CN1450913A - Combination use of bisphosphonates, estrogenic agents and optionally estrogens - Google Patents
Combination use of bisphosphonates, estrogenic agents and optionally estrogens Download PDFInfo
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- CN1450913A CN1450913A CN01815091A CN01815091A CN1450913A CN 1450913 A CN1450913 A CN 1450913A CN 01815091 A CN01815091 A CN 01815091A CN 01815091 A CN01815091 A CN 01815091A CN 1450913 A CN1450913 A CN 1450913A
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- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
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Abstract
This invention comprises methods of treating bone disorders and lowering blood LDL levels comprising administration of a bisphosphonate, and compound of the formula (I) or (II), wherein Z is a moiety selected from the group of (a), (b), or (c); wherein: R1 is selected from H, OH or the C1-C12 alkyl ethers thereof, benzyloxy, or halogen; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety (1); R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof, and optionally an estrogen.
Description
The present invention relates to use substituted indole compound and bisphosphonates to unite and be used to strengthen bone and treatment, prevent, suppress or alleviate the osteopathia method of (comprising osteoporosis and Paget) with one or more optional estrogen, and relevant Pharmaceutical composition and medicine box.
Background technology
EP 0 802 183 A1 and United States Patent (USP) have been introduced the substituted indole compound of following formula for the 5th, 780, No. 497:
Or
And they are as the purposes of estrogenic drug, comprise treatment bone loss, cardiovascular disease, with endothelial tissue or endothelium sample hamartoplasia or misgrowth is relevant or because of its disease that causes and estrogen deficiency disease or syndrome.
EP 0 802 184 A1 that announced on October 22nd, 1997 have introduced the similar applications of following formula substituted indole compound.
Or
Similar benzazolyl compounds with following formula:
Or
Be described in United States Patent (USP) the 5th, 880, No. 137 (Miller etc.).
Filipponi P etc.: the ring-type clodronate is effective to prevent bone loss after the menopause: the comparative study of percutaneous Hormone Replacement Therapy.J?Bone?Min?Res?10：697-703,1995。
Explanation of the present invention
The present invention includes treatment, prevent, alleviate or suppress the method for mammal (preferred human) osteopathia (comprising osteoporosis or Paget), described method comprises and gives the following compositions that it needs the medicinal effective dose of mammal:
I) the bisphosphonates chemical compound of medicinal effective dose, for example (but being not limited to) alendronic Acid ester, risedronic acid ester, Tiludronic acid, ibandronic acid ester, she for phosphonate ester, clodronic acid ester, minodronic acid ester, pamidronic acid ester, Zometa, she blocks the pharmaceutically acceptable salt of phosphonate ester, Olpadronate, neridronic acid ester or these bisphosphonates chemical compounds; With
The ii) substituted indole compound of the following formula I of medicinal effective dose or II or its pharmaceutically acceptable salt:
Or
Wherein Z is selected from following part:
Or
Wherein:
R
1Be selected from H, OH or its C
1-C
12Ester (straight or branched) or C
1-C
12(straight or branched or ring-type) alkyl ether, benzyloxy or halogen; Or comprise the C of trifluoromethyl ethers and trichloromethyl ether
1-C
4Halogen ether.
R
2, R
3, R
5And R
6Independently be selected from H, OH or its C
1-C
12Ester (straight or branched) or C
1-C
12Alkyl ether (straight or branched or ring-type), halogen or comprise trifluoromethyl ethers and the C of trichloromethyl ether
1-C
4Halogen ether, cyano group, C
1-C
6Alkyl (straight or branched) or trifluoromethyl, but R worked as
1During for H, R
2Be not OH
R
4Be selected from H, OH or its C
1-C
12Ester (straight or branched) or C
1-C
12Alkyl ether (straight or branched or ring-type), benzyloxy, halogen or comprise trifluoromethyl ethers and the C of trichloromethyl ether
1-C
4Halogen ether, cyano group, C
1-C
6Alkyl (straight or branched) or trifluoromethyl;
X is selected from H, C
1-C
6Alkyl, cyano group, nitro, trifluoromethyl, halogen;
N is 1,2 or 3;
Y is selected from:
A) with the lower part:
R wherein
7And R
8Independently be selected from H, C
1-C
6Alkyl or optional by CN, C
1-C
6Alkyl (straight or branched), C
1-C
6Alkoxyl (straight or branched), halogen ,-OH ,-CF
3Or-OCF
3The phenyl that replaces; Perhaps R
7And R
8Be combined into-(CH
2)
p-, wherein p is the integer of 2-6, make to form a ring, described ring optional by at the most 3 be selected from following substituent group and replace: hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONH (C
1-C
4) alkyl ,-NH
2, C
1-C
4Alkyl amino, two-(C
1-C
4) alkyl amino ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl and-NO
2
B) five yuan of saturated, unsaturated or part unsaturated heterocycles, contain at the most two to be selected from-O-,-NH-,-N (C
1-C
4Alkyl)-,-N=and-S (O)
m-hetero atom, wherein m is the integer of 0-2, described heterocycle is optional independently to be selected from following substituent group replacement by 1-3: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Acyloxy, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H-,-CN-,-CONHR
1,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2R
1,-NHCOR
1,-CONH (C
1-C
4) alkyl ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl ,-NO
2With optional by 1-3 (C
1-C
4) phenyl that replaces of alkyl;
C) hexa-atomic saturated, unsaturated or part unsaturated heterocycle, contain at the most two to be selected from-O-,-NH-,-N (C
1-C
4Alkyl)-,-N=and-S (O)
m-hetero atom, wherein m is the integer of 0-2, described heterocycle is optional independently to be selected from following substituent group replacement by 1-3: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Acyloxy, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H-,-CN ,-CONHR
1,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2R
1,-NHCOR
1,-CONH (C
1-C
4) alkyl ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl ,-NO
2With optional by 1-3 (C
1-C
4) phenyl that replaces of alkyl;
D) seven yuan of saturated, unsaturated or part unsaturated heterocycles, contain at the most two to be selected from-O-,-NH-,-N (C
1-C
4Alkyl)-,-N=and-S (O)
m-hetero atom, wherein m is the integer of 0-2, described heterocycle is optional independently to be selected from following substituent group replacement by 1-3: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Acyloxy, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONHR
1,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2R
1,-NHCOR
1,-CONH (C
1-C
4) alkyl ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl ,-NO
2With optional by 1-3 (C
1-C
4) phenyl that replaces of alkyl; Or
E) bridging or condensed bicyclic heterocycle, contain 6-12 carbon atom and contain at the most two be selected from-O-,-NH-,-N (C
1-C
4Alkyl)-and-S (O)
m-hetero atom, wherein m is the integer of 0-2, described heterocycle is optional independently to be selected from following substituent group replacement by 1-3: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Acyloxy, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONHR
1,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2R
1,-NHCOR
1,-CONH (C
1-C
4) alkyl ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl ,-NO
2With optional by 1-3 (C
1-C
4) phenyl that replaces of alkyl;
And it is optional
Iii) one or more estrogen of medicinal effective dose or its pharmaceutically acceptable salt.
The preferred substituted indole compound of the present invention is chemical compound and the pharmaceutically acceptable salt thereof with above-mentioned formula I or II, wherein:
R
1Be selected from H, OH or its C
1-C
12Ester or alkyl ether, benzyloxy, halogen;
R
2, R
3, R
5And R
6Independently be selected from H, OH or its C
1-C
12Ester or alkyl ether, halogen, cyano group, C
1-C
6Alkyl or trihalomethyl group, preferred trifluoromethyl, but work as R
1During for H, R
2Be not OH;
R
4Be selected from H, OH or its C
1-C
12Ester or alkyl ether, benzyloxy, halogen, cyano group, C
1-C
6Alkyl or trihalomethyl group;
X is selected from H, C
1-C
6Alkyl, cyano group, nitro, trifluoromethyl, halogen;
Y is with the lower part
R
7And R
8Independently be selected from H, C
1-C
6Alkyl or be combined into-(CH
2)
p-, wherein p is the integer of 2-6, make to form a ring, described ring optional by at the most 3 be selected from following substituent group and replace: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONH (C
1-C
4) alkyl ,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl and-NO
2
Above-mentioned R
7And R
8The ring that is connected to form can include but not limited to aziridine, azetidine, pyrrolidine, piperidines, hexa-methylene amine or heptamethylene amine ring.
