CN101146765A - Tetrahydronaphthalene derivatives, method for the production and the use thereof in the form of antiphlogistics - Google Patents
Tetrahydronaphthalene derivatives, method for the production and the use thereof in the form of antiphlogistics Download PDFInfo
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- CN101146765A CN101146765A CNA2006800092011A CN200680009201A CN101146765A CN 101146765 A CN101146765 A CN 101146765A CN A2006800092011 A CNA2006800092011 A CN A2006800092011A CN 200680009201 A CN200680009201 A CN 200680009201A CN 101146765 A CN101146765 A CN 101146765A
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Abstract
The invention relates to poly-substituted tetrahydronaphtalene derivatives of formula (I) and to a method for the production and the use thereof in the form of antiphlogistics.
Description
Technical field
The present invention relates to tetrahydro naphthaline derivatives, its preparation method and as the application of antiphlogiston.
Background technology
Known open chain NSAID (non-steroidal anti-inflammatory drug) in prior art (DE10038639 and WO02/10143).The anti-inflammatory action that the experiment proved that these compounds is uncorrelated with the metabolism of not expecting, and these compounds the non-steroidal glucocorticosteroid or the equally good with it effect of performance at least that are better than describing so far.
The invention provides other NSAID (non-steroidal anti-inflammatory drug).
Summary of the invention
The present invention relates to the compound of general formula (I),
Wherein
R
1And R
2Be hydrogen atom, hydroxyl, halogen atom, the optional (C that replaces independently of one another
1-C
10)-alkyl, (C
1-C
10)-alkoxyl group, (C
1-C
10)-alkylthio, (C
1-C
5)-perfluoroalkyl, cyano group, nitro or-NR
9R
9aGroup,
Or R
1And R
2Form together and be selected from group-O-(CH
2)
n-O-,-O-(CH
2)
n-CH
2-,-O-CH=CH-,-(CH
2)
N+2-,-NH-(CH
2)
N+1-,-N (C
1-C
3-alkyl)-(CH
2)
N+1-and-group of NH-N=CH-, wherein n=1 or 2, and terminal Sauerstoffatom and/or carbon atom and/or nitrogen-atoms are connected with the ring carbon atom of direct neighbor,
R
11Be hydrogen atom, hydroxyl, halogen atom, cyano group, the optional (C that replaces
1-C
10)-alkyl, (C
1-C
10)-alkoxyl group, (C
1-C
10)-alkylthio or (C
1-C
5)-perfluoroalkyl,
R
12Be hydrogen atom, hydroxyl, halogen atom, cyano group, the optional (C that replaces
1-C
10)-alkyl or (C
1-C
10)-alkoxyl group,
R
3By 1-3 hydroxyl, a 1-3 halogen atom and/or 1-3 (C
1-C
5The optional C that replaces of)-alkoxyl group
1-C
10-alkyl,
Optional (the C that replaces
3-C
7)-cycloalkyl,
The optional heterocyclic radical that replaces,
The optional aryl that replaces, or
Monocycle or bicyclic heteroaryl, it is independently from each other by one or more that following group is optional to be replaced:
Itself can be by 1-3 hydroxyl or 1-3-COOR
13The optional replacement of group
(C
1-C
5)-alkyl,
(C
1-C
5)-alkoxyl group,
Halogen atom, hydroxyl ,-NR
9R
9aGroup and
Outer methylene radical,
And optional 1-4 nitrogen-atoms and/or 1-2 Sauerstoffatom and/or 1-2 sulphur atom and/or 1-2 ketone group of containing, this group are connected with radicals X by any position and can choose wantonly in one or more positions and be hydrogenated,
R
4Be hydroxyl ,-OR
10Group or-O (CO) R
10Group,
R
5Be optional part or complete fluorizated (C
1-C
10)-alkyl, (C
3-C
7) cycloalkyl, (C
1-C
8) alkyl-(C
3-C
7) cycloalkyl, (C
2-C
8) thiazolinyl-(C
3-C
7) cycloalkyl, heterocyclic radical, (C
1-C
8) alkyl heterocyclic, (C
2-C
8)-thiazolinyl heterocyclic radical, aryl, (C
1-C
8) alkylaryl, (C
2-C
8) alkenyl aryl, (C
2-C
8)-alkynyl aryl, monocycle or bicyclic heteroaryl, it is by 1-2 ketone group, a 1-2 (C
1-C
5)-alkyl, a 1-2 (C
1-C
5)-alkoxyl group, a 1-3 halogen atom and/or 1-2 outer methylene radical chosen wantonly and replaced and contain 1-3 nitrogen-atoms and/or 1-2 Sauerstoffatom and/or 1-2 sulphur atom, (C
1-C
8) miscellaneous alkyl aryl, (C
2-C
8) thiazolinyl heteroaryl or (C
2-C
8) the alkynyl heteroaryl, this group is connected with the naphthane system by any position and can chooses wantonly in one or more positions and is hydrogenated,
R
6Be hydrogen atom, halogen atom or the optional (C that replaces
1-C
10) alkyl,
R
7And R
8Be hydrogen atom, halogen atom, the optional (C that replaces independently of one another
1-C
10)-alkyl, cyano group are (C together
1-C
10)-alkylidene group or be the optional (C that replaces with the carbon atom of naphthane system
3-C
6)-cycloalkyl ring;
Perhaps
R
6And R
7Form 5 to 8 yuan of saturated or undersaturated carbocyclic rings of condensed or heterocycle together, it is by 1-2 ketone group, a 1-2 (C
1-C
5)-alkyl, a 1-2 (C
1-C
5A)-alkoxyl group and/or 1-4 halogen atom is optional to be replaced;
R
1And R
8Form 5 to 8 yuan of saturated or undersaturated carbocyclic rings of condensed or heterocycle together, it is by 1-2 ketone group, a 1-2 (C
1-C
5)-alkyl, a 1-2 (C
1-C
5A)-alkoxyl group and/or 1-4 halogen atom is optional to be replaced,
R
9And R
9aBe hydrogen atom, (C independently of one another
1-C
5)-alkyl or-(CO)-(C
1-C
5)-alkyl,
R
10Be (C
1-C
10)-alkyl or any hydroxyl protecting group,
R
13Be hydrogen atom or (C
1-C
5)-alkyl, and
X be group-C (=O)-,-C (=S)-,-C (=O)-NH-,-C (=S)-NH-,-S (O)
m(wherein m=1 or 2) ,-C (=O)-O-,-C (=S)-O-or group-(CH
2)
p-(wherein p=1,2 or 3), if wherein X contains carbonyl or thiocarbonyl group functional group, then this functional group is connected with group-NH-in the general formula (I),
Condition is if R
3Be the optional (C that replaces
1-C
10)-alkyl, then X can not be-(CH
2)
p-group;
The compound of described general formula (I) be any stereoisomer or steric isomer mixture form or as acceptable salt of pharmacology or derivative.
The invention further relates to the preparation method of the compound of general formula as herein described (I).
The invention further relates to pharmaceutical composition, it comprises compound and one or more pharmaceutical carriers or the vehicle of one or more general formulas (I).
The invention still further relates to the application that the compound of general formula (I) is used to prepare the pharmaceutical composition with anti-inflammatory action.
The invention still further relates to the compound of general formula (IV) and the application of compound that these compounds are used to prepare above-mentioned general formula (I),
Substituent R wherein
1To R
12Has above-mentioned connotation.
Embodiment
Definition
Term halogen atom or halogen are meant fluorine, chlorine, bromine or iodine atom.Preferred fluorine, chlorine or iodine atom.
The alkyl of mentioning in the definition of general formula (I) can be a straight or branched, typical example such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl or n-pentyl, 2,2-dimethyl propyl, 2-methyl butyl or 3-methyl butyl and hexyl, heptyl, nonyl, decyl and ramose derivative by any way thereof.The alkyl that preferably contains 1-10, a 1-8 or 1-5 carbon atom.Special preferable methyl or ethyl.
Abovementioned alkyl can be by 1-5, preferred 1-3 be independently from each other hydroxyl, cyano group, nitro ,-COOR
13, (C
1-C
5)-alkoxyl group, halogen atom ,-NR
9R
9a, fluorizated (C partially or completely
1-C
3)-alkyl is optional to be replaced.Alkyl can be preferably by 1-3 halogen atom and/or 1-3 hydroxyl and/or 1-3 cyano group and/or 1-3-COOR
13Group replaces.Fluorine atom, hydroxyl, methoxyl group and/or cyano group are represented particularly preferred subgroup substituting group.
1-3 hydroxyl and/or 1-3-COOR
13Group is that another organizes particularly preferred alkyl substituent.In this respect, preferred especially hydroxyl.
The example of suitable partially or completely fluorinated alkyl is following partially or completely fluorizated group: methyl fluoride, difluoromethyl, trifluoromethyl, fluoro ethyl, 1,1-two fluoro ethyls, 1,2-two fluoro ethyls, 1,1,1-trifluoroethyl, tetrafluoro ethyl, pentafluoroethyl group.Wherein preferred trifluoromethyl or pentafluoroethyl group.The fluorizated group is also referred to as perfluoroalkyl fully.The optional reagent that uses can be bought in synthetic, or the synthetic prior art of having delivered that belongs to of corresponding reagent, or can use delivered synthetic similarly.
Thiazolinyl has the two keys of at least one C=C, can be straight or branched.The thiazolinyl that preferably has 2-8 carbon atom.
