CN1342144A - N-substituted benzoyl indoles as estrogenic agents - Google Patents
N-substituted benzoyl indoles as estrogenic agents Download PDFInfo
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- CN1342144A CN1342144A CN00804545A CN00804545A CN1342144A CN 1342144 A CN1342144 A CN 1342144A CN 00804545 A CN00804545 A CN 00804545A CN 00804545 A CN00804545 A CN 00804545A CN 1342144 A CN1342144 A CN 1342144A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract
The present invention provides compounds of formula (A) wherein R1, R2 and R3 are independently selected from hydrogen, halogen, C1-C6 alkoxy, -CF3, -NO2, cyano, C1-C6 alkyl, trifluoromethyl, -OH or the C1-C12 esters (straight chain or branched) or C1-C12 alkyl ethers thereof, or C1-C6 halogenated ethers, preferably C1-C3 halogenated ethers, including trifluoromthyl ether and trichloromethyl ether; R4 and R5 are independently selected from H or benzyl, the benzyl group being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, -CF3, or halogen; X is H, C1-C6 alkyl, or CF3; Z is O or S; n is 2 or 3; Y is selected from: a) a moiety of the formula -NR'R' wherein R' is C1-C6 lower alkyl; or b) a moiety selected from the group of (B), (C), (D) or (E); or a pharmaceutically acceptable salt thereof, as well as pharmaceutical formulations and methods of treating or preventing disease states or syndromes which are caused or associated with an estrogen deficiency or an excess of estrogen utilizing these compounds.
Description
The present invention relates to the benzoyl benzazolyl compounds that the new N-as estrogenic replaces, and pharmaceutical composition, use the methods of treatment of these compounds and prepare their method.
Background of invention
Estrogen replacement therapy has been set up as preventing osteoporotic treatment selection [C.Christiansen, R.Lindsay, Estrogen, Bone Loss andPreservation, Osteoporosis International, 1,15-21 (1990)] among the women.The shortcoming of this treatment (downside) is when oestrogenic hormon is individually dosed, does not promptly have the relativity of progestogen, and the proliferative effect in uterus can take place, and makes the patient have the risk of carcinoma of endometrium.Although not clear, hormone replacement therapy is relevant with the increase of the sickness rate that breast tumor forms.On-steroidal estrogen antagonist medicine, for example tamoxifen has been used for the treatment of mammary cancer.The also known maintenance bone mass of this medicine, as the poor estrogen agonist of bone, yet it still is the agonist of uterine cancer cell.More in recent years estrogen antagonist medicine, Lilly ' s raloxifene is an on-steroidal antiestrogen thing, it shows further tissue selectivity.When having the desirable properties of saving bone, proved that in animal model it stimulates uterine growth than tamoxifen with less degree.In addition, clinical data in recent years confirms the ametria intimal hyperplasia.The summary of organizing selective action [G.L.Evans and R.T.Turner, Tissue Selective Actions of Estrogen Analogs, Bone, 17, no.4,1815-1905 (1995)] to estrogen analogue has appearred in recent years.
Indoles as the application of oestrogenic hormon antagonistic by Von Angerer, ChemicalAbstracts, 99 volumes, No.7 (1983), Abstract No.53886u report.Also referring to J.Med.Chem.1990,33,2635-2640; J.Med.Chem.1987,30,131-136.Also referring to Ger.Offen., DE3821148A1 891228 and WO96/03375.The place that the compound of these prior aries and compound of the present invention have some similar, but function difference.For the compound that contains basic amine, do not exist phenyl to stablize side chain, be used for these compounds report data presentation they have more weak combining than The compounds of this invention and estrogen receptor, the compound that contains basic side chain shows that in rat uterus some acts on to the uterus.
WOA95 17383 (Kar Bio AB) shows the indoles antiestrogen that has long linear, and another relevant patent WOA93 10741 has described the 5-oxyindole of other side chain of adding with similar description.
US5496844 (Inai etc.) instruction has the N-benzazolyl compounds of the active replacement of potential estrogen antagonist, and it is used for the treatment of the disease that oestrogenic hormon relies on, for example do not ovulate infertility, prostatomegaly, osteoporosis, mammary cancer, carcinoma of endometrium and melanoma.
People such as Jones are at its article Antiestrogens.2.