The most preferred substituted indole compound of the present invention is chemical compound and the pharmaceutically acceptable salt thereof with above-mentioned formula formula I or II, wherein R
1Be OH; R
2-R
6The same definition; X is selected from Cl, NO
2, CN, CF
3Or CH
3Y is with the lower part
And R
7And R
8Link together and be-(CH
2)
r-, wherein r is the integer of 4-6, forms an optional quilt 3 rings that are selected from following substituent group replacement at the most: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONH (C
1-C
4) alkyl ,-NH
2, C
1-C
4Alkyl amino, two-(C
1-C
4) alkyl amino ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl and-NO
2
In another embodiment of the invention, work as R
7And R
8Link together and be-(CH
2)
pIn-time, wherein p is the integer of 2-6, preferred 4-6, and so the ring that forms is optional is selected from C by 1-3
1-C
3Alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro ,-substituent group of CN replaces.
The present invention includes sulfate, sulfamate and the sulfuric ester of the phenolic group of substituted indole.The easy sulfur trioxide prepared in reaction of sulfate by described free phenol compounds and amine (for example pyridine, trimethylamine, triethylamine etc.) complexation.Sulfamate can prepare by for example handling described free phenol compounds with the sulfonamides chlorine of required amino or alkyl amino or dialkyl amido in the presence of the pyridine at suitable alkali.Sulfuric ester can suitable alkali for example in the presence of the pyridine with described free phenol and required alkanesulfonyl chloride prepared in reaction.In addition, the present invention includes the chemical compound of the phosphate ester that contains phenol and the chemical compound of dialkyl phosphate.Phosphate ester can prepare by described phenol and suitable chlorine phosphatase reaction.Dialkyl phosphate can hydrolysis produce the free phosphorus acid esters.Generate under the situation of required dialkyl phosphinic acid ester of described phenol also claimed described phosphinate when time phosphonic chloride reaction of described phenol and required dialkyl group.
The present invention includes the acceptable substituted indole salt that generates with mineral acid or organic acid additive reaction.Mineral acid for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, nitric acid and organic acid for example acetic acid, propanoic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, LOMAR PWA EINECS 246-676-2, camphorsulfonic acid, benzenesulfonic acid all are operable acid.Known have alkaline nitrogen compound can with many different acid (Bronsted acid and aprotic acid) complexation, usually preferably give the The compounds of this invention of acid-addition salts form.In addition, the present invention includes the quaternary ammonium salt of chemical compound described herein.These salt can be by for example alkyl halide or benzyl halide react and prepare with the nucleophilic amine of described side chain and suitable reactive alkylating agent.
The present invention includes and strengthen bone and treatment, suppress, alleviate or prevent the method for following disease: osteopathia (comprises that Paget and osteoporosis (comprise the osteoporosis that steroid causes, postmenopausal osteoporosis)), hypercalcemia that tumor causes and pernicious molten bone osteopathia, shift bone degraded and the broken ring of multiple myeloma characteristic bone that causes by cancer (for example breast carcinoma and carcinoma of prostate), bone is rebuild disease, the molten bone osteopathia of hypercalcemia that tumor causes and malignant tumor.Dosage regimen of the present invention also can be used for reducing the risk of receiver's fracture and the method for generation.
These methods include needs mammal to give the substituted indole a kind of disclosed by the invention of bisphosphonates and medicinal effective dose to it, and chooses one or more estrogen of medicinal effective dose wantonly.Described medication can be therapeutic or preventive usage.The preferred substituted indole compound that wherein is used for these methods is 1-[4-(2-azepan-1 base (Azepan-lyl)-ethyoxyl)-benzyl]-2-(4-hydroxyl-phenyl)-3-Methyl-1H-indole-5-phenol (being also referred to as TSE-424) and 2-(4-hydroxyl-phenyl)-3-methyl isophthalic acid-(4-(2-piperidines-1-base-ethyoxyl)-benzyl)-IH-indole-5-phenol (being also referred to as ERA-923).
The present invention includes in conjunction with bisphosphonates chemical compound and optional estrogen and use following formula III or first subclass substituted indole compound of IV or the method for its pharmaceutically acceptable salt:
Or
Comprising R
1, R
2, R
3, R
4, R
5, R
6, n, X and Y the same definition of variable substituent group.
Preferred substituted indole compound is chemical compound and the pharmaceutically acceptable salt thereof of above-mentioned formula III or IV in first subclass compound, wherein:
R
1Be selected from H, OH or its C
1-C
12Ester or alkyl ether, benzyloxy or halogen;
R
2, R
3, R
5And R
6Independently be selected from H, OH or its C
1-C
12Ester or alkyl ether, halogen, cyano group, C
1-C
6Alkyl or trihalomethyl group, preferred trifluoromethyl, but work as R
1During for H, R
2Be not OH;
R
4Be selected from H, OH or its C
1-C
12Ester or alkyl ether, benzyloxy, halogen, cyano group, C
1-C
6Alkyl or trihalomethyl group;
X is selected from H, C
1-C
6Alkyl, cyano group, nitro, trifluoromethyl, halogen;
Y is with the lower part
R
7And R
8Independently be selected from H, C
1-C
6Alkyl or be combined into-(CH
2)
p-, wherein p is the integer of 2-6, make to form a ring, described ring optional by at the most 3 be selected from following substituent group and replace: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONH (C
1-C
4) alkyl ,-NH
2, C
1-C
4Alkyl amino, two C
1-C
4Alkyl amino ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl and-NO
2
Above-mentioned R
7And R
8The ring that is connected to form can include but not limited to aziridine, azetidine, pyrrolidine, piperidines, hexa-methylene amine or heptamethylene amine ring.
Most preferred substituted indole compound is chemical compound and the pharmaceutically acceptable salt thereof of said structure formula I or II, wherein R in first subclass compound
1Be OH; R
2-R
6The same definition; X is selected from Cl, NO
2, CN, CF
3Or CH
3Y is with the lower part
And R
7And R
8Link together and be-(CH
2)
r-, wherein r is the integer of 4-6, forms an optional quilt 3 rings that are selected from following substituent group replacement at the most: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONH (C
1-C
4) alkyl ,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl and-NO
2
In another embodiment of first subclass compound, work as R
7And R
8Link together and be-(CH
2)
pIn-time, wherein p is the integer of 2-6, preferred 4-6, and so the ring that forms is optional is selected from C by 1-3
1-C
3Alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro ,-substituent group of CN replaces.
