CN1893953A - Tricyclic 1-((3-indol-3-yl)carbonyl)piperazine derivatives as cannabinoid cb1 receptor agonists - Google Patents
Tricyclic 1-((3-indol-3-yl)carbonyl)piperazine derivatives as cannabinoid cb1 receptor agonists Download PDFInfo
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Abstract
The invention relates to tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivative having the general Formula (I) wherein X is CH2, O or S; R represents 1-3 substituents independently selected from H, (C1-4)alkyl, (C1-4)alkyloxy and halogen; R1 is (C5-8)cycloalkyl; R2 is H or (C1-4)alkyl; R3, R3', R4' R4', R5, R5' and R6' are independently hydrogen or (C1-4)-alkyl, optionally substituted with (C1-4)alkyloxy, OH or halogen; R6 is hydrogen or (C1-4)alkyl, optionally substituted with (C1-4)alkyloxy, OH or halogen; or R6 forms together with R7 a 4-7 membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O and S; R7 forms together with R6 a 4-7 membered saturated heterocydic ring, optionally containing a further heteroatom selected from O and S; or R7 is H, (C1-4)alkyl or (C3-5)cycloalkyl, the alkyl groups being optionally substituted with OH, halogen or (C1-4)alkyloxy; or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivatives, and to the use of these derivatives in the treatment of pain, such as peri-operative pain, chronic pain neuropathic pain, cancer pain, and pain and spasticity associated with multiple sclerosis.
Description
The present invention relates to trinucleated 1-[(indol-3-yl) carbonyl] bridged piperazine derivatives, comprise their pharmaceutical composition and these trinucleated 1-[(indol-3-yls) carbonyl] application of bridged piperazine derivatives in treatment, especially treatment of pain.
Treatment of pain often is subjected to the restriction of available side effects of pharmaceutical drugs up till now.To serious pain, opioid is widely used for medium.These reagent are cheap and effective, but have serious and life-threatening potentially side effect, and the most significant is respiration inhibition and muscle rigidity.In addition, the dosage of the opioid that can use is felt sick, the restriction of vomiting, constipation, pruritus and urine retention, often causes the patient to select to accept not good enough pain control, and is reluctant to suffer these painful side effect.And, the hospitalization that these side effect often cause needs of patients to prolong.Opioid is highly habit-forming, and is medicines of listing catalogue in many areas.Therefore, need new analgesic, it is compared with the product of present use, has the side effect feature of improvement in identical analgesic dose.
Accumulating about cannabinoid agonists and having evidence as the potentiality of analgesic and anti-inflammatory agent.Relate to 2 types Cannabined receptor, i.e. cannabinoid CB 1 receptor, it mainly is positioned at the central nervous system, but it also express by peripheral neurons, and in other peripheral tissues, express lower degree; With cannabinoid CB2 receptor, its major part is positioned at immunocyte (Howlett, A.C. etc.: International Union of Pharmacology.XXVII.Classifi-cation of Cannabinoid Receptors.Pharmacol.Rev.
54, 161-202,2002).Although the CB2 receptor has involved in the immunity and the anti-inflammatory response of regulation and control cannabinoid, cannabinoid receptor agonists is proposed recently, especially those that work at the CB1 receptor can be used for the treatment of pain and (see Iversen, L. and Chapman, V.Current Opinion inPharmacology
2, 50-55,2002 and document wherein).United States Patent (USP) 4,939,138 (Sterling Drug Inc.) disclose the WIN55 as analgesic, 212-2, (R)-(+)-[2,3-dihydro-5-methyl-[(morpholinyl) methyl] pyrrolo-[1,2,3-de]-1, the 4-Benzoxazinyl]-mesylate of (1-naphthyl) ketone.This chemical compound is prototype (Eissenstat etc., the J.Med.Chem. of aminoalkyl indole
38, 3094-3105,1995), the latter is effective cannabinoid CB 1 receptor agonist, it can produce the anti-pain sensation effect with the identical effect of morphine in the animal model of acute pain, lasting inflammatory pain and neuropathic pain.
WIN55212-2 (mesylate)
In WO 2001/58869 (Bristol-Myers Squibb Comp.), disclose as closely-related pyrrolo-[1,2,3-de]-1 on the structure of the Cannabined receptor adjusting control agent that is used for the treatment of respiratory disorder, 4-benzoxazine carbamyl derivant.In EP 0 393 766 (Duphar Intern.Res.B.V.), the similar trinucleated 3-amido-4-indole derivant as the 5-HT receptor antagonist is disclosed.
Known cannabinoid agonists is normally highly lipophilic, and water insoluble.Thereby the cannabinoid agonists that need have the character of improvement is as therapeutic agent.
For this reason, the invention provides trinucleated 1-[(indol-3-yl with general formula I) carbonyl] bridged piperazine derivatives
Formula 1
Wherein
X is CH
2, O or S;
R represents 1-3 substituent group, and it is independently selected from H, (C
1-4) alkyl, (C
1-4) alkoxyl and halogen;
R
1Be (C
5-8) cycloalkyl;
R
2Be H or (C
1-4) alkyl;
R
3, R
3', R
4, R
4', R
5, R
5' and R
6' be hydrogen or (C independently
1-4) alkyl, the latter is randomly by (C
1-4) alkoxyl, OH or halogen replace;
R
6Be hydrogen or (C
1-4) alkyl, the latter is randomly by (C
1-4) alkoxyl, OH or halogen replace; Or R
6And R
7Form the saturated heterocycle of 4-7 unit together, it randomly contains other hetero atom that is selected from O and S;
R
7And R
6Form the saturated heterocycle of 4-7 unit together, it randomly contains other hetero atom that is selected from O and S; Or
R
7Be H, (C
1-4) alkyl or (C
3-5) cycloalkyl, alkyl is randomly by (C
1-4) alkoxyl, OH or halogen replace; Or its pharmaceutically acceptable salt, as the agonist of cannabinoid CB 1 receptor, it can be used for the treatment of pain, peri-operation period (peri-operative) pain for example, chronic pain, neuropathic pain, cancerous pain and pain and the spasm relevant with multiple sclerosis.
1-[(indol-3-yl of the present invention) carbonyl] the tricyclic ring core structure of bridged piperazine derivatives is 2,3-dihydro-pyrrolo-[3,2,1-ij] quinoline, this moment, X was CH
22,3-dihydro-pyrrolo--[1,2,3-de]-1, the 4-benzoxazine, this moment, X was an oxygen; With 2,3-dihydro-pyrrolo-[1,2,3-de]-1, the 4-benzothiazine, this moment, X was a sulfur.
When X was oxygen, chemical compound of the present invention usually was described among the WO 2001/58869 (the same), as the Cannabined receptor adjusting control agent that is used for the treatment of respiratory disorder.Wherein preferably these adjusting control agents are differentiated and be the CB2 receptor modulators.Disclosed 2 in WO 2001/58869,3-dihydro-pyrrolo-[1,2,3-de]-1,4-benzoxazine derivatives are characterised in that, have (4-morpholinyl) methyl chains of the 3-position that is attached to benzoxazine ring.Has (C by position in correspondence
5-8) the cycloalkyl side chain, this feature can provide the chemical compound with CB1 agonist activity, can be with trinucleated 1-[(indol-3-yl of the present invention) carbonyl] among bridged piperazine derivatives and the WO 2001/58869 those differentiate.
As employed in the definition of formula I, term (C
1-4) alkyl refers to have alkyl side chain or the unbranched 1-4 of a having carbon atom, resembles butyl, isobutyl group, the tert-butyl group, propyl group, isopropyl, ethyl and methyl.
At term (C
1-4) in the alkoxyl, (C
1-4) alkyl has implication as defined above.
Term (C
5-8) cycloalkyl refers to have the saturated cyclic alkyls of 5-8 carbon atom, and thereby can represent cyclopenta, cyclohexyl, suberyl or ring octyl group.
Term halogen refers to F, Cl, Br or I.
In the definition of formula I, R
6Can with R
7Form 4-7 unit saturated heterocyclic together, this means R
6With its institute bonded carbon atom together with R
7With its bonded nitrogen-atoms complete together formations 4-7 unit of institute saturated rings, azetidine for example, pyrrolidine, piperidines, or 1H-azepine encircles.Such ring can contain other O or S-hetero atom, to form ring, and morpholine for example, thiomorpholine, tetrahydro-thiazoles-or the isothiazole ring.
The trinucleated 1-[(indol-3-yl of preferred formula I) carbonyl] bridged piperazine derivatives is that wherein R is H, and R
1Be cyclopenta or cyclohexyl.