Alkynyl has at least one C ≡ C triple bond, can be straight or branched.The alkynyl that preferably has 2-8 carbon atom.
The alkoxyl group of mentioning in the definition of general formula (I) can be a straight or branched, for example can be methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy or n-pentyloxy, 2,2-dimethyl propoxy-, 2-methyl butoxy or 3-methyl butoxy.Preferred C
1-C
5-and C
1-C
3-, C
1-C
8-and C
1-C
10-alkoxyl group.Preferred especially methoxy or ethoxy.
The alkylthio of mentioning in the definition of general formula (I) can be a straight or branched, for example be methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, uncle's butylthio or positive penta sulfenyl, 2,2-dimethyl propylene sulfenyl, 2-methyl butylthio or 3-methyl butylthio.Preferred C
1-C
5-alkylthio.Preferred especially methylthio group or ethylmercapto group.
Can have the above substituting group identical of this paper on the alkyl of above-mentioned alkoxyl group and alkylthio to the substituting group of alkyl general description.The preferred substituents of alkoxyl group and alkylthio is independently from each other halogen atom (particularly fluorine and/or chlorine), hydroxyl and cyano group.
Substituting group-NR
9R
9aFor example be meant-NH
2,-NH (CH
3) ,-N (CH
3)
2,-NH (C
2H
5) ,-N (C
2H
5)
2,-NH (C
3H
7) ,-N (C
3H
7)
2,-NH (C
4H
9) ,-N (C
4H
9)
2,-NH (C
5H
11) ,-N (C
5H
11)
2,-NH (CO) CH
3, NH (CO) C
2H
5,-NH (CO) C
3H
7,-NH (CO) C
4H
9,-NH (CO) C
5H
11
Cycloalkyl is meant saturated cyclic group, and it is by one or more hydroxyl, halogen atom, (C of being selected from
1-C
5)-alkyl, (C
1-C
5)-alkoxyl group ,-NR
9R
9aGroup ,-COOR
13Group ,-optional replacement of group of CHO, cyano group, and have 3-7 ring carbon atom, for example cyclopropyl, methyl cyclopropyl, cyclobutyl, methyl cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, suberyl, methyl suberyl.
(C
1-C
8) alkyl-(C
3-C
7) cycloalkyl R
5Be meant by straight or branched (C
1-C
8The cycloalkyl (as defined above) that)-alkyl unit (as defined above) links to each other with loop systems.These examples of groups are-(CH
2)-cycloalkyl ,-(C
2H
4)-cycloalkyl ,-(C
3H
6)-cycloalkyl ,-(C
4H
8)-cycloalkyl ,-(C
5H
10)-cycloalkyl, wherein cycloalkyl is defined as mentioned above.
(C
2-C
8) thiazolinyl-(C
3-C
7) cycloalkyl R
5Be meant by straight or branched (C
2-C
8The cycloalkyl (as defined above) that)-thiazolinyl unit links to each other with loop systems.These examples of groups are-(CH=CH)-cycloalkyl ,-[C (CH
3)=CH]-cycloalkyl ,-[CH=C (CH
3)]-cycloalkyl ,-(CH=CH-CH
2)-cycloalkyl ,-(CH
2-CH=CH)-cycloalkyl ,-(CH=CH-CH
2-CH
2)-cycloalkyl ,-(CH
2-CH=CH-CH
2)-cycloalkyl ,-(CH
2-CH
2-CH=CH)-cycloalkyl ,-(C (CH
3)=CH-CH
2)-cycloalkyl ,-(CH=C (CH
3)-CH
2)-cycloalkyl.
Alkylidene group or outer alkylidene group are meant the group with 1-10 carbon atom, and it is connected with this system (ring or chain) by outer two keys.Preferred (C
1-C
5)-and (C
1-C
3)-alkylidene group, preferred especially outer methylene radical.
Heterocyclic radical is to contain one or more heteroatomic non-aromaticity cyclic groups, can be for example tetramethyleneimine, imidazolidine, pyrazolidine or piperidines.Heterocyclic radical of the present invention also comprises perhydro quinoline and perhydro isoquinoline 99.9.
For heterocyclic radical and heteroaryl, the example of suitable substituents is the substituting group from following group: the optional C that replaces
1-C
5-alkyl, hydroxyl, (C
1-C
5)-alkoxyl group ,-NR
9R
9a, halogen, cyano group ,-COOR
13,-CHO.These substituting groups can also be chosen wantonly with the nitrogen-atoms of heterocyclic radical or assorted Fang Ji and be connected; In this definition, also comprise the N-oxide compound.
Aryl among the present invention is aromaticity or the part aromaticity carbon ring group with 6 to 14 carbon atoms, and it has a ring such as phenyl or phenylene, or has a plurality of condensed ring such as naphthyl or anthryl.The example that can mention is phenyl, naphthyl, tetralyl, anthryl, indanyl and indenyl.Preferred optional phenyl and the naphthyl that replaces.
Aryl can be in any suitable position that causes stable compound by one or more be selected from hydroxyl, halogen, by 1-3 hydroxyl or-COOR
13The optional C that replaces
1-C
5-alkyl or C
1-C
5-alkoxyl group, cyano group ,-CF
3Replace with the group of nitro.
Aryl can be partially hydrogenated, therefore, substitutes except that the substituting group of above detailed description or as the substituent of above detailed description, can also have ketone group and/or outer alkylidene group.Partially hydrogenated phenyl is meant for example cyclohexadienyl, cyclohexenyl or cyclohexyl.Partially hydrogenated replacement naphthalene system is for example 1-Tetralone an intermediate of Sertraline or 2-Tetralone an intermediate of Sertraline.
(C
1-C
8) alkylaryl is by straight or branched (C
1-C
8The above-described aryl that)-alkyl unit (as defined above) is connected with loop systems.
(C
2-C
8) alkenyl aryl is by straight or branched (C
2-C
8The above-described aryl that)-thiazolinyl unit (as defined above) is connected with loop systems.
(C
2-C
8) the alkynyl aryl is by straight or branched (C
2-C
8The above-described aryl that)-alkynyl unit (as defined above) is connected with loop systems.
Monocycle or bicyclic heteroaryl can be chosen wantonly and contain 1-9 group that is selected from nitrogen-atoms, Sauerstoffatom, sulphur atom or ketone group, wherein can have maximum 4 nitrogen-atoms, maximum 2 Sauerstoffatoms, maximum 2 sulphur atoms and/or maximum 2 ketone groups.These groups can close with any subgroup and exist.Heteroaryl can be hydrogenated in one or more positions.
Bicyclic heteroaryl can be for example pyridine, pyrazine, pyrimidine, pyridazine, triazine, azepine indolizine (azaindolizine), 2H-and 4H-pyrans, 2H-and 4H-thiapyran, furans, thiophene, 1H-and 4H-pyrazoles, 1H-and 2H-pyrroles, oxazole, thiazole, furazan, 1H-and 4H-imidazoles, isoxazole, isothiazole, oxadiazole, triazole, tetrazolium, thiadiazoles.
Bicyclic heteroaryl can be a phthalidyl for example, thio phenyl phthalidyl (thiophthalidyl), indyl, pseudoindoyl, indolinyl, dihydro-iso indolyl, indazolyl, benzothiazolyl, the indoles ketone group, the indoline ketone group, the isoindole ketone group, the xylylenimine ketone group, benzofuryl, benzimidazolyl-, benzo [b] thienyl, benzo [c] thienyl, the dihydro-isoquinoline base, dihydroquinoline base; benzoxazine ketone group, the phthalazines ketone group, dihydro phthalazines ketone group, quinolyl, isoquinolyl, quinolonyl, the isoquinolone base, quinazolyl, quinoxalinyl, the cinnolines base, phthalazinyl, the dihydro phthalazinyl, 1,7-or 1, the 8-naphthyridinyl, the tonka bean camphor base, isocoumarinyl, the indolizine base, isobenzofuran-base, azaindolyl, the azepine pseudoindoyl, pyrrolo-[1,5-a] pyridyl, the furo pyridyl, the furo pyrimidyl, the furo pyrazinyl, the furo pyridazinyl, dihydro benzo furyl, dihydrofuran and pyridyl, dihydrofuran and pyrimidyl, dihydrofuran and pyrazinyl, dihydrofuran and pyridazinyl, dihydro benzo furyl.
If heteroaryl is a hydrogenant partially or completely, then the present invention includes wherein R3 and be for example THP trtrahydropyranyl, the 2H-pyranyl, the 4H-pyranyl, piperidyl, tetrahydro pyridyl, the dihydropyridine base, 1H-pyridin-2-ones base, 1H-pyridine-4-ketone group, the 4-aminopyridine base, 1H-pyridin-4-ylideneaminyl, chromanyl, different chromanyl, the thiochroman base, decahydroquinolyl, tetrahydric quinoline group, the dihydroquinoline base, 5,6,7,8-tetrahydrochysene-1H-quinoline-4-ketone group, the Decahydroisoquinolinpreparation base, tetrahydro isoquinolyl, the dihydro-isoquinoline base, 3,4-dihydro-2H-benzo [1,4] oxazinyl, 1,2-dihydro [1,3] benzoxazine-4-ketone group, 3,4-dihydrobenzo [1,4] oxazine-4-ketone group, 3,4-dihydro-2H-benzo [1,4] thiazinyl, 4H-benzo [1,4] thiazinyl, 1,2,3,4-tetrahydroquinoxaline base, 1H-cinnolines-4-ketone group, 3H-quinazoline-4-one base, 1H-quinazoline-4-one base, 3,4-dihydro-1H-quinoxaline-2-ketone group, 2,3-1,2,3,4-tetrahydrochysene [1,5] naphthyridinyl, dihydro-1H-[1,5] naphthyridinyl, 1H-[1,5] naphthyridines-4-ketone group, 5,6,7,8-tetrahydrochysene-1H-naphthyridines-4-ketone group, 1,2-dihydro pyrido [3,2-d] [1,3] oxazine-4-ketone group, octahydro-1H-indyl, 2,3-dihydro-1H-indyl, octahydro-2H-pseudoindoyl, 1,3-dihydro-2H-pseudoindoyl, 1,2-dihydro-indazol base, 1H-pyrrolo-[2,3-b] pyridyl, 2,3-dihydro-1H-pyrrolo-[2,3-b] pyridyl, 2, the compound of the formula (I) of 2-dihydro-1H-pyrrolo-[2,3-b] pyridine-3-ketone group.