A sub-class of the substituted indole compound is preferably the following compounds or a pharmaceutically
Acceptable salt thereof:
5 - Benzyloxy-2 - (4 - ethoxy - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl
Yl]-1H-indole;
5 - benzyloxy-2 - phenyl-3 - methyl-1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -
1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1 - [4 - (2 - aza ring heptane-1 - yl - acetic
Oxy) - benzyl]-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1 - [4 - (2 - 2-isopropyl-amino-1 - yl -
Ethoxy) - benzyl]-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1 - [4 - (2 - butyl - methyl-1 - yl - acetic
Oxy) - benzyl]-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1 - {4 - dimethylamino) ethoxy] benzyl
Yl}-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1 - {4 - [2 - (2 - methyl - piperidin-1 - yl) -
Ethoxy] - benzyl}-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1 - {4 - [2 - (3 - methyl - piperidin-1 - yl) -
Ethoxy] - benzyl}-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1 - {4 - [2 - (4 - methyl - piperidin-1 - yl) -
Ethoxy] - benzyl}-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1-{4 - [2 - ((cis) -2,6 - dimethyl - piperazine
-1 - yl) - ethoxy] - benzyl}-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl - {4 - [2 - (1,3,3 - trimethyl-6 - aza -
Bicyclo [3.2.1] oct-6 - yl) - ethoxy] - benzyl}-1H-indole;
(1S, 4R) -5 - benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-{4 - [2 - (2 - aza - bicyclo
[2.2.1] hept-2 - yl) - ethoxy] - benzyl}-1H-indole;
5 - Benzyloxy-2 - (4 - fluoro - phenyl) -3 - methyl-1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) -
Benzyl]-1H-indole;
5 - Benzyloxy-2 - (4 - fluoro - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -
1H-indole;
5 - Benzyloxy-2 - (4 - chloro - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -
1H-indole;
5 - benzyloxy-2 - [3,4 - methylenedioxy - phenyl] -3 - methyl-1 - [4 - (2 - piperidin-1 - yl ethoxy
Yl) - benzyl]-1H-indole;
5 - benzyloxy-2 - [4 - isopropoxy - phenyl] -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) -
Benzyl]-1H-indole;
5 - benzyloxy-2 - [4 - methyl - phenyl] -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl
Yl]-IH-indole;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -5 - benzyloxy-2 - (3 - benzyloxy - benzene
Yl) -3 - methyl-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy-3 - fluoro - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxycarbonyl
Yl) - benzyl]-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy-3 - fluoro - phenyl) -3 - methyl-1 - [4 - (2 - aza ring heptane-1 - yl
- Ethoxy) - benzyl]-1H-indole;
5 - benzyloxy-2 - (3 - methoxy - phenyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -3 - methyl
Yl-1H-indole;
5 - benzyloxy-3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -2 - (4 - trifluoro - methoxy-
Yl - phenyl)-1H-indole;
(2 - {4 - [5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl - indol-1 - yl methyl] - phenoxy
Yl} - ethyl) - cyclohexyl - amine;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1 - {4 - methyl-piperazin-1 - yl) - ethoxy
Yl] - benzyl}-1H-indole;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -5 - benzyloxy-2 - (3 - methoxy - phenyl
Yl) -3 - methyl-1H-indole;
4 - {3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indole};
4 - {3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indol-2 - yl} - phenyl
Phenol;
3 - methyl - 2 - phenyl - 1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indole-5 - phenol;
4 - {5 - methoxy-3 - methyl-1 - {4 - [2 - (piperidin-1 - yl) - ethoxy] - benzyl}-1H-indole -
2 - group} - phenol;
2 - (4 - methoxy - phenyl) -3 - methyl-1 - {4 - [2 - (piperidin-1 - yl) - ethoxy] - benzyl}-1H-
Indol-5 - phenol;
5 - methoxy -2 - (4 - methoxy - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl
Yl]-IH-indole;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -5 - methoxy -2 - (4 - methoxy - phenyl
Yl) -3 - methyl-1H-indole;
2 - (4 - ethoxy - phenyl) -3 - methyl-1 - [4 - (2 - (piperidin-1 - yl - ethoxy) - benzyl]-1H-
Indol-5 - phenol;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -2 - (4 - ethoxy - phenyl) -3 - methyl-
-1H-indole-5 - phenol;
4 - {5 - fluoro-3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indol-2 - yl} -
Phenol;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -3 - methyl-2 - phenyl-1H-indole -
5 - phenol;
2 - (4 - hydroxy - phenyl) -3 - methyl-1 - [4 - (2 - pyrrolidin-1 - yl - ethoxy) - benzyl]-1H-indole
Indole -5 - phenol;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -2 - (4 - hydroxy - phenyl) -3 - methyl -
1H-indole-5 - phenol;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -2 - (4 - hydroxy - phenyl) -3 - methyl -
1H-indole-5 - phenol;
1 - [4 - (2-Azocan-1-yl - ethoxy) - benzyl] -2 - (4 - hydroxy - phenyl) -3 - methyl-1H-indole
Indole -5 - phenol;
2 - (4 - hydroxy - phenyl) -3 - methyl-1 - [4 - (2 - dimethyl-1 - yl - ethoxy) - benzyl]-1H-indole
Indole -5 - phenol;
2 - (4 - hydroxy - phenyl) -3 - methyl-1 - [4 - (2 - 2-ethyl-1 - yl - ethoxy) - benzyl]-1H-indole
Indole -5 - phenol;
1 - [4 - (2 - dipropylamino - ethoxy) - benzyl] -2 - (4 - hydroxy - phenyl) -3 - methyl-1H-indole
Indole -5 - phenol;
1 - [4 - (2 - 2-butylamino - ethoxy) - benzyl] -2 - (4 - hydroxy - phenyl) -3 - methyl-1H-indole
Indole -5 - phenol;
1 - [4 - (2 - diisopropylamino - ethoxy) - benzyl] -2 - (4 - hydroxy - phenyl) -3 - methyl-1H-
Indol-5 - phenol;
1 - {4 - [2 - (butyl - methyl - amino) - ethoxy] - benzyl} -2 - (4 - hydroxy - phenyl) -3 - methyl -
1H-indole-5 - phenol;
2 - (4 - hydroxy - phenyl) -3 - methyl-1 - {4 - [2 - (2 - methyl - piperidin-1 - yl) - ethoxy] - benzyl
Yl}-1H-indole-5 - phenol;
2 - (4 - hydroxy - phenyl) -3 - methyl-1 - {4 - [2 - (3 - methyl - piperidin-1 - yl) - ethoxy] - benzyl
Yl}-1H-indole-5 - phenol;
2 - (4 - hydroxy - phenyl) -3 - methyl-1 - {4 - [2 - (4 - methyl - piperidin-1 - yl) - ethoxy] - benzyl
Yl}-1H-indole-5 - phenol;
1 - {4 - [2 - (3,3 - dimethyl - piperidin-1 - yl) - ethoxy] - benzyl} -2 - (4 - hydroxy - phenyl) -3 -
Methyl-1H-indol-5 - phenol;
1 - {4 - [2 - ((cis) -2,6 - dimethyl - piperidin-1 - yl) - ethoxy] - benzyl} -2 - (4 - hydroxy -
Phenyl) -3 - methyl-1H-indol-5 - phenol;
2 - (4 - hydroxy - phenyl) -1 - {4 - [2 - (4 - hydroxy - piperidin-1 - yl) - ethoxy] - benzyl} -3 - methyl
Yl-1H-indole-5 - phenol;
(1S, 4R) -1 - {4 - [2 - (2 - aza - bicyclo [2.2.1] hept-2 - yl) - ethoxy] - benzyl} -2 - (4 -
Hydroxy - phenyl) -3 - methyl-1H-indol-5 - phenol;
2 - (4 - hydroxy - phenyl) -3 - methyl-1 - {4 - [2 - (1,3,3 - trimethyl-6 - azabicyclo [3.2.1]
Oct-6 - yl) - ethoxy] - benzyl}-1H-indole-5 - phenol;
2 - (4 - fluoro - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indole -
5 - phenol;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -2 - (4 - fluoro - phenyl) -3 - methyl-1H-
Indol-5 - phenol;
2 - (3 - methoxy - 4 - hydroxy - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl
Yl]-1H-indole-5 - phenol;
2 - benzo [1,3] dioxol-5 --3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxycarbonyl
Yl) - benzyl]-1H-indole-5 - phenol;
2 - (4 - isopropoxy - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-
Indol-5 - phenol;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -2 - (4 - isopropoxy - phenyl) -3 - methyl
Yl-1H-indole-5 - phenol;
2 - (4 - cyclopentyloxy - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-
Indol-5 - phenol;
3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -2 - (4 - trifluoromethyl-phenyl)-1H-
Indol-5 - phenol;
3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -2 - p-tolyl-1H-indol-5 -
Phenol;
2 - (4 - chloro - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indole -
5 - phenol;
2 - (2,4 - dimethoxy - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -
1H-indole-5 - phenol;
2 - (3 - hydroxy - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indole
-5 - Phenol;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -2 - (3 - hydroxy - phenyl) -3 - methyl -
1H-indole-5 - phenol;
2 - (3 - fluoro-4 - hydroxy - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -
1H-indole-5 - phenol;
2 - (3 - fluoro-4 - hydroxy - phenyl) -3 - methyl-1 - [4 - (aza ring heptane-1 - yl - ethoxy) - benzyl
Yl]-1H-indole-5 - phenol;
2 - (3 - methoxy - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indole
Indole -5 - phenol;
3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -2 - (4 - (Trifluoromethoxy) - phenyl) -
1H-indole-5 - phenol;
3 - chloro -2 - (4 - hydroxy - phenyl) -1 - [4 - (2 - pyrrolidin-1 - yl - ethoxy) - benzyl]-1H-indole
-5 - Phenol;
3 - chloro -2 - (4 - hydroxy - phenyl) -1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indole -
5 - phenol;
3 - chloro -2 - (4 - hydroxy - phenyl) -1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl]-1H-
Indol-5 - phenol;
3 - chloro -2 - (4 - hydroxy-2 - methyl - phenyl) -1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -
1H-indole-5 - phenol;
2 - (4 - hydroxy - phenyl) -3 - ethyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indole
-5 - Phenol;
5 - hydroxy-2 - (4 - hydroxy - phenyl) -1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indole
-3 - Carbonitrile;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -5 - hydroxy-2 - (4 - hydroxy - phenyl) -
1H-indole-3 - carbonitrile;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - chloro-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl
Yl]-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - chloro-1 - [4 - (2 - aza ring heptane-1 - yl - ethoxycarbonyl
Yl) - benzyl]-1H-indole;
5 - Benzyloxy-2 - (2 - methyl - 4 - benzyloxy - phenyl) -3 - chloro-1 - [4 - (2 - piperidin-1 - yl - ethoxycarbonyl
Yl) - benzyl]-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - ethyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl
Yl]-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl)-3 - cyano-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl
Yl]-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl)-3 - cyano-1 - [4 - (2 - aza ring heptane-1 - yl - acetic
Oxy) - benzyl]-1H-indole;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -2 - (4 - hydroxy - phenyl) -3 - methyl -
1H-indole-5 - phenol dipropionate;
1 - [4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl] -2 - (4 - hydroxy - phenyl) -3 - methyl -
1H-indole-5 - diamyl phenol ester;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -1 - [4 - (3 - piperidin-1 - yl - propoxy) - benzyl] -3 -
Methyl-1H-indole;
2 - (4 - hydroxy - phenyl) -3 - methyl-1 - {4 - [3 - (piperidin-1 - yl) - propoxy] - benzyl}-1H-indole
Indole -5 - phenol;
2 - (4 - hydroxy - phenyl) -1 - [3 - methoxy - 4 - (2 - piperidin-1 - yl - ethoxy) - benzyl] -3 - methyl
Yl-1H-indole-5 - phenol;
2 - (4 - hydroxy - phenyl) -1 - [3 - methoxy - 4 - (2 - aza ring heptane-1 - yl - ethoxy) - benzyl
Yl] -3 - methyl-1H-indol-5 - phenol;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1 - [3 - methoxy - 4 - (2 - piperidin-1 - yl -
Ethoxy) - benzyl]-1H-indole;
5 - Benzyloxy-2 - (4 - benzyloxy - phenyl) -3 - methyl-1 - [2 - methoxy - 4 - (2 - aza-cycloheptane
-1 - Yl - ethoxy) - benzyl]-1H-indole;
2 - (4 - hydroxy - phenyl) -3 - methyl-1 - [4 - (2 - piperidin-1 - yl - ethoxy) - benzyl]-1H-indole
-5 - Phenol.
