CN109180586A - Hexahydro azatropylidene -4- base oxybenzamide class compound as Rho kinase inhibitor - Google Patents

Hexahydro azatropylidene -4- base oxybenzamide class compound as Rho kinase inhibitor Download PDF

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CN109180586A
CN109180586A CN201811176331.5A CN201811176331A CN109180586A CN 109180586 A CN109180586 A CN 109180586A CN 201811176331 A CN201811176331 A CN 201811176331A CN 109180586 A CN109180586 A CN 109180586A
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azatropylidene
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周立宏
赵芹江
王光辉
张洁
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Chengdu Univeristy of Technology
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Abstract

The present invention relates to hexahydro azatropylidene -4- base oxybenzamide class compounds and/or their officinal salt and preparation method thereof shown in Formulas I, they can be used for treating and/or preventing disease relevant to the inhibition of Myosin light chain phosphatase phosphorylation that the inhibition of Rho kinases and/or Rho- are kinase mediated, and the composition containing the compound.Wherein, to R1And R2The restriction of two substituent groups is as disclosed in the claims.

Description

Hexahydro azatropylidene -4- base oxybenzamide class as Rho kinase inhibitor Close object
Technical field
The invention belongs to field of medicinal chemistry, and in particular to hexahydro azatropylidene -4- base new described in claim Oxybenzamide class compound and its physiologically acceptable salt, their preparation and they treat and/or prevent and Rho Use in the relevant disease of the inhibition of the inhibition of kinases and/or the kinase mediated Myosin light chain phosphatase phosphorylation of Rho- On the way.
Technical background
Uehata et al. reports small GTPase RhoA through agonist for the first time in Nature (1997,389,990-994) It stimulates and activates, cause RhoA to be converted into active GTP- combining form from inactive GDP- combining form, later in conjunction with simultaneously Activate Rho kinases.Known two kinds of isoform Rho kinases 1 and Rho kinases 2.Rho kinases 2 is in vascular smooth muscle cells and endothelium It is expressed in cell.The RhoA activation that Rho kinases 2 is combined through active GTP-, leads to flesh of the smooth muscle cell by mediated phosphorylation The inhibition of immunoglobulin light chains phosphatase activity and thus up-regulation myosin adjust light chain activity and calcium sensitization.
Known Rho- kinases involves in vessel retraction, the generation (Gokina including myogenic tonus and smooth muscle excess shrinkage Et al., J.Appl.Physiol.2005,98,1940-8), bronchial smooth muscle shrink (Yoshii et al., Am.J.Resp.Cell Mol.Biol.20,1190-1200), asthma (Setoguchi et al., Br J Pharmacol.2001, 132,111-8；Nakahara et al., Eur J 2000,389,103) and chronic obstructive pulmonary disease (COPD, Maruoka, Nippon Rinsho, 1999,57,1982-7), hypertension, pulmonary hypertension (Fukumoto et al., Heart, 91,391-2, 2005, Mukai et al., Nature 1997,389,990-4) and ocular hypertension and it is intraocular pressure-regulated (Honjo et al., Invest.Ophthalmol.Visual Sci.2001,42,137-144), endothelial dysfunction (Steioff et al., Eur.J.Pharmacol.2005,512,247-249), angina pectoris (Masumoto et al., Circ 2002,105,1545-47, Shimokawa et al., JCP, 2002,40,751-761), nephrosis, it is including hypertension induction, non-hypertensive induction and sugared Urinate characteristic of disease nephrosis, kidney failure and peripheral arterial occlusion disease (PAOD) (Wakino et al., Drug News Perspect.2005, 18,639-43), myocardial infarction (Demiryurek et al., Eur J Pharmacol.2005,527,129-40, Hattori Et al., Circulation, 2004,109,2234-9), cardiomegaly and failure (Yamakawa et al., Hypertension 2000,35,313-318, Liao et al., Am J Physiol Cell Physiol.2006,290, C661-8, Kishi etc. People, Circ 2005,111,2741-2747), coronary heart disease, atherosclerosis, restenosis (Pacaud et al., Arch.Mal.Coeur 2005,98,249-254, Retzer et al., FEBS Lett 2000,466,70, Negoro et al., Biochem Biophys Res Commun1999,262,211), osteoporosis, endocrine dysfunction such as hyperaldosteronism Disease, central nervous system disorder such as neuronal degeneration and spinal cord injury (Hara et al., JNeurosurg 2000,93,94), brain Ischemic (Uehata et al., Nature 1997,389,990；Satoh et al., Life Sci.2001,69,1441-53；Hitomi Et al., Life Sci 2000,67,1929；Yamamoto et al., J Cardiovasc Pharmacol.2000,35,203- 11), cerebral angiospasm (Sato et al., Circ Res 2000,87,195；Kim et al., Neurosurgery 2000,46, 440), pain, such as neuropathic pain (Tatsumi et al., Neuroscience 2005,131,491；Inoue et al., Nature medicine 2004,10,712), cancer occur and progress, wherein Rho kinase inhibition have shown that inhibit tumour it is thin Intracellular growth and the tumor of transfer form (Itoh et al., Nature Medicine 1999,5,221；Somlyo et al., ResCommun 2000,269,652), angiogenesis (Uchida et al., Biochem Biophys Res2000,269,633-40；Gingras Et al., Biochem J 2000,348,273), vascular smooth muscle cell proliferation and movement (Tammy et al., Circ.Res.1999,84,1186-1193；Tangkijvanich et al., Atherosclerosis 2001,155,321- 327), endothelial cell proliferation, endothelial cell shrink and movement (Oikawa et al., Biochem.Biophys.Res.Commun.2000,269,633-640), stress fiber forms (Kimura et al., Science 1997,275,1308-1311；Yamashiro et al., J.Cell Biol.2000,150,797-806), thrombosis venereal disease Disease (Kikkawa et al., FEBS Lett.2000,466,70-74；Bauer et al., Blood 1999,94,1665-1672, Klages et al., J Cell Biol 1999,144,745；Retzer et al., Cell Signal2000,12,645) and it is white thin Born of the same parents assemble (Kawaguchi et al., Eur J Pharmacol.2000,403:203-8；Sanchez-Madrid et al., J Immunol.2003,171,1023-34, Sanchez-Madrid et al., J Immunol.2002,168,400-10) it is inhaled with bone It receives (Chellaiah et al., J Biol Chem.2003,278,29086-97).Na/H exchanges movement system activation (Kawaguchi et al., Eur J Pharmacol.2000,403:203-8), Alzheimer disease (Zhou et al., Science 2003,302,1215-1217), interior suction protein activation (Fukata et al., J.Biol.Chem., 1998,273,5542-5548) And SREB (sterol response binding member) signal transduction and its to the effect of lipid-metabolism (Lin et al., Circ.Res., 92, 1296-304,2003).