Monocycle or bicyclic heteroaryl can be selected from by 1-3 hydroxyl or 1-3-COOR by one or more
13The optional C that replaces of group
1-C
5-alkyl or C
1-C
5The substituting group of-alkoxyl group, halogen atom and/or outer methylene radical is optional to be replaced.If possible, then substituting group can also be chosen wantonly directly and is connected with heteroatoms (as nitrogen-atoms).The present invention also comprises the N-oxide compound.
(C
1-C
8) miscellaneous alkyl aryl is by straight or branched (C
1-C
8The above-described heteroaryl that)-alkyl unit (as defined above) is connected with loop systems.
(C
2-C
8) the thiazolinyl heteroaryl is by straight or branched (C
2-C
8The above-described heteroaryl that)-thiazolinyl unit (as defined above) is connected with loop systems.
(C
2-C
8) the alkynyl heteroaryl is by straight or branched (C
2-C
8The above-described heteroaryl that)-alkynyl unit (as defined above) is connected with loop systems.
(C
1-C
8) alkyl heterocyclic is by straight or branched (C
1-C
8The above-described heterocyclic radical that)-alkyl unit (as defined above) is connected with loop systems.
(C
2-C
8) the thiazolinyl heterocyclic radical is by straight or branched (C
2-C
8The above-described heterocyclic radical that)-thiazolinyl unit (as defined above) is connected with loop systems.
(C
2-C
8) the alkynyl heterocyclic radical is by straight or branched (C
2-C
8The above-described heterocyclic radical that)-alkynyl unit (as defined above) is connected with loop systems.
Suitable hydroxyl protecting group all is a conventional hydroxyl protecting group, particularly organic C well known by persons skilled in the art
1-C
10The silicon ether of acid or ester, C
1-C
5Ether, benzyl oxide or benzyl ester.The detailed description of conventional hydroxyl protecting group is referring to T.W.Greene, P.G.M.Wuts " Protective Groupsin Organic Synthesis ", 2nd edition, John Wiley﹠amp; Sons, 1991).Protecting group preferably alkyl-, aryl-or the silyl that mix to replace by alkylaryl, for example trimethyl silyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS) or triisopropyl silyl (TIPS) or other conventional hydroxyl protecting group (for example methoxymethyl, methoxy ethoxy methyl, ethoxyethyl group, tetrahydrofuran base, THP trtrahydropyranyl group).
Because the existence of asymmetric center, the compound of general formula of the present invention (I) exists as steric isomer.The present invention relates to all possible steric isomer as racemoid and enantiopure form.The term steric isomer comprise also that therefore that steric isomer wherein of the present invention may exist and the present invention also relate to diastereomer and the regional isomer and the tautomer (as the keto-enol tautomerism body) that might exist.
Compound of the present invention can also be the form with the acceptable anionic salt of pharmacology, for example is the form of hydrochloride, vitriol, phosphoric acid salt, Pivalate, maleate, fumarate, tartrate, benzoate, mesylate, Citrate trianion or succinate.
The present invention also comprises the suitable derivative or the prodrug of pharmacology of the compound of general formula (I).Derivative or prodrug be meant the compound of general formula (I) for example or in vivo metabolism be ester, ether or the acid amides of other compound of the compound of general formula (I).Suitable compound is referring to for example HansBundgaard (writing), Design of Prodrugs, Elsevier, Amsterdam1985.
Preferred embodiment
A subgroup of the compound of general formula of the present invention (I) is R wherein
7And R
8Be hydrogen atom, halogen atom, the optional (C that replaces independently of one another
1-C
10)-alkyl, cyano group are (C together
1-C
10)-alkylidene group or be the optional (C that replaces with the carbon atom of naphthane system
3-C
6The compound of)-cycloalkyl ring.
Another subgroup of the compound of general formula of the present invention (I) is R wherein
6And R
7Form 5 to 8 yuan of saturated or undersaturated carbocyclic rings of condensed or heterocyclic compound together, described carbocyclic ring or heterocycle are by 1-2 ketone group, a 1-2 (C
1-C
5)-alkyl, a 1-2 (C
1-C
5A)-alkoxyl group and/or 1-4 halogen atom is optional to be replaced.
Another subgroup of the compound of general formula of the present invention (I) is R wherein
1And R
8Form 5 to 8 yuan of saturated or undersaturated carbocyclic rings of condensed or heterocyclic compound together, described carbocyclic ring or heterocycle are by 1-2 ketone group, a 1-2 (C
1-C
5)-alkyl, a 1-2 (C
1-C
5A)-alkoxyl group and/or 1-4 halogen atom is optional to be replaced.
Another subgroup of the compound of general formula of the present invention (I) is R wherein
1And R
2Be hydrogen atom, hydroxyl, halogen atom, the optional (C that replaces independently of one another
1-C
10)-alkyl, (C
1-C
10)-alkoxyl group, (C
1-C
10)-alkylthio, (C
1-C
5)-perfluoroalkyl, cyano group, nitro or-NR
9R
9aThe compound of group.
Another subgroup of the compound of general formula of the present invention (I) is R wherein
1And R
2Form together and be selected from group-O-(CH
2)
n-O ,-O-(CH
2)
n-CH
2-,-O-CH=CH-,-(CH
2)
N+2-,-NH-(CH
2)
N+1-,-N (C
1-C
3-alkyl)-(CH
2)
N+1-and-compound of the group of NH-N=CH-, wherein n=1 or 2, and terminal Sauerstoffatom and/or carbon atom and/or nitrogen-atoms are connected with the ring carbon atom of direct neighbor.
The compound of preferred general formula (I) be wherein X be group-C (=O)-,-C (=O)-NH-,-SO
2-or-CH
2The compound of-group.
Another compound of organizing preferred general formula (I) is R wherein
4Be hydroxyl or group-OR
10Compound.Especially preferred R wherein
4It is the compound of hydroxyl.
Another compound of organizing preferred general formula (I) is R wherein
5Be (C
1-C
5)-alkyl or fluorizated (C partially or completely
1-C
5)-alkyl, aryl, (C
1-C
8) alkylaryl, (C
2-C
8) alkenyl aryl, (C
3-C
7) cycloalkyl, (C
1-C
8) alkyl (C
3-C
7) cycloalkyl or (C
2-C
8) thiazolinyl (C
3-C
7) compound of cycloalkyl.The preferred compound of this respect is R wherein
5Be (C
1-C
5)-alkyl or fluorizated (C partially or completely
1-C
5The compound of)-alkyl.The particularly preferred compound of this respect is R wherein
5It is the compound of trifluoromethyl or pentafluoroethyl group.
Another compound of organizing preferred general formula (I) is R wherein
7Be halogen atom or the optional methyl that replaces or the compound of ethyl.
Another compound of organizing preferred general formula (I) is R wherein
7And R
8Each methyl naturally, or form the compound of cyclopropyl with the carbon atom of naphthane system.Particularly preferred compound is R wherein
7And R
8Each is the compound of methyl naturally.
Another compound of organizing preferred general formula (I) is R wherein
3Be the optional aryl that replaces or the compound of heteroaryl.The particularly preferred compound of this respect is that wherein aryl or heteroaryl are selected from naphthyl, benzofuryl, pyrazolo [1,5-a] pyridyl, phenyl, phthalidyl, pseudoindoyl, indolinyl, dihydro-iso indolyl, the dihydro-isoquinoline base, thio phenyl phthalidyl; benzoxazine ketone group, the phthalazines ketone group, quinolyl, isoquinolyl, quinolonyl, the isoquinolone base, indazolyl, benzothiazolyl, chromanyl, different chromanyl, quinazolyl, quinoxalinyl, the cinnolines base, phthalazinyl, 1,7-or 1, the 8-naphthyridinyl, the indoline ketone group, the xylylenimine ketone group, benzimidazolyl-or indyl.The particularly preferred group of this respect is naphthyl, benzofuryl, quinoxalinyl and pyrazolo [1, a 5-a] pyridyl.
A subgroup of the compound of general formula (I) is a substituent R wherein
11And R
12Be hydrogen atom, halogen atom, particularly fluorine independently of one another, the compound of cyano group or methoxyl group.
In preferred subgroup, substituent R
11And R
12Each is hydrogen atom naturally.