1Structure-ActivityStudies in a Series of 3-Aroy1-2-arylbenzo[b] thiopheneDerivatives Leading to [6-Hydroxy-2-(4-hydroxy phenyl) benzo[b] thien-3-yl] [4-[2-(1-piperidinyl) ethoxy] phenyl] metha none Hydrochloride (LY156758); a Remarkably EffectiveEstrogen Antagonist with Only Minimal Intrinsic Estrogenicity; J.Med.Chem.1984; 27,1057-1066 describes a series of 3-aroyl-2-aryl benzo [b] thiophene derivants as the agent of on-steroidal estrogen antagonist.
The compound that the present invention describes is blended estrogen agonist/antagonistic, has potential use aspect treatment osteoporosis, endometriosis, prostatomegaly, mammary cancer and the carcinoma of endometrium.
Invention is described
The invention provides the Benzazole compounds of the N-replacement of formula (I):
Wherein:
R
1, R
2And R
3Be selected from H, halogen, C respectively
1-C
12Alkoxyl group (straight or branched or ring-type) ,-CF
3,-NO
2, cyano group, C
1-C
6Alkyl (straight or branched), trifluoromethyl ,-OH or their C
1-C
12Ester (straight or branched), or C
1-C
6Halogenated ethers, preferred C
1-C
3Halogenated ethers comprises trifluoromethyl ethers and trichloromethyl ether;
R
4And R
5Be selected from H or benzyl respectively, benzyl is optionally by C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-CF
3, or halogen replace;
X is H, C
1-C
6Alkyl or CF
3
Z is O or S;
N is 2 or 3;
Y is selected from:
A) group of following formula:
Wherein R ' is identical or different C
1-C
6Low alkyl group, or
B) be selected from following group:
Or its pharmaceutically useful salt.
If ester, then R
1, R
2And R
3Example be C
2-C
12Alkyl ester, for example-OC (=O) (C
1-C
6Alkyl) ester.
The example of alkyl is methyl, ethyl, n-propyl, sec.-propyl and normal-butyl.
The example of alkoxyl group is methoxyl group, oxyethyl group, positive propoxy, isopropoxy and n-butoxy.
R
1And R
2Example be H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-CF
3, and NO
2R
3And R
4Example be H, the example of X is a methyl.
Preferred group of the present invention is R wherein
1, R
2And R
3Be selected from H, C respectively
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-CF
3With-NO
2And R
4, R
5, X, Z, n and Y be formula I compound or its pharmaceutically useful salt as defined above.
Another preferred group of The compounds of this invention is that wherein Z is O and R
1, R
2, R
3And R
4Be compound or its pharmaceutically useful salt of H.Preferred R
5Be H.Most preferred is that wherein Y is the compound of piperidine ring in these general and inferior general groups.
The present invention includes by with pharmaceutically acceptable salt inorganic or that the organic acid addition reaction forms.Mineral acid, for example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid, nitric acid and organic acid, for example acetate, propionic acid, citric acid, toxilic acid, oxysuccinic acid, tartrate, phthalic acid, succsinic acid, methylsulfonic acid, toluenesulphonic acids, naphthene sulfonic acid, camphorsulfonic acid, Phenylsulfonic acid are useful.The preferably salt of The compounds of this invention is hydrochloric acid, Hydrogen bromide and acetate.
Compound of the present invention is the part estrogen agonist, shows high estrogen receptor avidity, yet, being different from many oestrogenic hormon, many these compounds do not cause generally and increase natural or the uterus wet weight that synthetic estrogen is relevant.These compounds are antiestrogenic in the uterus, can resist the trophism of the estrogen agonist in uterine cancer cell fully.In addition, compound can be used as estrogen agonist in osseous tissue.Because the tissue selectivity character of these compounds, they are used for the treatment of or prevent Mammals by estrogen deficiency or excessive disease or the syndromes that causes or be correlated with of oestrogenic hormon.
The present invention is by reducing cholesterol and prevent that the bone loss has the ability that is similar to estrogen agonist.These compounds are used for the treatment of many excessive or lack the disease cause by oestrogenic hormon, comprise osteoporosis, prostatomegaly, male baldness, ovarian cancer, infertility, mammary cancer, carcinoma of endometrium, cardiovascular disorder, contraception, presenile dementia, understanding decline and other CNS disease and some cancer, comprise melanoma, carcinoma of prostate, colorectal carcinoma, CNS cancer etc.In addition, these compounds be used in postclimacteric women's hormone replacement therapy or wherein oestrogenic hormon to replenish will be hormone replacement therapy in useful other estrogen deficiency symptom.