Therefore, the Myosin light chain phosphatase phosphorylation kinase mediated to Rho- kinases and/or Rho-, which has, inhibits effect The compound of fruit can be used for treating and/or preventing being related to angiocarpy and non-cardiovascular of the Rho- kinases as the main or secondary cause of disease Disease, such as hypertension, pulmonary hypertension, ocular hypertension, retinopathy and glaucoma, peripheral circulation obstacle, Peripheral arterial occlusion Disease (PAOD), coronary heart diseases and angina pectoris, cardiomegaly, heart failure, ischemic disease, ischemic organ failure (terminal organ damage), fibroid lung, fibrosis liver, hepatic failure, nephrosis, it is including hypertension induction, non-hypertensive induction And nephrosis, kidney failure, fibrosis kidney, glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), Adult respiratory distress syndrome (ARDS), thrombotic disorders, apoplexy, cerebral angiospasm, cerebral ischemia, pain such as neuropathic pain, It is neuronal degeneration, spinal cord injury, Alzheimer disease, premature labor, erectile dysfunction, endocrine dysfunction, artery sclerosis, preceding Column gland hypertrophy, diabetes and diabetic complication, reangiostenosis, atherosclerosis, inflammation, itself are exempted from metabolic syndrome Epidemic disease, AIDS, osteopathy such as osteoporosis, digestive tract bacterial infection, sepsis, cancer development and progress, such as breast, knot The cancer and its transfer of intestines, prostate, ovary, brain and lung.
There are also other relevant patents or document reports, such as WO2001/64238 to describe and can be used as neuroprotective agent Optionally by the-heterocycle of (CH2) 16-O- (CH2) 0-6- ,-(CH2) 0-6-S- (CH2) 0-6- or-(CH2) 0-6- connection Replaced isoquinolin -5- sulfamide derivative.WO2004/106325 (ScheringAG) is described to be taken at 1, isoquinolin ring The prodrug of Rho- kinase inhibitor Fasudil with ether or ester group.WO2001/039726, which is generally depicted, can be used for treating The cyclohexyl derivatives that-O- (C0-C10) alkyl-heteroaryl of microorganism infection replaces.JP10087629A, which is described, can be used for It is derivative to treat such as isoquinolin of gastritis cancer or ulcer of the disease as caused by helicobacter pylori (Heliobacter pylori) Object.The isoquinilone derivatives can be replaced by OH at 1, preferably carry out 5- by X- [(C1-C6) alkylidene)] 0-1-Y and replace, wherein X can be oxygen and Y can be aryl or heterocycle.Hagihara et al. (Bioorg.Med.Chem.1999,7,2647- 2666) it discloses for treating 6- benzyloxy-isoquinolin by the microbial infection of H. pylori.US 5,480,883 summarizes It discloses as EGF and/or pdgf receptor inhibitor, formula " the Ar I-X-Ar II " compound that can be used for inhibiting cell Proliferation, Wherein X can be (CHR1) m-Z- (CHR1) n, such as Z-CH2, and wherein Z can be O, and R1 is hydrogen or alkyl, and ArI can be especially The isoquinolines optionally replaced, the C3-7 monocycle saturated heterocyclic system that Ar II especially can optionally replace.WO2005/030791 (Merck&Co.) it briefly discloses as potassium channel inhibitors, for treating arrhythmia cordis, apoplexy, congestive heart failure Deng isoquinolinone derivatives, optionally replaced at 6 by group (CReRf) pOR43, it is example that wherein p, which can be zero, R43, Such as (C3-C10) naphthenic base optionally replaced by NR51R52, wherein R51 and R52 can be hydrogen, (C1-C6) alkyl etc.；Or R43 is group R81, is defined as having 1,2,3 or 4 heteroatomic 4-6 member insatiable hunger and/or is saturated monocyclic heterocycles；And in 4 quilts Replaced the aryl optionally replaced or heteroaryl ring of Direct Bonding.WO2005/030130 (Merck&Co.) summary discloses work It, can be 1 for potassium channel inhibitors, the isoquinilone derivatives for treating arrhythmia cordis, apoplexy, congestive heart failure etc. Position is optionally substituted by a hydroxyl group and is optionally replaced by group (CReRf) pOR43 at 6, and it is for example optionally that wherein p, which can be zero, R43, (C3-C10) naphthenic base replaced by NR51R52, wherein R51 and R52 can be hydrogen, (C1-C6) alkyl etc.；Or R43 is group R81 is defined as having 1,2,3 or 4 heteroatomic 4-6 member insatiable hunger and/or is saturated monocyclic heterocycles；And at 4 by Direct Bonding Replaced the aryl or heteroaryl ring optionally replaced.WO 03/053330 (Ube), which is briefly described, can be used as the suppression of Rho- kinases The isoquinolinone derivatives of preparation.