...
First subclass compound can be by EP 0 802183 A1 and the United States Patent (USP) of announcing on October 22nd, 1997 the 5th, 780, the method of introducing in No. 497 or produce by other method known in the art, the theme of described patent is attached among the present invention by reference.Aryloxy group-alkyl-the dialkylamine or the aryloxy group-alkyl-cyclammonium that are used as intermediate in the production of above-claimed cpd can be as disclosed method production and uses among the WO 99/19293 that announced on April 22nd, 1999, and the theme of described patent also is attached among the present invention by reference.
Can be used for second subclass substituted indole compound of the present invention and comprise formula V or (VI) chemical compound or its pharmaceutically acceptable salt down:
Or
Comprising R
1, R
2, R
3, R
4, R
5, R
6, n, X and Y the same definition of variable substituent group.
Preferred substituted indole compound is following chemical compound and pharmaceutically acceptable salt and ester in second subclass compound:
(E)-and N, N-diethyl-3-{4-[5-hydroxyl-2-(4-hydroxyl-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide;
1 (E)-N-tert-butyl group-3-{4-[5-hydroxyl-2-(4-hydroxyl-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide;
(E)-pyrrolidinyl-3-{4-[5-hydroxyl-2-(4-hydroxyl-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide;
(E)-and N, N-dimethyl-3-{4-[5-hydroxyl-2-(4-hydroxyl-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide;
(E)-and N, N-dibutyl-3-{4-[5-hydroxyl-2-(4-hydroxyl-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide;
(E)-and the N-butyl, N '-methyl-3-{4-[5-hydroxyl-2-(4-hydroxyl-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide;
(E)-morpholino (morpholinino)-3-{4-[5-hydroxyl-2-(4-hydroxyl-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide;
(E)-3-{4-[5-hydroxyl-2-(4-hydroxyl-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide;
(E)-and N, methyl-3-{4-[5-hydroxyl-2-(4-hydroxyl-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide;
(E)-and N, N-dibutyl-3-{4-[5-hydroxyl-2-(4-fluoro-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide;
(E)-and the N-butyl, N '-methyl-3-{4-[5-hydroxyl-2-(4-fluoro-phenyl)-3-methyl-indole-1-ylmethyl]-phenyl }-acrylamide.
Second subclass indole substituted compound can be produced by method described in EP 0 802 184 A1 that announced on October 22nd, 1997 or by other method known in the art, and described patent is attached among the present invention by reference.
Can be used for the 3rd subclass compound of the present invention and comprise following formula VII and VIII chemical compound or its pharmaceutically acceptable salt:
Or
Wherein n is 1,2 or 3, comprises R
1, R
2, R
3, R
4, R
5, R
6, n, X and Y the same definition of variable substituent group.
Preferred compound in the 3rd subclass substituted indole is following chemical compound or its pharmaceutically acceptable salt or ester:
2-(4-hydroxyl-phenyl)-3-methyl isophthalic acid-[4-(3-N, N-dimethyl-1-base-third-1-alkynyl)-benzyl]-1H-indole-5-phenol;
2-(4-hydroxyl-phenyl)-3-methyl isophthalic acid-[4-(3-piperidines-1-base-third-1-alkynyl)-benzyl]-1H-indole-5-phenol;
2-(4-hydroxyl-phenyl)-3-methyl isophthalic acid-[4-(3-pyrrolidine-1-base-third-1-alkynyl)-benzyl]-1H-indole-5-phenol.
The 3rd subclass substituted indole compound can be produced by the 5th, 880, No. 137 (Miller etc.) middle methods of introducing of United States Patent (USP) or by other method known in the art, and described patent is attached among the present invention by reference.
All chemical compounds in first, second and the 3rd the subclass substituted indole compound of the present invention can further be further divided into more preferably chemical compound and the pharmaceutically acceptable salt thereof with above-mentioned formula I-VIII, wherein:
R
1Be selected from H, OH or its C
1-C
12Ester or alkyl ether, halogen;
R
2, R
3, R
4, R
5And R
6Independently be selected from H, OH or its C
1-C
12Ester or alkyl ether, halogen, cyano group, C
1-C
6Alkyl or trihalomethyl group, preferred trifluoromethyl, but work as R
1During for H, R
2Be not OH;
X is selected from H, C
1-C
6Alkyl, cyano group, nitro, trifluoromethyl, halogen;
Y is with the lower part
R
7And R
8Independently be selected from H, C
1-C
6Alkyl or be combined into-(CH
2)
p-, wherein p is the integer of 2-6, make to form a ring, described ring optional by at the most 3 be selected from following substituent group and replace: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONH (C
1-C
4) alkyl ,-NH
2, C
1-C
4Alkyl amino, two C
1-C
4Alkyl amino ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl and-NO
2
Above-mentioned R
7And R
8The ring that is connected to form can include but not limited to aziridine, azetidine, pyrrolidine, piperidines, hexa-methylene amine or heptamethylene amine ring.
The most preferred substituted indole compound of the present invention is chemical compound and the pharmaceutically acceptable salt thereof with said structure formula I-VIII, wherein R
1Be OH; R
2-R
6The same definition; X is selected from Cl, NO
2, CN, CF
3Or CH
3Y is with the lower part
And R
7And R
8Link together and be-(CH
2)
r-, wherein r is the integer of 4-6, forms an optional quilt 3 rings that are selected from following substituent group replacement at the most: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONH (C
1-C
4) alkyl ,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl and-NO
2
In another embodiment of substituted indole of the present invention, work as R
7And R
8Link together and be-(CH
2)
pIn-time, wherein p is the integer of 2-6, preferred 4-6, and so the ring that forms is optional is selected from C by 1-3
1-C
3Alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro ,-substituent group of CN replaces.