Compound of the present invention also can be used for treating the method for bone loss, and described bone loss can be formed and the imbalance of the sorption of old tissue causes by new bone tissue indivedual, causes the net loss of bone to produce.This bone loss produces in the individuality of following scope, especially through women without offspring, accept the women of uterus excising operation, accept or accepted long-term corticosteroid treatment people, hypogenitalism the people and suffer from the people of hypercortisolism.The special requirement that is used for the bone recovery also can be advised at the operation of the human body of suffering from fracture, defective bone structures and acceptance and bone photo pass and/or these compounds of people's use of the false branch of transplanting.Except above-mentioned these problems, these compounds can be used for treating osteoarthritis, hypocalcemia, hypercalcemia, osteitis deformans, osteomalacia, osteohalsiteresis, multiple myeloma and have other form to the cancer of osseous tissue deleterious effect.The method for the treatment of above-mentioned disease is understood to include one or more compounds of the present invention or its pharmaceutically useful salt to the individual administration medicine significant quantity of this treatment of needs.The present invention also comprises pharmaceutical composition, and it comprises one or more compounds of the present invention and/or its pharmaceutically useful salt and one or more pharmaceutically useful carriers, vehicle etc.
Also understanding dosage, treatment plan and the administering mode of these compounds will will be judged by related doctor according to disease of being treated and individual the variation.The administration of preferred one or more compounds of the present invention begins with low dosage, and increases until obtaining required effect.
Effective administration of these compounds can about 0.1mg/ days an about 1000mg/ days effective dose provide, preferred administration will be with individually dosed or two or more separate doses about 10mg/ days-Yue 600mg/ days.This dosage can be used active compound of the present invention targeted therapy person's blood dosing by any way, comprises oral, parenteral (comprising intravenously, intraperitoneal and subcutaneous injection) and through skin.Be used for this disclosure, percutaneous dosing is understood to include all liners that pass human body surface and body passage, comprises the administration of epithelium and mucosal tissue.This administration can be carried out with washing lotion, creme, foaming agent, patch, suspension agent, solution and suppository (rectum and vagina) with compound of the present invention or its pharmaceutically useful salt.
The oral preparations that contains active compound of the present invention can comprise any conventional oral form of using, and comprises tablet, capsule, cheek form, lozenge, lozenge and liquid oral, suspension agent or solution.Capsule can contain active compound and inert filler and/or thinner, for example pharmaceutically useful starch (for example corn, potato or tapioca (flour)), sucrose, artificial sweetener, cellulose powder, for example mixture of crystallization and Microcrystalline Cellulose, flour, gelatin, natural gum etc.Useful tablet formulation can be by conventional drawing method; wet granulation or the preparation of dried prilling process and use pharmaceutically useful thinner; binding agent; lubricant; disintegrating agent; suspend or solubilizing agent; include but not limited to Magnesium Stearate; stearic acid; talcum; Sodium Lauryl Sulphate BP/USP; Microcrystalline Cellulose; calcium carboxymethylcellulose; Polyvinylpyrolidone (PVP); gelatin; Lalgine; gum arabic; xanthan gum; Trisodium Citrate; composition silicate; lime carbonate; glycine; dextrin; sucrose; Sorbitol Powder; Lin Suanergai; calcium sulfate; lactose; kaolin; mannitol; sodium-chlor; talcum; dry starch and Icing Sugar.Oral preparations of the present invention can adopt standard delay or time-delay delivery formulations to change the absorption of active compound.Suppository can be prepared by traditional material, comprises theobroma oil, contains or do not contain the fusing point of additional wax with change suppository, and glycerine.Can also use water soluble suppository bases, for example the different molecular weight polyethylene glycol class.
The present invention also provides the method for preparation I compound, and it comprises one of following: a) with the compound of following formula:
Or its reactive derivative, for example carboxylic acid halides, wherein n, R
1, R
2, Z and Y be as defined above, the compound of acylations following formula:
R wherein
3, R
4, R
5With X be as defined above, obtain formula I compound; Or b) make the compound of following formula:
Wherein X, Z, R
1, R
2, R
3, R
4And R
5Be as defined above, hal represents halogen, chlorine or bromine for example, and the amine reaction of following formula:
H-Y (V) wherein Y is as defined above, obtains formula I compound, or c) debenzylation R wherein
4And/or R
5Be the formula I compound of the benzyl that optionally replaces, obtain wherein R
4And/or R
5Be the formula I compound of hydrogen, or e) esterification R wherein
1, R
2Or R
3At least one be that the formula I compound of hydroxyl is its ester derivative.