It especially needs to propose, is two Chinese invention patents of French Sanofi-Aventis limited liability company application, Authorization Notice No. is respectively CN101573354B and CN101616909B.This two Chinese invention patents report a kind of 6- and replace Isoquinolin and isoquinolinone derivatives, they can be used for treat and/or prevent with Rho kinases and/or Rho it is kinase mediated The related disease of Myosin light chain phosphatase phosphorylation.
CN101573354B discloses the isoquinolin and isoquinolinone derivatives of the substitution of the 6- as shown in formula II,
Wherein R1 is H or OH；R2 is R ', C (O) NH- (CrC6) alkyl, C (O) NHR ', C (O)-NH (C2-C6) alkene Base, C (O)-NH (C2-C6) alkynyl, C (O)-NH (C1-C6) alkylidene-R '；Or R2 is that (C1-C4) alkylene is connect with cyclammonium Base, wherein (C1-C4) alkylidene from the cyclammonium ring different carbon atoms formed the second key, and with the carbon atom one on cyclammonium It rises and forms second 4-8 member ring；R3 is H, and R4 is H；R5 is H；R6 is H, (C1-C8) alkyl, (C1-C6) alkylidene-R；R7 is H, halogen, (C1-C6) alkyl；R8 is H；η is 1,2,3 or 4；M is 3；And L is O (CH2) p and is connected to the 4 of piperidine ring Position；P is 0,1,2,3 or 4；Wherein R ' is (C3-C8) naphthenic base, (C5-Cltl) heterocycle or (C6-Cltl) aryl；Wherein exist In group R2, R6 and R7, alkyl, alkylidene or naphthenic base can optionally be replaced by OH, OCH3 one or many；Wherein exist In R2, R6 and R7, alkyl or alkylidene can optionally be optionally substituted by halogen one or many: wherein in group RjPR6, (C6- Cltl) aryl and (C5-Cltl) heterocycle be it is unsubstituted or be independently selected from appropriate group below replace it is primary or more Secondary suitable element, OH, C (O)-(C1-C6) alkyl, (C " C6) alkyl, (C " C6) alkylidene-OH, O- (C1-C6) alkyl and O-C (O)- (C1-C6) alkyl；Wherein (C6-Cltl) aryl refers to aromatic ring or comprising two aromatics that are condensed or being otherwise coupled to The ring system of ring；And wherein (C5-Cltl) heterocycle refers to that wherein one or more carbon atoms can be by one or more hetero atoms The mono- or bicyclic ring system replaced；And/or their alloisomerism and/or tautomeric form and/or their officinal salt.
CN101616909B similarly discloses the isoquinolin and isoquinolinone derivatives of the substitution of the 6- as shown in formula II,
But it is different to the limitation of substituent group.Wherein R1 is H, OH or NH2；R2 is H, halogen or (C1-C6) alkane Base；R3 is H；R4 is that H or (C1-C6) burn base；R5 is H or halogen；R6 is that (C1-C6) sub- burn base-C (O) NH- (C1-C6) is burnt Base, (C1-C6) MS-C (O) N [(C1-C6) burns base]2, C (O) (C1-C6) alkyl, C (O) R ', C (O)-(C1-C6) alkylidene- R'；R7 is H, halogen or (C1-C6) alkyl；R8 is H, halogen or (C1-C6) alkyl；η is I；M is 3；L is 0, and L is connected to 4 of piperidine ring；Wherein: R ' is (C3-C8) naphthenic base, (C5-Cltl) heterocycle or (C6-Cltl) aryl；Wherein in residue Alkyl, alkylidene or naphthenic base are optionally by OH, OCH in R4, R6 and R73、NH2、NHCH3Or N (CH3)2Replace primary or more It is secondary；Wherein (C6-Cltl) aryl is unsubstituted in residue R6 or is optionally substituted by halogen one or many.
Summary of the invention
The present invention describes compound of formula I and/or their officinal salt
Wherein, R1For
R2For
Asterisk (*) indicates that the key and the nitrogen-atoms of amide or lactams are connected.
It is important to note that presently disclosed research achievement, is us in initial synthesized compound (portion Point content sees the patent that granted patent number is ZL201510098553.X) on the basis of, carry out further structural modification and excellent Obtained from change, bioactivity is totally better than the homologous series compound developed before this.
The invention further relates to be used as drug (or medicament) compound of formula I and/or its officinal salt preparation prevention and/ Or the purposes in the drug of the following disease for the treatment of, i.e. hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, outer All dyshaemia, peripheral arterial occlusive disease, ischemic organ failure and as caused by ischemic organ failure Terminal organ damage, coronary heart disease, heart failure, angina pectoris, cerebral ischemia, fibroid lung, fibrosis liver, hepatic failure, fibrosis kidney, Glomerulosclerosis, kidney failure, organ hypertrophy, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome (ARDS), thrombotic Disease, cerebral angiospasm, neuronal degeneration, peripheral arterial occlusive disease, artery sclerosis, metabolic syndrome, itself is exempted from apoplexy Epidemic disease.The organ hypertrophy refers to that cardiomegaly or hypertrophy of the prostate, artery sclerosis refer to atherosclerosis.
The invention further relates to pharmaceutical preparation (or pharmaceutical composition), containing a effective amount of at least one compound of formula I and/ Or the excipient and carrier of its officinal salt, physiology tolerance, and there are also other additives and/or other activity in due course Ingredient.Drug can be administered orally, such as with pill, tablet, spraying piece (lacquered tablets), coating tablet, particle Agent, hard and Perle, solution, syrup, emulsion, suspension or aerosol mixtures form.But application can also as follows into Row: per rectum administration, such as with suppository form；Or parenteral, such as through it is intravenous, intramuscular or subcutaneously with inject solution or It is transfused solution, micro-capsule, implant or the form for being implanted into stick；Or percutaneous or local administration, such as with ointment, solution or tincture shape Formula；Or it is administered with other approach, for example with aerosol or form of nasal sprays.