The compound of the general formula (I) of particularly preferred one group of above definition is R wherein
1, R
2, R
11And R
12Be hydrogen atom, halogen atom, hydroxyl, the optional (C that replaces independently of one another
1-C
10)-alkyl or (C
1-C
10)-alkoxyl group, R
3Be optional aryl or the heteroaryl that replaces, R
4Be hydroxyl ,-OR
10Group or-O (CO) R
10Group, R
5Be optional part or complete fluorizated (C
1-C
10) alkyl, R
6Be hydrogen atom, halogen atom or the optional (C that replaces
1-C
10)-alkyl, R
7And R
8Be the optional (C that replaces independently of one another
1-C
10)-alkyl, be (C together
1-C
10)-alkylidene group or be the optional (C that replaces with the carbon atom of naphthane system
3-C
6)-cycloalkyl ring, R
10Be (C
1-C
10)-alkyl, and X be group-C (=O)-,-C (=O)-NH-,-S (O)
m-(wherein m equals 1 or 2) or-(CH
2)
p-(wherein p equal'ss 1,2 or 3) compound.
The compound of the general formula (I) of very particularly preferably one group above definition is R wherein
1And R
2Be hydrogen atom, hydroxyl or methoxyl group independently of one another, R
11And R
12Each is hydrogen atom naturally, R
3Be naphthyl, benzofuryl, quinoxalinyl or pyrazolo [1,5-a] pyridyl, R
4Be hydroxyl, R
5Be trifluoromethyl, R
6Be hydrogen atom, R
7And R
8Each methyl naturally, and X be group-C (=O)-,-C (=O)-NH-,-SO
2-and-CH
2-one of compound.
Above-mentioned subgroup and point out with regard to its general and/or specific connotation that as preferred substituted every kind further may make up and think equally and comprise within the scope of the present invention.
The preparation method
The compound of general formula of the present invention (I) can obtain by several different methods.Preparation method described below is a part of the present invention equally.
Unless otherwise indicated, substituting group and top " summary of the invention " part of using during following method is described comprise that the definition of pointing out in " embodiment " part has identical connotation.
The feature of a kind of method (method A) of the compound that is used to prepare general formula (I) of the present invention is
A) randomly add inorganic or organic acid or Lewis acid and make the open chain carbonyl compound of general formula (II) be cyclized into the compound of general formula (III),
B) make the compound of general formula (III) be converted into the compound of general formula (IV) by methods known in the art with the amino hydroxyl that substitutes,
With
C) be selected from general formula R
3-X-Nu (wherein Nu is the freestone group), R
3-N=C=O or R
3The compound of-N=C=S reaction, and randomly substitute carbonylic oxygen atom by methods known in the art with sulphur atom subsequently makes the compound of general formula (IV) be converted into the compound of general formula (I).
Substituent R
1To R
12Has above-indicated connotation.
For example can make the compound of general formula (III) be converted into corresponding trinitride by methods known in the art (nucleophilic substitution) with the amino hydroxyl that substitutes in the above step b), the primary amine that trinitride is reduced to general formula (IV) then under appropriate condition be finished.
Introduce amino another kind may comprise the compound that makes general formula (III) and Burgess reagent react (Tetrahedron Lett.2002,43,3887-3890), the heterocycle of gained is ruptured, this step can be finished by methods known in the art.
What describe in the step c) is known in the art with the optional alternative carbonylic oxygen atom of sulphur, can realize by for example reacting with La Weisong reagent or thiophosphoric anhydride.
The compound R that uses in the step c)
3The suitable example of freestone group Nu among the-X-Nu is halogen atom or leavings group for example acetic ester, tosylate, methanesulfonates or trifluoromethanesulfonic acid ester group.Therefore, R
3-X-Nu for example belongs to the halogenide class of carboxylic acid, sulfonic acid or-sulfinic acid or the ester of these sour mixed anhydride classes and chloroformic acid, toluenesulphonic acids, methylsulfonic acid and trifluoromethanesulfonic acid.
The another kind of method (method B) that is used to prepare the compound of general formula (I) of the present invention comprises compound and the general formula R that makes above-mentioned general formula (IV)
3The compound reaction of-CHO, and the imines of reduction gained.
At last, the another kind of method (method C) that is used to prepare the compound of general formula (I) of the present invention comprises compound and phosgene or the thiophosgene reaction that makes general formula (IV), makes isocyanic ester or the lsothiocyanates and the general formula R of gained subsequently
3-OH or R
3-NH
2Compound reaction, obtain the compound of general formula (I), wherein X have described in the claim 1-C (=O)-NH-,-C (=S)-NH-or-C (=O)-connotation of O-.
The feature of the another kind of method (method D) of the compound that is used to prepare general formula (I) of the present invention is
A) make the compound and the general formula R of general formula (VI)
5-C (=O)-COOR
13The alpha-keto carboxylic acid or the Lewis acid of alpha-keto carboxylic acid ester player's property in office carry out alkene reaction under existing, obtain the compound of general formula (VII),
R wherein
8Be (C
1-C
10)-alkyl,
R wherein
7And R
8Has (C together
1-C
10The connotation of)-alkylidene group,
B) compound of general formula (VII) is reduced to the aldehyde of general formula (IIa),
R wherein
7And R
8Has (C together
1-C
10The connotation of)-alkylidene group,
With
C) by aldehyde (IIa) being converted into the compound of general formula (I), wherein R with method like the aforesaid method category-A
7And R
8Has (C together
1-C
10The connotation of)-alkylidene group.
Substituent R
1To R
13Has above-mentioned connotation.
What use in the step b) of method D is known in the art with carboxylic acid or carboxylicesters selective reduction as the method for aldehyde.
Modify R optional can comprising in method D
7And R
8Reactions steps.Therefore, for example can be with (the C in the intermediate (IIa)
1-C
10The hydrogenation of)-alkylidene group, thus wherein radicals R is provided
7And R
8One of have the connotation of hydrogen atom and another group is (C
1-C
10The compound of the general formula of)-alkyl (I).
(C in the intermediate (IIa)
1-C
10)-alkylidene group can also be as the substrate of hydrohalogenation.The synthetic end product that obtains under this situation is a radicals R wherein
7And R
8One of have the connotation of hydrogen atom and another group is (C
1-C
10The compound of the general formula of)-alkyl (I).
At last, can also be to (the C in the intermediate (IIa)
1-C
10)-alkylidene group carries out cycloaddition reaction.The preferred especially cyclopropanization reaction of this respect obtains wherein radicals R
7And R
8Has the synthetic compound end product of the general formula (I) of (the optional replacement) cyclopropane ring connotation with ring carbon atom.
To those skilled in the art, fully aware of in method D to radicals R
7And R
8These modifications might not on intermediate (IIa), carry out, also can choose wantonly in the complete back time in synthetic and carry out.These variants in the reactions steps order are also included within the present invention equally.
Biologic activity
The anti-inflammatory action of the compound of testing general formula (I) by test Oleum Tiglii inductive inflammation in rat and mouse in experimentation on animals (J.Exp.Med. (1995), 182,99-108).For this purpose, the Oleum Tiglii in ethanol is locally applied on the animal ear.Oleum Tiglii simultaneously or before 2 hours similarly part or systemic administration test substances.After 16 to 24 hours, measuring the ear recast is measuring of inflammatory edema, measures peroxidase activity as measuring that granulocyte moves, and measures elastin activity measuring as the neutrophil leucocyte migration.In this test, the compound of general formula (I) all suppresses three kinds of above-mentioned inflammatory parameters behind the topical and after the whole body administration.
Study combining of each material and glucocorticoid receptor (GR) and other steroid receptor (mineralcorticoid receptor (MR), PgR (PR) and androgen receptor (AR)) by the acceptor of reorganization preparation.The cytosol prepared product of the Sf9 cell of the recombinate shape virus infection of use coding GR carries out combination research.With reference substance [
3H]-dexamethasone compares, and these materials demonstrate has higher affinity to GR.Therefore, the compound among the embodiment 3L is recorded IC
50(GR)=36nM, and IC
50(PR)〉1 μ M.
Think GR mediation the pair cell factor, adhesion molecule, enzyme and other proinflammatory factor transcribe that to suppress be the main molecules mechanism of glucocorticosteroid anti-inflammatory action.This suppress by GR and other transcription factor for example the interaction of AP-1 and NF-κ-B produce (summary) referring to Cato ACB. and Wade E., BioEssays18,371-378,1996.
The compound of general formula of the present invention (I) suppresses the secretion of the cytokine IL-8 that is caused by lipopolysaccharides (LPS) among the human monocyte cell line THP-1.The concentration of cytokine is by the ELISA kit measurement of commercially available acquisition in the supernatant liquor.The compound exhibits IC50 of embodiment 3E (IL8)=1 μ mol suppresses, with respect to standard substance [
3H]-efficient of dexamethasone is 11%.
Modal not one of the expectation function of glucocorticoid treatment is that so-called " steroid diabetes " is [referring to Hatz, H.J., Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, [Glucocorticoids:ImmunologicalPrinciples, Pharmacology and Therapy Guidelines], WissenschaftlicheVerlagsgesellschaft mbH, Stuttgart, 1998].Its reason be since by inducing the total free aminoacids that produces to this enzyme of being responsible for and by protein degradation (the katabolism effect of glucocorticosteroid) at liver moderate stimulation glyconeogenesis.Catabolic key enzyme is that tyrosine changes basic ammonia enzyme (TAT) in the liver.Can measure the activity of this enzyme in the liver homogenate thing by photometric measurement, it is metabolic good the measuring of not expecting of glucocorticosteroid.Induce for measuring TAT, after giving test substances, put to death animal in 8 hours, take out liver, measure the TAT activity in the homogenate.In this test, has under the dosage of anti-inflammatory action their only little degree ground or do not induce tyrosine to change basic ammonia enzyme at the compound of general formula (I).