Be used for carrying out aforesaid method method a) → e) and be well known in the prior art and/or illustrate in following scheme.
Compound of the present invention can be by method preparation well known in the prior art, and for example initial or core indoles can be by the general method preparation of following scheme 1.
Scheme 1
Synthetic α-the bromoketone (b) by the suitable replacement of heating in DMF of the initial indoles of 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-Methyl-1H-indole and required aniline (a) are to form indoles (c).(amino ethoxy) of the present invention phenylformic acid side chain can be by Jones etc., J.Med.Chem., 1984,27 volumes, the general method of the instruction among the No.8 1057-1066 or preparation as shown in scheme 2, and be coupled on the core Benzazole compounds through the method for scheme 3.
Scheme 2
Scheme 3
Embodiment 1[5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indoles-1-yl]-[4-(the 2-piperidines-
1-base-oxyethyl group)-phenyl]-ketone (methanone)
To the initial indoles of 2.42g (0.00577mol) (c), (5-benzyloxy-2-(4-benzyloxy-phenyl)-3-Methyl-1H-indole) in deep cooling (78 ℃) solution of the anhydrous THF of 60ml at N
2Under add 2.6g (0.00866mol) acyl chlorides (h), (4-(2-piperidines-1-base-oxyethyl group) benzoyl chlorine, hydrochloride) stirred 20 minutes down at-78 ℃.In reaction mixture, drip 22ml (0.0216mol) two (trimethyl silyl) sodium amide (the 1.0M solution in THF), stirred 30 minutes down at-78 ℃.Make reaction mixture reach 0 ℃ 4 hours, at room temperature 1 hour subsequently.Add the 100ml ethyl acetate in crude product mixture, with (2 * 50ml) washings of aqueous carbonic acid hydrogen sodium.Collect organic phase, water (2 * 50ml), the saturated brine washing, remove, use dried over mgso, filtration and in rotatory evaporator, be evaporated to dried.Crude product obtains the 1.25g yellow solid through HPLC.
Mp＝48-51℃；
1H?NMR(DMSO)7.55-7.30(m，11H)，7.24-7.16(m，5H)，6.94-
6.88(m，5H)，5.18(s，2H)，5.05(s，2H)，4.09(t，2H，J＝5.8Hz)，2.19(t，2H，J＝
5.8Hz)，2.41-2.38(m，4H)，2.21(s，3H)，1.51-1.35(m，6H)；IR?3440，2900，1610
Cm
-1MS eI m/z 651 (M+); CHN is to C
43H
42N
2O
40.25H
2The calculated value of O.
Embodiment 2[5-hydroxyl-2-(4-hydroxyl-phenyl)-3-methyl-indoles-1-yl]-[4-(2-piperidines-1-base-
Oxyethyl group)-phenyl]-ketone
In the solution of 0.78g (0.00120mol) [5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indoles-1-yl]-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-ketone (as mentioned above) in the accurate ethanol of the anhydrous THF of 5ml and 5ml at N
2The 10%Pd/C that adds 1.4ml (0.0120mol) cyclohexadiene and 0.39g (half of benzyloxy initial substance quality) down at room temperature stirs and spends the night.Filter reaction mixture is evaporated to dried in rotatory evaporator.In crude product, add the 100ml ethyl acetate, the organic phase water (2 * 50ml), the saturated brine washing, remove, use dried over mgso, filtration and in rotatory evaporator, be evaporated to dried.Crude product obtains the 0.30g light yellow solid through HPLC.Mp=127-130 ℃;
1H NMR (DMSO) 9.47 (s, 1H), 9.17 (s, 1H), 7.48 (d, 2H, J=8.6Hz), 7.21 (d, 1H, J=8.8Hz), 7.03 (d, 2H, J=8.4Hz), 6.90-6.85 (m, 3H), 6.69-6.62 (m, 3H), 4.07 (q, 2H, J=5.8Hz), 2.62 (t, 2H, J=5.8Hz), 2.40-2.39 (m, 4H), 2.15 (s, 3H), 1.52-1.47 (m, 6H); IR 3440,2900,1610cm
-1MS eI m/z 471 (M+); CHN is to C
29H
30N
2O
40.5H
2The calculated value of O.