Pharmaceutical preparation of the invention is prepared in a manner of known per se and be known to those skilled in the art, in addition to formula Outside Compound I and/or their officinal salt and/or their prodrug, pharmaceutical inert inorganic and/or organic carrier are used Substance and/or additive.For the preparation of pill, tablet, coating tablet and hard gelatin capsule, may use such as lactose, Cornstarch or derivatives thereof, talcum, stearic acid or its salt etc..The carrier mass of Perle and suppository have for example fat, Wax, semisolid and liquid polyol, natural or fixed oil etc..It is suitable for preparing solution, for example injects solution or emulsion or syrup The carrier mass of agent has such as water, salt water, alcohol, glycerol, polyalcohol, sucrose, inverted sugar, glucose, vegetable oil.It is suitable for Micro-capsule, implant or the carrier mass for being implanted into stick, such as the copolymer of glycolic acid and lactic acid.Pharmaceutical preparation usually contains about 0.5 To the compound of formula I of about 90% weight and/or their officinal salt and/or their prodrug.In pharmaceutical preparation activity at The amount normally about 0.5 of compounds of formula I and/or their officinal salt and/or their prodrug is to about 1000mg, preferably from about 1 To about 500mg.
Other than the active constituent of Formulas I and/or their officinal salt and carrier mass, pharmaceutical preparation can contain one kind Or multiple additives, such as filler, disintegrating agent, adhesive, lubricant, wetting agent, stabilizer, emulsifier, preservative, sweet taste Agent, colorant, corrigent, aromatic, thickener, diluent, buffer substance, solvent, solubilizer, the examination for obtaining depot effect Agent, salt, coating agent or the antioxidant for changing osmotic pressure.They can also containing two or more compound of formula I and/or they Officinal salt.It, can be according to medicine to the selection of individual compound when pharmaceutical composition contains two or more compound of formula I The specific overall pharmacological property of object preparation.For example, the shorter height potent compound of acting duration can with effect compared with Low long-acting compound combination.Permitted flexibility makes it possible to compound for substituent group selection in compound of formula I Biology and physicochemical properties carry out numerous controls, thus, it is possible to select it is this kind of needed for compound.In addition, in addition at least one Outside kind compound of formula I and/or its officinal salt, pharmaceutical preparation can also contain one or more other therapeutic or preventative work Property ingredient.
When using compound of formula I, dosage can change, agent in grace period and according to conventional with known to doctor Amount should be suitable for the individual instances of every kind example.It depends on for example applied particular compound, the property of treated disease With severity, method of application and scheme or whether that is treated be acute or chronic disease or prevented.Suitable agent Amount can be established using clinical method known to medical domain.In general, result needed for being obtained in the adult for weighing about 75kg Daily dose is about 0.01 to about 100mg/kg, preferably from about 0.1 to about 50mg/kg, especially about 0.1 to about 10mg/kg (at every kind In the case of with mg/kg batheroom scale).Especially in the case where applying relatively large amount, if daily dose can be divided into stem portion, such as 2, The application of 3 or 4 parts.In general, according to individual behavior, it may be necessary to deviate the daily dose upward or downward.
In addition, compound of formula I can be used as preparing among the synthesis of other compounds, particularly other drugs active constituent Body can for example be obtained by introducing substituent group or modification functional group by compound of formula I.
Under normal circumstances, however it remains the protecting group in coupling reaction products therefrom can then be removed by standard method It goes.For example, the tert. butyl protection group, particularly tertbutyloxycarbonyl as amido protecting form can be and being handled with trifluoroacetic acid Deprotection, that is, be converted into amino.As explained, it is also possible to generate functional group by suitable precursor group after coupling reaction. In addition, can then carry out officinal salt from the conversion to compound of formula I or pro-drug by known method.
In most cases, the reaction mixture of the final compound containing Formulas I or intermediate is post-processed, such as It is necessary to purify product by conventional method well known by persons skilled in the art to fruit.For example, synthesized compound is available Well known method such as crystallization, chromatography or reversed-phased high performace liquid chromatographic (RP-HPLC) are based on such as compound size, charge Or other hydrophobic separation methods are purified.Similarly, well known method such as amino acid sequence analysis, NMR, IR and mass spectrum Method (MS) can be used for characterizing the compounds of this invention.
Therefore, following embodiment is a part of the invention, is not intended to limit the present invention for illustrating.
It should be intended that, the active modification of the various embodiments of the non-substantial effect present invention is included in disclosed herein The scope of the invention in.