Medical indications
Because the compound of general formula of the present invention (I) has anti-inflammatory action, have antianaphylaxis, immunosuppression and anti-proliferative effect in addition, so they can be used as the medicine that is used for the treatment of or prevents the following pathological state of patient, particularly Mammals and philtrum.
At this, following indication represented in term " disease ":
(i) with inflammation, allergy and/or the relevant tuberculosis of hyperplasia process:
The chronic obstructive pulmonary disease of-any cause, particularly bronchial asthma
The bronchitis of-various causes
-all types of restrictive lung diseases, particularly sequoiosis
-all types of pulmonary edema, particularly toxic pulmonary edema
-sarcoidosis and granulomatosis, particularly Boeck disease
(ii) relevant rheumatism/autoimmune disorder/joint disease with inflammation, allergy and/or hyperplasia process:
-all types of rheumatisms, particularly rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica
-reactive arthritis
The inflammatory soft tissue disease of-other cause
-with the relevant arthritic symptom of degenerative arthritis (joint disease)
-traumatic arthritis
The collagenosis of-any cause, for example systemic lupus erythematous, scleroderma, polymyositis, dermatomyositis, siogren's syndrome, Still syndrome, Felty syndrome
(iii) with inflammation and/or the relevant allergy of hyperplasia process:
-all types of anaphylaxis, for example angioedema, hay fever, sting, to anaphylaxis, anaphylactic shock, urticaria, the contact dermatitis of medicine, blood derivatives, contrast medium etc.
(iv) vascular inflammation (vasculitis):
-polyarteritis nodosa, temporal arteritis, erythema nodosum
(v) with inflammation, allergy and/or the relevant tetter of hyperplasia process:
-atopic dermatitis (particularly children)
-psoriatic
-pityriasis rubra pilaris
The red spot disease that-multiple deleterious effect such as radiation, chemical substance, burn etc. cause
-bullous dermatosis
-lichen albus
-pruritus (for example pruritus of irritated cause)
-seborrheic eczema
-rosacea
-pemphigus vulgaris
-hebra's disease
-balanitis
-vulvitis
-baldness such as alopecia areata
-epidermis t cell lymphoma
(vi) with inflammation, allergy and/or the relevant ephrosis of hyperplasia process:
-nephrotic syndrome
-all ephritis
(vii) with inflammation, allergy and/or the relevant hepatopathy of hyperplasia process:
-acute hepatic necrosis
For example viral, the toxic of-various causes or drug-induced acute hepatitis
-chronic progressive external and/or Chronic Intermittent hepatitis
(viii) with inflammation, allergy and/or the relevant gastrointestinal illness of hyperplasia process:
-regional enteritis (clone disease)
-ulcerative colitis
-gastritis
-reflux esophagitis
The gastro-enteritis of-other cause such as congenital sprue
(ix) the rectum disease relevant with inflammation, allergy and/or hyperplasia process:
-anal eczema
-anal fissure
-hemorrhoid
-Te Fa rectitis
(x) with inflammation, allergy and/or the relevant illness in eye of hyperplasia process:
-anaphylactic keratitis, uveitis, iritis
-conjunctivitis
-marginal blepharitis
-optic neuritis
-choroiditis
-sympathetic ophthalmia
(xi) with inflammation, allergy and/or the relevant otolaryngologic disease of hyperplasia process:
-allergic rhinitis, hay fever
-external otitis is as contacting the external otitis that eczema, infection etc. cause
-otitis media
(xii) with inflammation, allergy and/or the relevant neuropathy of hyperplasia process:
The cerebral edema that-cerebral edema, particularly tumour cause
-multiple sclerosis
-acute encephalomyelitis
-meningitis
-various types of epileptic seizuress are as infantile spasm
(xiii) with inflammation, allergy and/or the relevant hemopathy of hyperplasia process:
-acquired hemolytic anemia
-idiopathic thrombocytopenia
(xiv) with inflammation, allergy and/or the relevant tumor disease of hyperplasia process:
-kemia
-malignant lymphoma
-lymphogranulomatosis
-lymphosarcoma
-extensively shift, particularly breast cancer, bronchogenic carcinoma and prostate cancer are relevant
Extensively shift
(xv) with inflammation, allergy and/or the relevant endocrinopathy of hyperplasia process:
-internal secretion socket of the eye disease
-thyroid crisis
-de Quervain thyroiditis
-Hashimoto thyroiditis
-Basedow's disease
(xvi) organ and tissue grafts, graft versus host disease
(xvii) serious shock state, for example anaphylactic shock, systemic Inflammatory response syndrome (SIRS)
(xviii) with inflammation, allergy and/or the relevant vomiting of hyperplasia process
-for example in the relevant vomiting of cell toxicant, make up with the 5-HT3 antagonist
(xix) pain of inflammation cause, for example pain in the back.
(xx) replacement therapy in the following illness:
-congenital primary adrenal functional defect, for example congenital A/G syndrome
-acquired primary adrenal functional defect, for example Addison's disease, autoimmune adrenalitis, infection, tumour, transfer etc.
-congenital Secondary cases adrenal insufficiency, for example congenital hypopituitarism
-acquired Secondary cases adrenal insufficiency for example infects back, tumour etc.The medicine that proof contains the steric isomer of general formula I has special result to following illness:
1. tuberculosis
2. wind-wetness syndrome/autoimmune disorder
3. tetter
4. degenerative arthritis
5. vasculitis
6. graft versus host disease (GVH disease)
7. serious shock state
8. with inflammation, allergy and/or the relevant vomiting of hyperplasia process
9. inflammation dependency pain.
In addition, the compound of general formula of the present invention (I) can be used for treating and prevent more than do not mention but use other pathologic conditions of synthetic glucocorticoid in the prior art (this respect be referring to Hatz, HJ, Glucocorticoide:Immunologische Grundlagen, Pharmakologieund Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998).
The detailed description of above-mentioned all indications is referring to Hatz, HJ, Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998.
For the therapeutic action in the above-mentioned pathologic conditions, the proper dosage difference, depend on intensity, patient's (for example height, body weight, sex etc.), the administering mode of the compound of general formula (I) for example and want sanatory character and severity, and still be the curative use as prophylactic agent.
The present invention relates to the application that claimed compound is used for pharmaceutical compositions.
In addition, the present invention also provides:
(i) one of compound of general formula of the present invention (I) or their mixture are used for preparation and are used for the treatment of or the preventing inflammation process, especially for the application of pharmaceutical composition of treatment (aforesaid) " disease ";
(ii) be used for the treatment of or the preventing inflammation process, particularly treat the method for (aforesaid) " disease ", described method comprises the compound of the general formula (I) of administration pharmacy effective dose, wherein said amount alleviates or suppresses this disease or symptom, and the patient who wherein described compound is needed this treatment, particularly people;
The pharmaceutical composition that (iii) has anti-inflammatory action especially for treatment (aforesaid) " disease ", wherein said composition comprises one of compound of general formula of the present invention (I) or their mixture and randomly comprises at least a pharmaceutical excipient and/or carrier.
When per daily dose comprised 1 μ g to 100000 μ g compound of the present invention/kg body weight, can be expected at usually had gratifying result in the animal.For bigger Mammals, people for example, the per daily dose of recommendation is 1 μ g to 100000/kg body weight.Preferred dosage is 10 to 30000
μ g/kg body weight, more preferred dose are 10 to 10000 μ g/kg body weight.For example, this dosage easily administration every day more than once.For treatment acute shock (for example anaphylactic shock), can be significantly higher than the single dose of above-mentioned dosage.
In the manner known to persons skilled in the art by with processing such as carrier substance, the weighting agent of described activeconstituents in being usually used in pharmaceutical technology, the material that influences disintegration, tackiness agent, wetting agent, lubricant, absorption agent, thinner, correctives, tinting materials, and be converted into the form of medication of expectation based on the medicine medicine of described new compound.To this, referring to Remington ' sPharmaceutical Science, 15
ThEdition, Mack Publishing Company, EastPennsylvania (1980).
For oral administration, tablet, coated tablet, capsule, pill, powder, granule, lozenge, suspensoid, emulsion or solution are suitable especially.
The preparation that is used to inject with infusion can be used for administered parenterally.
Suitably prepd crystal suspensoid can be used for intra-arterial injection.
Be used for the moisture of injection or oily solution agent or suspensoid and store (depot) preparation accordingly being used for intramuscularly.
Described new compound can be used for rectal administration with suppository, capsule, solution (as the form of enema) and ointment form, is used for whole body and topical therapeutic.
Described new compound can be used for its pulmonary administration with the form of aerosol and inhalation.
Use part for eye, external auditory meatus, middle ear, nasal cavity and paranasal sinus, and described new compound can be used as the form of drops, ointment, spirit and gelifying agent in suitable pharmaceutical preparation and uses.
The preparation that can be used for topical application is gelifying agent, ointment, fatty ointments, ointment, paste, dusting, suspensoid, emulsion and solution.The dosage of compound in these preparations of general formula (I) should be 0.01%-20%, to obtain enough pharmacotoxicological effects.
The present invention also comprises the compound as the general formula of the present invention (I) of therapeutic activity composition.In addition, the present invention also comprise as the compound of the general formula of the present invention (I) of therapeutic activity composition and one or more pharmacy suitable and acceptable vehicle and carrier.
