CN1331857C - Fused-polycyclic compounds - Google Patents

Fused-polycyclic compounds Download PDF

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CN1331857C
CN1331857C CN 200510106367 CN200510106367A CN1331857C CN 1331857 C CN1331857 C CN 1331857C CN 200510106367 CN200510106367 CN 200510106367 CN 200510106367 A CN200510106367 A CN 200510106367A CN 1331857 C CN1331857 C CN 1331857C
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CN1743312A (en
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浮田辰三
寺川良司博
和田一辉
中田彩
酒井敦子
小川航司
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Tanabe Seiyaku Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals

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Abstract

The present invention provides a novel a condensed polycyclic compound useful as a phosphodiesterase 4 inhibitor, which is shown by the formula [I]: or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same.

Description

Fused-polycyclic compounds
Technical field
The present invention relates to phosphodiesterase 4 (" PDE4 ") is had excellent inhibiting new fused-polycyclic compounds (pyrazine and isoquinoline compound or naphthalene compound) and pharmaceutical composition or comprises the PDE4 inhibitor of described compound as active ingredient.
Background technology
The second messenger is decomposed and inactivation by phosphodiesterase (" PDE ") as cAMP and cGMP in the known cell.The inhibition of PDE causes the raising of interior cAMP of cell and cGMP level.Knownly PDE can be divided into several isozymes, every kind of isozyme is in substrate (cAMP, cGMP) specificity, aspect difference such as distribution in the body, and in isozyme, 4 type PDE (" PDE ") decompose cAMP specifically.
The active inhibition of also known PDE4 can be blocked the release (J.Med.Cell.Cardiol.21 (Supp.II) of inflammatory mediator, S61 (1989)), the PDE4 inhibitor suppresses the production of TNF α and is used for the treatment of (WO98/14432 such as various inflammatory diseasess, WO98/09961, USP6,011,060, WO98/02440, WO97/23457 and WO97/22585), described TNF α is the cytokine that the response immunostimulation discharges from mononuclear phagocyte.
Theophylline, representational PDE inhibitor has been used to treatment of asthma so far.Yet it is nonspecific that the PDE of theophylline suppresses activity, and it shows cardiotonic drug and maincenter activity and bronchial smooth muscle relaxation activity.Therefore, because this side effect must this medicine of careful attention.Therefore, expected to develop the new medicament that can selectivity suppresses the PDE4 in the PDE isozyme, described PDE4 especially major part is present in bronchial smooth muscle and the inflammatory cell.Expect that this medicament is the promising medicine that is used to prevent and treat asthma or inflammatory diseases.
On the other hand, the specific compound of pyrazine and isoquinoline 99.9 type, particularly 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine also [1,2-b] isoquinoline 99.9 show that central nervous system suppresses and hypotensive activity.Indian J.Chem., the 13rd volume, 230-237 (1975)
Suppress the compound of active naphthalene type as having PDE4, USP6005106 discloses wherein that nitrogen-atoms is attached directly to the compound that naphthalene is partly gone up 1 place, pyridine ring position, but does not have open wherein carbon atom to be attached directly to the compound that naphthalene is partly gone up 1 place, pyridine ring position.
Summary of the invention
The fused-polycyclic compounds that the inventor had furtherd investigate and found to contain pyrazine and isoquinoline 99.9 or naphthalene part has excellent anti--PDE4 activity, has established the present invention thus, and is as mentioned below.
The invention provides new fused-polycyclic compounds (pyrazine and isoquinoline compound or naphthalene compound) as the PDE4 inhibitor.The present invention also provides and comprises the pharmaceutical composition of described compound as active ingredient.
Therefore, the present invention relates to the fused-polycyclic compounds of formula [1]:
Figure C20051010636700051
Wherein, R 1And R 2Identical or different and each be selected from the group of hydroxyl and lower alkoxy naturally; Ring A 0Be the following formula group:
Figure C20051010636700052
Or
Figure C20051010636700053
Work as A 0When being the following formula group:
Figure C20051010636700054
Ring A is that (1) replaces or unsubstituted phenyl ring or replacement or unsubstituted aromatic heterocycle,
Perhaps
Work as A 0When being the following formula group:
Figure C20051010636700061
Ring A is (2) following formula group:
Figure C20051010636700062
Wherein n is the integer of 1-6,
When ring A is the phenyl ring that replaces or replacement or unsubstituted aromatic heterocyclic group, R 3Be (1) hydrogen atom, formula :-(CH 2) m-R 31Group or formula :-CO-R 32Group;
Perhaps
When ring A is unsubstituted phenyl ring, R 3Be (2) formula :-(CH 2) m-R 31Group or formula :-CO-R 32Group;
R 31Be hydrogen atom, aryl, hydroxyl, amino, carboxyl, lower alkoxycarbonyl or lower alkylthio;
R 32Be aryl, low alkyl group, hydroxyl low-grade alkyl or amino low alkyl group;
M is the integer of 1-6;
Q is the singly-bound that is connected with ring A; And
R aAnd R bIdentical or different, and each is selected from the group of hydrogen atom and acyl group naturally,
Or its pharmaceutical salts.
The invention still further relates to and comprise pharmaceutical composition or the PDE4 inhibitor of compound of the present invention as active ingredient.
Implement best mode of the present invention
When compound of the present invention [1] when containing aryl, the example of aryl comprise the list of 6-14 carbon atom-, two-or three cyclic groups such as phenyl, naphthyl, anthryl and phenanthryl.Especially preferred phenyl ring in the middle of them.R in the compound [I] aAnd R bThe example of acyl group comprise low-grade alkane acidyl, and preferred ethanoyl.Symbol " n " refers to the integer of 1-6, preferred 2-4, more preferably 3.
When ring A was replacement or unsubstituted aromatic heterocycle, the example of described aromatic heterocycle comprised 5-to 6-unit the monocyclic aromatic heterocyclic group, particularly pyridine ring that comprises 1-3 nitrogen-atoms, pyrimidine ring, pyrazine ring, pyridazine ring etc.
When ring A was the aromatic heterocycle of the phenyl ring that replaces or replacement, phenyl ring or aromatic heterocycle can contain 1-3 and be selected from for example lower alkoxy (methoxyl group, oxyethyl group, isopropoxy etc.), the substituting group of hydroxyl and halogen atom (chlorine, fluorine, bromine etc.).