Specific embodiment
Embodiment 1:4- ((1- (3,5- difluorobenzyl) -7- oxo azatropylidene -4- base) oxygroup)-N- (2- ((furans -2- base Methyl) sulfenyl) ethyl) and benzamide preparation
Step 1: N- (3- cyclobutenyl) phthalimide (compound number 1)
N- (3- cyclobutenyl) phthalimide is added in potassium phthalimide (407.0g, 2.2mol) In n,N-Dimethylformamide (1200mL) solution of (270.0g, 2.0mol), add potassium iodide (3.32 g, 20.0mmol).Oil bath heating is reacted about 3 hours to 130 DEG C, and TLC monitors (petroleum ether: ethyl acetate=1:1) until reaction Completely.3000g mixture of ice and water quenching reaction is added, methyl tertiary butyl ether(MTBE) extracts (1000mL*3), merges organic phase, washing (1000mL*3).Organic phase is dried, filtered through Anhydrous potassium carbonate, evaporating solvent under reduced pressure, obtains 400.0g white solid, as N- (3- cyclobutenyl) phthalimide, HPLC purity 98.4% (254nm) are directly used in next step.202.1 (M+H of mass spectrum+)。
Step 2: 3- butene-1-amine (compound number 2)
By hydrazine hydrate (20.0g, 0.40mol) be added N- (3- butene-1-yl) phthalimide (40.2g, In ethyl alcohol (200mL) solution 0.20mol).Reaction solution is heated to back flow reaction about 1.5 hours, cooling, and the dense salt of 40mL is added dropwise Acid, stirring 10min are filtered later.Filtrate 5M potassium hydroxide aqueous solution tune pH value to 7-8, filtering, filtrate methyl tertbutyl Ether extracts (100mL*4), merges organic phase, and Anhydrous potassium carbonate dries, filters, and evaporating solvent under reduced pressure obtains 11.5g white solid, As 3- butene-1-amine, yield 81%.72.1 (M+H of mass spectrum+)。
Step 3: N- (3- butene-1-yl)-2- chloroacetamide (compound number 3)
3- butene-1-amine (10.7g, 0.15mol) tetrahydrofuran is added in triethylamine (30.4g, 0.30mol) In (100mL) solution.Ice-water bath cooling, is added dropwise 2- chloracetyl chloride (20.3g, 0.18mol).After dripping off, ice-water bath, room temperature are removed Lower reaction about 3 hours, TLC monitors (petroleum ether: ethyl acetate=1:1) until the reaction is complete.200mL ethyl acetate is added, then With saturated common salt water washing (100mL*3).After organic phase is dried over anhydrous sodium sulfate, filtering, evaporating solvent under reduced pressure, residue mixing Object is purified by silica gel column chromatography (eluent is petroleum ether: ethyl acetate=20:1) and obtains 14.4g orange, as N- (3- Butene-1-yl)-2- chloroacetamide, yield 65%.148.0 (M+H of mass spectrum+)。
1H NMR(400MHz,CDCl3) δ: 8.80 (s, 1H), 5.75-5.71 (m, 1H), 5.10 (dd, J=7.2Hz, 1H), 4.95 (dd, J=7.2Hz, 1H), 4.35 (s, 2H), 3.26 (t, 2H), 2.25-2.21 (m, 2H)
Step 4: N- (3- butene-1-yl)-2- iodoacetamide (compound number 4)
N- (3- butene-1-yl)-2- chloroacetamide (14.8g, 0.10 mol) is added in potassium iodide (49.8g, 0.30mol) Acetone (200mL) solution in.Overnight, TLC monitors (petroleum ether: ethyl acetate=1:1) until the reaction is complete for reaction at room temperature. In remaining mixture plus 300mL water, (500mL*3) is extracted with dichloromethane in evaporating solvent under reduced pressure.Merge organic phase, through anhydrous After sodium sulphate is dry, filtering, evaporating solvent under reduced pressure, remaining mixture is purified by silica gel column chromatography that (eluent is petroleum ether: acetic acid Ethyl ester=5:1) obtain 22.7g light yellow oil, as N- (3- butene-1-yl)-2- iodoacetamide, yield 95%.Mass spectrum 240.0(M+H+).Step 5: 5- hydroxyl azatropylidene -2- ketone (compound number 5)
In methylene chloride (80mL) solution of N- (3- butene-1-yl)-2- iodoacetamide (23.9g, 0.10mol), first Boron trifluoride monohydrate (38.6g, 0.45mol) and boron triethyl (6.9g, 0.07 mol) are added afterwards.It reacted at room temperature Night.Absorb upper transparent liquid, remaining part evaporating solvent under reduced pressure.The hydrochloric acid that 60mL1M is added dropwise into remaining mixture is water-soluble Liquid, drop finish, and oil bath heating is to the reaction was continued 4 hours after 100 DEG C.After removing organic solvent under reduced pressure, it is added into remaining mixture Then potassium carbonate (55.3g, 0.40mol) is added portionwise in 100mL methanol, be stirred to react at room temperature 10 hours.Filtering, decompression are steamed Except solvent, remaining mixture is purified by silica gel column chromatography (eluent is methylene chloride: methanol=4:1) and obtains 7.7g brown oil Object, as 5- hydroxyl azatropylidene -2- ketone, yield 60%.130.1 (M+H of mass spectrum+)。
1H NMR(400MHz,DMSO-d6)δ:9.20(br s,1H),3.31-3.22(m,3H),2.62(br s,1H), 2.25-2.10(m,2H),1.92-1.87(m,2H),1.65-1.62(m,2H).
Step 6: 5- ((t-Butyldimethylsilyl) oxygroup) azatropylidene -2- ketone (compound number 6)
In n,N-Dimethylformamide (100mL) solution of 5- hydroxyl azatropylidene -2- ketone (12.9g, 0.10mol), first Imidazoles (10.2g, 0.15mol), N, N- lutidines -4- amine (2.5g, 0.02mol) and tert-butyldimethylsilyl chloride are added afterwards Silane (18.1g, 0.12mol).Overnight, TLC monitors (petroleum ether: ethyl acetate=1:1) until the reaction is complete for reaction at room temperature. 300g mixture of ice and water is added, (500mL*3) is extracted with dichloromethane.Merge organic phase, after being dried over anhydrous sodium sulfate, mistake Filter, evaporating solvent under reduced pressure, remaining mixture are purified by silica gel column chromatography (eluent is petroleum ether: ethyl acetate=1:1) and obtain 13.4g white solid, as 5- ((t-Butyldimethylsilyl) oxygroup) azatropylidene -2- ketone, yield 55%.244.2 (M+ of mass spectrum H+).Step 7: 5- ((t-Butyldimethylsilyl) oxygroup) -1- (3,5- difluorobenzyl) azatropylidene -2- ketone (compound number For 7)
Under ice-water bath, 5- ((fert-butyidimethylsilyl is added portionwise in sodium hydrogen (60% mineral oil powder, 14.4g, 0.36mol) Silicon substrate) oxygroup) azatropylidene -2- ketone (29.2g, 0.12mol) tetrahydrofuran (200mL) solution in.It is stirred to react after five minutes, Ice-water bath is removed, the reaction was continued at room temperature 30 minutes, is added 3,5-, bis- fluorobenzyl bromide (26.9g, 0.13mol).It reacted at room temperature Night, TLC monitor (petroleum ether: ethyl acetate=1:1) until the reaction is complete.100mL saturated common salt is added in evaporating solvent under reduced pressure (200mL*3) is extracted with ethyl acetate in water.Merge organic phase, after being dried over anhydrous sodium sulfate, filtering, evaporating solvent under reduced pressure, Obtain 42.8 g brown oils, as 5- ((t-Butyldimethylsilyl) oxygroup) -1- (3,5- difluorobenzyl) azatropylidene -2- ketone Crude product is directly used in next step.HPLC purity 76.5% (254nm).