Particularly preferably be the three ring 1-[(indol-3-yls of formula I) carbonyl] bridged piperazine derivatives, R wherein, R
2, R
3, R
3', R
4', R
5, R
5' and R
6' be H; R
4, R
6And R
7Be H or (C independently
1-4) alkyl; Or R
6And R
7Form the saturated heterocycle of 5-or 6-unit together, and R
4Be H or (C
1-4) alkyl.
At X is under the situation of O, further preferred these isomers, and wherein the spatial chemistry in the 3-position of benzoxazine ring is (R).
Usually, by the known method of organic chemistry filed, can prepare trinucleated 1-[(indol-3-yl of the present invention) carbonyl] bridged piperazine derivatives.
For example, can prepare the trinucleated 1-[(indol-3-yl of formula I from the condensation of formula II chemical compound and formula III chemical compound) carbonyl] piperazine, in formula II, R, R
1, R
2Have as previously defined implication with X, C (O) Y represents carboxylic acid or its activatory derivant, for example carboxylate or carboxylic acid halides, and preferred acyl chlorides or acylbromide, in formula III, R
3-R
7Have as previously defined implication.R in the formula III chemical compound
7When representing hydrogen, in condensation reaction, may essential its bonded nitrogen-atoms of temporary protection.For will be in building-up process the functional group of temporary protection, suitable protecting group is known in the art, for example, sees Wuts; P.G.M. and Greene, T.W.:Protective Groups in Organic Synthesis, Third Edition; Wiley, New York, 1999.When C (O) Y represents carboxylic acid (that is, Y is a hydroxyl), can be following assisting of coupling reagent, realize condensation reaction, described coupling reagent is carbonyl dimidazoles for example, dicyclohexyl carbodiimide etc., in solvent, react, for example dimethyl formamide or dichloromethane.When C (O) Y represents carboxylic acid halides (that is, Y is a halogen), can be having in the presence of the alkali (for example triethylamine), in solvent (for example dichloromethane), carry out condensation with the amine derivative of formula III.As C (O) when Y represents carboxylate, can be at high temperature, carry out direct condensation with the amine derivative of formula III.
Formula II formula III
The chemical compound of formula III can obtain from the commercial channel, is prepared by literature method known to those skilled in the art or to the improvement of literature method.For example, as M.E.Jung and J.C.Rohloff (J.Org.Chem.
50, 4909-4913,1985) and described, use Reducing agent for example lithium aluminium hydride reduction or borine-oxolane complex, by reduction, can prepare the chemical compound of formula III to diketopiperazine.As C.J.Dinsmore and D.C.Bershore (Tetrahedron
58, 3297-3312,2002) and described, by number of ways, can prepare diketopiperazine.
By literature method known to those skilled in the art or to the improvement of literature method, can prepare formula II chemical compound.For example, by with at least 2 normal highly basic for example n-BuLi handle, then with alkylating agent (C for example
1-4) alkyl halide handles, by C (O) Y is wherein represented carboxylic acid and R
2Be the alkylation of the formula II chemical compound of hydrogen, can preparing wherein, C (O) Y represents carboxylic acid and R
2Be (C
1-4) the formula II chemical compound of alkyl.
Use acylating agent,, can prepare formula II chemical compound by acylation to formula IV chemical compound.For example, by handling with trifluoroacetic anhydride in solvent (for example dimethyl formamide), at high temperature use sodium hydrate aqueous solution by hydrolysis then, can obtaining wherein from formula IV chemical compound, Y be the formula II chemical compound of hydroxyl.Through type IV chemical compound and oxalyl chloride react in solvent (for example sym.-tetrachloroethane), reset at high temperature then, and can preparing wherein, Y is the formula II chemical compound of chlorine.Use the synthetic (Chem.Rev. of Fischer indole
69, 227-250,1969), can go out formula IV chemical compound from formula V compound.
Formula IV formula V formula VI
Perhaps, use (J.Med.Chem. such as Wijngaarden
36, 3693-3699,1993) or (J.Org.Chem. such as Hwu
59, 1577-1582,1994) and the improvement of described method or these methods, can go out formula II chemical compound from formula V compound.
By literature method known to those skilled in the art or to the improvement of literature method, can prepare formula V chemical compound.For example, catalyst being arranged for example in the presence of the Nickel dichloride. (II), use for example sodium borohydride of Reducing agent, by reduction, can going out wherein from formula VI compound, X be CH
2Formula V chemical compound.For example, catalyst being arranged for example in the presence of the Nickel dichloride. (II), by coupling reaction, for example, 2-chloroquinoline and (C
5-8) reaction of cycloalkyl grignard reagent, can prepare formula VI chemical compound.
By X wherein is the reaction of formula VII chemical compound and the formula VIII chemical compound of OH or SH, forms ether or thioether, carries out reduction and the reductive cyclization of nitro to amine subsequently, and can preparing wherein, X is the formula V chemical compound of O or S.For example, for example potassium carbonate and catalyst can carry out etherification reaction for example in the presence of the potassium iodide at alkali.For example, for example in the presence of the palladium carbon, use hydrogen, can reduce and cyclisation at catalyst.
Formula VII formula VIII formula IX
Formula VII chemical compound and formula VIII chemical compound can obtain from commercial channels, prepare by literature method known to those skilled in the art or to the improvement of literature method.For example, use for example bromine of bromating agent, for example in the methanol, can go out formula VIII chemical compound from formula IX compound at solvent.
The technical staff can recognize equally, by with substituent R and R
3-R
7In the suitable conversion reaction of some corresponding functional group, can obtain different formula I three ring 1-[(indol-3-yls) carbonyl] bridged piperazine derivatives.For example, alkali is being arranged for example in the presence of the potassium carbonate, by R wherein
7Be the formula I chemical compound and (C of hydrogen
1-4) alkyl halide or functionalized (C
1-4) reaction of alkyl halide, can prepare wherein R
7Be (C
1-4) alkyl or (C
3-5) the formula I chemical compound of cycloalkyl, its alkyl can be by OH, halogen or (C
1-4) the alkoxyl replacement.
The trinucleated 1-[(indol-3-yl of formula I) carbonyl] salt of bridged piperazine derivatives and they contains at least one chiral centre, therefore exists as stereoisomer, comprises enantiomer and diastereomer.The present invention includes aforesaid stereoisomer in its scope and each R of formula I chemical compound and S enantiomer and their salt, it is substantially free of other enantiomer, promptly with being lower than 5%, being preferably lower than 2%, especially being lower than other enantiomer of 1%, mixture with such enantiomer of arbitrary proportion comprises and contains the racemic mixture of two kinds of enantiomer of equivalent basically.
This area obtains the asymmetric synthesis of pure stereoisomer or the method for chiral separation as everyone knows, for example, synthetic with chiral induction, or be raw material with commercially available chiral material, or separation of stereoisomers, for example use the chromatograph on the Chiral Media, or by the crystallization with the chirality counter ion.
By handle the free alkali of formula I chemical compound with mineral acid or organic acid, can obtain pharmaceutically acceptable salt, described mineral acid is hydrochloric acid for example, hydrobromic acid, phosphoric acid, and sulphuric acid, described organic acid is ascorbic acid for example, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic, succinic acid, propanoic acid, acetic acid, methanesulfonic acid etc.
Chemical compound of the present invention can with solvation not and exist with the form of pharmaceutically acceptable solvent (for example water, ethanol etc.) solvation.Usually, for purpose of the present invention, think that the form of solvation is equal to the not form of solvation.
The present invention also provides pharmaceutical composition, and it comprises the trinucleated 1-[(indol-3-yl with general formula I) carbonyl] bridged piperazine derivatives, or its pharmaceutically acceptable salt, it mixes mutually with acceptable accessories and other therapeutic agent of choosing wantonly.It is compatible with other composition of compositions that term " acceptable " refers to, and harmless to its receptor.Compositions comprises those of the administration that for example is applicable in per os, the Sublingual, subcutaneous, intravenous, peridural, the sheath, intramuscular, transdermal, lung, partial or rectum etc., all is with the unit dosage forms administration.
For oral administration, active component can be made discrete unit, tablet for example, and capsule, powder, granule, solution, suspension, etc.
For parenteral, pharmaceutical composition of the present invention can be contained in the container of unit dose or multiple dose, the injection of scheduled volume for example, for example in air-tight bottle and ampoule, also can be deposited under cryodesiccated (freeze dried) condition, only need add aseptic liquid-carrier, for example water before use.
After such mixing acceptable accessories, for example as the document Gennaro of standard, A.R. etc., Remington:The Science and Practice ofPharmacy (20th Edition, Lippincott Williams ﹠amp; Wilkins is 2000, especially referring to Part5:Pharmaceutical Manufacturing) described, active component can be pressed into solid dosage unit, pill for example, tablet, or be processed into capsule, suppository or patch.By means of pharmaceutically acceptable liquid, can be with activating agent as fluid composition, for example as the injected articles of solution, suspension, form of emulsion, or as spray, nasal spray for example.