In target compound of the present invention (I), preferred compound is a fused-polycyclic compounds, wherein encircles A 0Be the following formula group:
Figure C20051010636700071
And the example comprises pyrazine and isoquinoline compound by formula [I-A] expression:
Wherein each symbol has the implication identical with above-mentioned definition.The compound of preferred formula [1-A] is R wherein 1And R 2Identical or different and each alkoxyl group naturally; Ring A is selected from lower alkoxy, the phenyl ring that group replaced of hydroxyl and halogen atom by 1-3; And R 3Be those of hydrogen atom.In the compound of above-mentioned formula [1-A], more preferably R wherein 1And R 2Identical or different and each be selected from the group of methoxyl group and oxyethyl group naturally; Ring A is selected from isopropoxy, the phenyl ring that group replaced of hydroxyl and halogen atom by 1-3; And R 3Be those of hydrogen atom.Especially particularly preferred compound is 6-[4-(isopropoxy) phenyl]-8,9-dimethoxy-1,3,4,6,11,11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 or 6-[4-fluorophenyl also]-8,9-dimethoxy-1,3,4,6,11,11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 also.
Another preferred formula [I] compound of the present invention is a fused-polycyclic compounds, wherein A 0Be the following formula group:
And the example comprises the naphthalene compound by formula [1-B] expression
Figure C20051010636700082
Wherein each symbol has the implication identical with above-mentioned definition.In above-claimed cpd, more preferably R wherein 1And R 2Identical or different and each lower alkoxy naturally; R aAnd R bIdentical or different and each be selected from the group of ethanoyl and hydrogen atom naturally; With n be the compound of 3 formula [1-B].The formula that is more preferably [I-B] compound is R wherein 1And R 2Identical or different and each lower alkoxy naturally; R aAnd R bEach naturally hydrogen atom and n be 3 those.In them, particularly preferred compound is 6,7-dimethoxy-1-[2-(1,3-dioxo hexanaphthene-2-yl)] pyridin-4-yl]-2,3-two [methylol] naphthalene.
In addition, the present invention comprises that in its scope PDE4 suppresses reagent (PDE4 inhibitor), and it comprises the pyrazine of formula [I-C] and isoquinoline compound (derivative) or its pharmaceutical salts as active ingredient:
Figure C20051010636700091
R wherein 1And R 2Identical or different and each hydroxyl or lower alkoxy naturally.
As above-claimed cpd [I-C], preferred R wherein 1And R 2Identical or different and each those of lower alkoxy naturally, more preferably R wherein 1And R 2Identical or different and each be selected from those of group of methoxyl group and oxyethyl group naturally.Particularly preferred compound is 8, and 9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine be [1,2-b] isoquinoline 99.9 also.
[I] is in radicals R at substituting group when compound of the present invention 1, R 2And R 3In and/or the ring A in and/or 1,3,4,6,11,11a-six hydrogen-2H-pyrazine also [1,2-b] when isoquinoline 99.9 partly contains unsymmetrical carbon, because it can exist described unsymmetrical carbon with any form in the multiple steric isomer (diastereomer, enantiomer), and the present invention also comprises any or its mixture in these steric isomers.
Formula of the present invention [I] or [I-C] compound, or its pharmaceutical salts has excellent PDE4 and suppresses active, and be used for prevention or treat various PDE4-relative diseases.The example of this disease comprises various types of inflammatory diseasess and anaphylactic disease, particularly, and asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, anaphylaxis conjunctivitis, vernal conjunctivitis, eosinophilia, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, regional ileitis, reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, osteoarthropathy etc.Compound formula of the present invention [I], [I-C] or its pharmaceutical salts have strong bronchoconstriction and suppress active, can be used as the bronchoconstriction inhibitor.
In addition, the inventor has been found that having PDE4 suppresses regenerative therapy (for example osteoarthritis) (the Japanese patent application 2001-154064 that active compound is used for accelerating union of bone fracture or richets, 2001-154048 corresponds respectively to PCT/JP02/04931 and PCT/JP02/04930).Therefore, compound formula of the present invention [I] or [I-C] or its pharmaceutical salts are with acting on the active ingredient of accelerating union of bone fracture with the composition of treatment richets cartilage disease (for example osteoarthritis).
Compound of the present invention [I] and compound [I-C] optionally suppress PDE4, therefore almost are free from side effects.In addition, it is less and as the advantage of medicine high safety that compound of the present invention [I] and compound [I-C] have toxicity.For example, with 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine also [1,2-b]-isoquinoline 99.9 with single dose (100mg/kg) to mouse (the BDF1 strain, male, n=3) subcutaneous administration and check progress 1 day.As a result, do not observe death.
Can be with free form or with the clinical use of the form of its pharmaceutical salts compound of the present invention [I] and compound [I-C].The pharmaceutical salts of compound [I] comprises the salt with mineral acid, example hydrochloric acid salt, vitriol, phosphoric acid salt or hydrobromate, or with organic acid salt, as acetate, fumarate, oxalate, Citrate trianion, mesylate, benzene sulfonate, tosylate or maleate.In addition, when containing carboxyl in the above-claimed cpd molecule, the example of pharmaceutical salts comprises the salt with alkali, as basic metal (for example sodium salt, sylvite) or alkaline-earth metal (for example calcium salt).
Compound of the present invention [I], compound [I-C] or its pharmaceutical salts comprise molecule inner salt or its additive and its solvate or hydrate.
Can oral or administered parenterally compound of the present invention [I], compound [I-C] or its pharmaceutical salts, and can be mixed with conventional pharmaceutical preparation such as tablet, granule, capsule, powder, injection or inhalation.
According to route of administration, and patient's age, weight and disease condition can change compound of the present invention [I], compound [I-C], or the dosage of its pharmaceutical salts.For example, when with the injection administration, it is typically about 0.01-10mg/kg/ days, preferably approximately 0.03-3mg/kg/ days.When with oral preparation drug administration, it is typically about 0.1-30mg/kg/ days, preferred 0.3-10mg/kg/ days.
Can prepare compound of the present invention [I] or [I-C] with following method.
[preparation of pyrazine and isoquinoline compound [I-A]]
In the fused-polycyclic compounds of formula of the present invention [I], for example can prepare pyrazine and isoquinoline compound [I-A], wherein R according to following reaction scheme 3Be formula :-(CH 2) m-R 31Group (compound [I-A 1]) or R 3Be formula :-CO-R 32Group (compound [I-A 2]).
Figure C20051010636700111
X wherein 1Be that leavings group such as halogen atom and remaining symbol have the implication identical with above-mentioned definition.
In above-claimed cpd of the present invention [I-A], by compound [XIII] and compound [XI] reaction can be prepared compound [I-A 1], the R in its Chinese style [I-A] 3Be formula :-(CH 2) m-R 31Group.This reaction can be carried out under the existence of suitable alkali (for example triethylamine, salt of wormwood etc.).Can use the 1-3 mole for 1 mole compound [XIII] or compound [XI], the alkali of preferred 1.2-1.5 mole.Can under 100 ℃, react preferred 0 ℃ to 30 ℃ at-10 ℃.
In above-claimed cpd of the present invention [I-A], by compound [XIII] and compound [XII] reaction can be prepared compound [I-A 2], the R in its Chinese style [I-A] 3Be formula :-CO-R 32Group.Can under the existence of the condensing agent of routine (for example dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride/I-hydroxybenzotriazole monohydrate etc.), carry out producing compound [I-A between compound [XIII] and the compound [XII] 2] reaction.