Randomly, the compound of general formula of the present invention (I) can also be prepared and/or administration with other activeconstituents.
Therefore, the invention still further relates to the composition of combined therapy or combination, the compound of its formula of (I) or its pharmacologically acceptable salts perhaps contain the pharmaceutical composition and (randomly in same composition) or the administration successively simultaneously of one or more medicines that is used for the treatment of one of above-mentioned case illness of compound or its pharmacologically acceptable salts of general formula (I).For example, for the treatment of rheumatoid arthritis, osteoarthritis, COPD (chronic obstructive pulmonary disease), asthma or allergic rhinitis, can be with compound and one or more drug regimens that is used for the treatment of this illness of general formula of the present invention (I).When giving this combination by suction, then the medicine that will make up can be selected from the following medicine of listing:
The PDE4 inhibitor comprises PDE4D isoform inhibitor;
Selectivity beta 2 adrenoreceptor agonists, for example Metaprel, Respifral, Racemic isoproterenol, salbutamol, salbutamol, formoterol, Sha Moteluo, terbutaline, Orciprenaline, bitolterol mesilate, pirbuterol or indacaterol;
Muscarinic receptor antagonist (for example M1, M2 or M3 antagonist, for example optionally M3 antagonist), for example ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;
Chemokine receptor function conditioning agent (for example CCR1 receptor antagonist); Or
P38 kinase function inhibitor.
For another aspect of the present invention, use the compound of this and general formula (I) or the combination of its pharmacologically acceptable salts to be used for the treatment of COPD, asthma or allergic rhinitis, it can be through sucking or oral and xanthine (for example aminophylline or theophylline) combination medicine-feeding, and xanthine also can be through sucking or oral administration.
Embodiment
The cis/trans name of using in following examples is meant 1 and 2 substituent position of the saturated rings of naphthane system.This respect, cis are meant that (defining according to Cahn-Ingold-Prelog sequence rule) the optimum substituting group on the carbon atom 1 is positioned at axial position, and the optimum substituting group on the carbon atom 2 is positioned at the equator to the position; Perhaps (defining according to Cahn-Ingold-Prelog sequence rule) the optimum substituting group on the carbon atom 1 is positioned at the equator to the position, and the optimum substituting group on the carbon atom 2 is positioned at axial position.Correspondingly, transly be meant that these two the optimum substituting groups on the carbon atom 1 and carbon atom 2 all are positioned at axial position or all are positioned at the equator to the position under each situation.
Embodiment 1: the compound of general formula (III) synthetic
6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1,2-diphenol (cis and trans-isomer(ide))
With 1.75g (5.67mmol) 4-(3-fluoro-2-p-methoxy-phenyl)-2-hydroxyl-4,4-dimethyl-2-trifluoromethyl valeral is dissolved in the 20ml methylene dichloride, adds the 2.6ml trifluoroacetic acid.Reactant was stirred 24 hours under nitrogen atmosphere and room temperature.Be to handle, with reaction soln and toluene vacuum-evaporation three times, then through chromatogram purification: 1.28g cis-6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1,2-diphenol and 300mg be trans-6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1,2-diphenol (90%).
Cis-6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1, the 2-diphenol:
1H-NMR (300MHz, CDCl
3): δ/ppm=1.45 (s, 3H), 1,59 (s, 3H), 1.81 (d, 1H), 2.08 (d, 1H), 2.56 (d, 1H), 3.18 (d, 1H), 3.94 (d, 3H), 5.03 (d, 1H), 7.03 (dd, 1H), 7.31 (ddd, 1H).
Trans-6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1, the 2-diphenol:
1H-NMR (300MHz, CDCl
3): δ/ppm=1.52 (s, 3H), 1.55 (s, 3H), 1.83 (dd, 1H), 1.87-1.90 (m, 2H), 2.42 (d, 1H), 3.95 (d, 3H), 4.68 (dd, 1H), 6.99-7.06 (m, 2H).
Similar to aforesaid method, obtain following compound:
6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1,2-diphenol (cis and trans-isomer(ide) mixture)
7-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1,2-diphenol (cis and trans-isomer(ide) mixture)
Embodiment 2: compound synthetic of reading aloud formula (IV):
Embodiment 2A: cis-1-amino-6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-tetrahydrochysene Betanaphthol
A) 7-fluoro-6-methoxyl group-5,5-dimethyl-2,2-dioxo-3a-trifluoromethyl-3a, 4,5,9b-tetrahydrochysene-3-oxygen base-2 λ
*6
*-thia-1-azepine-ring penta [a] naphthalene-1-benzyl formate
With 2.00g (6.48mmol) 6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1,2-diphenol and 5.12g (16.2mmol) Burgess reagent is dissolved among the 50mlTHF, and, at room temperature stirred then 12 hours nitrogen atmosphere and 65-70 ℃ of following the stirring 7 hours.With reaction soln vacuum-evaporation, and with resistates through chromatogram purification: 1.66g (51%).
1H-NMR(300MHz，CDCl
3)：δ/ppm＝1.54(s，3H)，1.59(s，3H)，2.01(d，1H)，2.29(d，1H)，3.95(d，3H)，5.36(d，1H)，5.44(d，1H)，5.95(s，1H)，6.97(dd，1H)，7.19(dd，1H)，7.35-7.42(m，5H)。
B) cis-1-amino-6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-tetrahydrochysene Betanaphthol
With 1.2g (2.38mmol) 7-fluoro-6-methoxyl group-5,5-dimethyl-2,2-dioxo-3a-trifluoromethyl-3a, 4,5,9b-tetrahydrochysene-3-oxygen base-2 λ
*6
*-thia-1-azepine-ring penta [a] naphthalene-1-benzyl formate is dissolved in the 12ml diox, behind the adding 8ml4N HCl solution, handles twice 20 minutes down at 250 watts and 140 ℃ in microwave oven.For handling, with the solution for vacuum evaporation, under 0 ℃, pH is adjusted to 14 with the 4N sodium hydroxide solution, use ethyl acetate extraction three times.The organic phase that merges is washed with saturated nacl aqueous solution, use dried over sodium sulfate, filter and vacuum concentration: 41% expectation product.
1H-NMR(300MHz，CDCl
3)：δ/ppm＝1.36(s，3H)，1.49(s，3H)，1.78(s，1H)，1.95(d，1H)，3.83(d，3H)，4.03(s，1H)，7.12(dd，1H)，7.51(dd，1H)。
Embodiment 2B: anti-form-1-amino-6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-tetrahydrochysene Betanaphthol
A) 1-azido--6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-tetrahydrochysene Betanaphthol
Under nitrogen atmosphere and room temperature, with 420mg (1.27mmol) tetrabromomethane and 454mg (1.14mmol) 1, two (diphenylphosphine) ethane (DiPhos) of 2-add 130mg (0.422mmol) 6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1 is in the solution of 2-cis-diphenol in the 4.5ml methylene dichloride.Also can use 1,2-cis/trans-diphenol mixture replacing 1,2-cis-diphenol begins this reaction in a similar manner.After at room temperature stirring 3 hours, add the 20ml ether, stir after 5 minutes, leach the precipitation of gained, with the ether washing, and vacuum evaporating solvent.Obtain the 200mg crude product, be used for next step reaction without being further purified.
190mg (0.512mmol) crude product is mixed with the DMSO solution (the 150mg sodiumazide in the 5ml methyl-sulphoxide at room temperature stirred 24 hours) that 2ml contains sodiumazide.Reaction soln was at room temperature stirred 3 hours, and nitrogen atmosphere and 40-45 ℃ of following the stirring 3 hours.For handling, 5ml water is added in the reaction mixture, use ethyl acetate extraction 3 times.The organic phase that merges is washed with saturated nacl aqueous solution, use dried over sodium sulfate, filtration, vacuum concentration, and through the column chromatography purifying: the 80mg title compound.
1H-NMR(300MHz，CDCl
3)：δ/ppm＝1.52(s，3H)，1.56(s，3H)，1.84(dd，1H)，1.97(s，1H)，2.25(d，1H)，3.98(d，3H)，4.48(d，1H)，6.93(dd，1H)，7.07(dd，1H)。
B) anti-form-1-amino-6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-tetrahydrochysene Betanaphthol
311mg (4.76mmol) zinc powder is added 1.22g (3.66mmol) 1-azido--6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3, in the mixture of 4-tetrahydrochysene Betanaphthol and 450mg (8.42mmol) ammonium chloride in 9.7ml ethanol and 3.3ml water, then mixture was stirred 30 minutes under 90 ℃ and nitrogen atmosphere.After being cooled to room temperature, add the 25ml ethyl acetate, add the 1.22ml ammonia soln, mixture was stirred 5 minutes and filtered.Use the saturated sodium-chloride water solution wash filtrate, use dried over sodium sulfate, filter and vacuum concentration.Crude product is through post column chromatography purifying: the 950mg title compound.