Embodiment 3
4-(2-piperidines-1-base-oxyethyl group)-benzoyl chloride hydrochloride salt
Title compound such as Jones, Charles D., Journal of MedicinalChemistry, 1984,27 volumes, No.8, the described preparation of 1057-1066 page or leaf.
(1.0g 3.7mmol) at room temperature adds thionyl chloride (0.3ml, 4.4mmol) solution in the 10ml chloroform in the solution in the 50ml chloroform to acid hydrochloride 1.The solution that obtains kept 6 hours down at 60 ℃.The reaction mixture cool to room temperature dilutes with hexane.Make reaction mixture be cooled to 0 ℃ subsequently, by the acyl chloride hydrochloride that filters, dry separation obtains, 2, it need not purifying and is used for the acylations step.
Estrogen receptor combination/competition experiments purpose: be used for determining at the compound of estrogen receptor (ER) combination with the competition of 17 beta estradiols.The mode of accepting extensively that is used for estrogen effect is through its high-affinity receptor protein.Therefore demonstration can regulate the physiological process relevant with estrogen effect in conjunction with the compound of ER ability.
Method: be subjected to body preparation: cross and express the Chinese hamster ovary celI of estrogen receptor at 150mm
2The charcoal that applies in the DMEM+10% dextran in the dish is grown in the foetal calf serum of peeling off.Plate PBS washed twice is used 10mM Tris-HCl, pH7.4,1mM EDTA washing 1 time.Cell is placed on cell suspending liquid on ice subsequently by scraping the surface results.Cell triggers with twice 10 seconds with portable mechanical tissue pulverizer and pulverizes, and crude preparation by using centrifugal 20 minutes at 12000xg rotates the cytosol that obtained not having ribosome in 60 minutes at 100000xg then, with the cytosol freeze-drying, stores down at-80 ℃.The protein concn of cytosol uses BSA to determine as reference standard protein with the BCA test.In conjunction with test conditions:
Competition experiments is at 96 orifice plate (polystyrene of total input [3H]-17 beta estradiol of combination＜2.0%
*) in carry out, it is triplicate to collect each data point.With 100 μ g/100 μ l be subjected to the body preparation five equilibrium in each hole, when estimating 100x and 500x competitor concentration, in pre-competition process, add the 2.5nM[3H of 50 μ l volumes] Sa of 17 beta estradiols+competitor (or buffer reagent).For measuring IC
50, when estimating the competitor of 12 concentration, only use 0.8nM[3H] and 17 beta estradiols.Plate was at room temperature cultivated 2.5 hours, when culturing process finishes, each hole adds the charcoal (5% applies the gac of 0.05%69K dextran) that the ice-cooled dextran of 150 μ l applies, plate descended centrifugal 5 minutes at 4 ℃ with 900xg immediately, take out 200 μ l supernatant liquors and be used for scintillation counting, whichever at first take place, sample count down to 2% or 10 minute.
Because polystyrene absorbs a small amount of [3H] 17 beta estradiols, contains radioactivity and cytosol, but the hole that charcoal useless is handled be included in quantitative obtainable isotropic substance.In addition, contain radioactivity but the hole that do not contain cytosol adds charcoal handles to determine the DPM that can not remove of [3H] 17 beta estradiols.Use Corning#25880-96 96 orifice plates, because they show in conjunction with minimum estradiol in these trials.Interpretation of result:
With one group of quenched standard radioactive count per minute (CPM) is converted into per minute automatically with Beckman LS7500 scintillometer and changes in quality (DPM) to obtain the H# of each sample.Estradiol uses following formula in conjunction with % in the presence of 100 or 500 times of competitors in order to calculate: ((DPM sample-do not remove with charcoal DPM)/(DPM estradiol-do not remove with charcoal DPM)) * 100%=estradiol is in conjunction with %
For obtaining IC
50Curve, in conjunction with % with respect to [compound] trace, IC
50By being up to the compound generation that shows＞10% competition under the 500x competitor concentration.Reference compound:
Different reference compounds are estimated, measured their IC
50Concentration.These required compound concentrations of [3H] 17 beta estradiols of displacement 50% are:
Estradiol: 0.08 μ M
Tamoxifen: 4.50 μ M
Raloxifene: 0.04 μ M
17 α-two-hydrogen equilin: 0.15 μ M test-results:
For compound applicability of the present invention is described, the compound of embodiment 2 is with respect to the standard tamoxifen, i.e. (Z)-2-[4-(1,2-phenylbenzene-1-butylene base)-phenoxy group]-N, the N-dimethyl amine, and raloxifene, i.e. [6-hydroxyl-2-(4-hydroxyl-phenyl)-benzo [b] thiene-3-yl-]-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-ketone is tested.Should understand 17 beta estradiols as standard and in receptor binding assays, have 100% combination.