Can use the 1-5 mole for 1 mole compound [XIII] or compound [XII], the condensing agent of preferred 1.1-1.5 mole.Can be at-10 ℃ to 100 ℃, react under preferred 0 ℃ to 30 ℃.
By (for example using halogenating agent; thionyl (two) chlorine; oxalyl chloride) handles compound [XII] it being converted into corresponding acyl halide, and in the presence of alkali (for example triethylamine), the acyl halide that produces reacted with compound [XIII] and also can prepare compound [I-A 2].
[XII] can use the 1-3 mole for 1 mole compound, the halogenating agent of preferred 1.1-1.5 mole.Can use the 1-4 mole to 1 mole of above-mentioned acyl halide or compound [XIII], preferred 1.1-1.5 mole alkali.Can be at-20 ℃ to 40 ℃, react under preferred 0 ℃ to 30 ℃.
In addition, by with activator (chloromethane isobutyl carbonate butyl ester for example, Vinyl chloroformate etc.) and alkali (triethylamine for example, N-methylmorpholine, diisopropylethylamine etc.) handle compound [XII] it being converted into corresponding mixed acid anhydride, and the mixed acid anhydride that produces reacted with compound [XIII] also can prepare compound [I-A 2].
[XII] can use the 1-4 mole for 1 mole compound, preferred 1.1-1.5 mole activator.[XII] can use the 1-4 mole to 1 mole compound, the alkali of preferred 1.1-1.5 mole.Can be at-50 ℃ to 50 ℃, preferred-20 ℃ are reacted under 30 ℃.
The intermediate that can prepare the formula [XIII] that is used to prepare The compounds of this invention [I-A] according to for example following reaction scheme.
Boc: tert-butoxycarbonyl
R wherein 4Be low alkyl group, and remaining symbol have and as above define identical implication.
By the esterification of routine, for example at ethanol/Acetyl Chloride 98Min., the existence of ethanol/thionyl (two) chlorine/hydrogenchloride etc. can be carried out from the reaction of compound [II-A] preparation compound [IV] down.
By using conventional condensing agent (for example dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride/I-hydroxybenzotriazole monohydrate etc.) can carry out the reaction for preparing compound [VI] from compound [IV] and compound [V].
After using phosphoryl chloride or these compounds of phosphorus pentachloride condensation, can carry out from the reaction of compound [VI] preparation compound [VII] down in the existence of the reductive agent of routine (for example platinum oxide/hydrogen, palladium on carbon/hydrogen etc.).
By using conventional condensing agent (for example N,N'-carbonyldiimidazole etc.) can carry out the reaction for preparing compound [IX] from compound [VII] and compound [VIII].Alternatively, by with activator (isobutyl chlorocarbonate for example, Vinyl chloroformate etc.) and alkali (for example triethylamine, N-methylmorpholine etc.) handle compound [VIII] so that it is converted into mixed acid anhydride, and the mixed acid anhydride that produces reacted with compound [VII] can prepare compound [IX].
By handling compound [IX] with acid (for example trifluoroacetic acid, hydrochloric acid etc.), then heating can produce the intramolecular cyclization of the compound [IX] of compound [X].
(for example borine-methyl-sulfide mixture can carry out the reaction that reducing compound [X] produces compound [XIII] under the existence of lithium aluminum hydride and two (2-methoxy ethoxy) aluminum hydride etc. at suitable reductive agent.
In the compound of formula [XIII], wherein encircling A is phenyl ring or replacement or the unsubstituted aromatic heterocycle (compound [1-A that replaces 3]) those belong in the scope of target compound of the present invention.
[preparation of naphthalene compound [I-B]]
In the compound of formula of the present invention [I], for example can prepare naphthalene compound [I-B] according to following reaction scheme.
Figure C20051010636700141
R wherein A1And R B1Identical or different and each acyl group naturally, remaining symbol has the implication identical with above-mentioned definition.
In above-claimed cpd of the present invention [I-B], by compound [II-B] and compound [III-B] reaction can be prepared compound [I-B 1], the R in its Chinese style [I-B] aAnd R bEach is acyl group naturally.This reaction can be under the existence of dewatering agent (for example diacetyl oxide, trifluoroacetic anhydride etc.), carry out under by the temperature that can reach of heating/heat.
In above-claimed cpd of the present invention [I-B], by with compound [I-B 1] carry out conventional de-acyl reaction and can prepare compound [I-B 2], the R of its Chinese style [I-B] aAnd R bEach is hydrogen atom naturally.For example, de-acyl reaction can carry out under the existence of suitable nucleophilic reagent (for example sodium methylate, sodium ethylate, sodium hydroxide, lithium hydroxide etc.).For 1 mole compound [I-B 1] can use the 1-4 mole, the nucleophilic reagent of preferred 1.2-2 mole.Reaction can preferably be carried out under 5-20 ℃ with ice-cooled or at room temperature react.
According at JP-5-229987, the method for instructing among the A can prepare the intermediate that is used to prepare compound [I-B], compound [II-B].
[preparation of pyrazine and isoquinoline compound [I-C]]
For example use compound [IV] and wherein encircle the corresponding initial compounds of formula [V] that A is the unsubstituting phenenyl ring, with can prepare pyrazine of the present invention and isoquinoline compound [I-C] in the similar approach described in the situation of above-claimed cpd [I-A].
By further will be at the R of the compound that obtains as mentioned above 1, R 2And R 3And/or the substituting group of ring among the A be converted into the substituting group of other expectation, also can prepare above-claimed cpd of the present invention [I] and compound [I-C].Substituent kind according to expectation can suitably select to transform substituent method.For example, by inciting somebody to action wherein R 1And/or R 2For formula [I] compound of the correspondence of hydroxyl and alkylating agent (for example methyl-sulfate, methyl halide etc.) reaction under the existence of alkali (for example sodium hydroxide, sodium hydride, salt of wormwood, sodium methylate etc.) can prepare wherein R 1And/or R 2Target compound for the formula [I] (or formula [I-C]) of lower alkoxy.
Can use the 1-8 mole for 1 mole compound [I] (or compound [I-C]), preferred 1.2-2.2 mole alkylating agent.Reaction can be at 0-50 ℃, carries out under preferred 10-40 ℃.
Ordinary method with this area can randomly be converted into pharmaceutical salts with compound [I] or the compound [I-C] that obtains like this.