1H-NMR(300MHz，CDCl
3)：δ/ppm＝1.42(s，3H)，1.46(s，3H)，1.61(dd，1H)，1.77(bs，2H)，2.20(d，1H)，3.84(d，3H)，3.88(s，1H)，5.63(s，1H)，6.98(dd，1H)，7.10(dd，1H)。
Embodiment 3: the compound of general formula (I) synthetic
Embodiment 3A: N-(cis-6-fluoro-2-hydroxy-5-methyl oxygen base-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1-yl) naphthalene-2-methane amide
With 4-Dimethylamino pyridine (73mg, 0.60mmol) solution and 2-naphthalene carbonyl chloride (84mg in DMF (0.4ml), 0.44mmol) solution in DMF (0.8ml) adds cis-1-amino-6-fluoro-5-methoxyl group-4 successively, 4-dimethyl-2-Trifluoromethyl-1,2,3,4-tetrahydrochysene Betanaphthol (100mg, 0.40mmol) in the solution in DMF (0.8ml), and the mixture of gained at room temperature stirred spend the night.For handling, add sodium bicarbonate solution (3ml, the semi-saturation aqueous solution) and ethyl acetate (6ml), after the extraction, separate organic phase and concentrated.With three of gained crude product/, obtain the 28mg title compound once the HPLC-MS purifying.
HPLC:3.4min (method A).
MS(ESI)：m/z461。
1H-NMR(CDCl
3，400MHz)：δ/ppm＝1.52(s，3H)，1.67(s，3H)，2.12(m，2H)，3.30(broad?s)，3.97(s?br，3H)，5.67(d，1H)，6.93-7.07(m，3H)，7.57(m，2H)，7.91(m，4H)，8.36(s，1H)。
Embodiment 3B: N-(cis-6-fluoro-2,5-dihydroxyl-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-naphthane-1-yl) naphthalene-2-methane amide
Be dissolved in remaining 2/3rds crude products of synthetic among the above embodiment 3A in the methylene dichloride (0.5ml) and be cooled to-40 ℃, under this temperature, add boron tribromide solution (1ml, 1.0M, in methylene dichloride, 1.0mmol), mixture under agitation is warmed to room temperature, and keeps spending the night.For handling, in ice bath, add solution of potassium carbonate (1.5ml, the semi-saturation aqueous solution), the gained mixture was stirred in ice bath 15 minutes, dilution and with ethyl acetate extraction (3ml), it is also concentrated to separate organic phase.Resistates through the HPLC-MS purifying, is obtained the 88mg title compound.
HPLC:3.1min (method A).
MS(ESI)：m/z447。
1H-NMR(CDCl
3，400MHz)：δ/ppm＝1.56(s，3H)，1.69(s，3H)，2.13(s，2H)，5.43(d，1H)，5.66(d，1H)，6.88-7.03(m，3H)，7.57(m，2H)，7.92(m，4H)，8.37(s，1H)。
Similar to the foregoing description 3A with 3B, obtain the compound of following general formula (I):
Embodiment 4: other compound of general formula (I) synthetic
Embodiment 4: 6-fluoro-5-methoxyl group-4,4-dimethyl-1-[(pyrazolo [1,5-a] pyridine-3 ylmethyl) amino]-the 2-Trifluoromethyl-1,2,3,4-tetrahydrochysene Betanaphthol, (cis-isomeride)
With cis-1-amino-6-fluoro-5-methoxyl group-4,4-dimethyl-2-Trifluoromethyl-1,2,3,4-tetrahydrochysene Betanaphthol (62mg, 0.20mmol) and pyrazolo [1,5-a] pyridine-3-formaldehyde (30mg (0.20mmol) is dissolved in the dimethylbenzene in (5.0ml), (0.085ml 0.40mmol) and at 150 ℃ stirred 3 hours down to add the tetraethoxide phthalein.Except that after desolvating, with methyl alcohol (1.0ml) and tetrahydrofuran (THF) (1.0ml) absorption of residual excess, and the adding sodium borohydride (22mg, 0.58mmol).Add the entry termination reaction after at room temperature 3 hours.Vacuum is removed methyl alcohol and tetrahydrofuran (THF).The water dichloromethane extraction, the organic phase dried over sodium sulfate.Remove and to desolvate, with after chromatogram purification (silica gel, hexane/ethyl acetate 3: 7) obtains the 26mg title compound.
1H-NMR(300MHz，d
6-DMSO)：δ/ppm＝1.39(s，3H)，1.46(s，3H)，1.85(d，1H)，2.07(d，1H)，3.83(d，3H)，3.94(s，1H)，3.98(d，1H)，4.06(d，1H)，5.92(br，1H)，6.85(td，1H)，7.07-7.23(m，3H)，7.63(d，1H)，7.98(s，1H)，8.62(d，1H)。
The HPLC method is described
Method A:
Waters Alliance2795, Waters Photo Diode Array2996 (200-320nm), Micromass ZQ; Post Micra NPS ODS2 (33 * 4.6mm, 1.5 μ m); Gradient, the 0-90% acetonitrile of Yu Shuizhong (0.01% formic acid) (0.01% formic acid) (4.5min.), 90% acetonitrile of Yu Shuizhong (0.01% formic acid) (0.01% formic acid) is (2min); Flow velocity 0.8ml/min.
Method B:
Waters Pump515, Waters Dual Absorbance Detector2487 (254nm), Micromass ZQ; Post X-Terra (150 * 4.6mm, 5 μ m); The 54-95% acetonitrile (0.01% formic acid) (0.01% formic acid) of gradient in water (10min); Flow velocity 1ml/min.
Method C:
Waters Pump616, Hitachi L-4000 (254nm); Post Chromasil C8 (150 * 4.6mm, 5 μ m); The 30-95% acetonitrile (0.01% formic acid) (0.01% formic acid) of gradient in water (15min.), 95% acetonitrile of Yu Shuizhong (0.01% formic acid) (0.01% formic acid) is (15min); Flow velocity 1ml/min.
Method D:
Hewlett-Packard 1100 Pump, HP1100 Detector (200-320nm), Micromass PLCZ; Post Micra NPS ODS 2 (33 * 4.6mm, 1.5 μ m); The 0-90% acetonitrile (0.01% trifluoroacetic acid) (0.01% trifluoroacetic acid) of gradient in water (4.5min), 90% acetonitrile of Yu Shuizhong (0.01% trifluoroacetic acid) (0.01% trifluoroacetic acid) is (2min); Flow velocity 0.8ml/min.
Claims (17)
1. the compound of general formula (I),
Wherein
R
1And R
2Be hydrogen atom, hydroxyl, halogen atom, the optional (C that replaces independently of one another
1-C
10)-alkyl, (C
1-C
10)-alkoxyl group, (C
1-C
10)-alkylthio, (C
1-C
5)-perfluoroalkyl, cyano group, nitro or-NR
9R
9aGroup,
Or R
1And R
2Form together and be selected from group-O-(CH
2)
n-O-,-O-(CH
2)
n-CH
2-,-O-CH=CH-,-(CH
2)
N+2-,-NH-(CH
2)
N+1-,-N (C
1-C
3-alkyl)-(CH
2)
N+1-and-group of NH-N=CH-, wherein n is 1 or 2, and terminal Sauerstoffatom and/or carbon atom and/or nitrogen-atoms be connected with the ring carbon atom of direct neighbor,
R
11Be hydrogen atom, hydroxyl, halogen atom, cyano group, the optional (C that replaces
1-C
10)-alkyl, (C
1-C
10)-alkoxyl group, (C
1-C
10)-alkylthio or (C
1-C
5)-perfluoroalkyl,
R
12Be hydrogen atom, hydroxyl, halogen atom, cyano group, the optional (C that replaces
1-C
10)-alkyl or (C
1-C
10)-alkoxyl group,
R
3By 1-3 hydroxyl, a 1-3 halogen atom and/or 1-3 (C
1-C
5The optional C that replaces of)-alkoxyl group
1-C
10-alkyl,
Optional (the C that replaces
3-C
7)-cycloalkyl,
The optional heterocyclic radical that replaces,
The optional aryl that replaces, or
Monocycle or bicyclic heteroaryl, it is independently from each other by one or more that following group is optional to be replaced:
Itself can be by 1-3 hydroxyl or 1-3-COOR
13The optional replacement of group
(C
1-C
5)-alkyl,
(C
1-C
5)-alkoxyl group,
Halogen atom, hydroxyl ,-NR
9R
9aGroup and
Outer methylene radical,
And optional 1-4 nitrogen-atoms and/or 1-2 Sauerstoffatom and/or 1-2 sulphur atom and/or 1-2 ketone group of containing, this group are connected with radicals X by any position and can choose wantonly in one or more positions and be hydrogenated,
R
4Be hydroxyl ,-OR
10Group or-O (CO) R
10Group,
R
5Be optional part or complete fluorizated (C
1-C
10)-alkyl, (C
3-C
7) cycloalkyl, (C
1-C
8) alkyl-(C
3-C
7) cycloalkyl, (C
2-C
8) thiazolinyl-(C
3-C
7) cycloalkyl, heterocyclic radical, (C
1-C
8) alkyl heterocyclic, (C
2-C
8)-thiazolinyl heterocyclic radical, aryl, (C
1-C
8) alkylaryl, (C
2-C
8) alkenyl aryl, (C
2-C
8)-alkynyl aryl,
Monocycle or bicyclic heteroaryl, it is by 1-2 ketone group, a 1-2 (C
1-C
5)-alkyl, a 1-2 (C
1-C
5)-alkoxyl group, a 1-3 halogen atom and/or 1-2 outer methylene radical chosen wantonly and replaced and contain 1-3 nitrogen-atoms and/or 1-2 Sauerstoffatom and/or 1-2 sulphur atom,
(C
1-C
8) miscellaneous alkyl aryl, (C
2-C
8) thiazolinyl heteroaryl or (C
2-C
8) the alkynyl heteroaryl, this group is connected with the naphthane system by any position and can chooses wantonly in one or more positions and is hydrogenated,
R
6Be hydrogen atom, halogen atom or the optional (C that replaces
1-C
10) alkyl,
R
7And R
8Be hydrogen atom, halogen atom, the optional (C that replaces independently of one another
1-C
10)-alkyl, cyano group are (C together
1-C
10)-alkylidene group or be the optional (C that replaces with the carbon atom of naphthane system
3-C
6)-cycloalkyl ring;
Perhaps
R
6And R
7Form 5 to 8 yuan of saturated or undersaturated carbocyclic rings of condensed or heterocycle together, it is by 1-2 ketone group, a 1-2 (C
1-C
5)-alkyl, a 1-2 (C
1-C
5A)-alkoxyl group and/or 1-4 halogen atom is optional to be replaced;
Perhaps
R
1And R
8Form 5 to 8 yuan of saturated or undersaturated carbocyclic rings of condensed or heterocycle together, it is by 1-2 ketone group, a 1-2 (C
1-C
5)-alkyl, a 1-2 (C
1-C
5A)-alkoxyl group and/or 1-4 halogen atom is optional to be replaced;
R
9And R
9aBe hydrogen atom, (C independently of one another
1-C
5)-alkyl or-(CO)-(C
1-C
5)-alkyl,
R
10Be (C
1-C
10)-alkyl or any hydroxyl protecting group,
R
13Be hydrogen atom or (C
1-C
5)-alkyl, and
X be group-C (=O)-,-C (=S)-,-C (=O)-NH-,-C (=S)-NH-,-S (O)
m(wherein m=1 or 2) ,-C (=O)-O-,-C (=S)-O-or group-(CH
2)
p-(wherein p=1,2 or 3), if wherein X contains carbonyl or thiocarbonyl group functional group, then this functional group is connected with group-NH-in the general formula (I),
Condition is if R
3Be the optional (C that replaces
1-C
10)-alkyl, then X can not be-(CH
2)
p-group,
The compound of described general formula (I) be any stereoisomer or steric isomer mixture form or as acceptable salt of pharmacology or derivative.