Step 8: 5- hydroxyl -1- (3,5- difluorobenzyl) azatropylidene -2- ketone (compound number 8)
5- ((t-Butyldimethylsilyl) is added in tetrabutyl ammonium fluoride (english abbreviation TBAF, 86.3g, 0.33mol) Oxygroup) -1- (3,5- difluorobenzyl) azatropylidene -2- ketone (HPLC 76.5%, 39.6g, 0.082mol) anhydrous tetrahydro furan In (500mL) solution.It reacts 10 hours at room temperature, TLC monitors (petroleum ether: ethyl acetate=1:1) until the reaction is complete.Decompression Solvent is evaporated off, 500mL ethyl acetate is added, with saturated common salt water washing (200mL*3).Merge organic phase, through anhydrous sodium sulfate After drying, filtering, evaporating solvent under reduced pressure obtains 40.5g pale brown oil object, as 5- hydroxyl -1- (3,5- difluorobenzyl) azepine Zhuo -2- ketone crude product is directly used in next step.HPLC purity 54.1% (254nm).
Step 9: 7- oxo -1- (3,5- difluorobenzyl) azatropylidene -4- base methanesulfonates (compound number 9)
The two of 5- hydroxyl -1- (3,5- difluorobenzyl) azatropylidene -2- ketone (HPLC 54.1%, 24.5g, 0.052mol) In chloromethanes (200mL) solution, it is added triethylamine (15.2g, 0.15mol).Ice-water bath cooling, dropwise addition methanesulfonic acid acid anhydride (17.4g, 0.10mol).Drop finishes, and removes ice-water bath, and overnight, TLC monitors (petroleum ether: ethyl acetate=1:1) until anti-for reaction at room temperature It should be complete.(100mL*2) is washed with water.After organic phase is dried over anhydrous sodium sulfate, filtering, evaporating solvent under reduced pressure, residue mixing Object is purified by silica gel column chromatography (eluent is petroleum ether: ethyl acetate=2:1) and obtains 12.7g faint yellow solid, as 7- oxo- 1- (3,5- difluorobenzyl) azatropylidene -4- base methanesulfonates, yield 73.3%.A batch is done in repetition.334.1 (M+H of mass spectrum+)。
Step 10: 4- ((1- (3,5- difluorobenzyl) -7- oxo azatropylidene -4- base) oxygroup)-N- (2- ((furans -2- base Methyl) sulfenyl) ethyl) benzamide (compound number 10)
In the N of 7- oxo -1- (3,5- difluorobenzyl) azatropylidene -4- base methanesulfonates (16.7g, 0.05mol), N- bis- In methylformamide (100mL) solution, N- (3- (diethylamino) propyl) -4- hydroxybenzamide N- (2- is sequentially added ((furans -2- ylmethyl) sulfenyl) ethyl) -4- hydroxybenzamide (13.9g, 0.05mol) and Anhydrous potassium carbonate (20.7g, 0.15mol).Overnight to 90 DEG C of reactions, TLC monitors (petroleum ether: ethyl acetate=1:1) until the reaction is complete to oil bath heating.Add Enter 300mL water, be extracted with ethyl acetate (300mL*3), organic phase uses saturated common salt water washing (200mL*3) again.Organic phase warp After anhydrous sodium sulfate is dry, filtering, evaporating solvent under reduced pressure, remaining mixture is purified by silica gel column chromatography that (eluent is dichloromethane Alkane: methanol=10:1) obtain 11.4g weak yellow foam shape solid, as 4- ((1- (3,5- difluorobenzyl) -7- oxo azatropylidene - 4- yl) oxygroup)-N- (2- ((furans -2- ylmethyl) sulfenyl) ethyl) benzamide, yield 44.3%.515.2 (M+H of mass spectrum+)。1H NMR(400MHz,DMSO-d6)δ:8.56(br s,1H),7.88(d,2H),7.51(m,1H),7.03(d, 2H), 6.82(s,2H),6.70(s,1H),6.42(m,1H),6.19(m,1H),5.01(s,2H),3.85(s,2H), 3.65-3.43 (m,5H),2.81(t,2H),2.29-1.86(m,6H).