Aforesaid method being used for preparing target compound [I] or compound [I-C] not only can utilize the initial sum midbody compound in above description and reaction scheme illustrated, and can utilize its salt or reactive derivative, and it has no adverse effect to reaction.The example of this salt comprises and following salt, metal such as sodium, potassium, lithium, calcium, magnesium etc.; Organic bases such as pyridine, triethylamine or diisopropylethylamine; The mineral acid example hydrochloric acid, sulfuric acid, nitric acid, Hydrogen bromide or phosphoric acid; With organic acid such as acetate, oxalic acid, citric acid, Phenylsulfonic acid, phenylformic acid, propanedioic acid, citric acid, formic acid, fumaric acid, toxilic acid, methylsulfonic acid, tosic acid or trifluoroacetic acid.
In addition; when compound of the present invention [I] or compound [I-C]; when perhaps initial compounds comprises functional group, can use each functional group with the form of protection, can remove described protection form when not required when it becomes with aforesaid form or by introducing suitable protecting group.
Can or carry out above-mentioned each reaction with appropriate solvent.Can unrestrictedly use any solvent as long as it has no adverse effect to reaction, this solvent can be selected from for example diox, glycol dimethyl ether, N,N-DIMETHYLACETAMIDE, dimethyl formamide, hexamethyl phosphoric triamide (HMPA), pregnancy is for inferior phosphoryl triamide (HMPT), benzene, tetrahydrofuran (THF), toluene, dimethylbenzene, ethyl acetate, lower alcohol (methyl alcohol, ethanol, Virahol etc.), methylene dichloride, chloroform, tetracol phenixin, 1,3-dimethyl-2-imidazolone, acetate, diethyl ether, diisopropyl ether, glycol dimethyl ether, methyl-sulphoxide, acetone, butanone, acetonitrile, water, and composition thereof.
When according to the present invention when this uses, term " low alkyl group " means and contains 1-6 carbon atom, the straight or branched alkyl of preferred 1-4 carbon atom.Term " lower alkoxy " means and contains 1-6 carbon atom, the straight or branched alkoxyl group of preferred 1-4 carbon atom.Term " halogen atom " means fluorine, chlorine, bromine or iodine atom.Term " acyl group " means low-grade alkane acidyl, and the example comprises and contains 1-6 carbon atom, the straight or branched acyl group of preferred 2-4 carbon atom.Term " lower alcohol " means the alcohol (for example, methyl alcohol, ethanol, Virahol etc.) of 1-6 carbon atom.
Embodiment
The purpose of explanation rather than restriction shows the specific embodiment by above illustrational prepared in various methods compound of the present invention (I) below for example.
Embodiment 1
(1) 2-amino-3-(3, the 4-dihydroxyphenyl) propionic acid (98.6g) is dissolved in the formic acid (900ml), adds diacetyl oxide (300ml) in addition.At room temperature stirred the mixture 3 hours.Under reduced pressure concentrated reaction solution adds distilled water in the residue that produces, and under reduced pressure further enriched mixture.Residue is dissolved in the distilled water (150ml), under ice-cooling, adds 10M aqueous sodium hydroxide solution (150ml) and methyl-sulfate (95ml) in addition.Add three parts of methyl-sulfates (285ml altogether) in addition every 30 fens clockwise mixtures, during drip 10M aqueous sodium hydroxide solution (290ml), temperature of reaction is remained below 40 ℃, and the pH value is remained on pH5-9.At room temperature stir the mixture and spend the night, add 10M aqueous sodium hydroxide solution (50ml) then in addition.At room temperature mixture was stirred 30 minutes in addition.With sulfuric acid the pH value of mixture is adjusted to pH2, and adds ethyl acetate to mixture.By the dried over mgso organic layer, and under reduced pressure concentrate.Residue is suspended in the ethanol (1300ml), and under ice-cooling other dripping acetyl chloride (280ml).At room temperature stirred the mixture 3 days.The vapourisation under reduced pressure solvent adds residue with methylene dichloride.Wash organic layer with wet chemical,, and under reduced pressure concentrate to produce buttery 2-amino-3-(3, the 4-Dimethoxyphenyl) ethyl propionate (111g) by dried over mgso.
MS(m/z)：253(M +)
(2) compound (111g) and the triethylamine (73.6ml) that obtains in top (1) is dissolved in the methylene dichloride (300ml), under ice-cooling, drips Benzoyl chloride (51.1ml) in addition.Add saturated sodium bicarbonate aqueous solution, and wash organic layer,, and under reduced pressure concentrate by dried over mgso with saturated brine.Crystal by filtering collecting precipitation with diethyl ether is to produce 3-(3, the 4-Dimethoxyphenyl)-2-(phenylcarbonyl group amino) ethyl propionate (144g).
Fusing point: 82-83 ℃
MS(m/z)：357(M +)
(3) compound (71.5g) that obtains in top (2) is dissolved in the phosphoryl chloride (200ml), heated mixt spends the night under refluxing.By the evaporative removal phosphoryl chloride, dilute residue with methylene dichloride.Use the wet chemical purging compound,, and under reduced pressure concentrate by dried over mgso.Dissolved residue in ethanol adds spissated hydrochloric acid (20ml) toward the there, and under reduced pressure further concentrates.Residue is dissolved in the methyl alcohol (200ml), to wherein adding platinum dioxide (1g).Under the pressure (3 normal atmosphere) of hydrogen, at room temperature stirred the mixture 4 hours.By filter removing undissolved material, and concentrated filtrate under reduced pressure.Residue is dissolved in the chloroform,,, and under reduced pressure concentrates by dried over mgso with saturated sodium bicarbonate aqueous solution and saturated brine washing.Crystal by filtering collecting precipitation is to produce 6,7-dimethoxy-1-phenyl-3-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline (54.4g).
Fusing point: 215-217 ℃ (decomposition)
MS(m/z)：341(M +)
(4) with the 2-[(tert.-butoxy) carbonylamino] acetate (21.6g) is dissolved in the tetrahydrofuran (THF) (75ml), and drip triethylamines (18.7ml) and isobutyl chlorocarbonates (17.4ml) down in addition at-20 ℃, and under-10 ℃, stirred the mixture 5 minutes.Drip the suspension of compound (38.2g) in tetrahydrofuran (THF) (110ml) of acquisition in (3) in the above to mixture, at room temperature stir the mixture and spend the night.Concentrated reaction solution under reduced pressure, and use chloroform extraction.With saturated sodium bicarbonate aqueous solution and saturated brine washing extraction liquid,, and under reduced pressure concentrate by dried over mgso.Crystallized product from diethyl ether, the crystal of collecting generation by filtration is to produce the 2-{2-[(tert.-butoxy) carbonylamino] ethanoyl }-6,7-dimethoxy-1-phenyl-3-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline (31.7g).
Fusing point: 166-167 ℃
MS(m/z)：498(M +)
(5) compound (31.7g) that obtains in (4) in the above under ice-cooling adds trifluoroacetic acid (60ml), and stirs the mixture 1 hour.Concentrated reaction solution under reduced pressure, and product is dissolved in the chloroform, neutralize with triethylamine.With saturated sodium bicarbonate aqueous solution and saturated brine purging compound,, and under reduced pressure concentrate by dried over mgso.Dissolved residue in toluene (350ml), and under refluxing heated mixt 3 hours.By the evaporative removal solvent, by filtering collecting precipitation to produce 8 with ethyl acetate, 9-dimethoxy-6-phenyl-2,3,11,11a-tetrahydrochysene-6H-pyrazine be [1,2-b] isoquinoline 99.9-1 also, 4-diketone (20.6g).