In order to prepare solid dosage unit, estimate to use conventional additive, filler for example, coloring agent, polymeric binding agent etc.Usually, can use not can the interferon activity compound functions any pharmaceutically acceptable additive.Activating agent of the present invention can comprise the lactose that uses with suitable amount, starch, cellulose derivative etc., or its mixture with its suitable carriers of using as solid composite.For parenteral, can use aqueous suspension, isoosmotic saline solution and aseptic injection solution, it contains pharmaceutically acceptable dispersant and/or wetting agent, for example propylene glycol or butanediol.
The present invention also comprises pharmaceutical composition, as mentioned before, its be applicable to that the packaging material of described compositions are combined, described packaging material comprise the description about the use of compositions in purposes as previously described.
Find trinucleated 1-[(indol-3-yl of the present invention) carbonyl] bridged piperazine derivatives is the agonist of CB1 receptor, as using Chinese hamster ovary celI measured in people CB1 reporter assay.Determining the receptors bind and the active method of external biological of Cannabined receptor adjusting control agent, is well-known in the art.Usually, the chemical compound that the receptor contact of expression will be tested, and measure in conjunction with or to the stimulation or the inhibition of functional response.
For the measurement function reaction, the DNA of separated coding CB1 receptor (preferred people's receptor) gene expresses in proper host cell.Such cell can be a Chinese hamster ovary cell, but other cell also is suitable.Preferably, cell is the mammal source.
Make up the method for the CB1 express cell system of reorganization, be (Sambrook etc., Molecular Cloning:a Laboratory Manual, ColdSpring Harbor Laboratory Press well-known in the art, Cold Spring Harbor, latestedition).By expressing the proteic DNA that coding needs, can realize receptor expression.So far, the technology that is used to connect other sequence and makes up suitable expression system all is well-known in the art.The solid phase technique of use standard can make up part or all of DNA of coding desirable proteins synthetically, preferably comprises restriction site, connects with convenient.The suitable control element of transcribing and translating of the coded sequence that comprises can be offered the dna encoding sequence.As everyone knows, can obtain can be with the host of numerous kinds compatible expression system now, comprise the prokaryote host, for example antibacterial and eukaryote host, yeast for example, plant cell, insect cell, mammalian cell, bird cell etc.
Then, make the cells contacting experimental compound of expressed receptor, with observe in conjunction with or to the stimulation or the inhibition of functional response.
Perhaps, can use the isolated cells film of CB1 (or CB2) receptor that contains expression, measure the combination of chemical compound.
In order to measure combination, can use radiolabeled or fluorescently-labeled chemical compound.The most radiolabeled cannabinoid probe of Shi Yonging be [
3H] CP55940, it has approximately identical affinity to CB1 with the CB2 binding site.
Another kind of mensuration comprises by detecting second message,second messenger's reaction, the variation of for example measuring receptor-mediated cAMP or map kinase approach, screening cannabinoid CB 1 agonist compound.Thereby, such method comprise the CB1 receptor on host cell surface expression and with cellular exposure in experimental compound.Then, measure second message,second messenger's reaction.Depend on the effect of experimental compound behind the bind receptor, second message,second messenger's level can reduce or raise.
Except direct measurement for example the cAMP level in the cell that exposes, the cell of DNA of second kind of coding reporter gene that can use except transfection the receptor coding DNA also transfection, this report expression of gene is associated with receptor activation.Usually, by any response element that the change level to the second message,second messenger reacts, can control reporter gene and express.Suitable reporter gene is LacZ for example, alkali phosphatase, firefly luciferase and green fluorescent protein.The principle that such trans-activation is measured is well-known in the art, and is documented in for example Stratowa, Ch, Himmler, A. and Czernilofsky, A.P., Curr.Opin.Biotechnol.
6, 574 (1995).In order to select to the activated agonist compound of CB1 receptor, EC
50Be worth necessary＜10
-5M, preferably＜10
-7M.
This chemical compound can be used for the treatment of pain, peri-operation period pain for example, chronic pain, neuropathic pain, cancerous pain and pain and the spasm relevant with multiple sclerosis.
Cannabinoid agonists of the present invention also can be used for the treatment of other obstacle potentially, comprises multiple sclerosis, spasticity, inflammation, glaucoma, nausea and vomiting, loss of appetite, sleep disorder, respiratory disorder, allergy, epilepsy, migraine, cardiovascular disorder, neural degeneration obstacle, anxiety, traumatic brain injury and apoplexy.
This chemical compound also can be united use with other medicines, and for example for example opioid and NSAID (non-steroidal anti-inflammatory drug) (NSAID) of analgesic comprises the COX-2 selective depressant.
Can give the people with compound administration of the present invention, with relief of symptoms with enough amounts and time enough.Illustrative ground can be the 0.001-50mg/kg body weight to people's dosage level scope, and preferred dose is the 0.01-20mg/kg body weight.
The following examples have been explained the present invention.
Embodiment 1
(R)-and 3-cyclohexyl-2,3-dihydro-6-(4-ethyl piperazidine-1-base carbonyl) pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate
To the D-N-Boc-Cyclohexylglycine (25.0g, 97.2mmol) in the solution in dimethyl formamide (200ml), add sodium bicarbonate (24.5g, 291.6mmol) and methyl iodide (6.66ml, 106.9mmol).Under nitrogen, with mixture at stirring at room 64h.The mixture that obtains is distributed between dichloromethane and water.Use the dichloromethane extraction water layer, and the organic layer that merges with the salt water washing, through dried over sodium sulfate with concentrate.With the crystal that normal heptane washing obtains, obtain D-N-Boc-Cyclohexylglycine methyl ester (25.65g, 94.5mmol).
To D-N-Boc-Cyclohexylglycine methyl ester (25.65g, 94.5mmol) in the solution in methanol (200ml) and oxolane (100ml), add calcium chloride (21.0g, 189mmol) and sodium borohydride (14.3g, 378mmol).Under nitrogen, with mixture at stirring at room 30min.Pour the mixture that obtains into frozen water,, and between dichloromethane and water, distribute with the neutralization of 5N hydrochloric acid.Use the dichloromethane extraction water layer, and the organic layer that merges with saturated sodium carbonate liquor and salt water washing, through dried over sodium sulfate with concentrate.From the heptane crystalline residue, obtain thick (R)-N-Boc-2-cyclohexyl ethyl alcohol amine (29.38g, 94.5mmol).
At 0 ℃, to thick (R)-N-Boc-2-cyclohexyl ethyl alcohol amine (29.38g, 94.5mmol) and triphenyl phasphine (37.2g, the 141.8mmol) mixture in toluene (150ml), add the diisopropyl azo-2-carboxylic acid (19.5ml, 99.2mmol).Stir after 1 hour, at 0 ℃, (12.1ml 104.0mmol) adds mixture with the 2-bromophenol.At 0 ℃, stirred reaction mixture 2h in room temperature, stirs 20h.The mixture that obtains is distributed between dichloromethane and water.Use the dichloromethane extraction water layer, and the organic layer that merges with 2N sodium hydroxide solution and salt water washing, through dried over sodium sulfate with concentrate.By the purification by flash chromatography residue, be used in 0-10% (v/v) eluent ethyl acetate in the heptane, obtain (R)-2-(2-t-butoxycarbonyl amino-2-cyclohexyl ethyoxyl) bromobenzene (12.80g, 32.1mmol).
At 120 ℃, with (R)-2-(2-t-butoxycarbonyl amino-2-cyclohexyl ethyoxyl) bromobenzene (500mg, 1.26mmol), four (triphenyl phasphine) palladium (0) (146mg, 0.126mmol) and the mixture of sodium tert-butoxide (181mg 1.88mmol) in toluene (4.0ml) be exposed to microwave irradiation 10min.The mixture that obtains is distributed between dichloromethane and water.Use the dichloromethane extraction water layer, and the organic layer that merges with the salt water washing, through dried over sodium sulfate with concentrate.By the purification by flash chromatography residue, be used in 0-17% (v/v) eluent ethyl acetate in the heptane, obtain (R)-4-tertbutyloxycarbonyl-3-cyclohexyl-3,4-dihydro-2H-1, the 4-benzoxazine (270mg, 0.85mmol).Repeat this reaction 13 times with identical scale, obtain identical intermediate and (be total to 3.98g, 12.5mmol).