The present invention includes sulfate, sulfamate and the sulfuric ester of these substituted indole phenolic group.The easy sulfur trioxide prepared in reaction of sulfate by described free phenol compounds and amine (for example pyridine, trimethylamine, triethylamine etc.) complexation.Sulfamate can prepare by for example handling described free phenol compounds with the sulfonamides chlorine of required amino or alkyl amino or dialkyl amido in the presence of the pyridine at suitable alkali.Sulfuric ester can for example react described free phenol and required alkanesulfonyl chloride in the presence of the pyridine at suitable alkali and prepare.In addition, the present invention includes the phosphate compound that contains phenol and the chemical compound of dialkyl phosphate.Phosphate ester can prepare by described phenol and suitable chlorine phosphatase reaction.Dialkyl phosphate can hydrolysis produce the free phosphorus acid esters.Generate under the situation of required dialkyl phosphinic acid ester of described phenol also claimed phosphinate when time phosphonic chloride reaction of described phenol and required dialkyl group.
The present invention includes the acceptable salt of the substituted indole that generates with mineral acid or organic acid additive reaction.Mineral acid for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, nitric acid and organic acid for example acetic acid, propanoic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, LOMAR PWA EINECS 246-676-2, camphorsulfonic acid, benzenesulfonic acid all are operable acid.People know, have alkaline nitrogen compound can with many different acid (Bronsted acid and aprotic acid) complexation, and preferably give the The compounds of this invention of acid-addition salts form usually.In addition, the present invention includes the quaternary ammonium salt of chemical compound described herein.These salt can be by for example alkyl halide or benzyl halide react and prepare with the nucleophilic amine of described side chain and suitable reactive alkylating agent.
When using estrogen, the estrogen that can be used for preparation of the present invention comprises estrone, estriol, 1,3,5,7-estratetraen-3-ol-17-one, female diene (estradiene), (.+-.)-Equilenin., ethinyl estradiol, 17 beta estradiols, 17 'alpha '-dihydroequilenins, 17 β-dihydroequilenin (United States Patent (USP) 2,834,712), 17 α-dihydroequilin, 17 β-dihydroequilin, menstranol and conjugated estrogens, for example Premarin of Wyeth-Ayerst Laboratories
Product (P.O.Box 8299, Philadelphia, and PA 19101, U.S.A.).Phytoestrogen (for example equol or enterolactone) also can be used for preparation of the present invention and method.The preferred embodiments of the invention comprise utilizes the conjugation hormone (Premarin of Wyeth-Ayerst Laboratories for example
Product) with one or more formulas of the present invention (I) or (III) Pharmaceutical composition and the Therapeutic Method of chemical compound.(Solvay Pharmaceuticals for example, Inc. is with trade name Estratab for esterified estriol
Product sold) also can be used for preparation of the present invention.In addition, being preferred for of the present invention is described applicable estrogenic salt, most preferably sodium salt.The example of these preferred salt is an estrone sodium sulfate, the sodium sulfate 1,3,5,7-estratetraen-3-ol-17-one, sodium sulfate 17 α-dihydroequilin, sodium sulfate 17 alpha-estradiols, sodium sulfate δ 8,9-dehydrogenation estrone, the sodium sulfate (.+-.)-Equilenin., sodium sulfate 17 β-dihydroequilin, sodium sulfate 17 'alpha '-dihydroequilenins, sodium sulfate 17 beta estradiols, sodium sulfate 17 β-dihydroequilenin, the 3-estrone sodium sulfate, 3-sodium sulfate 1,3,5,7-estratetraen-3-ol-17-one, 3-sodium sulfate 17 α-dihydroequilin, 3-sodium sulfate 3 beta-hydroxies-female-5 (10), 7-diene-17-ketone, 20-sodium sulfate 5 alpha-pregnanes-3 β-20R-glycol, 3-sodium sulfate 5 alpha-pregnanes-3 β, 16 salmefamols-20-ketone, 3-sodium sulfate δ (8,9)-dehydrogenation estrone, female-3 β of 3-sodium sulfate, 17 salmefamols, 3-sodium sulfate 3 beta-hydroxies-female-5 (10)-alkene-17-ketone or 3-sodium sulfate 5 alpha-pregnanes-3 β, 16 α, the 20R-triol.Preferred estrone salt includes but not limited to sodium salt and piperate salt.Wherein being used for most preferably estrogen of the present invention is trade name Premarin
The conjugated estrogens product.
Most preferred embodiment wherein of the present invention is the method for uniting the following component that gives the medicinal effective dose of mammal:
A) substituted indole compound, it is selected from: 1-[4-(2-azepan-1 base-ethyoxyl)-benzyl]-2-(4-hydroxyl-phenyl)-3-Methyl-1H-indole-5-phenol (being also referred to as TSE-424) and 2-(4-hydroxyl-phenyl)-3-methyl isophthalic acid-(4-(2-piperidines-1-base-ethyoxyl)-benzyl)-IH-indole-5-phenol (being also referred to as ERA-923), perhaps pharmaceutically acceptable salt of TSE-424 or ERA-923;
B) bisphosphonates chemical compound, it is selected from: alendronic Acid ester, risedronic acid ester, Tiludronic acid, ibandronic acid ester, she for phosphonate ester, clodronic acid ester, minodronic acid ester, pamidronic acid ester, Zometa, she blocks phosphonate ester, Olpadronate, neridronic acid ester, the perhaps salt of a kind of described bisphosphonates chemical compound of medicinal effective dose; And it is optional
C) conjugated estrogens, for example Wyeth-Ayerst Laboratories is with trade name Premarin
Product sold.
Certainly, the dosage, scheme and the mode that give these chemical compounds will change according to disease degree of being treated and individuality, and must judge through the medical practitioner.Give one or more bisphosphonates of the present invention and substituted indole compound described herein with low dosage when preferably beginning, increase dosage then gradually until reaching required treatment effect.
Can be effectively to give these chemical compounds in about 0.1mg/ days to about 500mg/ days with the effective dose.Preferably about 1mg/ days to about 200mg/ days, give with single dose or twice or more times divided dose.Any way that described dosage can use reactive compound of the present invention to enter to connect receiver's blood flow (comprising oral, parenteral (comprising intravenous, intraperitoneal and subcutaneous injection) and transdermal) gives.For the disclosure of invention, transdermal administration is interpreted as and comprises all administrations that see through body surface and body passageway endosexine (comprising epithelial tissue and mucosal tissue).Such administration can use lotion, emulsifiable paste, foam, patch, suspensoid, solution and the suppository (rectum and vagina) of The compounds of this invention or its pharmaceutically acceptable salt to carry out.
When the effective ingredient in preparation of the present invention and the method is 1-[4-(2-azepan-1 base-ethyoxyl)-benzyl]-when 2-(4-hydroxyl-phenyl)-3-Methyl-1H-indole-5-phenol (being also referred to as TSE-424) or its pharmaceutically acceptable salt, the preferred daily dose of oral administration is about 0.1mg/ days to about 50mg/ days, preferably about 2.5mg/ days to about 40mg/ days.
When the effective ingredient in preparation of the present invention and the method is 2-(4-hydroxyl-phenyl)-3-methyl isophthalic acid-(4-(2-piperidines-1-base-ethyoxyl)-benzyl)-1H-indole-5-phenol (being also referred to as ERA-923) or its pharmaceutically acceptable salt form, the preferred daily dose of oral administration is about 0.1mg/ days to about 200mg/ days, preferably about 2.5mg/ days to about 100mg/ days.
The oral formulations that contains reactive compound of the present invention can comprise any conventional peroral dosage form that uses, and comprises tablet, capsule, buccal, dragee, lozenge and liquid oral, suspensoid or solution.Capsule can contain for example mixture of crystalline cellulose and microcrystalline Cellulose, flour, gelatin, natural gum etc. of for example pharmaceutically acceptable starch of described reactive compound and inert filler and/or diluent (for example corn starch, potato starch or tapioca), sugar, artificial sweetening agent, Powderd cellulose.Effectively tablet formulation can pass through conventional pressed disc method, wet granulation or dry granulation method prepare, and use pharmaceutically acceptable diluent, binding agent, lubricant, disintegrating agent, suspensoid or stabilizing agent include but not limited to magnesium stearate, stearic acid, Pulvis Talci, sodium lauryl sulphate, microcrystalline Cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, arabic gum, xanthan gum, sodium citrate, complex silicate, calcium carbonate, glycine, dextrin, sucrose, Sorbitol, dicalcium phosphate, calcium sulfate, lactose, Kaolin, mannitol, sodium chloride, Pulvis Talci, dried starch and powdered sugar.Oral formulations of the present invention can use standard delay or time release formulation, to change the absorption of described reactive compound.The preparation of suppository formulations can comprise cocoa butter, adding or not add the wax that changes the suppository fusing point with traditional material, and glycerol.Also can use water soluble suppository bases, for example various molecular weight polyethylene glycol.