Fusing point: 265-267 ℃
MS(m/z)：352(M +)
(6) under nitrogen atmosphere, with ice-cooled borine-methyl-sulfide mixture (22.7ml), and the suspension of compound (20g) in tetrahydrofuran (THF) (500ml) of acquisition in wherein dripping (5) in the above.Heated mixt spends the night under refluxing, to wherein adding 6M hydrochloric acid (50ml), under reduced pressure by the evaporative removal solvent.Dilute residue with chloroform, wash,, and under reduced pressure concentrate by dried over mgso with aqueous sodium hydroxide washes.By silica gel column chromatography (elutriant; Chloroform: the residue of purifying generation methyl alcohol=9: 1).The dissolution of crystals that produces in chloroform and methanol mixture, and is added 4M hydrochloric acid in the ethyl acetate toward the there, by vapourisation under reduced pressure removal solvent.By filtering collecting precipitation with ethanol producing 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 dihydrochloride (7.6g) also.
Fusing point: 220-224 ℃ (decomposition)
MS(m/z)：324(M +)
(7) with 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine also [1,2-b] isoquinoline 99.9 dihydrochloride (compound that obtains in embodiment 1-(6)) (2g) is dissolved in N, in the dinethylformamide (10ml), to wherein adding salt of wormwood (2.8g) and bromotoluene (0.7ml), at room temperature stirred the mixture 3 hours.With chloroform diluting reaction solution,,, and under reduced pressure concentrate by dried over mgso with the saturated sodium bicarbonate aqueous solution washing.To precipitate (1.2g) and be dissolved in the chloroform,, remove solvent by vapourisation under reduced pressure to the 4M hydrochloric acid that wherein adds in the ethyl acetate.Recrystallized product to be producing 8 from ethanol, 9-dimethoxy-2-benzyl-6-phenyl-1,3,4,6,11, and 11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 dihydrochloride (1.2g) also.
Fusing point: 198-203 ℃ (decomposition)
MS(m/z)：414(M +)
Embodiment 2
(1) with 2-amino-3-(3, the 4-Dimethoxyphenyl) ethyl propionate (compound that obtains in embodiment 1-(1)) (15.2g), 4-isopropoxy phenylformic acid (10.8g), be dissolved in the methylene dichloride (120ml) with I-hydroxybenzotriazole monohydrate (9.2g), and under ice-cooling to wherein adding 1,3-dicyclohexylcarbodiimide (12.4g) at room temperature stirs the mixture and spends the night.Remove undissolved material by filtering,,, and under reduced pressure concentrate by dried over mgso with saturated sodium bicarbonate aqueous solution and saturated brine wash filtrate.Crystal by filtering collecting precipitation with ethyl acetate is to produce 3-(3, the 4-Dimethoxyphenyl)-2-{[4-(isopropoxy)-phenyl] carbonylamino } ethyl propionate.
Fusing point: 126-128 ℃
MS(m/z)：415(M +)
(2) to handle compound of acquisition in top (1) with generation 6-[4-(isopropoxy)-phenyl with extremely-(6) the similar method of embodiment 1-(3)]-8,9-dimethoxy-1,3,4,6,11,11a-six hydrogen-2H-pyrazine is [1,2-b]-isoquinoline 99.9 dihydrochloride (1g) also.
Fusing point: 180-185 ℃ (decomposition)
MS(m/z)：382(M +)
Embodiment 3-8
With with embodiment 1-(1) to-(6) or embodiment 2 similar methods handle corresponding initial compounds with compound listed in the generation table 1.
Table 1
Figure C20051010636700201
*: dihydrochloride
Embodiment 9-11
With with embodiment 1 in similarly method handle corresponding initial compounds with compound listed in the generation table 2.
Table 2
*: dihydrochloride
Embodiment 12
With 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine also [1,2-b] isoquinoline 99.9 (compound that obtains in embodiment 1-(6)) (3.2g) is dissolved in the methylene dichloride (20ml), adds chloromethyl methyl-sulfide (8.4ml) in addition, triethylamine (3.5ml) and 4-(dimethylamino) pyridine (61mg), and at room temperature stir the mixture and spend the night.With saturated sodium bicarbonate aqueous solution washing reaction solution, and under reduced pressure concentrate.By silica gel column chromatography (elutriant; Chloroform: ethyl acetate=9: the 1) residue of purifying generation.The precipitation (115mg) that produces is dissolved in the chloroform, and, removes solvent by vapourisation under reduced pressure to the 4M hydrochloric acid that wherein adds in the ethyl acetate.The recrystallization residue to be producing 8 from ethanol, 9-dimethoxy-2-(methylthiomethyl)-6-phenyl-1,3,4,6,11, and 11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 dihydrochloride (60mg) also.
Fusing point: 217-220 ℃ (decomposition)
MS(m/z)：384(M +)
Embodiment 13
(1) with 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine also [1,2-b] isoquinoline 99.9 (compound that obtains in embodiment 1-(6)) (1.6g) is dissolved in N, in the dinethylformamide (10ml), to wherein adding salt of wormwood (0.8g) and methyl bromoacetate (0.5ml), at room temperature stir the mixture and spend the night.With chloroform diluting reaction solution,,, and under reduced pressure concentrate by dried over mgso with the saturated sodium bicarbonate aqueous solution washing.By silica gel column chromatography (elutriant; Chloroform: ethyl acetate=9: 1) residue that produces of purifying to be producing 8,9-dimethoxy-2-methoxycarbonyl methyl-6-phenyl-1,3,4,6,11, and 11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 (940mg) also.
Fusing point: 110-113 ℃
MS(m/z)：396(M +)
(2) compound (920mg) that will be in the above obtains in (1) is dissolved in the tetrahydrofuran (THF) (20ml), to wherein adding 2 M aqueous sodium hydroxide solutions (1.3ml), at room temperature stirs the mixture 3 hours.With 2M hydrochloric acid neutralise mixt, and by vapourisation under reduced pressure removal solvent.Use the chloroform extraction residue,,, and under reduced pressure concentrate by dried over mgso with the saturated brine washing.The precipitation (639mg) that produces is dissolved in the chloroform, adds the 4M hydrochloric acid in the ethyl acetate in addition, and remove solvent by vapourisation under reduced pressure.The recrystallization residue to be producing 8 from ethanol, 9-dimethoxy-2-carboxymethyl-6-phenyl-1,3,4,6,11, and 11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 dihydrochloride (550mg) also.