Compound receptor binding assays-IC
50The transfection test
Embodiment 2 2.0 * 10
-7M concentration contrast %
1×10
-6M 0
1×10
-6M+
1nM estradiol 13
Tamoxifen 4.5 * 10
-6M concentration contrast %
1×10
-6M 0
1×10
-6M+
1nM estradiol 10
Raloxifene 4 * 10
-8M concentration contrast %
1×10
-6M 0
1×10
-6M+
1nM estradiol 0
Claims (14)
1. the compound of following formula or its pharmaceutically useful salt:
Wherein:
R
1, R
2And R
3Be selected from H, halogen, C respectively
1-C
6Alkoxyl group ,-CF
3,-NO
2, cyano group, C
1-C
6Alkyl (straight or branched), trifluoromethyl ,-OH or their C
1-C
12Ester (straight or branched) or C
1-C
12Alkyl oxide (straight or branched or ring-type), or C
1-C
6Halogenated ethers;
R
4And R
5Be selected from H or benzyl respectively, benzyl is optionally by C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-CF
3, or halogen replace;
X is H, C
1-C
6Alkyl or CF
3
Z is O or S;
N is 2 or 3;
Y is selected from:
A) group of following formula:
Wherein R ' is identical or different C
1-C
6Low alkyl group, or
B) be selected from following group:
2. the compound of claim 1, wherein R
1And R
2Be selected from H, C respectively
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-CF
3With-NO
2Or its pharmaceutically useful salt.
3. claim 1 or 2 compound, wherein Z is O.
4. one of any compound of claim 1-3, wherein R
3And R
4Be H.
5. one of any compound of claim 1-4, wherein R
1And R
2Be H.
6. one of any compound of claim 1-5, wherein n is 2.
7. one of any compound of claim 1-6, wherein Y is piperidine ring or its pharmaceutically useful salt.
8. the compound of claim 1, it is [5-benzyloxy-2-(4-benzyloxy phenyl)-3-skatole-1-yl]-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-ketone.
9. the compound of claim 1, it is [5-hydroxyl-2-(4-hydroxyl-phenyl)-3-skatole-1-yl]-[4-(2-piperidines-1-base-oxyethyl group) phenyl]-ketone, or its pharmaceutically useful salt.
10. treat or prevent the method for bone loss in Mammals, this method comprises to the compound of the claim 1 of the Mammals effective dosage of needs or its pharmaceutically useful salt.
11. treatment or prevention are caused or the method for relative morbid state or syndromes that by estrogen deficiency this method comprises to the compound of the claim 1 of the Mammals effective dosage of needs or its pharmaceutically useful salt in Mammals.
12. the method for treatment or preventing cardiovascular disease in Mammals, this method comprises to the compound of the claim 1 of the Mammals effective dosage of needs or its pharmaceutically useful salt.
13. the preparation formula I compound of claim 1 or the method for its pharmaceutically useful salt, it comprises one of following:
A) compound of usefulness following formula:
Or its reactive derivative, for example carboxylic acid halides, wherein n, R
1, R
2, Z and Y such as claim 1 definition, the compound of acylations following formula:
R wherein
3, R
4, R
5Define as above with X, obtain formula I compound; Or
B) make the compound of following formula:
Wherein X, Z, R
1, R
2, R
3, R
4And R
5Such as claim 1 definition, hal represents halogen, chlorine or bromine for example, and the amine reaction of following formula:
H-Y (V) wherein Y such as claim 1 definition, obtain formula I compound, or
C) debenzylation R wherein
4And/or R
5The formula I compound of optionally substituted claim 1 definition obtains wherein R
4And/or R
5Be the formula I compound of hydrogen, or
E) esterification R wherein
1, R
2Or R
3At least one be that the formula I compound of claim 1 definition of hydroxyl is its ester derivative.
