calcium polyglutamate crosslinked sodium alginate (2.9 g) was obtained.

Example Twenty-six KMUP-3 hydrochloride (7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethyl xanthine HCl, 24)

KMUP-3 (8.4 g) was dissolved in a solution of ethanol (100 mL) and 1N hydrochloric acid (60 mL), and reacted at 50 ° C for 20 minutes, cooled to obtain a yellow precipitate, and methanol was added at room temperature, and left overnight. Crystallization, filtration afforded yellow KMUP-3 hydrochloride (6.4 g).

Example 27 KMUP-2 hydrochloride (7-[2-[4-(2-methoxybenzene)piperazinyl]ethyl]-1,3-dimethyl xanthine HCl, 25)

KMUP-3 (8.0 g) was dissolved in a solution of ethanol (10 mL) and 1N hydrochloric acid (60 mL), and reacted at 50 ° C for 10 minutes. At room temperature, methanol was added and allowed to stand overnight for crystallization, and KMUP-3 salt was obtained by filtration. Acid salt (6.4 g).

Example 28 Preparation of KMUP-1-Zhankuic acid A(26) complex

Zhankuic acid A (8.0 g) was dissolved in ethanol (100 mL), and an aqueous sodium hydroxide solution (4 g / 60 mL) was added at room temperature to cause a solution of Zhankuic acid A sodium for use.

KMUP-1 hydrochloride (8.8 g) was dissolved in ethanol (150 mL), and a solution of Zhankuic acid A sodium was added and reacted at 50 ° C for 20 minutes. After cooling, a white precipitate was obtained. After removing NaCl by filtration, methanol was added at room temperature, and it was left to stand for recrystallization, and KMUP-1-Zhankuic acid A complex (15.6 g) was obtained by filtration.

Example 29 Preparation of KMUP-1-PGI ₂ Complex (27)

KMUP-1 hydrochloride (880 mg) was dissolved in a solution of ethanol (100 mL) and water (30 mL), and a solution of PGI ₂ sodium (1020 mg) dissolved in ethanol (300 mL) was added and reacted at 50 ° C for 20 minutes. The white precipitate was obtained by cooling, and methanol was added at room temperature, and left to stand for recrystallization, and the crystals were filtered to obtain KMUP-1-PGI ₂ complex (1620 mg).

Example 30 Formulation of KMUP-1 and Atorvastatin intermediates L-1

Atorvastatin intermediatesL-1 0.66g

KMUP-1 hydrochloride 0.44g

Lactose qs

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Lin, R.-J., Wu, B.-N., Lo, Y.-C., Shen, K.-P., Lin, Y.-T., Huang, C.-H. and Chen, I.-J. KMUP-1 relaxes rabbit corpus cavernosum smooth muscle in vitro and in vivo:involvement of cyclic GMP and K ⁺ Channels. Br. J. Pharmacol. 2002. 135:1159-1166.

Liu, C.-M., Lo, Y.-C., Wu, B.-N., Wu, W.-J., Chou, Y.-H., Huang C.-H., An, L .-M. and Chen, I.-J. cGMP-enhancing-an _1A / _1D -andrenoceptor blockade-derived inhibition of Rho-kinase by KMUP-1 provides optimal prostate relaxation and epithelial cell anti-proliferation efficiency. Prostate, 2007. 67:1397-1410.

Wu, B.-N., Chen, C.-W., Liou, S.-F., Yeh, J.-L., Chung, H.-H. & Chen, I.-J. Inhibition of proinflammatory Tumor necrosis factor- -Induced inducible nitric-oxide synthase by xanthine-based 7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethyl-xanthine(KMUP-1)and 7-[2 -[4-(4-nitrobenzene)piperazinyl]-ethyl]-1,3-dimethylxanthine(KMUP-3)in rat trachea:The involvement of soluble guanylate cyclase and protein kinase G. Mol. Pharmacol. 2006. 70:977- 985.

Wu, B.-N., Lin, R.-J., Lin, C.-Y., Shen, K.-P., Chiang, L.-C. & Chen, I.-J. A xanthine- Based KMUP-1 with cyclic GMP enhancing and K ⁺ channels opening activities in rat aortic smooth muscle. Br. J. Pharmacol. 2001. 134: 265-274.

Wu, B.-N., Lin, R.-J., Lo, Y.-C., Shen, K.-P., Wang, C.-C., Lin, Y.-T. and Chen, I.-J. KMUP-1, a xanthine derivative, induces relaxation of guinea-pig isolated trachea: the role of the epithelium, cyclic nucleotides and K ⁺ channels. Br. J. Pharmacol. 2004. 142: 1105-1114.

Wu, B.-N., Tu, H.-F., Welsh, DG and Chen, I.-J. KMUP-1 activates BK _Ca channels in basilar artery myocytes via cyclic nucleotide-dependent protein kinases. Br. J. Pharmacol. 2005. 146, 862-871.

X _b represents the rest of the structure of the statin drug

"........." bond contains carboxylic acid groups to form complex salts

() representative code

First image: (a) KMUP-1 hydrochloride (1), (b) KMUP-1 citrate (2) (c) schematic diagram of preparation of KMUP-1-statin complex

Figure 2: Schematic diagram of KMUP-1 quaternary ammonium piperazine complex salt

Figure 3: Schematic diagram of the tetra-ammonium piperazine complex salt of piperazine

Claims (5)

A complex salt compound selected from the group consisting of a derivative of a KMUP-based compound and a Statin-containing compound containing a carboxylic acid group. A compound salt compound according to claim 1, wherein the KMUP compound is selected from the group consisting of 7-2-4-(2-chlorophenyl)piperazinyl]ethyl]-1. 3-Dimethylxanthine (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine, KMUP-1), KMUP-2 (7-[2-[4-( 2-methoxybenzene)piperazinyl]ethyl]-1,3-dimethyl xanthine); and KMUP-3(7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethyl xanthine). A compound salt compound containing a carboxylic acid group according to the first aspect of the patent application, wherein the Statin compound containing a carboxylic acid group is selected from the group consisting of the following Statin compounds: atorvastatin (Atorvastatin), cerivastatin (Cerivastatin) ), fluvastatin, lovastatin, mevastatin, Pravastatin, rosuvastatin, and simvastatin. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and an effective amount of a main component selected from the group consisting of a derivative of a KMUP compound and a Statin compound containing a carboxylic acid group. Things. The pharmaceutical composition of claim 4, wherein the KMUP compound is selected from the group consisting of KMUP-1(7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1 , 3-dimethylxanthine), KMUP-2(7-[2-[4-(2-methoxybenzene)piperazinyl]ethyl]-1,3-dimethylxanthine); KMUP-3(7-[2-[4-(4- Nitrobenzene)piperazinyl]ethyl]-1,3-dimethyl xanthine); Its carboxylic acid group-containing Statin compound is selected from the group consisting of the following Statin compounds: atorvastatin, cerivastatin, fluvastatin, and rivastatin. (Lovastatin), mevastatin, Pravastatin, Rosuvastatin, and Simvastatin.