At 70 ℃, stir (R)-4-tertbutyloxycarbonyl-3-cyclohexyl-3,4-dihydro-2H-1, the 4-benzoxazine (3.98g, 12.5mmol), the mixture 50min of 5N hydrochloric acid (10ml) and ethanol (10ml).Vacuum is removed ethanol, and residue is distributed between dichloromethane and the 2N sodium hydroxide solution.Use the dichloromethane extraction water layer, and the organic layer that merges with the salt water washing, through dried over sodium sulfate with concentrate.Obtain (R)-3-cyclohexyl-3,4-dihydro-2H-1, the 4-benzoxazine (2.72g, 12.5mmol).
With (R)-3-cyclohexyl-3,4-dihydro-2H-1, the 4-benzoxazine (2.72g 12.5mmol) is dissolved in N, dinethylformamide (20ml), and at 0 ℃ of adding sodium nitrite (949mg, 13.8mmol) solution in water (3.0ml).Then, at 0 ℃, add 5N hydrochloric acid (6.0ml).At 0 ℃, stirred reaction mixture 1h distributes between ethyl acetate and water then.Use the ethyl acetate extraction water layer, and the organic layer that merges with the salt water washing, through dried over sodium sulfate with concentrate.The residue that obtains is dissolved in ether (50ml),, is added in the lithium aluminium hydride reduction (1.0M in the oxolane at 0 ℃; 9.51ml, 9.51mmol).At 0 ℃, stirred reaction mixture 1h uses the frozen water cancellation then.Ethyl acetate is added mixture,, and use the ethyl acetate washing leaching cake by the plug of celite filtering mixt.Distribute filtrate, and use the ethyl acetate extraction water layer.With the organic layer of salt water washing merging, through dried over sodium sulfate and concentrated.By the purification by flash chromatography residue, be used in 0-17% (v/v) eluent ethyl acetate in the heptane, obtain (R)-4-amino-3-cyclohexyl-3,4-dihydro-2H-1, the 4-benzoxazine (1.47g, 6.33mmol).
With ethyl pyruvate (882mg 7.59mmol) adds (R)-4-amino-3-cyclohexyl--3,4-dihydro-2H-1,4-benzoxazine (1.47g, 6.33mmol) solution in ethanol (40ml).At stirring at room reactant mixture 15min.In reactant mixture, (10%v/v is in ethanol to add sulphuric acid; 8.0ml).With reaction mixture refluxed 2h.Mixture is cooled to room temperature, and between ethyl acetate and sodium carbonate liquor, distributes.Use the ethyl acetate extraction water layer, and the organic layer that merges with the salt water washing, through dried over sodium sulfate with concentrate.By the purification by flash chromatography residue, be used in 0-10% (v/v) eluent ethyl acetate in the heptane, obtain (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, 4-benzoxazine-5-Ethyl formate (1.49g, 4.76mmol).
To (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, and 4-benzoxazine-5-Ethyl formate (1.49g, 4.76mmol) in the solution in ethanol (50ml), adding 4N sodium hydroxide (5.94ml, 23.8mmol).At 70 ℃ of 40min that stir the mixture.Vacuum is removed ethanol, uses in the 2N hydrochloric acid and residue, and distributes between dichloromethane and water.Use the dichloromethane extraction water layer, and the organic layer that merges with the salt water washing, through dried over sodium sulfate with concentrate.Residue is dissolved in quinoline (20ml), add then copper powder (453mg, 7.13mmol).At 210 ℃, 1h stirs the mixture.In room temperature, ethyl acetate and water are added mixture, through the plug of celite filtering mixt, and use the ethyl acetate washing leaching cake.With 5N hcl acidifying filtrate, and distribute.Use the ethyl acetate extraction water layer, with the organic layer of 1N hydrochloric acid and salt water washing merging, through dried over sodium sulfate and concentrated.By the purification by flash chromatography residue, be used in 0-10% (v/v) eluent ethyl acetate in the heptane, obtain (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, the 4-benzoxazine (984mg, 4.08mmol).
Flow down at nitrogen, to (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, the 4-benzoxazine (80mg, the 0.33mmol) solution in sym.-tetrachloroethane (2.0ml), under agitation add oxalyl chloride (46mg, 0.36mmol).Mixture was heated 1 hour at 120 ℃.Mixture is cooled to room temperature, add triethylamine (36mg, 0.36mmol) and the N-ethyl piperazidine (45mg, 0.40mmol).Mixture at stirring at room 18h, is distributed between dichloromethane and water then.Use the dichloromethane extraction water layer, and the organic layer that merges with the salt water washing, through Na
2SO
4Dry and concentrated.By the brown oil that purification by flash chromatography obtains, use 5% (v/v) methanol in dichloromethane produces the motif compound of free alkali form as eluant.By (the 2M solution in ether 0.5ml) adds in the solution of free alkali in ether (2ml) and ethanol (1ml), can realize that hydrochlorate forms with hydrochloric acid.Vacuum is removed solvent, and is drying precipitated, obtain solid, shaped motif compound (1: 1 hydrochlorate) (70mg, 0.17mmol).
1H NMR (400MHz, CD
3OD) δ 1.00-1.40 (6H, m), 1.38 (3H, t, J7.3), 1.58 (1H, d, J12.4), 1.62-1.70 (1H, m), 1.70-1.80 (2H, m), 1.80-1.90 (1H, m), 3.10-3.70 (6H, m), 3.25 (2H, q, J7.3), and 4.20-4.60 (4H, m), 4.71 (1H, dd, J3.0,12.6), 6.66 (1H, d, J7.8), 7.08 (1H, t, J7.8), 7.22 (1H, d, J7.8), 7.74 (1H, s); EsIMS:m/z=382.2[M+H]
+, 268.2; [α]
D 22-18.5 ° (c=1.4mg/ml is in methanol).
Embodiment 2
(R)-and 3-cyclohexyl-2, the 3-dihydro-6-[(S)-and octahydro-2H-pyrido [1,2-a] pyrazine-2-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate
To (S)-(+)-1-(tertbutyloxycarbonyl)-Pipecolic Acid (2.00g, 8.72mmol) in the solution in dichloromethane (30ml), add glycine methyl ester hydrochloride (1.09g, 8.72mmol), 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (2.01g, 10.46mmol), I-hydroxybenzotriazole (1.22g, 9.04mmol) and triethylamine (2.43ml, 17.4mmol).Flow down at nitrogen, stirred the mixture 18 hours.With 0.5M hydrochloric acid (20ml), water (2 * 20ml) and the mixture that obtains of saline (20ml) washing, through dried over sodium sulfate with concentrate, obtain colorless oil (S)-1-(tertbutyloxycarbonyl) piperidines-2-carboxyl glycine methyl ester (2.47g, 8.23mmol).
(2.46g 8.20mmol) was dissolved in the trifluoroacetic acid (10ml), with the solution stirring that obtains 1 hour with (S)-1-(tertbutyloxycarbonyl) piperidines-2-carboxyl glycine methyl ester.Remove trifluoroacetic acid then, obtain colourless oil, it is dissolved in methanol (85ml), and the adding triethylamine (9.0ml, 64.6mmol).The mixture 4h that heating obtains under refluxing.Then, concentrated solution obtains the oil of light orange, with it from heptane 48%, ether 48%, recrystallization in the 2-propanol 4% obtains (the S)-octahydro-1 of white crystal shape, 4-dioxo-2H-pyrido [1,2-a] pyrazine (0.66g, 3.90mmol).
With (S)-octahydro-1, and 4-dioxo-2H-pyrido [1,2-a] pyrazine (0.5g, (1M is in oxolane 2.98mmol) to add the solutions of lithium aluminium hydride that stirs by part ground; 11.9ml, 11.9mmol).The mixture 0.5h that heating obtains under refluxing.Then, cooling solution to 0 ℃, and dropwise water (1.35ml), 1M sodium hydroxide solution (0.45ml), water (1.35ml) is handled then.Add oxolane (10ml),, filter then solution stirring 0.5h.With oxolane (2 * 5ml) washing leaching cakes, the filtrate and the cleaning mixture that concentrate to merge, produce yellow oily (S)-octahydro-2H-pyrido [1,2-a] pyrazine (0.29g, 2.07mmol).