14. pharmaceutical composition, it contains one of any compound or its pharmaceutically useful salt and the pharmaceutically useful carrier of claim 1-9.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26241399A | 1999-03-04 | 1999-03-04 | |
| US09/262,413 | 1999-03-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1342144A true CN1342144A (en) | 2002-03-27 |
Family
ID=22997395
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00804545A Pending CN1342144A (en) | 1999-03-04 | 2000-02-22 | N-substituted benzoyl indoles as estrogenic agents |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1159268A1 (en) |
| JP (1) | JP2002538141A (en) |
| CN (1) | CN1342144A (en) |
| AR (1) | AR022797A1 (en) |
| AU (1) | AU3859400A (en) |
| CA (1) | CA2364914A1 (en) |
| MX (1) | MXPA01008911A (en) |
| WO (1) | WO2000051983A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100506795C (en) * | 2003-06-18 | 2009-07-01 | 中国科学院上海药物研究所 | Indene ketone diindyl class compound, preparation method and medical use thereof |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5998402A (en) | 1996-04-19 | 1999-12-07 | American Home Products Corporation | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents |
| US7632955B2 (en) | 2001-12-13 | 2009-12-15 | National Health Research Institutes | Indole compounds |
| US6933316B2 (en) | 2001-12-13 | 2005-08-23 | National Health Research Institutes | Indole compounds |
| US7528165B2 (en) | 2001-12-13 | 2009-05-05 | National Health Research Institutes | Indole compounds |
| WO2004026823A1 (en) * | 2002-09-20 | 2004-04-01 | Pfizer Products Inc. | Amide and sulfonamide ligands for the estrogen receptor |
| US7250440B2 (en) | 2003-08-12 | 2007-07-31 | Wyeth | (Hydroxyphenyl)-1H-indole-3-carbaldehyde oxime derivatives as estrogenic agents |
| US7456289B2 (en) | 2004-12-31 | 2008-11-25 | National Health Research Institutes | Anti-tumor compounds |
| RS54165B1 (en) | 2008-04-16 | 2015-12-31 | Karo Bio Ab | Novel estrogen receptor ligands |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR950701317A (en) * | 1992-05-08 | 1995-03-23 | 오오쓰까 아끼히꼬 | Indole Derivative |
| SK281737B6 (en) * | 1996-04-19 | 2001-07-10 | American Home Products Corporation | 2-phenylindol compounds, pharmaceutical composition containing them and their use |
-
2000
- 2000-02-22 JP JP2000602211A patent/JP2002538141A/en active Pending
- 2000-02-22 CA CA002364914A patent/CA2364914A1/en not_active Abandoned
- 2000-02-22 CN CN00804545A patent/CN1342144A/en active Pending
- 2000-02-22 AU AU38594/00A patent/AU3859400A/en not_active Abandoned
- 2000-02-22 WO PCT/US2000/004386 patent/WO2000051983A1/en not_active Application Discontinuation
- 2000-02-22 MX MXPA01008911A patent/MXPA01008911A/en unknown
- 2000-02-22 EP EP00917652A patent/EP1159268A1/en not_active Withdrawn
- 2000-03-01 AR ARP000100898A patent/AR022797A1/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100506795C (en) * | 2003-06-18 | 2009-07-01 | 中国科学院上海药物研究所 | Indene ketone diindyl class compound, preparation method and medical use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002538141A (en) | 2002-11-12 |
| EP1159268A1 (en) | 2001-12-05 |
| WO2000051983A1 (en) | 2000-09-08 |
| AU3859400A (en) | 2000-09-21 |
| CA2364914A1 (en) | 2000-09-08 |
| MXPA01008911A (en) | 2002-10-23 |
| AR022797A1 (en) | 2002-09-04 |
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| C53 | Correction of patent for invention or patent application | ||
| CB02 | Change of applicant information |
Applicant after: Wyeth Corp. Applicant before: American Home Products Corp. |
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Free format text: CORRECT: APPLICANT; FROM: AMERICAN HOME PRODUCTS CORP. TO: WYETH CORP. |
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| C12 | Rejection of a patent application after its publication | ||
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