The medicinal effective dose of bisphosphonates and substituted indole and estrogen (when the present invention uses) should be understood to reduce the risk of osteopathia or described disease or the dosage of its generation.Preferred described chemical compound is under the medical professional instructs, effectively to keep or to increase the dosed administration of receiver's bone density.
The bisphosphonates chemical compound of these methods can according to known technique scheme and dosage give.Alendronate sodium (Merck ﹠amp for example; Co., Inc. is with title Fosamax
Sale) being used for the treatment of the osteoporotic recommended dose of postmenopausal women is 10mg/ days, is used to prevent that the osteoporotic recommended dose of postmenopausal women from being 5mg/ days.(Sanofi Pharmaceuticals is with trade name Skelid for Disodium tiludronate
Sell) can once take with 400mg/ days oral dose.(MGI Pharma, Inc is with Didronel for Alendronate for she
Title sell) recommendation intravenous injection daily dose be the 7.5mg/kg body weight/day, used continuously three days.Risedronic acid ester (ActonelTM; Procter and Gamble Pharmaceuticals and Hoechst Marion Roussel co-market) obtain FDA approval and be used for bone Paget (30-mg tablet), the risedronic acid ester shows in clinical trial effectively.
Estrogen can give according to scheme known in the art or dosage among the present invention.For example preferred Premarin
The conjugated estrogens sheet can be according to the 3302-3305 page or leaf, Physicians ' Desk Reference, and the 54th edition, 2000, Medical Economics Company, Inc., Montvale, NJ 07645-1742 introduces and gives.Other can be used for commercially available estrogen of the present invention and comprises OGEN
(piperazine estrone sulfate tablet), ESTRATAB
(esterified estriol tablet), ESTRACE
Estradiol vaginal cream, CLIMARA
(estradiol transdermal system), ESTRADERM
(transdermal system), MENEST
TM(esterified estriol tablet), ORTHO-EST
(piperazine estrone sulfate tablet), CENESTIN
TM(synthetic conjugated estrogens), ALORA
(estradiol transdermal system), ESTINYL
(ethinyl estradiol) and VIVELLE
And VIVELLE-DOT
(estradiol transdermal system).All these commercially available estrogen products can be according to Physicians ' Desk Reference, and the 54th edition, the relevant portion introduction gives in 2000.
The listed controversies in hormone replacement in the elderly mediating recipe of following table gauge lattice can obtain in the U.S. and/or Europe.Common name trade name size oral estrogen yoke closes premarin (natural) Premarin 0.3,0.625,0.9,1.25,2.5mg conjugated estrogens (synthesizing) Cenestin 0.625,0.9mg esterified estriol (75-80% OES Estratab 0.3,0.625,1.25, the sulphuric acid 1,3,5,7-estratetraen-3-ol-17-one that 2.5mg6-15% is obtained by plant sterol) piperazine estrone sulfate Ogen Ortho-Est 0.625,1.25,2.5mg estradiol micronized Estrace 0.5,1.0,2.0mg raloxifene (selective estrogen receptor modulators) Evista 60mg esterified estriol and methylestosterone Estratest 1.25mg esterified estriol and
2.5mg?methylestosterone
Estratest HS 0.625mg esterified estriol and
1.25mg methylestosterone estradiol valerate Climaval 1mg, 2mg estradiol Elleste Solo 1mg, 2mg estradiol Estrofem 2mg estradiol Estrofem Forte 4mg piperazine estrone sulfate Harmogen 1.5mg associating: estrone Hormonin 1.4mg
Estradiol 0.6mg
Estriol 0.27mg estradiol valerate Progynova 1mg, 2mg estradiol Zumenon 1mg, 2mg transdermal estrogen estradiol Alora (twice weekly) discharges 0.025 every day, 0.0375
Climara (once in a week) 0.05,0.075,0.1mg is female
Estraderm (twice weekly) glycol (is selected according to different product
Fem Patch (once in a week) dosage)
Vivelle (twice weekly) estradiol Dermestril estradiol Estraderm 25,50,100 μ g estradiol Evorel (Systen) 25,50,100 μ g estradiol Fematrix 25,50,75,100 μ g estradiol Menorest, 40,80 μ g
Progynova TS 25,37.5,50,75 μ g estradiol And TS Forte 50,100 μ g
(Climara) vagina closes the premarin vagina female phenol emulsifiable paste of Premarin dienestrol emulsifiable paste estradiol Ortho alkene 0.625mg/g piperazine estrone sulfate Estring 0.1mg/g estradiol micronized Ogen vagina emulsifiable paste 7.5 μ g with the estrogen yoke
Estrace vagina emulsifiable paste 1.5mg/g
1.0mg/g
In these methods, unite give two groups of chemical compounds must be by the medical professional according to receiver's situation and be that prevention or treatment disease are determined.Giving described two kinds of chemical compounds can begin maybe a kind of medicine can be introduced in the another kind of ongoing scheme simultaneously.For the bisphosphonates administration than the short-term limit, for example she can preferably give the substituted indole compound scheme earlier, after it can and proceed to this time limit at successive administration during the bisphosphonates administration for the Alendronate infusion.
Unite in the method for the present invention give three groups of chemical compounds equally must be by the medical professional according to receiver's situation and be that prevention or treatment disease are determined.To prophylactic treatment, for example a kind of substituted indole of coupling the present invention and alendronic Acid ester and one or more estrogen prevent osteoporosis, and the administration of all chemical compounds can begin to give maybe a kind of chemical compound can be introduced in the ongoing dosage regimen of other chemical compound simultaneously in the scheme.For the bisphosphonates administration than the short-term limit, for example she preferably begins substituted indole compound and one or more estrogenic dosage regimens earlier, after it can and proceed to this time limit at successive administration during the bisphosphonates administration for the Alendronate infusion.
The Pharmaceutical composition of preferred the inventive method provides with unit dosage forms, for example tablet or capsule.In described dosage form, chemical compound is subdivided into the unit dose that comprises the suitable dose active component; Unit dosage forms can be packaged composition, for example parcel powder, the bottle that liquid agent is housed, ampoule, pre-filled syringe or sachet.Unit dosage forms can be for example capsule or tablet itself, or the also any described compositions of the right quantity of packaged form.
The substituted indole compound of preparation of the present invention and bisphosphonates medicine and estrogen (when using) give with separate dosage units, for example independent pill, tablet, powder etc., or be mixed into a kind of preparation and give.After the optimal dosage of having determined benzazolyl compounds and described bisphosphonates in the preparation, can preferably both be blended into a kind of preparation to make things convenient for medication.In addition, should be understood that preparation of the present invention also can comprise or not comprise other medicinal active ingredient.
The present invention also comprises medicine box or the packing that is designed for the pharmaceutical formulation in scheme of the present invention or the method.These medicine boxs be preferably designed for the administration time of regulation or in the cycle every day oral administration, optimizing prescriptions orally give every day quantity, and carry out assembly with indication the single oral formulations that need take every day in described scheme or in the cycle or combination oral formulations.Preferred each medicine box comprises the oral tablet that need take every day, and a kind of oral tablet comprises all described composite reagent daily doses in the part embodiment, and each chemical compound medication is independently preparation or compositions in other embodiments.Most preferably described packing or medicine box have schedule or the operation instruction of every day weekly, instruct and take suitable compositions at suitable date or time.
In preferred embodiments, packing of the present invention or medicine box will comprise the preparation of the independent oral dose of each component of the present invention.For example use every day in the regulation scheme: a kind of bisphosphonates of daily dose (alendronic Acid ester, the risedronic acid ester, Tiludronic acid, the ibandronic acid ester, she is for phosphonate ester, the clodronic acid ester, the minodronic acid ester, the pamidronic acid ester, Zometa, she blocks phosphonate ester, Olpadronate or neridronic acid ester) or its pharmaceutically acceptable salt tablet and a kind of oral substituted indole compound of the present invention (preferred 1-[4-(2-azepan-1 base-ethyoxyl)-benzyl]-2-(4-hydroxyl-phenyl)-3-Methyl-1H-indole-5-phenol or 2-(4-hydroxyl-phenyl)-3-methyl isophthalic acid-(4-(2-piperidines-1-base-ethyoxyl)-benzyl)-1H-indole-5-phenol) or the preparation of its pharmaceutically acceptable salt and the Premarino of the daily dose of choosing any one kind of them
The conjugated estrogen tablet.Certainly any or each described component can be divided into multidose and give in the every day of the course of treatment in medicine box or packing.In another preferred embodiment, medicine box or packing comprise the supply in January of component of the present invention, for example the 28-31 of each component days dosage.