2. the compound of claim 1, wherein X be group-C (=O)-,-C (=O)-NH-,-SO
2-or-CH
2-.
3. claim 1 or 2 compound, wherein R
4Be hydroxyl or group-OR
10
4. the compound of each of aforementioned claim, wherein R
5Be optional part or complete fluorizated (C
1-C
10)-alkyl.
5. the compound of each of aforementioned claim, wherein R
7And R
8Each is methyl naturally, or forms cyclopropyl with the carbon atom of naphthane system.
6. the compound of each of aforementioned claim, wherein R
3Be optional aryl or the heteroaryl that replaces.
7. the compound of claim 6, the aryl or the heteroaryl of wherein said optional replacement are selected from naphthyl, benzofuryl, pyrazolo [1,5-a] pyridyl, phenyl, phthalidyl, pseudoindoyl, indolinyl, dihydro-iso indolyl, the dihydro-isoquinoline base, thio phenyl phthalidyl; benzoxazine ketone group, the phthalazines ketone group, quinolyl, isoquinolyl, quinolonyl, the isoquinolone base, indazolyl, benzothiazolyl, quinazolyl, quinoxalinyl, the cinnolines base, phthalazinyl, 1,7-or 1, the 8-naphthyridinyl, the indoline ketone group, the xylylenimine ketone group, chromanyl, different chromanyl, benzimidazolyl-or indyl.
8. the compound of each of aforementioned claim, it is used to prepare medicine.
9. the compound of each of claim 1 to 7 is used to prepare and is used for the treatment of or the application of the pharmaceutical composition of preventing inflammation process.
10. method that is used for the treatment of or prevents the inflammatory process among the patient is characterized in that each the compound of general formula (I) to the claim 1 to 7 of patient's administration pharmacy effective dose of this treatment of needs or prevention.
11. a medicine, its contain at least a claim 1 to 7 each compound and one or more pharmaceutically acceptable carriers and/or vehicle.
12. the preparation method of the compound of each of claim 1 to 7 is characterized in that:
A) randomly add inorganic or organic acid or Lewis acid and make the open chain carbonyl compound of general formula (II) be cyclized into the compound of general formula (III),
B) by making the compound of general formula (III) be converted into the compound of general formula (IV) with the amino hydroxyl that substitutes,
With
C) by be selected from general formula R
3-X-Nu (wherein Nu is the freestone group), R
3-N=C=O or R
3The compound of-N=C=S reaction, and randomly substitute carbonylic oxygen atom with sulphur subsequently makes the compound of general formula (IV) be converted into the compound of general formula (I),
Substituent R wherein
1To R
12Has the connotation of pointing out in the claim 1 to 7 with X.
13. the preparation method of the compound of each of claim 1 to 7 is characterized in that making the compound and the general formula R of the general formula described in the claim 12 (IV)
3-(CH
2)
vThe compound of-CHO (wherein v is 0,1 or 2) reaction, and, obtain the compound of general formula (I) with the hydrogenation of imines of gained, wherein X have point out in the claim 1-(CH
2)
p-connotation, and substituent R
1To R
12Has the connotation of pointing out in the claim 1 to 7.
14. the preparation method of the compound of each of claim 1 to 7 is characterized in that making compound and the phosgene or the thiophosgene reaction of the general formula described in the claim 12 (IV), makes isocyanic ester or the lsothiocyanates and the general formula R of gained subsequently
3-OH or R
3-NH
2Compound reaction, obtain the compound of general formula (I), wherein X have point out in the claim 1-C (=O)-NH-,-C (=S)-NH-or-C (=O)-the O-connotation, and substituent R
1To R
12Has the connotation of pointing out in the claim 1 to 7.
15. the preparation method of the compound of each of claim 1 to 7 is characterized in that
A) make the compound and the general formula R of general formula (VI)
5-C (=O)-COOR
13The alpha-keto carboxylic acid or the Lewis acid of alpha-keto carboxylic acid ester player's property in office carry out alkene reaction under existing, obtain the compound of general formula (VII),
R wherein
8Be (C
1-C
10)-alkyl,
R wherein
7And R
8Has (C together
1-C
10The connotation of)-alkylidene group,
B) compound of general formula (VII) is reduced to the aldehyde of general formula (IIa),
R wherein
7And R
8Has (C together
1-C
10The connotation of)-alkylidene group,
With
C) with claim 12 in the method pointed out similar, aldehyde (IIa) is converted into the compound of general formula (I), wherein R
7And R
8Has (C together
1-C
10The connotation of)-alkylidene group,
Substituent R wherein
1To R
13Has the connotation of pointing out in the claim 1 to 7.
16. the compound of general formula (IV) is used to prepare each the application of compound of general formula (I) of claim 1 to 7,
Substituent R wherein
1To R
13Has the connotation of pointing out in the claim 1 to 7.
17. the compound of formula (IV),
Substituent R wherein
1To R
13Has the connotation of pointing out in the claim 1 to 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005017326.8 | 2005-04-14 | ||
| DE102005017326A DE102005017326A1 (en) | 2005-04-14 | 2005-04-14 | Tetrahydronaphthalene derivatives, process for their preparation and their use as anti-inflammatory agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101146765A true CN101146765A (en) | 2008-03-19 |
Family
ID=36608763
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800092011A Pending CN101146765A (en) | 2005-04-14 | 2006-04-13 | Tetrahydronaphthalene derivatives, method for the production and the use thereof in the form of antiphlogistics |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1868986A1 (en) |
| JP (1) | JP2008535890A (en) |
| CN (1) | CN101146765A (en) |
| CA (1) | CA2598208A1 (en) |
| DE (1) | DE102005017326A1 (en) |
| WO (1) | WO2006108712A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1958934A1 (en) * | 2007-02-16 | 2008-08-20 | Bayer Schering Pharma Aktiengesellschaft | Tetrahydronaphthalenylamides, a process for their production and their use as anti-inflammatory agents |
| SG178174A1 (en) | 2009-07-31 | 2012-03-29 | Cadila Healthcare Ltd | Novel compounds as modulators of glucocorticoid receptors |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2665443B1 (en) * | 1990-08-03 | 1992-11-06 | Lucien Laboratoires | DERIVATIVES OF AMINO-4-METHYL-1-TETRALINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| DE19723722A1 (en) * | 1997-05-30 | 1998-12-10 | Schering Ag | Nonsteroidal progestogens |
| DE10038639A1 (en) * | 2000-07-28 | 2002-02-21 | Schering Ag | New and known N-aryl 2-hydroxy-omega-arylalkanamide derivatives, useful e.g. for treating inflammatory diseases such as rheumatism |
-
2005
- 2005-04-14 DE DE102005017326A patent/DE102005017326A1/en not_active Ceased
-
2006
- 2006-04-13 JP JP2008505846A patent/JP2008535890A/en active Pending
- 2006-04-13 EP EP06742671A patent/EP1868986A1/en not_active Withdrawn
- 2006-04-13 CA CA002598208A patent/CA2598208A1/en not_active Abandoned
- 2006-04-13 CN CNA2006800092011A patent/CN101146765A/en active Pending
- 2006-04-13 WO PCT/EP2006/003781 patent/WO2006108712A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2008535890A (en) | 2008-09-04 |
| WO2006108712A1 (en) | 2006-10-19 |
| DE102005017326A1 (en) | 2007-03-29 |
| CA2598208A1 (en) | 2006-10-19 |
| EP1868986A1 (en) | 2007-12-26 |
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Open date: 20080319 |