Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/63—One oxygen atom
  • C07D213/64—One oxygen atom attached in position 2 or 6
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to 1-substituted benzyl-5-trifluoromethyl-2-(1H)pyridones.
• the invention also relates to their preparation and medical use.
• Fibrosis can occur in a variety of organs or tissues, causing a decrease in parenchymal cells in the organs or tissues, and an increase in fibrous connective tissue, which can eventually lead to destruction of organs or tissues and dysfunction, and even organ failure.
• extensive research has been conducted on the mechanism, diagnostic methods and control measures of organ or tissue fibrosis.
• considerable progress has been made in some aspects, but some key problems remain unresolved.
• pyridone has anti-inflammatory, antipyretic, lowering serum uric acid levels, and relieving pain.
• 1-phenyl-l-phenyl-2(lH)-pyridone (Pirfenidone) has the best activity and low toxicity.
• pirfenidone PFD
• the efficacy of pirfenidone, (pirfenidone, PFD) in anti-fibrosis has been confirmed by more in vitro and animal experiments.
• pirfenidone has the effect of preventing or even reversing the accumulation of ECM and preventing or even reversing the occurrence of fibrosis and scar formation (Shimizu T, Fukagawa M, Kuroda T, etal.
• Pirfenidone retained collagen accumulatio n in the remnant kidney in rats with partial nephrectomy.
• Kidney Int, 1997,52 (Suppl 63 ) ⁇ S239-243; Raghu G, Johnson WC, Lockhart D, Et al. Treatment of idiopathic pu Imonary fibrosis with a new antifibrotic agent, pirfenidone. Am J Respir Crit Care Me d, 1999, 159: 1061-1069).
• the substituent R represents F, Cl, Br, I, a saturated linear hydrocarbon group, an oxo saturated linear hydrocarbon group, or a halogenated saturated linear hydrocarbon group.
• the position of the substituent group R on the benzene ring has an ortho, meta, para position and the like.
• Pirfenidone has been marketed in Japan in 2008 for indications for the treatment of pulmonary fibrosis. However, pirfenidone and its derivatives have little effect. The clinical daily dose of pirfenidone reached 2400 mg.
• WO2007053685 WO2006122154 discloses a class of compounds having p38 kinase inhibition which are useful in the treatment of fibrotic diseases. Its structure is shown in Structure III: Structure III Wherein: 1 1 to 4 is 11, alkyl, substituted alkyl, alkenyl, haloalkyl, nitroalkyl, hydroxyalkyl, alkoxy, phenyl, substituted phenyl, halogen, hydroxy, alkoxy An alkyl group, a carboxyl group, an alkoxycarbonyl group or the like; 1 to 5 are 11, a halogen, an alkoxy group, or a hydroxyl group.
• WO2007062167 also discloses certain compounds having p38 kinase inhibition, which are also useful in the treatment of various fibrosis. Some of these structures are as follows:
• Chinese Patent Application No. 200710034357 also discloses a similar compound having some of the above structures having anti-fiber Activity, while also disclosing a compound having structure IV having an anti-fibrotic active structure IV
• German patent DE4343528 reports that a class of compounds has an insecticidal action in agriculture and has the following structural formula V.
• B is a heterocyclic ring such as furan ring, imidazole, pyridine or pyridone; wherein a compound such as structural formula VI is included (
• EP 259048, EP 367410, EP 398499 report that a class of compounds have an insecticidal action in agriculture and have the following structural formula VII.
• Structural formula IX It contains a class of compounds of formula X:
• European Patent EP 488 220 reports that a class of compounds has a herbicidal action and has the following structural formula XI.
• the above compounds have various and multiple substituents in the structure, whether it is a pyridine ring or a benzene ring at the 1-position of the pyridine ring, and have a complicated structure, and there is no report on anti-fibrosis. At the same time, the compound is more fat-soluble due to the larger number of fluorine atoms in the molecule.
• DE 10 2004 027 359 discloses a class of compounds which modulate the dopamine 3 receptor, which are useful in the treatment of Parkinson's disease and schizophrenia. It has the following structural formula XII.
• A is: a hydrocarbon chain of 4 to 6 atoms, and one or two methyl groups may be substituted on the carbon chain.
• One or two carbon atoms in the carbon chain may be substituted by other atoms such as oxygen, carbonyl, and sulfur.
• Rl and R2 are: H; CN; N0 2; a halogen atom; OR 5; NR 6 R 7 ; C (0) w R 6 R 7; 0-C (0) w R 6 R 7; Ci -C 6 of An alkyl group; a halogen alkyl group of -C 6 or the like.
• the 1-substituted benzyl-5-trifluoromethyl-2-(1H)pyridinone compound provided by the present invention has a structure of the formula (XIII).