Flow down at nitrogen, to (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, the 4-benzoxazine (100mg, 0.41mmol) in the solution in sym.-tetrachloroethane (2.0ml), under agitation add oxalyl chloride (58mg, 0.46mmol).At 120 ℃, with mixture heated 1.5h.Mixture is cooled to room temperature, add triethylamine (46mg, 0.46mmol) and (S)-octahydro-2H-pyrido [1,2-a] pyrazine (70mg, 0.50mmol).Mixture at stirring at room 19h, is distributed between dichloromethane and water then.Use the dichloromethane extraction water layer, and the organic layer that merges with the salt water washing, through Na
2SO
4Dry and concentrated.By the brown oil that purification by flash chromatography obtains, be used in 50% in the normal heptane (v/v) eluent ethyl acetate, be used in 0-17% (v/v) methanol-eluted fractions in the ethyl acetate then, obtain motif compound as free alkali.By (the 2M solution in ether 1ml) adds in the solution of free alkali in ether (2ml) and ethanol (2ml), realizes that hydrochlorate forms with hydrochloric acid.Vacuum is removed solvent, and is drying precipitated, obtain solid, shaped motif compound (1: 1 hydrochlorate) (78mg, 0.18mmol).
1H NMR (400MHz, CD
3OD) δ 1.00-1.35 (6H, m), 1.50-2.05 (11H, m), 3.00-3.10 (1H, m), and 3.10-3.30 (3H, m), 3.40-3.55 (3H, m), 4.20-4.30 (2H, m), 4.50-4.70 (2H, m), 4.71 (1H, dd, J3.0,12.6), 6.67 (1H, d, J7.2), 7.08 (1H, t, J7.8), 7.21 (1H, d, J7.2), 7.74 (1H, s); EsIMS:m/z=408.2[M+H]
+, 268.2; [α]
D 22-27.5 ° (c=5.8mg/ml is in methanol).
Embodiment 3
(S)-and 3-cyclohexyl-2, the 3-dihydro-6-[(S)-and eight oxygen-2H-pyrido [1,2-a] pyrazine-2-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate
Use embodiment 2 described methods, use according to the method for embodiment 1 (the S)-3-cyclohexyl-2 from the preparation of L-N-Boc-Cyclohexylglycine, the 3-pyrrolin is [1,2,3-de]-1 also, and the 4-benzoxazine has prepared motif compound.
1H NMR (400MHz, CD
3OD) δ 1.00-1.35 (6H, m), 1.50-2.05 (11H, m), 3.05 (1H, t, J10.4), 3.10-3.30 (3H, m), 3.40-3.55 (3H, m), and 4.20-4.30 (2H, m), 4.30-4.60 (2H, m), (4.71 1H, dd, J3.0,12.6), 6.66 (1H, d, J8.0), 7.08 (1H, t, J8.0), 7.22 (1H, d, J8.0), 7.73 (1H, s); EsIMS:m/z=408.2[M+H]
+, 268.2; [α]
D 22+ 14.4 ° (c=1.3mg/ml is in methanol).
Embodiment 4
(R)-and 3-cyclohexyl-2, the 3-dihydro-6-[(S)-3, and 4-lupetazin-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate
At 0 ℃, to (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, and the 4-benzoxazine (600mg, 2.49mmol) at N, in the solution in the dinethylformamide (5.0ml), the adding trifluoroacetic anhydride (0.311ml, 2.73mmol).Mixture at stirring at room 5h, is distributed between dichloromethane and water then.Use the dichloromethane extraction water layer, and the organic layer that merges with the salt water washing, through Na
2SO
4Dry and concentrated.By the purification by flash chromatography residue, be used in 0-25% (v/v) eluent ethyl acetate in the heptane, obtain (R)-3-cyclohexyl-6-trifluoromethyl carbonyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, the 4-benzoxazine (628mg, 1.86mmol).
To (R)-3-cyclohexyl-6-trifluoromethyl carbonyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, and (628mg 1.86mmol) 1, in the solution in the 4-two alkane (20ml), adds 4N NaOH (5.0ml) to the 4-benzoxazine.Mixture was refluxed 42 hours, use 5N hydrochloric acid then, be acidified to pH1, and between dichloromethane and water, distribute.Use the dichloromethane extraction water layer, and the organic layer that merges with the salt water washing, through Na
2SO
4Dry and concentrated, obtain thick (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, 4-benzoxazine-6-formic acid (572mg).
To (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, 4-benzoxazine-6-formic acid (120mg, 0.421mmol) and (S)-1, (62mg is 0.547mmol) at N for the 2-lupetazin, in the solution in the dinethylformamide (3.0ml), add 1-(3-dimethylaminopropyl)-3-ethyl carbodiimides (97mg, 0.505mmol) and I-hydroxybenzotriazole (68mg, 0.505mmol).Mixture at stirring at room 18h, is distributed between dichloromethane and water then.Use the dichloromethane extraction water layer, and the organic layer that merges with the salt water washing, through Na
2SO
4Dry and concentrated.By the purification by flash chromatography residue, be used in 0-20% (v/v) methanol-eluted fractions in the ethyl acetate, obtain motif compound as free alkali.By with hydrochloric acid (the 2M solution in ether; 0.5ml) add the solution of free alkali in ether (2ml) and ethanol (1ml), realize that hydrochlorate forms.Vacuum is removed solvent, and is drying precipitated, obtain solid, shaped motif compound (1: 1 hydrochlorate) (84mg, 0.20mmol).
1H?NMR(400MHz，CD
3OD)δ1.00-1.35(5H，m)，1.39(3H，d，J4.8)，1.58(1H，d，J12.0)，1.60-1.70(1H，m)，1.70-1.82(3H，m)，1.82-1.90(1H，m)，2.96(3H，s)，3.20-3.70(5H，m)，4.20-4.30(2H，m)，4.40-4.70(2H，m)，4.71(1H，d，J10.0)，6.67(1H，d，J8.2)，7.08(1H，t，J8.2)，7.21(1H，d，J8.2)，7.74(1H，s)；EsIMS：m/z＝382.1[M+H]
+，268.1
Embodiment 5
Also the method with embodiment 4 is used to prepare following chemical compound:
Use (S)-2-methyl piperazine to replace (S)-1,2-lupetazin, preparation 5A:(R)-3-cyclohexyl-2, the 3-dihydro-6-[(S)-and 3-methyl piperazine-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate.
EsIMS:m/z=368[M+H]
+, 267.8; [α]
D 22-44.4 ° (c=2.3mg/ml is in methanol).
Use cis-2, the 6-lupetazin replaces (S)-1,2-lupetazin, preparation 5B:(R)-3-cyclohexyl-2,3-dihydro-6-[(cis)-3,5-lupetazin-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate.
EsIMS:m/z=382.1[M+H]
+, 267.6; [α]
D 22-19.6 ° (c=2.8mg/ml is in methanol).
Use N methyl piperazine to replace (S)-1,2-lupetazin, preparation 5C:(R)-3-cyclohexyl-2,3-dihydro-6-[4-methyl piperazine-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate.
EsIMS:m/z=368[M+H]
+, 268; [α]
D 22-20.3 ° (c=3.0mg/ml is in methanol).
Embodiment 6
(R)-and 3-cyclohexyl-2,3-dihydro-6-[(cis)-2,6-lupetazin-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate
To (cis)-2, the 6-lupetazin (900mg, 8.49mmol) and in the solution of sodium bicarbonate (0.2ml saturated solution) in THF (5ml), add benzyl bromide a-bromotoluene (1.02ml, 8.49mmol).At 80 ℃, mixture was exposed to microwave irradiation 15 minutes.Vacuum is removed solvent, uses the sodium bicarbonate solution debris, and uses dichloromethane extraction.By the purification by flash chromatography residue, be used in 5-10% (v/v) methanol-eluted fractions in the dichloromethane, obtain clarifying buttery 1-N-benzyl-(cis)-3, the 5-lupetazin (900mg, 4.40mmol).
To (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, and 4-benzoxazine-6-formic acid (362mg, 1.23mmol) in the solution in dichloromethane (20ml), the adding oxalyl chloride (0.215ml, 2.46mmol).At stirring at room 2h, vacuum is removed solvent then with the navy blue mixture, obtains (R)-3-cyclohexyl-2 of blue solid shape, and the 3-pyrrolin is [1,2,3-de]-1 also, and 4-benzoxazine-6-formic acid acyl chlorides (380mg, 1.23mmol).
To (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, 4-benzoxazine-6-formic acid acyl chlorides (380mg, 1.23mmol) and N, (0.2ml is 1.3mmol) in the solution in dichloromethane (20ml) for the N diisopropyl ethyl amine, be added in 1-N-benzyl-(cis)-3 in the dichloromethane (5ml), the 5-lupetazin (250mg, 1.2mmol), then at stirring at room mixture 16h.Mixture is distributed between sodium bicarbonate solution and dichloromethane.Separate organic layer, and vacuum is removed solvent.By the purification by flash chromatography residue, be used in 0-5% (v/v) methanol-eluted fractions in the dichloromethane.By adding hydrochloric acid (the 2M solution in ether to the free alkali in dichloromethane (1ml); 2ml), realize that hydrochlorate forms.Filtering-depositing, and dry, obtain light blue pulverous (R)-3-cyclohexyl-2,3-dihydro-6-[(cis)-4-benzyl-2,6-lupetazin-1-base-carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate (240mg, 0.51mmol).