Fusing point: 214-217 ℃ (decomposition)
MS(m/z)：382(M +)
Embodiment 14
With 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine also [1,2-b] isoquinoline 99.9 (in embodiment 1-(6) obtain compound) (1.6g) is dissolved in the methylene dichloride (10ml), and under ice-cooling other adding triethylamine (0.8ml) and Benzoyl chloride (0.6ml), stirred the mixture 30 minutes.With saturated sodium bicarbonate aqueous solution washing reaction solution,, and under reduced pressure concentrate by dried over mgso.By silica gel column chromatography (elutriant; Chloroform: ethyl acetate=9: 1) purifying residue.The residue that produces is dissolved in the chloroform,, removes solvent by vapourisation under reduced pressure to the 4M hydrochloric acid that wherein adds in the ethyl acetate.Crystallized product from ethyl acetate, by filter collecting the crystal that obtains like this producing 8,9-dimethoxy-2-benzoyl-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 dihydrochloride (656mg) also.
Fusing point: 229-233 ℃ (decomposition)
MS(m/z)：428(M +)
Embodiment 15
Handle corresponding initial compounds to produce with method similar to Example 14 as compound listed in the table 3.
Table 3
Figure C20051010636700231
*: hydrochloride
Embodiment 16
(1) with 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine also [1,2-b] isoquinoline 99.9 (in embodiment 1-(6) obtain compound) (1.6g) is dissolved in the methylene dichloride (10ml), and under ice-cooling other adding triethylamine (0.8ml) and benzyloxy Acetyl Chloride 98Min. (0.8ml), stirred the mixture 30 minutes.With saturated sodium bicarbonate aqueous solution washing reaction solution,, and under reduced pressure concentrate by dried over mgso.By silica gel column chromatography (elutriant; Chloroform: ethyl acetate=9: 1) residue that produces of purifying to be producing 8,9-dimethoxy-2-benzyloxy ethanoyl-6-phenyl-1,3,4,6,11, and 11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 (1.1g) also.
Fusing point: 100-103 ℃
MS(m/z)：472(M +)
(2) compound (1.1g) that obtains in (1) in the above adds thioanisole (274 μ l) and trifluoroacetic acid (20ml), and at room temperature stirs the mixture 2 hours.Concentrated reaction solution under reduced pressure, and residue is dissolved in the chloroform, with the saturated sodium bicarbonate aqueous solution washing,, and under reduced pressure concentrate by dried over mgso.By silica gel column chromatography (elutriant; Chloroform: purifying residue acetone=9: 1) is dissolved in the residue (447mg) that produces in the chloroform.4M hydrochloric acid in mixture adding ethyl acetate, and vapourisation under reduced pressure solvent.The recrystallization residue to be producing 8 from ethanol, 9-dimethoxy-2-hydroxyacetyl-6-phenyl-1,3,4,6,11, and 11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline hydrochloride (1.1g) also.
Fusing point: 210-214 ℃ (decomposition)
MS(m/z)：382(M +)
Embodiment 17
(1) with the 2-[(tert.-butoxy) carbonylamino] acetate (1g) is dissolved in the tetrahydrofuran (THF) (4ml), under-20 ℃, to wherein dripping triethylamine (0.8ml) and isobutyl chlorocarbonate (0.8ml), and under-10 ℃, stirred the mixture 5 minutes.Drip 8 to mixture, 9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine is (1.6g) suspension in methylene dichloride (15ml) of [1,2-b] isoquinoline 99.9 (in embodiment 1-(6) obtain compound) also, at room temperature stirs the mixture and spend the night.Concentrated reaction solution under reduced pressure, and use dichloromethane extraction.Wash extraction liquid with saturated sodium bicarbonate aqueous solution,, and under reduced pressure concentrate by dried over mgso.By silica gel column chromatography (elutriant; Chloroform: ethyl acetate=4: 1) residue that produces of purifying to be producing 8,9-dimethoxy-2-(tertbutyloxycarbonyl) glycyl-6-phenyl-1,3,4,6,11, and 11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 (872mg) also.
Fusing point: 81-84 ℃
MS(m/z)：481?(M +)
(2) compound (241mg) that obtains in (1) in the above adds trifluoroacetic acid (0.5ml), and at room temperature stirs the mixture 1 hour.Be added in 4M hydrochloric acid in the ethyl acetate to mixture, and concentrated reaction solution under reduced pressure.Add toluene to residue, and enriched mixture once more under reduced pressure.The residue that recrystallization produces from the mixed solvent of ethanol and ethyl acetate, producing 8,9-dimethoxy-2-glycyl-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 dihydrochloride (190mg) also.
Fusing point: 228-233 ℃ (decomposition)
MS(m/z)：381(M +)
Embodiment 18
With 6,7-dimethoxy-1-(1-hydroxyl pyridin-4-yl)-2,3-two (acetoxyl methyl)-naphthalene (2.23g) is suspended in the diacetyl oxide (5ml), and under ice-cooling to wherein adding hydroresorcinol (0.71g).At room temperature stir the mixture and spend the night, and reacted 6 hours in addition down at 90 ℃.The reaction soln of brown is cooled to room temperature, and under reduced pressure concentrates.Add sodium bicarbonate aqueous solution to residue, and use the ethyl acetate extraction mixture.With salt water washing organic layer,, and concentrate by dried over mgso.By silica gel column chromatography (elutriant; Chloroform: acetone=10: 1) the purifying residue is to produce raw product (1.0g), and it is further by Chromatron (solvent; Chloroform: purifying acetone=10: 1), and from diethyl ether crystallization to produce 6,7-dimethoxy-1-[2-(1,3-dioxo hexanaphthene-2-yl) pyridin-4-yl]-2,3-two (acetoxyl methyl)-naphthalene (580mg).
Fusing point: 210-213 ℃
Embodiment 19
The compound (440mg) that will obtain in embodiment 18 is suspended in the methyl alcohol (3ml), and under ice-cooling, add sodium methylate in addition (28% methanol solution, 0.495ml).At room temperature stirred the mixture 30 minutes, during mixture be dissolved in the solution, but produce crystal settling thereafter.Use ice-cooled reaction soln, and its pH value is adjusted into pH4 with 1M hydrochloric acid.By filtering the crystal of collecting precipitation, wash with water to produce 6,7-dimethoxy-1-[2-(1,3-dioxo hexanaphthene-2-yl) pyridin-4-yl]-2,3-two (methylol)-naphthalene (320mg).
Fusing point:＞220 ℃
Experiment
Experiment 1:PDE4 suppresses active
(preparation of partially purified PDE4 sample)
The homogenate of the centrifugal lung of extracing from the Hartley male guinea pig, the supernatant liquor classification that produces by the anion-exchange chromatography slurry.The fraction that satisfies following condition 1 to 4 is merged so that the partial purification sample of phosphodiesterase 4 to be provided.