• R1 to R4, R12 are selected from the group consisting of: H, CN, N0 2 , hydroxy, amino, halogen atom, a C 6 alkoxy group, NR ⁇ R 1 OR 13 , C(0)R 14 , 0-C(0 R 14 R 15 , an alkyl group of -C 6 , a haloalkyl group of dC 6 , an alkenyl group of C 2 -C 6 , a carboxyl group, a carboxylic acid ester; wherein R1 to R4, R12 are not simultaneously H, R 14 , R 15 is selected from the group consisting of: -C 6 alkyl, in the structure of NI ⁇ R 11 and OR 13 , R 1Q and R 11 are selected from: H, -C 6 hydroxyalkyl, esterified -C 6 hydroxyalkyl, a -C 6 alkoxyalkyl group, or a structural formula XIV, and R 1Q and R 11 are not simultaneously H; OR
• R5 is selected from the group consisting of: H, -C 6 alkyl, -C 6 haloalkyl, -C 6 hydroxyalkyl, C 2 -C 6 alkenyl;
• X is selected from N, CH 2;
• Y is selected from N, 0, C;
• n is: 1 ⁇ 6;
• the salt may be hydrochloride, sulfate, phosphate, perchlorate, methanesulfonate, triflate, formate, acetate, propionate, butyrate, horse Acidate, succinate, trifluoroacetate, succinate, salicylate, DL-aspartate, D-aspartate, L-aspartate, DL- Glutamate, D-glutamate, L-glutamate, glycerate, succinate, stearate, DL-tartrate, D-tartrate, L-tartaric acid Salt, ( ⁇ ) mandelate, (R)-(-)mandelate, (S)-(+)-mandelate, citrate, mulate, maleate, malonate, Benzoate, DL-malate, D-malate, L-malate, hemi-malate, 1-adamantane acetate, 1-adamantane carboxylate, sulphate,
• one of R1 to R4 and R12 is NR 1 ⁇ 11 or OR 13 .
• the present invention further preferably, when one of R1 to R4 and R12 is NR 1 ⁇ 11 or OR 13 , the remaining substituent is 11.
• the present invention also provides a process for the preparation of the above compounds.
• the preparation method roadmap is as follows:
• the starting material trifluoromethylpyridone is a commercial starting material.
• 5-trifluoromethyl-2(1H)pyridone is reacted with the substituted benzyl bromide, DMSO is used as a solvent, and potassium carbonate is used as an acid binding agent.
• reaction formula I For the simple amino-substituted compound, after the nitro derivative is prepared according to the reaction formula I, an amino-substituted product is obtained under the reduction of iron hydroxide hydrochloride, and the corresponding reaction reagent is worth the target product. See Reaction Scheme II.
• reaction formula III For a compound in which an amino group is bonded to a heterocyclic ring through a fatty side chain, after an amino group is prepared according to Reaction Formula II, it is reacted with a heterocyclic compound having a halogenated alkyl side chain, DMF is used as a solvent, potassium carbonate is used as an acid binding agent, and iodine is used. Sodium is used as a catalyst. See reaction formula III.
• a hydroxyethylamino substituent can be obtained according to the reaction formula II, reacted with thionyl chloride to obtain a chloroethylamino compound, and then reacted with a heterocyclic compound to obtain a target product. See reaction formula IV.
• Reaction formula IV The above compounds can be used to prepare a broad spectrum fibrotic drug.
• the present invention is based on the above prior art, introducing a substituent on the benzene ring of the benzyl group at the 1-position of the pyridone, in particular introducing an amino group or a substituted amino group, and introducing a heterocyclic ring through the alkyl chain on the amino group.
• a new class of pyridone compounds and their salts are obtained. Due to the introduction of substituents on the phenyl ring, the activity of these compounds is greatly increased.
• the Applicant has found that on the basis of 1-benzyl-5-trifluoromethylpyridone, the phenyl group is further modified, and the phenyl group is modified with a substituent amino group, and an unexpected effect is obtained, and the obtained compound has Compared with existing pyridone compounds Has a relatively high efficacy.
• such a heterocyclic-containing compound can be made into various salts, which is advantageous for various liquid preparations.
• Figure 1 is a renal pathology HE staining (X 200 ) in Example 28;
• Figure 2 is a renal pathology Masson staining (X 200) in Example 28.
• the cells were cultured in a DMEM medium containing 5% calf serum using a thiazole blue (MTT) method, and the cells were made into a cell suspension of 3 X OVml, and 100 ⁇ l per well was seeded in a 96-well plate. After the cells were attached, the medium containing 1% calf serum containing different concentrations of compound and flufenidone (AKF-PD) was changed, and 3 duplicate wells were set for each concentration. After 48 and 72 hours after dosing, the solution was added to each well (the medium was formulated to 5 mg/ml, and stored in the dark after filtration).
• MTT thiazole blue
• Compound 3 was synthesized according to the method of the present invention.
• Each rat was anesthetized by intraperitoneal injection of 0. 35 ml/100 g of 10% chloral hydrate, and then fixed on a rat fixation plate. First soak the back skin with water, then tighten the skin, use the elbow surgery to cut the skin to the hair, routine disinfection towel.
• CMCNa powder is added to a suitable 0.9% physiological saline solution to prepare a CMCNa solution having a concentration of 0.5%, and the following groups of drugs are prepared by using 0.5% CMCNa solution as a solvent.
• Rats in each group were intraperitoneally injected with 10% chloral hydrate (0. 7_0. 9ml/100g) on the 11th day after operation, and the obstructed kidney tissue was fixed with 4% formaldehyde and embedded in paraffin. 4 m thick sections, HE staining and Masson staining.
• renal interstitial lesions were scored according to 8 indicators: renal tubular epithelial vacuoles Denaturation, tubular dilatation, tubular atrophy, red blood cell cast, protein cast, interstitial edema, interstitial fibrosis, interstitial inflammatory cell infiltration, and the mean value was calculated as the tubulointerstitial damage index of the specimen. Scoring Criteria References: Radford MG Jr, Donadio JV Jr, Bergstral EJ, et al. Predicting renal outcome in IgA nephropathy . J Am Soc Nephrol, 1997, 8(2): 199-207.
• Compound 315mg/kg is effective in the treatment of renal fibrosis.

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• 2010
  • 2010-05-24 KR KR1020117030958A patent/KR101478133B1/ko not_active Expired - Fee Related
  • 2010-05-24 EP EP10780057.5A patent/EP2474533B1/en not_active Not-in-force
  • 2010-05-24 US US13/322,153 patent/US8377932B2/en not_active Expired - Fee Related
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