Embodiment 2:4- ((1- ((4- methoxyphenyl) acetenyl) -7- oxo azatropylidene -4- base) oxygroup)-N- (4- (2- Morpholinyl ethyl) phenyl) benzamide preparation
Step 1: 5- ((t-Butyldimethylsilyl) oxygroup) -1- ((4- methoxyphenyl) acetenyl) azatropylidene -2- ketone (compound number 11)
Under ice-water bath, 5- ((fert-butyidimethylsilyl is added portionwise in sodium hydrogen (60% mineral oil powder, 14.4g, 0.36mol) Silicon substrate) oxygroup) azatropylidene -2- ketone (29.2g, 0.12mol) tetrahydrofuran (200mL) solution in.It is stirred to react after five minutes, Ice-water bath is removed, the reaction was continued at room temperature 30 minutes, and 1- (bromoacetylene base) -4 methoxybenzenes (27.4g, 0.13mol) are added.Room Overnight, TLC monitors (petroleum ether: ethyl acetate=1:1) until the reaction is complete to the lower reaction of temperature.100mL is added in evaporating solvent under reduced pressure (200mL*3) is extracted with ethyl acetate in saturated salt solution.Merge organic phase, after being dried over anhydrous sodium sulfate, filtering, decompression is steamed Except solvent, 45.7g brown oil, as 5- ((t-Butyldimethylsilyl) oxygroup) -1- ((4- methoxyphenyl) acetylene are obtained Base) azatropylidene -2- ketone crude product, it is directly used in next step.HPLC purity 68.9% (254nm).
Step 2: 5- hydroxyl -1- ((4- methoxyphenyl) acetenyl) azatropylidene -2- ketone (compound number 12)
5- ((t-Butyldimethylsilyl) is added in tetrabutyl ammonium fluoride (english abbreviation TBAF, 86.3g, 0.33mol) Oxygroup) -1- ((4- methoxyphenyl) acetenyl) azatropylidene -2- ketone (HPLC 68.9%, 44.5g, 0.082mol) it is anhydrous In tetrahydrofuran (500mL) solution.It reacts 10 hours at room temperature, TLC monitors (petroleum ether: ethyl acetate=1:1) until reaction Completely.500mL ethyl acetate is added, with saturated common salt water washing (200mL*3) in evaporating solvent under reduced pressure.Merge organic phase, through nothing After aqueous sodium persulfate is dry, filtering, evaporating solvent under reduced pressure obtains 46.6g pale brown oil object, as 5- hydroxyl -1- ((4- methoxyl group Phenyl) acetenyl) azatropylidene -2- ketone crude product, it is directly used in next step.HPLC purity 51.8% (254nm).
Step 3: 7- oxo -1- ((4- methoxyphenyl) acetenyl) azatropylidene -4- base methanesulfonates (compound number For 13)
In 5- hydroxyl -1- ((4- methoxyphenyl) acetenyl) azatropylidene -2- ketone (HPLC 51.8%, 26.0g, 0.052 Mol it in methylene chloride (200mL) solution), is added triethylamine (15.2g, 0.15mol).Ice-water bath cooling, is added dropwise methanesulfonic acid acid anhydride (17.4g, 0.10mol).Drop finishes, and removes ice-water bath, and overnight, TLC monitors (petroleum ether: ethyl acetate=1:1) for reaction at room temperature Until the reaction is complete.(100mL*2) is washed with water.After organic phase is dried over anhydrous sodium sulfate, filtering, evaporating solvent under reduced pressure is remained Remaining mixture is purified by silica gel column chromatography (eluent is petroleum ether: ethyl acetate=2:1) and obtains 14.7g yellow solid, as 7- Oxo -1- ((4- methoxyphenyl) acetenyl) azatropylidene -4- base methanesulfonates, yield 83.8%.A batch is done in repetition.Mass spectrum 338.1(M+H+)。
Step 4: 4- ((1- ((4- methoxyphenyl) acetenyl) -7- oxo azatropylidene -4- base) oxygroup)-N- (4- (2- Morpholinyl ethyl) phenyl) benzamide (compound number 14)
In 7- oxo -1- ((4- methoxyphenyl) acetenyl) azatropylidene -4- base methanesulfonates (16.9g, 0.05mol) N,N-Dimethylformamide (100mL) solution in, sequentially add 4- hydroxy-n-(4- (2- morpholinyl ethyl) phenyl) benzene first Amide (16.3g, 0.05mol) and Anhydrous potassium carbonate (20.7g, 0.15mol).Overnight to 90 DEG C of reactions, TLC is monitored oil bath heating (petroleum ether: ethyl acetate=1:1) until the reaction is complete.300 mL water are added, are extracted with ethyl acetate (300mL*3), it is organic Mutually use saturated common salt water washing (200mL*3) again.After organic phase is dried over anhydrous sodium sulfate, filtering, evaporating solvent under reduced pressure, residue Mixture is purified by silica gel column chromatography (eluent is methylene chloride: methanol=10:1) and obtains 13.6g orange foam shape solid, as 4- ((1- ((4- methoxyphenyl) acetenyl) -7- oxo azatropylidene -4- base) oxygroup)-N- (4- (2- morpholinyl ethyl) phenyl) Benzamide, yield 47.9%.568.3 (M+H of mass spectrum+)。
1H NMR(400MHz,DMSO-d6)δ:10.45(br s,1H),8.15(d,2H),7.58(d,2H),7.50(d, 2H),7.25(d,2H),6.99-6.95(m,4H),3.92(s,3H),3.61-3.53(m,5H),3.30-3.21(m, 2H), 2.74(t,2H),2.66(t,2H),2.43-2.38(m,4H),2.23-1.88(m,6H).
Other compounds can be used and be obtained with the approximate synthetic method of compound 10 or 14, representational such as following table It is shown:
The measurement of Rho kinase activity
For the Rho kinase inhibiting activity for measuring developed hexahydro azatropylidene -4- base oxybenzamide class compound, I Referring to other Rho kinase inhibitors activity determination method, determine IC50Value.
Measurement reagent: active people recombinates ROCK II (the recombined human ROCK-II residue 11- of the end N- His6- label 552), fluorescein-AKRRRLSSLRA-COOH (as peptide substrates) are purchased from JPT Peptide Technologies (Germany)； Adenosine -5 '-triguaiacyl phosphate (ATP), bovine serum albumin(BSA) (BSA), dimethyl sulfoxide (DMSO), 4- (2- hydroxyethyl) piperazine -1- Ethanesulfonic acid (Hepes), Brij-35, three (hydroxymethyl)-aminomethane (Tris) of dithiothreitol (DTT) (DTT), magnesium chloride, NaOH, 1M HCl and EDTA are purchased from Sigma-Aldrich (branch company of BeiJing, China).