Can be used for carrier or excipient systems that solid orally ingestible of the present invention (preferred film coated tablet or capsule) comprises active substituted indole medicine disclosed by the invention and following component:
A) filler and disintegrating agent component, account for total preparation about 5% to about 82% (weight), preferred described preparation about 30% to about 80%, wherein about 4% to about 40% of total preparation comprises one or more pharmaceutically acceptable disintegrating agents;
B) optional wetting agent, account for described compositions about 0.2% to about 5% (weight), for example be selected from the sugar ester of sodium lauryl sulphate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, sorbitan fatty acid esters, Polyethylene Glycol, castor oil derivatives, docusate sodium, quaternary ammonium compound, fatty acid and the glyceride of fatty acid;
C) lubricant, account for described compositions about 0.2% to about 10% (weight), for example be selected from magnesium stearate or other Metallic stearates (for example calcium stearate or zinc stearate), fatty acid ester (for example sodium stearyl fumarate), fatty acid (for example stearic acid), aliphatic alcohol, behenic acid glyceride, mineral oil, paraffin, hydrogenated vegetable oil, leucine, Polyethylene Glycol, lauryl sulphate acid slaine and sodium chloride;
D) optional fluidizer, account for described compositions about 0.1% to about 10% (weight), be selected from fluidizer known in the art, comprise silicon dioxide, Pulvis Talci, Metallic stearates, calcium silicates or lauryl sulphate acid slaine.
Although preparation of the present invention can use non-coating or non-encapsulation solid form, preferred coating or encapsulation final composition.Described pharmacology's compositions can be chosen wantonly and use the film-coat coating, preferably account for described total composition about 0.3% to about 8% (weight).The film-coat that is used for preparation of the present invention is known in the art, generally is made up of polymer (being generally the polymer of Cellulosed molded article), coloring agent and plasticizer.In film-coated preparation, can comprise other composition for example wetting agent, sugar, flavoring agent, oil and lubricant, to give described some characteristic of film coating.Compositions of the present invention and preparation can also hybrid process be solid, put into capsule then, for example gelatine capsule.
Above-mentioned filler component can be used filler or the adhesive component that is used for solid orally ingestible known in the art.Pharmaceutically acceptable filler or binding agent are selected from filler known in the art or binding agent, include but not limited to lactose, microcrystalline Cellulose, sucrose, mannitol, calcium phosphate, calcium carbonate, Powderd cellulose, maltodextrin, Sorbitol, starch or xylitol.
Coupling or replace above-mentioned filler component materials, preparation of the present invention uses disintegrating agent.These disintegrating agents can be selected from disintegrating agent known in the art, comprise pregelatinized starch and sodium starch glycollate.Other useful disintegrating agent comprises cross-linking sodium carboxymethyl cellulose, crospovidone, starch, alginic acid, sodium alginate, clay (for example veegum or xanthan gum), cellulose wadding condensate, ion exchange resin or effervescent system, for example uses food acids (for example citric acid, tartaric acid, malic acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, aspartic acid, arabo-ascorbic acid, glutamic acid and succinic acid) and basic carbonate component (for example sodium bicarbonate, calcium carbonate, magnesium carbonate, potassium carbonate, ammonium carbonate etc.) effervescent system.Can be used for disintegrating agent of the present invention account for described compositions about 4% to about 40% (weight), preferred about 15% to about 35%, more preferably from about 20% to about 35%.In preparation of the present invention, some component can have multiple function, and for example not only as filler but also as disintegrating agent, such component can be called fills the dosage form disintegrating agent, and its function in particular formulations may be a kind of, even its character has multifunctionality.
Pharmaceutical formulation of the present invention and carrier or excipient systems also preferably contain a kind of antioxidant or antioxidant blends, most preferably ascorbic acid.Operable other antioxidant comprises sodium ascorbate and ascorbic palmitate, preferably with a certain amount of ascorbic acid coupling.The preferable range of described antioxidant is about 0.5% to about 15% (weight), most preferably is about 0.5% to about 5% (weight).
Pharmaceutical formulation of the present invention contains active medicine and the carrier or the excipient systems of medicinal effective dose, and described carrier or excipient systems comprise:
A) filler and disintegrating agent component, account for described preparation about 50% to about 87%, and described preparation about 4% to about 40% comprise one or more disintegrating agents;
B) wetting agent accounts for about 0.5% to about 2.7% of described preparation;
C) lubricant accounts for about 0.2% to about 5.5% of described preparation;
D) fluidizer accounts for about 0.1% to about 5.5% of described preparation.
More than cited preparation percentage ratio represent a)-d) percentage by weight of cited component gross weight.Above-mentioned preparation also preferably contains optional antioxidant ingredients, preferred ascorbic acid, concentration be described preparation about 0.5% to about 5.5% (weight).Described preparation also preferably is contained in the pharmaceutically acceptable capsule example gel capsule, or with the about 0.3% film-coat coating to about 8% (weight) that accounts for described preparation.
The present invention also comprises pharmaceutical carrier or the excipient systems that can be used for Pharmaceutical composition, and one or more chemical compounds of the present invention or its pharmaceutically acceptable salt of the present invention are active component in the said composition.These pharmaceutical carriers or excipient systems comprise by weight:
A) filler and disintegrating agent component, account for described preparation about 54% to about 80%, wherein disintegrating agent account for described total preparation about 4% to about 40% (weight);
B) wetting agent accounts for about 0.55% to about 2.5% of described preparation;
C) lubricant accounts for about 0.2% to about 5.5% of described preparation;
D) fluidizer accounts for about 0.1% to about 5.0% of described preparation.
Preferred above-mentioned carrier or excipient systems are also optional and preferably contain antioxidant ingredients, preferred ascorbic acid, and concentration is about 0.1% to about 5.0% (weight).
Carrier of the present invention or excipient systems comprise:
A) filler and disintegrating agent component, as mentioned above, account for described preparation about 50% to about 87%, wherein disintegrating agent account for described preparation about 25% to about 35% (weight);
B) wetting agent accounts for about 0.55% to about 2.7% of described preparation;
C) lubricant accounts for about 0.2% to about 5.5% of described preparation;
D) fluidizer accounts for about 0.1% to about 5.5% of described preparation;
E) antioxidant ingredients, preferred ascorbic acid, concentration is about 0.1% to about 5.5% (weight).
Correspondingly, the present invention also provides a kind of product, this product comprises formula I or II chemical compound or its pharmaceutically acceptable salt and bisphosphonates or its pharmaceutically acceptable salt of above definition, and choose any one kind of them or multiple estrogen or its pharmaceutically acceptable salt, described product as combination preparation simultaneously, separately or sequential administration be used for the treatment of the mammal osteopathia.
The present invention also provides a kind of Pharmaceutical composition, said composition comprises formula I or II chemical compound or its pharmaceutically acceptable salt and bisphosphonates or its pharmaceutically acceptable salt of above definition, and chooses any one kind of them or multiple estrogen or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
Embodiment 1. acetic acid TSE-424-dissolution formulations
*According to the actual adjusting formula ratio of tiring of TSE-424 free alkali.Carry out corresponding adjusting with lactose.
| Composition | Do not contain ascorbic acid | Contain ascorbic acid |
| Micronization acetic acid TSE-424 * | ????10.00 | ????10.00 |
| Lactose NF high fluidity | ????33.10 | ????31.60 |
| Microcrystalline Cellulose NF (Avicel PH101) | ????25.00 | ????25.00 |
| Starch 1500 | ????20.00 | ????20.00 |
| Sodium lauryl sulphate NF | ????1.50 | ????1.50 |
| Sodium starch glycollate | ????10.00 | ????10.00 |
| Ascorbic acid USP | ????-- | ????1.5 |
| Syloid?244?FP | ????0.15 | ????0.15 |
| Magnesium stearate | ????0.25 | ????0.25 |
The preparation of last table 1 preparation is to mix the described excipient of part in pelletization, and a part adds in last blend step with dry powder.The solubility curve figure of described preparation proves that medicine almost discharged 90% in 30 minutes.Therefore, the unique combination of disintegrating agent and solubility diluent adds graininess and powdery solid be incorporated into and guarantees the fastest release of medicine in the described compositions.