To (R)-3-cyclohexyl-2,3-dihydro-6-[(cis)-4-benzyl-2,6-lupetazin-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate (200mg, 0.42mmol) in the solution in ethanol (5ml), add 10% palladium carbon (10mg).Under nitrogen atmosphere, at stirring at room mixture 16h.Filtering mixt, vacuum are removed solvent, obtain white solid motif compound (100mg, 0.26mmol).
1H NMR (400Hz, CD
3OD) δ 1.03-1.39 (5H, m), 1.49 (6H, d, J7.2), 1.55-1.87 (6H, m), 3.47 (4H, m), 4.29 (2H, m), 4.72 (1H, d, J9.8), 4.80 (2H, m), 6.66 (1H, d, J7.5), 7.09 (1H, m, J7.7), 7.19 (1H, d, J8.9), 7.66 (1H, s); EsIMS:m/z=382.3[M+H]
+, 268; [α]
D 22-17.0 ° (c=2.4mg/ml is in methanol).
Embodiment 7
(R)-and 3-cyclohexyl-2,3-dihydro-6-[(cis)-3,4,5-tri methyl piperazine-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate
To (R)-3-cyclohexyl-2,3-dihydro-6-[(cis)-3,5-lupetazin-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate (100mg, 0.26mmol) in the solution in ethanol (10ml), adding formaldehyde (37%, in water; 1ml, 12.5mmol) and triacetic acid base sodium borohydride (200mg, 0.93mmol).With mixture stirring at room 30 minutes.Vacuum is removed solvent.By the purification by flash chromatography residue, be used in 1-10% (v/v) methanol-eluted fractions in the dichloromethane, obtain motif compound as free alkali.By with hydrochloric acid (the 2M solution in ether; 2ml) be added in free alkali in the dichloromethane (1ml), realize that hydrochlorate forms.Filtering-depositing, and dry, obtain motif compound (1: 1 hydrochlorate).EsIMS:m/z=396.1[M+H]
+, 268; [α]
D 22-19.6 ° (c=2.1mg/ml is in methanol).
Embodiment 8
(R)-and 3-cyclohexyl-2,3-dihydro-6-[(cis)-3,5-dimethyl-4-ethyl piperazidine-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate
According to embodiment 7 described methods, use acetaldehyde to replace formaldehyde, prepared motif compound.EsIMS:m/z=410.3[M+H]
+, 268; [α]
D 22-17.8 ° (c=2.0mg/ml is in methanol).
Embodiment 9
(R)-and 3-cyclohexyl-2,3-dihydro-6-[(cis)-3,5-dimethyl-4-(2-hydroxyethyl) piperazine-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate is to (R)-3-cyclohexyl-2,3-dihydro-6-[(cis)-3,5-lupetazin-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate (120mg, 0.31mmol) in the solution in acetonitrile (3ml), add ethylene bromohyrin (0.024ml, 0.34mmol).At 150 ℃, mixture was exposed to microwave irradiation 30 minutes.Filtering mixt, and vacuum is removed solvent.Use HPLC (Waters Xterra[RP18,5 μ m] 30mm * 10mm post, through 25 minutes 10-100%[v/v in water] acetonitrile gradient, 0.1% trifluoroacetic acid buffer, in the 254nm UV detection), the purification residue obtains the motif compound as trifluoroacetic acid (TFA) salt.By adding hydrochloric acid (the 2M solution in ether to the tfa salt in dichloromethane (1ml); 2ml), realize that hydrochlorate forms.Filtering-depositing, and dry, obtain motif compound (20mg, 0.04mmol).
1H NMR (400Hz, CD
3OD) δ 1.01-1.39 (5H, m), 1.44 (6H, d, J5.3), 1.56-1.85 (6H, m), 3.32 (2H, d, J14.2), 3.54 (2H, s), 3.72 (2H, m), 3.82 (0.5H, m), 3.93 (1.5H, d, J4.5), 4.24-4.28 (3H, m), 4.36-4.40 (0.5H, d, J11.6), 4.52 (1.5H, d, J13.1), 4.69 (1H, d, J10.1), 6.66 (1H, d, J7.5), 7.06-7.10 (1H, m) 7.20 (1H, d, J8.0), 7.75 (1H, s); EsIMS:m/z=426.1[M+H]
+, 268; [α]
D 22-18.3 ° (c=2.2mg/ml is in methanol).
Embodiment 10
(R)-and 3-cyclohexyl-2,3-dihydro-6-[(cis)-3,5-dimethyl-4-(2-methoxy ethyl) piperazine-1-base carbonyl] pyrrolo-[1,2,3-de]-1,4-benzoxazine hydrochlorate
Use embodiment 9 described methods, use the 2-bromo-ethyl-methyl ether to replace ethylene bromohyrin, prepared motif compound.
EsIMS:m/z=440[M+H]
+, 268; [α]
D 22-20.8 ° (c=2.5mg/ml is in methanol).
Embodiment 11
(rac)-and 4-cyclopenta-5,6-dihydro-1-(4-ethyl piperazidine-1-base carbonyl)-4H-pyrrolo-[3,2,1-ij] quinoline hydrochloride
Refrigerative 2-chloroquinoline (8.2g in Xiang Zaibing/methanol bath, 50mmol) with [1, two (the diphenyl phosphine)-ethane of 2-] (200mg 0.38mmol) in the solution in ether (20ml), added brominated amyl group magnesium (the 2M solution in ether to dichloro nickel (II) through 15 minutes; 25.5ml, 51mmol).Stirred the brown solution obtain then 30 minutes, and removed ice bath, with mixture restir 10 minutes.Then, reaction mixture to 0 ℃ again, and add saturated ammonium chloride solution (40ml) lentamente.Pour the reactant mixture that obtains into separatory funnel, and reuse ether (60ml) and saturated ammonium chloride solution (60ml) dilution.Separate organic layer, and (2 * 100ml) wash water layers with ether.Dry (MgSO
4) Organic substance that merges, to filter, vacuum is removed solvent, remaining buttery 2-cyclopenta quinoline (9.98g, 50.4mmol).
Refrigerative 2-cyclopenta quinoline in Xiang Zaibing/methanol bath (7.95g, 40.3mmol) and Nickel dichloride. (II) hexahydrate (1.63g, 6.85mmol) in the solution in methanol (120ml), add through 1.5h portions ground sodium borohydride (6.1g, 161.2mmol).Remove cooling bath, will react again and stir 30 minutes.Vacuum is removed methanol then.In the black precipitate that obtains, add 2M hydrochloric acid (100ml), then with the alkalization of 10M potassium hydroxide.Mixture is poured in the separatory funnel, and (4 * 200ml) extract with ether.Dry (MgSO
4) organic layer that merges, to filter, vacuum is removed solvent, produces the 2-cyclopenta-1,2,3 of light brown oily, the 4-tetrahydroquinoline (7.45g, 37.1mmol).
To 2-cyclopenta-1,2,3, (4.0g 20mmol) in the solution in oxolane (15ml), adds ethyl bromide acetone (about 90% purity to the 4-tetrahydroquinoline; 1.38ml, 9.9mmol), stirring reaction 15h.The precipitation that filtration obtains, and wash with oxolane (20ml).Vacuum evaporation filtrate.The residue that obtains is dissolved in oxolane (10ml) and the 2-methyl cellosolve (10ml), and solution is dropwise added magnesium chloride (II) (1.05g, 11mmol) reflux solution in 2-methyl cellosolve (10ml).With reaction mixture refluxed 2h, (1.05g 11mmol), continues to reflux and spends the night to add another part magnesium chloride (II) then.The cooling reactant, and vacuum is removed solvent.The brown oil that obtains is dissolved in dichloromethane (150ml), and with 2M HCl (50ml), saturated potassium carbonate (50ml) and saline (50ml) washing.Dry (MgSO
4) Organic substance, filter, and vacuum is removed solvent.33-67% (v/v) dichloromethane of use in heptane, the oil by purification by flash chromatography obtains produces 4-cyclopenta-5,6-dihydro-4H-pyrrolo-[3,2,1-ij] quinoline-1-formic acid ethyl ester (1.45g, 4.9mmol).
To 4-cyclopenta-5,6-dihydro-4H-pyrrolo-[3,2,1-ij] (1.45g 4.9mmol) in the solution in water (10ml) and ethanol (15ml), adds sodium hydroxide (1.96g to quinoline-1-formic acid ethyl ester, 49mmol), and with reaction mixture refluxed heated overnight (about 14h).The cooling reactant, and with 5M HCl acidify.The white precipitate that filtration obtains, vacuum drying, the 4-cyclopenta-5 of generation white solid, 6-dihydro-4H-pyrrolo-[3,2,1-ij] quinoline-1-formic acid (1.13g, 4.2mmol).