Continuous mode: with No. 1 buffer (25mM Tris-HCl, pH 7.4,5mM MgCl2,2mMDTT, 0.02% (w/ V) BSA and 3%DMSO) by hexahydro azatropylidene -4- base oxybenzamide diluted chemical compound to be measured to concentration appropriate.With No. 2 Buffer (25mM Tris-HCl, pH 7.4,5mM MgCl2,2mM DTT and 0.02% (w/v) BSA) is dilute by ROCK II enzyme It releases to the concentration of 100ng/ml.Peptide substrates and ATP are diluted to the concentration of 5 μM and 120 μM respectively with No. 2 buffers.By 4 μ l Testing compound solution and the 4 diluted enzymes of μ l in 384 hole microtiter plates (Greiner, Bio-One, Frickenhausen, Germany) in mixing, the solution starting kinase reaction that 4 μ l contain peptide substrates and ATP is added.It is cultivated one hour in 32 DEG C of insulating boxs Afterwards, 40 μ l Hepes-NaOH containing 100mM, pH 7.4,0.015% (v/v) Brij-35,45mM EDTA and 0.227% are added The solution of chip coating agent 1 (Caliper Lifescience Inc, Hopkinton, MA) reacts to terminate.Then according to (referring to J.Biomol.Screening 9 (5), 409-416,2004) in 3000 instrument of Caliper described in Pommereau et al. The phosphorylation of detection substrate peptide on device.Separation condition are as follows: pressure -1.3psi, upstream voltage -1562V, downstream voltage -500V take Sample time 200ms.Positive control tests (instead of No. 1 buffer of compound) and negative control experiments (instead of No. 1 of compound Buffer and No. 2 buffers for replacing ROCK II) it is carried out in parallel on respective plate.
Measurement result: to the part hexahydro azatropylidene -4- base oxybenzamide class compound determination in above-described embodiment Activity.Wherein it is as shown in the table for representational determination of activity result.
Compound number pIC50
10 +++
14 ++++
15 ++++
17 ++++
19 ++++
21 +++
22 +++
24 +++
25 +++
28 +++
29 +++
30 +++
31 ++++
33 ++++
34 ++++
35 ++++
36 +++
38 ++++
42 +++
43 +++
44 +++
46 +++
49 +++
50 +++
51 +++
54 +++
55 +++
56 ++++
59 +++
60 ++++
62 +++
66 +++
Remarks: the activity provided is expressed as IC50With 10 for bottom negative logarithm (pIC50), wherein
+: pIC50< 3.0；
++: 3.0≤pIC50< 4.0；
+++: 4.0≤pIC50< 5.0；
5.0≤pIC of ++++:50< 6.0；
+++ ++: 6.0≤pIC50。

Claims (6)

1. compound of formula I and/or their officinal salt
Wherein, R1For
R2For
Asterisk (*) indicates that the key and the nitrogen-atoms of amide or lactams are connected.
2. at least one compound of formula I described in claim 1 and/or its officinal salt are in preparation Rho kinase inhibitor class Purposes in drug.
3. at least one compound of formula I described in claim 1 and/or its officinal salt are under preparation prevention and/or treatment Purposes in the drug of column disease: hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, peripheral circulation obstacle, Peripheral arterial occlusive disease, ischemic disease, coronary heart disease, heart failure, fibroid lung, fibrosis liver, hepatic failure, kidney Disease, organ hypertrophy, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome (ARDS), thrombosis disease, apoplexy, the cerebrovascular Spasm, neuronal degeneration, artery sclerosis, metabolic syndrome, autoimmune disease.
4. the purposes in claim 3, wherein the organ hypertrophy refers to that cardiomegaly or hypertrophy of the prostate, artery sclerosis refer to Be atherosclerosis.
5. at least one compound of formula I described in claim 1 and/or its officinal salt are under preparation prevention and/or treatment Purposes in the drug of column disease: angina pectoris, cerebral ischemia, ischemic organ failure and drawn by ischemic organ failure Terminal organ damage, the fibrosis kidney, glomerulosclerosis, kidney failure, peripheral arterial occlusive disease risen.
6. drug, it includes at least one compound of formula I described in a effective amount of claim 1 and/or its officinal salts, life The excipient and carrier of Neo-Confucianism tolerance, and there are also other additives and/or other active components in due course.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101573353A (en) * 2006-12-27 2009-11-04 塞诺菲-安万特股份有限公司 Substituted isoquinoline and isoquinolinone derivatives
CN101616909A (en) * 2006-12-27 2009-12-30 塞诺菲-安万特股份有限公司 Substituted isoquinoline 99.9 and isoquinolinone derivatives as the Rho-kinase inhibitor
CN104803914A (en) * 2015-03-05 2015-07-29 成都理工大学 Hexahydro-azepine oxy-benzamide compounds serving as Rho kinase inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101573353A (en) * 2006-12-27 2009-11-04 塞诺菲-安万特股份有限公司 Substituted isoquinoline and isoquinolinone derivatives
CN101616909A (en) * 2006-12-27 2009-12-30 塞诺菲-安万特股份有限公司 Substituted isoquinoline 99.9 and isoquinolinone derivatives as the Rho-kinase inhibitor
CN104803914A (en) * 2015-03-05 2015-07-29 成都理工大学 Hexahydro-azepine oxy-benzamide compounds serving as Rho kinase inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
叶发青 等: "《药物化学》", 30 June 2012, 浙江大学出版社 *

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