Condition:
(1) has cAMP-selective hydrolysis activity;
(2) described cAMP hydrolytic activity is not subjected to the influence of cGMP;
(3) described activity is not subjected to the inhibition of CI-930, and CI-930 is the inhibitor of PDE3 optionally; With
(4) described activity is subjected to the strongly inhibited of Rolipram, and Rolipram is the inhibitor of PDE4 optionally.
(PDE4 determination of activity)
Method (reference rings Nucleotide progress, the 10th volume, Raven press, New York, 69-92 page or leaf, 1979) according to the Thompson that contains some modification etc. is measured in the following manner.At first, (100 μ l) puts into glass test tube with partially purified PDE4 sample, and described PDE4 sample is used 50mM Tris-HCl damping fluid (pH8.0) dilution so that total substrate of about 10% can be hydrolyzed in advance.Add reaction buffer (50mM Tris-HCl, pH8.0,12.5mMMgCl to test tube 2, 10mM 2 mercapto ethanol, 200 μ l), to the solution that wherein adds the test compounds in methyl-sulphoxide as follows (100 times of dilutions, 5 μ l).With test tube 30 ℃ of preincubation 5 minutes, to wherein adding 2.5 μ M[ 3H] cAMP (3.7 kBq/200 μ l), reaction beginning (final concentration: 50mMTris-HCl, pH8.0,5mM MgCl 2, the 4mM 2 mercapto ethanol).After 30 ℃ of reactions in following 30 minutes, by test tube being transferred to cancellation reaction in the boiling water bath.After 90 seconds, test tube is transferred in the ice-water bath to reduce the temperature of reaction soln.After 30 ℃ of preincubation 5 minutes, (1mg/ml 100ul) adds test tube, and mixture was 30 ℃ of reactions 30 minutes with snake venom.By to wherein adding methyl alcohol (500 μ l) cancellation reaction, and reaction soln (1ml) is carried in (trade(brand)name: Dowex 1 * 8 is by Sigma preparation, 200 μ l) on the Dowex resin column.Then, with methyl alcohol (1ml) washing Dowex resin.Reaction soln is by pillar and merge the washes of post, measures its radioactivity.
In the blank group, only add damping fluid and do not have the enzyme sample, and in control group, add the enzyme sample, but only add methyl-sulphoxide rather than test compounds.The inhibiting rate of assessment and control group every kind of test compounds relatively.The IC of every kind of test compounds is assessed in use from the inhibiting rate under 3 or more concentration according to 4 parameter logarithmic equations of regression analysis 50Value.
(test compounds)
Compd A: 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine be [1,2-b] isoquinoline 99.9 also
Compd B: 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine be [1,2-b] isoquinoline 99.9 dihydrochloride also
Compound C: (6S, 11aS)-8,9-dimethoxy-6-phenyl dimethoxy-1,3,4,6,11,11a-six hydrogen-2H-pyrazine be [1,2-b] isoquinoline 99.9 dihydrochloride also
(result)
The PDE4 of every kind of test compounds suppresses active (IC 50) be 0.004 μ M.
Experiment 2: to the inhibition activity of antigen inductive bronchoconstriction
(step)
With anti-rabbit ovalbumin antiserum(antisera) (0.25mg/kg body weight, intravenously) passive sensitization Hartley male guinea pig (n=2).Next day, use Chloralosane (1 20 mg/kg, intravenously) anaesthetized guinea pig, and tracheostomy tube is inserted animal.Under artificial respiration, use fixedly animal of Tricuran (5mg/kg, intravenously).At administration of antigens (ovalbumin; 30 μ g/kg, intravenously) 2 minutes before with (1mg/kg) intravenous administration animal of test compounds (8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine be [1,2-b] isoquinoline 99.9 dihydrochloride also).By the Konzett-Roessler method (Naunyn-Schmeideberg ' s Archiv fur Experimentelle Pathologie undPharmakologie, the 195th volume, the 71st page, 1940) the assessment test compounds is to the influence (to the inhibition activity of bronchoconstriction) of tracheae.In control group, only antigen is administered to animal (n=2).
(result)
Test compounds is 84% to the inhibition activity (promptly being used the inhibiting rate of inductive bronchoconstriction by antigen) of bronchoconstriction.
Preparation
Preparation 1
(1) 2-amino-3-(3,4-dihydro phenyl) propionic acid (98.6g) is dissolved in the formic acid (900ml), adds diacetyl oxide (300ml) in addition, and at room temperature stirred the mixture 3 hours.Concentrated reaction solution under reduced pressure adds distilled water to residue, and enriched mixture once more under reduced pressure.Residue is dissolved in the distilled water (150ml), to wherein adding 10M aqueous sodium hydroxide solution (150ml) and methyl-sulfate (95ml).In addition, in 30 fens clockwise mixtures, divide to add methyl-sulfate (285ml altogether) three times, during drip 10M aqueous sodium hydroxide solution (290ml), temperature of reaction is remained below 40 ℃, and the pH value is remained on pH5-9.At room temperature stir the mixture and spend the night, add 10M aqueous sodium hydroxide solution (50ml) in addition, at room temperature stirred 30 minutes.With sulfuric acid the pH value of mixture is adjusted to pH2, and to wherein adding ethyl acetate.By the dried over mgso organic layer, and under reduced pressure concentrate.Residue is suspended in the ethanol (1300ml), and under ice-cooling to dripping acetyl chloride (280ml) wherein.At room temperature stirred the mixture 3 days.Remove solvent by vapourisation under reduced pressure, to wherein adding methylene dichloride.Wash organic layer with wet chemical,, and under reduced pressure concentrate to produce buttery 2-amino-3-(3, the 4-Dimethoxyphenyl) ethyl propionate (111g) by dried over mgso.
MS(m/z)：253(M +)
(2) compound (111g) and the triethylamine (73.6ml) that obtains in top (1) is dissolved in the methylene dichloride (300ml), under ice-cooling to wherein dripping Benzoyl chloride (51.1ml).Saturated sodium bicarbonate aqueous solution is added mixture, and wash organic layer,, and under reduced pressure concentrate by dried over mgso with saturated brine.Crystal by filtering collecting precipitation with diethyl ether is to produce 3-(3, the 4-Dimethoxyphenyl)-2-(phenylcarbonyl group amino) ethyl propionate (144g).
Fusing point: 82-83 ℃
MS(m/z)：357(M +)
(3) compound (71.5g) that obtains in top (2) is dissolved in the phosphoryl chloride (200ml), heated mixt spends the night under refluxing.The vapourisation under reduced pressure phosphoryl chloride dilutes residue with methylene dichloride.Use the wet chemical purging compound,, and under reduced pressure concentrate by dried over mgso.Dissolved residue in ethanol, to wherein adding concentrated hydrochloric acid (20ml), and enriched mixture under reduced pressure.Residue is dissolved in the methyl alcohol (200ml),, under hydrogen pressure (3 normal atmosphere), at room temperature stirred the mixture 4 hours to wherein adding platinum dioxide (1g).By filter removing undissolved material, and concentrated filtrate under reduced pressure.Residue is dissolved in the chloroform,,, and under reduced pressure concentrates by dried over mgso with saturated sodium bicarbonate aqueous solution and saturated brine washing.Crystal by filtering collecting precipitation is to produce 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, ethyl ester (54.4g).