To 4-cyclopenta-5, (342mg, 1.27mmol) in the solution in dichloromethane (20ml), (218 μ L 3.18mmol), and stir 1h with reactant mixture to 6-dihydro-4H-pyrrolo-[3,2,1-ij] quinoline-1-formic acid to add oxalyl chloride.Then, (436 μ L, 6.36mmol), reaction stirred is spent the night to add another part oxalyl chloride.Vacuum is removed solvent and unnecessary reagent then, remaining green solid.Green solid is dissolved in dichloromethane (20ml), dropwise add the N-ethyl piperazidine (323 μ L, 2.54mmol).The reactant mixture that obtains is stirred 1h, pour separatory funnel then into.With saturated potassium bicarbonate solution (20ml) and saline (20ml) washing organic layer, dry (MgSO
4), vacuum is removed solvent, remaining brown oil.By purification by flash chromatography oil, be used in 0-5% (v/v) methanol-eluted fractions in the dichloromethane, the generation motif compound (400mg, 1.09mmol).
1H?NMR(400MHz，CD
3OD)δ
H?1.31-1.43(4H，m)，1.45-1.79(6H，m)，1.87-1.96(1H，m)，2.05-2.24(2H，m)，2.30-2.37(1H，m)，2.90(1H，dt，J16.6，3.9)，3.03-3.20(3H，m)，3.26(2H，q，J7.5)，3.45-3.65(4H，m)，4.16-4.23(1H，m)，4.57(2H，d，J14.7)，6.99(1H，d，J7.1)，7.12(1H，t，J8.0)，7.48(1H，d，J8.0)，7.76(1H，s)；EsIMS：m/z?＝366.3[M+H]
+，252.1.
Embodiment 12
The product that will obtain in embodiment 11 carries out at Chiracel
The OD post (the chirality HPLC on the 2cm * 25cm) separates, with isohexane/isopropyl alcohol 92/8 (v/v) with 15ml/min flow velocity eluting.Use the UV detector, the wavelength detection product at 240nm obtains enantiomer 1; Retention time 24.18 minutes; Enantiomeric excess＞89% and enantiomer 2; Retention time 33.6 minutes; Enantiomeric excess＞92%
12A:(+)-and 4-cyclopenta-5,6-dihydro-1-(4-ethyl piperazidine-1-base carbonyl)-4H-pyrrolo-[3,2,1-ij] quinoline hydrochloride
(147mg 0.38mmol) in the solution in dichloromethane (5ml), adds hydrochloric acid (the 2M solution in ether to enantiomer 1; 0.5ml).Vacuum is removed unnecessary reagent and solvent, the motif compound of remaining white solid.
EsIMS:m/z=366.1[M+H]
+, 252.1; [α]
D 22+ 25.8 ° (c=2.6mg/ml is in methanol).
12B:(-)-and 4-cyclopenta-5,6-dihydro-1-(4-ethyl piperazidine-1-base carbonyl)-4H-pyrrolo-[3,2,1-ij] quinoline hydrochloride
(143mg 0.38mmol) in the solution in dichloromethane (5ml), adds hydrochloric acid (the 2M solution in ether to enantiomer 2; 0.5ml).Vacuum is removed unnecessary reagent and solvent, the motif compound of remaining white solid.
EsIMS:m/z=366.0[M+H]
+, 252.1; [α]
D 22-21.3 ° (c=2.4mg/ml is in methanol).
Embodiment 13
(+)-4-cyclohexyl-5,6-dihydro-1-(4-ethyl piperazidine-1-base carbonyl)-4H-pyrrolo-[3,2,1-ij] quinoline hydrochloride
(11.84ml 100mmol) in the solution in chlorobenzene (300ml), adds entry (300ml), naphthenic acid (35.88g successively to quinoline, 280mmol), and silver nitrate (1.36g, 8.0mmol), Ammonium persulfate. (22.82g, 100mmol) and trifluoroacetic acid (7.67g, 100mmol).Under agitation, with mixture heated to 140 ℃ 3h.Then, mixture is cooled to room temperature, with the solid sodium hydroxide alkalization, and vacuum is removed solvent.Then, with isohexane continuous extraction residue 18 hours, solvent evaporated under reduced pressure by the purification by flash chromatography residue, was used in 20% in the isohexane (v/v) eluent ethyl acetate, obtain yellow oily 2-cyclohexyl quinoline (2.66g, 12.61mmol).
(2.38g 37.82mmol) handles 2-cyclohexyl quinoline (2.66g, the 12.61mmol) solution in glacial acetic acid (25ml), and at stirring at room 4h, stir 18h at 40 ℃ then with sodium cyanoborohydride.Then, with 2M sodium hydroxide (200ml) treatment mixture, stir 30min, and be extracted into ethyl acetate (in 3 * 100ml).Then, water (the organic layer that 3 * 100ml) washings merge, use dried over sodium sulfate, vapourisation under reduced pressure is by the purification by flash chromatography residue, be used in 0-3% (v/v) eluent ethyl acetate in the isohexane, obtain the 2-cyclohexyl-1,2 of yellow oily, 3, the 4-tetrahydroquinoline (1.61g, 7.49mmol).
With (R)-(-)-2-hydroxyl-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinane-2-oxide (2.94g, 12.14mmol) the 2-cyclohexyl-1 of processing in ethanol (75ml), 2,3, and the 4-tetrahydroquinoline (2.61g, 12.14mmol), stir the mixture at 50 ℃, up to dissolving fully.Then, the vapourisation under reduced pressure mixture is 30ml up to cumulative volume, crystallization 3 hours.Filtering suspension liquid, the colourless precipitation of recrystallization in ethanol produces colourless crystalline solids (2.1g).This solid is handled with saturated sodium carbonate liquor (50ml), and be extracted into dichloromethane (in 2 * 50ml).Then, the organic layer that merges with dried over sodium sulfate, and vapourisation under reduced pressure obtain the 2-cyclohexyl-1,2,3 of non--racemic colorless oil, and the 4-tetrahydroquinoline (0.98g, 4.56mmol).By at Chiralcel
Chirality HPLC on the OJ post, with the 1ml/min flow velocity, with 97: 3 (v/v) eluting of isohexane/ethanol, detecting enantiomeric excess is 94%.Use the UV detector of 230nm wavelength, detect enantiomer, in the retention time of 8.4min (97%) and 9.4min (3%), eluting goes out enantiomer.
Follow the method for embodiment 1, the non--racemic 2-cyclohexyl-1,2,3 above using, the 4-tetrahydroquinoline replaces (R)-3-cyclohexyl-3,4-dihydro-2H-1, the 4-benzoxazine, obtain colorless solid motif compound (0.05g, 0.12mmol).
1H?NMR(400MHz，CDCl
3)δ
H1.05-1.26(5H，m)，1.48-1.87(9H，m)，2.01-2.11(1H，m)，2.30-2.39(1H，m)，2.70-3.12(6H，m)，3.44-3.52(2H，m)，3.96-4.13(3H，m)，4.53(2H，d，br，J14.1)，7.00(1H，d，J7.5)，7.16(1H，t，J7.4)，7.44(1H，d，J8.1)，7.59(1H，s)。EsIMS:m/z 380[M+H]
+, 266; [α]
D 22+ 42.6 ° (c=2.7mg/ml is in methanol).
Embodiment 14
(+)-(4-cyclohexyl-5,6-dihydro-1-(4-methyl piperazine-1-base carbonyl)-4H-pyrrolo-[3,2,1-ij] quinoline hydrochloride
According to embodiment 13 described methods, use N methyl piperazine to replace the N-ethyl piperazidine, prepared motif compound.
1H?NMR(400MHz，CDCl
3)δ
H?1.05-1.28(6H，m)，1.51-1.87(5H，m)，2.02-2.11(1H，m)，2.31-2.39(1H，m)，2.76-3.10(7H，m)，3.41-3.50(2H，m)，3.92-4.10(3H，m)，4.55(2H，d，br，J13.8)，7.00(1H，d，J7.1)，7.16(1H，t，J7.0)，7.44(1H，d，J8.1)，7.59(1H，s)。EsIMS:m/z 366[M+H]
+, 266; [α]
D 22+ 19.3 ° (c=1.5mg/ml is in methanol).