Fusing point: 215-217 ℃ (decomposition)
MS(m/z)：341(M +)
(4) with the 2-[(tert.-butoxy) carbonylamino] acetate (21.6g) is dissolved in the tetrahydrofuran (THF) (75ml), and drip triethylamines (18.7ml) and isobutyl chlorocarbonates (17.4ml) down in addition at-20 ℃, and under-10 ℃, stirred the mixture 5 minutes.Drip the suspension of compound (38.2g) in tetrahydrofuran (THF) (110ml) of acquisition in (3) in the above to mixture, at room temperature stir the mixture and spend the night.Concentrated reaction solution under reduced pressure, and use chloroform extraction.With saturated sodium bicarbonate aqueous solution and saturated brine washing extraction liquid,, and under reduced pressure concentrate by dried over mgso.Crystallized product from diethyl ether, the crystal of collecting generation by filtration is to produce the 2-{2-[(tert.-butoxy) carbonylamino] ethanoyl }-6,7-dimethoxy-1-phenyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, ethyl ester (31.7g).
Fusing point: 166-167 ℃
MS(m/z)：498(M +)
(5) compound (31.7g) that obtains in (4) in the above under ice-cooling adds trifluoroacetic acid (60ml), and stirs the mixture 1 hour.Concentrated reaction solution under reduced pressure, and product is dissolved in the chloroform, neutralize with triethylamine.With saturated sodium bicarbonate aqueous solution and saturated brine purging compound,, and under reduced pressure concentrate by dried over mgso.Dissolved residue in toluene (350ml), and under refluxing heated mixt 3 hours.Remove solvent by vapourisation under reduced pressure, by filtering collecting precipitation to produce 8 with ethyl acetate, 9-dimethoxy-6-phenyl-2,3,11,11a-tetrahydrochysene-6H-pyrazine be [1,2-b] isoquinoline 99.9-1 also, 4-diketone (20.6g).
Fusing point: 265-267 ℃
MS(m/z)：352(M +)
(6) under nitrogen atmosphere, with ice-cooled borine-methyl-sulfide mixture (22.7ml), and the solution of compound (20g) in tetrahydrofuran (THF) (500ml) of acquisition in wherein dripping (5) in the above.Heated mixt spends the night under refluxing, to wherein adding 6M hydrochloric acid (50ml), under reduced pressure by the evaporative removal solvent.Dilute residue with chloroform, wash,, and under reduced pressure concentrate by dried over mgso with aqueous sodium hydroxide washes.By silica gel column chromatography (elutriant; Chloroform: the residue of purifying generation methyl alcohol=9: 1).The dissolution of crystals that produces in chloroform and methanol mixture, and to the 4 M hydrochloric acid that wherein add in the ethyl acetate, is removed solvent by vapourisation under reduced pressure.By filtering collecting precipitation with ethanol producing 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine is [1,2-b] isoquinoline 99.9 dihydrochloride (7.6g) also.
Fusing point: 220-224 ℃ (decomposition)
MS(m/z)：324(M +)
Preparation 2
Use (2S)-2-amino-3-(3, the 4-dihydroxyphenyl) propionic acid (L-DOPA), repeat the step identical and produce that (6S, 11aS)-8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-six hydrogen-2H-pyrazine be [1,2-b] isoquinoline 99.9 dihydrochloride also with preparation 1.
Fusing point: 225-229 ℃ (decomposition)
MS(m/z)：324(M +)
Industrial usability
The fused-polycyclic compounds of formula of the present invention [I] or [I-C], perhaps its pharmaceutical salts has excellent PDE4 suppresses active and is used for prevention or treats various PDE4 relevant diseases, for example inflammatory and allergy The property disease, it comprises asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, idiocrasy Dermatitis, nettle rash, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, eosinocyte increases Many, psoriasis, rheumatoid arthritis, septic shock, chronic ulcerative colitis, limitation Ileitis, reperfusion injury, CGN, endotoxin shock, adult's respiratory distress is comprehensive Levy osteoarthropathy etc.
In addition, compound [I], compound [I-C] or its pharmaceutical salts, it is active component of the present invention, Have excellent bronchoconstriction and suppress active, and as the bronchoconstriction inhibitor.
In addition, compound [I], compound [I-C] or its pharmaceutical salts group that acts on accelerating union of bone fracture Compound and the composition that is used for the treatment of osteomalacia (for example osteoarthritis).

Claims (10)

1. the naphthalene compound of formula [I-B] or its pharmaceutical salts:
Figure C2005101063670002C1
Wherein, R 1And R 2Identical or different, and each has the alkoxyl group of 1-6 carbon atom naturally,
R aAnd R bIdentical or different, and each group that is selected from hydrogen atom naturally and has the acyl group of 1-6 carbon atom,
N is 3.
2. according to the compound or pharmaceutically acceptable salt thereof of claim 1, R wherein aAnd R bEach is hydrogen atom naturally.
3.6,7-dimethoxy-1-[2-(1,3-dioxo hexanaphthene-2-yl) pyridin-4-yl] and-2,3-two [methylol] naphthalene, or its pharmaceutical salts.
4. pharmaceutical composition, it comprises according to any one compound or pharmaceutically acceptable salt thereof in the claim 1 to 3 as active ingredient.
5. be used for preventing or treating the purposes of the medicine of PDE4 relative disease in preparation according to the compound of any one in the claim 1 to 3.
6. be used for preventing or treat the purposes of the medicine of inflammatory or anaphylactic disease in preparation according to the compound of any one in the claim 1 to 3.
7. according to the purposes of claim 6, wherein said inflammatory or anaphylactic disease are asthma, chronic obstructive pulmonary disease, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, anaphylaxis conjunctivitis, vernal conjunctivitis, eosinophilia, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, regional ileitis, reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome or osteoarthropathy.
8. bronchoconstriction inhibitor, it comprises according to any one compound or pharmaceutically acceptable salt thereof in the claim 1 to 3 as active ingredient.
9. the purposes that is used for accelerating union of bone fracture or is used for the treatment of the medicine of richets in preparation according to the compound of any one in the claim 1 to 3.
10. according to the purposes of claim 9, wherein richets is an osteoarthritis.
CN 200510106367 2001-08-09 2002-07-31 Fused-polycyclic compounds Expired - Fee Related CN1331857C (en)

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JP2001241502 2001-08-09
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JP2001241521 2001-08-09

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CN1331857C true CN1331857C (en) 2007-08-15

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