Embodiment 15
(-)-(4-cyclohexyl-5,6-dihydro-1-(4-ethyl piperazidine-1-base carbonyl)-4H-pyrrolo-[3,2,1-ij] quinoline hydrochloride
According to embodiment 13 described methods, use (S)-(+)-2-hydroxyl-5,5-dimethyl-4-phenyl-1,3, the 2-dioxaphosphorinane-2-oxide replaces (R)-(-)-2-hydroxyl-5,5-dimethyl-4-phenyl-1,3, the 2-dioxaphosphorinane-2-oxide, prepared non--racemic 2-cyclohexyl-1,2,3, the 4-tetrahydroquinoline.
By at Chiralcel
Chirality HPLC on the OJ post with the 1ml/min flow velocity, with 97: 3 (v/v) eluting of isohexane/ethanol, detects 2-cyclohexyl-1,2,3, and the enantiomeric excess of 4-tetrahydroquinoline intermediate is 86%.Use the UV detector of 230nm wavelength, the retention time at 8.4min (7%) and 9.4min (93%) detects enantiomer.According to embodiment 1 described method, use this non--racemic 2-cyclohexyl-1,2,3, the 4-tetrahydroquinoline replaces (R)-3-cyclohexyl-3,4-dihydro-2H-1, the 4-benzoxazine has prepared motif compound.
1H?NMR(400MHz，CDCl
3)δ
H1.05-1.26(5H，m)，1.48-1.87(9H，m)，2.01-2.11(1H，m)，2.30-2.39(1H，m)，2.70-3.12(6H，m)，3.44-3.52(2H，m)，3.96-4.13(3H，m)，4.53(2H，d，br，J14.1)，7.00(1H，d，J7.5)，7.16(1H，t，J7.4)，7.44(1H，d，J8.1)，7.59(1H，s)。EsIMS:m/z 380[M+H]
+, 266; [α]
D 22-28.4 ° (c=1.6mg/ml is in methanol).
Embodiment 16
(-)-(4-cyclohexyl-5,6-dihydro-1-(4-methyl piperazine-1-base carbonyl)-4H-pyrrolo-[3,2,1-ij] quinoline hydrochloride
According to embodiment 15 described methods, use N methyl piperazine to replace the N-ethyl piperazidine, prepared motif compound.
1H?NMR(400MHz，CDCl
3)δ
H1.05-1.28(6H，m)，1.51-1.87(5H，m)，2.02-2.11(1H，m)，2.31-2.39(1H，m)，2.76-3.10(7H，m)，3.41-3.50(2H，m)，3.92-4.10(3H，m)，4.55(2H，d，br，J13.8)，7.00(1H，d，J7.1)，7.16(1H，t，J7.0)，7.44(1H，d，J8.1)，7.59(1H，s)。EsIMS:m/z 366[M+H]
+, 266; [α]
D 22-46.2 ° (c=2.1mg/ml is in methanol).
Embodiment 17
The effect and the effectiveness of the people CB1 receptor that vitro detection is expressed in Chinese hamster ovary celI
With Chinese hamster ovary (CHO) cell suspension of expressing human CB1 receptor and luciferase reporter gene in the DMEM/F-12nut mixture that contains penicillin/streptomycin (50U/50 μ g/ml) and amphotericin B (1 μ g/ml) of phenol red/serum-free, and with 3 * 10
4The density of cells/well (100 μ l final volume) is inoculated in the 96 hole flat boards.Before mensuration, with the cell overnight incubation (about 18h, at 37 ℃, 5%CO
2/ 95% air).
In F12Nut Mix, dilution experiment chemical compound (10mM solution is in dimethyl sulfoxide) obtains the stock solution of 0.11mM to 0.11nM scope.(10 μ l) directly adds in the relevant hole with stock solution.Hatched dull and stereotyped 5 hours at 37 ℃, allow the agonist-inductive expression of luciferase.Under the low light level, in each hole, add LucLite substrate (Packard; Description reprovision according to the manufacturer; 100 μ l).Cover dull and stereotypedly with Top Seal, incubated at room 5 minutes, go up counting then at Packard TopCount (single photon counting, 0.01 minute gate time, 5 minutes count delay).
By least square and method per second is counted (CPS) and compound concentration (M) figure match " best fit " curve, obtain EC
50Value.Table 1 has shown the pEC that representational chemical compounds more of the present invention are obtained
50Value.
Table 1
Embodiment 18: the tail in mice beats incubation period
The training mice undisturbedly be sitting in the tail knocking device (Ugo Basile, Italy) in, measure tail simultaneously and beat incubation period.Point from the about 2.5cm in tip is exposed to photothermal focused beam with tail.Tail is beaten the interval that is defined as incubation period between application thermostimulation and the tail contraction.Use 12 seconds cut-off point, prevent tissue injury.The experimental compound of one of intravenous ground application media or 3 dosage (medium: saline 9g/l; Volume injected 10ml/kg), handle 4 groups of 8 mices.Before using experimental compound and behind administered compound,, measured tail and beaten incubation period with the interval (typically, 20,40 and 60 minutes) of rule.At T
MaxCalculated ED
50
Embodiment 2,4, and 14,15 and 16 chemical compound has significantly increased tail and beaten incubation period, ED
50＜5 μ mol/kg.
Claims (7)
1. the carbonyl trinucleated 1-[(indol-3-yl that has general formula I)] bridged piperazine derivatives or its pharmaceutically acceptable salt
Formula I
Wherein
X is CH
2, O or S;
R represents 1-3 substituent group, and it is independently selected from H, (C
1-4) alkyl, (C
1-4) alkoxyl and halogen;
R
1Be (C
5-8) cycloalkyl;
R
2Be H or (C
1-4) alkyl;
R
3, R
3', R
4, R
4', R
5, R
5' and R
6' be hydrogen or (C independently
1-4) alkyl, the latter is randomly by (C
1-4) alkoxyl, OH or halogen replace;
R
6Be hydrogen or (C
1-4) alkyl, the latter is randomly by (C
1-4) alkoxyl, OH or halogen replace; Or
R
6And R
7Form the saturated heterocycle of 4-7 unit together, it randomly contains other hetero atom that is selected from O and S;
R
7And R
6Form the saturated heterocycle of 4-7 unit together, it randomly contains other hetero atom that is selected from O and S; Or
R
7Be H, (C
1-4) alkyl or (C
3-5) cycloalkyl, alkyl is randomly by OH, halogen or (C
1-4) the alkoxyl replacement.
2. the carbonyl trinucleated 1-[(indol-3-yl of claim 1)] bridged piperazine derivatives, wherein R is H and R
1Be cyclopenta or cyclohexyl.
3. claim 1 or 2 trinucleated 1-[(indol-3-yl) carbonyl] bridged piperazine derivatives, wherein X is CH
2Or O.
4. carbonyl each trinucleated 1-[(indol-3-yl among the claim 1-3)] bridged piperazine derivatives, R wherein, R
2, R
3, R
3', R
4', R
5, R
5' and R
6' be H; R
4, R
6And R
7Be H or (C independently
1-4) alkyl; Or R
6And R
7Form the saturated heterocycle R of 5-or 6-unit together
4Be H or (C
1-4) alkyl.
5. carbonyl each trinucleated 1-[(indol-3-yl among the claim 1-4)] application of bridged piperazine derivatives in treatment.
6. pharmaceutical composition, it comprises among the claim 1-4 each trinucleated 1-[(indol-3-yl) carbonyl] bridged piperazine derivatives, and be used for its pharmaceutically acceptable carrier.
7. as the trinucleated 1-[(indol-3-yl of formula I of definition in the claim 1) carbonyl] bridged piperazine derivatives is used for the treatment of application in the medicine of pain in preparation.
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| EP03104768.1 | 2003-12-17 | ||
| EP03104768 | 2003-12-17 | ||
| US60/530,528 | 2003-12-17 |
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| CN100540005C CN100540005C (en) | 2009-09-16 |
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| US4939138A (en) * | 1988-12-29 | 1990-07-03 | Sterling Drug Inc. | 2- and 3-aminomethyl-6-arylcarbonyl-2,3-dihydropyrrolo(1,2,3-DE)-1,4-benzoxazines |
| DE4128015A1 (en) * | 1991-08-23 | 1993-02-25 | Kali Chemie Pharma Gmbh | 1,7-ANELLIZED 2- (PIPERAZINOALKYL) INDOL DERIVATIVES AND METHODS AND INTERMEDIATE PRODUCTS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING SUCH COMPOUNDS |
| CA2340445A1 (en) * | 1998-05-04 | 1999-11-11 | The University Of Connecticut | Novel analgesic and immunomodulatory cannabinoids |
| US6653304B2 (en) * | 2000-02-11 | 2003-11-25 | Bristol-Myers Squibb Co. | Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators for treating respiratory and non-respiratory diseases |
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