The wet granulation of preparation shown in the table 1 can be that described medicine and ascorbic acid are mixed with a part of lactose, microcrystalline Cellulose, pregelatinized starch and sodium starch glycollate.Sodium lauryl sulphate is soluble in water, in high-shear mixer, use so that various mixture of powders is granulated.Particulate matter is dried to moisture in fluidized bed dryer be 2-3%.The granularity of dried particles make its by blade is housed mill and use 20 orders or 30 mesh sieve are controlled.Silicon dioxide and remaining lactose, microcrystalline Cellulose, pregelatinized starch and sodium starch glycollate are mixed in tumbling mixer with levigated granule.Whole mixture prepares by adding magnesium stearate and mix in tumbling mixer.Tabletting uses the mould of suitable size to carry out on rotary tablet machine.Coating carries out in conventional coating pan, uses the coating suspensoid and realizes suitable film coating.Embodiment 2. modified model TSE-424 preparations
％w/w
aAccording to the actual adjusting formula ratio of tiring of TSE-424 free alkali.Adjust accordingly with lactose.
bWork in-process uses but does not appear in the end article.Embodiment 3.ERA-923 preparation
| Composition | 5% particulate matter |
| Micronization acetic acid TSE-424 a | ????5.00 |
| Lactose NF | ????41.00 |
| Microcrystalline Cellulose, NF | ????35.00 |
| Pregelatinized starch NF | ????10.00 |
| Sodium lauryl sulphate NF | ????1.50 |
| 1-ascorbic acid USP | ????1.50 |
| Sodium starch glycollate NF | ????5.50 |
| Magnesium stearate NF | ????0.50 |
| Pure water USP b | ????qs |
％w/w
aHydrochloride monohydrate.Adjusted.Regulate consumption (theoretical value=89.34%) according to actual tiring.
bWork in-process uses but does not appear in the end article.
| Composition | 10.86% particulate matter | 11.19% particulate matter | 17.5% particulate matter | 17.9% particulate matter |
| Micronization ERA-923 a | ????10.867 | ??11.193 | ????17.489 | ??17.909 |
| Lactose NF | ????29.000 | ??29.000 | ????17.380 | ??18.000 |
| Microcrystalline Cellulose, NF | ????40.633 | ??42.807 | ????38.000 | ??39.090 |
| Pregelatinized starch NF | ????10.000 | ??10.000 | ????14.630 | ??15.000 |
| Sodium lauryl sulphate NF | ????2.500 | ???-- | ????2.500 | ???-- |
| 1-ascorbic acid USP | ????1.500 | ??1.500 | ????1.500 | ??1.500 |
| Sodium starch glycollate NF | ????5.000 | ??5.000 | ????8.000 | ??8.000 |
| Magnesium stearate NF | ????0.500 | ??0.500 | ????0.500 | ??0.500 |
| Pure water USP b | ????qs | ??qs | ????qs | ??qs |
The ERA-923 tablet press is become the every weight tablet of 640mg at the most, to reach target dose (100mg at the most).Then tablet is carried out the film coating.Embodiment 4.5% particulate TSE-424
The preferred vector or the excipient systems that are used to prepare particulate matter (wherein a kind of active medicine of the present invention is about 2% to about 8% (weight), preferred about 5%) can be used following percentage by weight carrier or excipient component production: lactose is about 32% to about 38%, microcrystalline Cellulose is about 32% to about 38%, pregelatinized starch is about 12% to about 16%, ascorbic acid is about 1% to about 2%, sodium lauryl sulphate is about 1% to about 2%, sodium starch glycollate is about 4% to about 8%, silicon dioxide is about 0.1% to about 0.2%, magnesium stearate is about 0.3% to about 0.7%.
Use 5% particulate TSE-424 as effective ingredient, preparation of the present invention prepares with following particulate fraction and drying nest component. bullets composition Mg/ unit grain part: 1 acetic acid TSE-424 5.002 Ru Tang NF 26.603 microcrystalline cellulose NF 25.004 pregelatinization starch NF 10.005 ascorbic acid USP 1.506 Shi sodium dialkyl sulfate NF 1.507 Qiang guanidine-acetic acid starch Na NF 4.008 pure water USP Q.S.
73.60 drying nest: 9 Ru Tang NF (high fluidity) 9.7510 microcrystalline cellulose NF 10.0011 pregelatinization starch NF 4.0012 Qiang guanidine-acetic acid starch Na NF 2.0013 Yang SiClx NF 0.1514 dolomol NF 0.50
100.00
White Opadry I (YS-1-18027-A) film coating is applied to described tablet, the following compacting of described tablet:
TSE-424 dosage Tablet weight, mg Used film coating mg/ sheet5mg 100 6.0 10mg 200 8.0 20mg 400 13.0
Claims (20)
1. method for the treatment of the mammal osteopathia, this method comprise and give the following medicine that it needs the medicinal effective dose of mammal:
I) bisphosphonates or its pharmaceutically acceptable salt;
The ii) substituted indole compound of following formula I or II or its pharmaceutically acceptable salt:
Or
Wherein Z is selected from following part:
Or
Wherein:
R
1Be selected from H, OH or its C
1-C
12Ester or C
1-C
12Alkyl ether, benzyloxy or halogen; Or C
1-C
4Halogen ether comprises trifluoromethyl ethers and trichloromethyl ether;
R
2, R
3, R
5And R
6Independently be selected from H, OH or its C
1-C
12Ester or C
1-C
12Alkyl ether, halogen or C
1-C
4Halogen ether, cyano group, C
1-C
6Alkyl or trifluoromethyl, but R worked as
1During for H, R
2Be not OH;
R
4Be selected from H, OH or its C
1-C
12Ester or C
1-C
12Alkyl ether, halogen or C
1-C
4Halogen ether, benzyloxy, cyano group, C
1-C
6Alkyl or trifluoromethyl;
X is selected from H, C
1-C
6Alkyl, cyano group, nitro, trifluoromethyl, halogen;
N is 1,2 or 3;
Y is selected from:
A) with the lower part:
R wherein
7And R
8Independently be selected from H, C
1-C
6Alkyl or optional by CN, C
1-C
6Alkyl, C
1-C
6Alkoxyl (straight or branched), halogen ,-OH ,-CF
3Or-OCF
3The phenyl that replaces; Perhaps R
7And R
8Be combined into-(CH
2)
p-, wherein p is the integer of 2-6, make to form a ring, described ring optional by at the most 3 be selected from following substituent group and replace: hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONH (C
1-C
4) alkyl ,-NH
2, C
1-C
4Alkyl amino, two-(C
1-C
4) alkyl amino ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl and-NO
2
B) five yuan of saturated, unsaturated or part unsaturated heterocycles, contain at the most two to be selected from-O-,-NH-,-N (C
1-C
4Alkyl)-,-N=and-S (O)
m-hetero atom, wherein m is the integer of 0-2, described heterocycle is optional independently to be selected from following substituent group replacement by 1-3: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Acyloxy, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN-,-CONHR
1,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2R
1,-NHCOR
1,-CONH (C
1-C
4) alkyl ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl ,-NO
2With optional by 1-3 (C
1-C
4) phenyl that replaces of alkyl;
C) hexa-atomic saturated, unsaturated or part unsaturated heterocycle, contain at the most two to be selected from-O-,-NH-,-N (C
1-C
4Alkyl)-,-N=and-S (O)
m-hetero atom, wherein m is the integer of 0-2, described heterocycle is optional independently to be selected from following substituent group replacement by 1-3: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
2-C
4Acyloxy, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONHR
1,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2R
1,-NHCOR
1,-CONH (C
1-C
4) alkyl ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl ,-NO
2With optional by 1-3 (C
1-C
4) phenyl that replaces of alkyl;
D) seven yuan of saturated, unsaturated or part unsaturated heterocycles, contain at the most two to be selected from-O-,-NH-,-N (C
1-C
4Alkyl)-,-N=and-S (O)
m-hetero atom, wherein m is the integer of 0-2, described heterocycle is optional independently to be selected from following substituent group replacement by 1-3: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
2-C
4Acyloxy, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H-,-CN-,-CONHR
1,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2R
1,-NHCOR
1,-CONH (C
1-C
4) alkyl ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl ,-NO
2With optional by 1-3 (C
1-C
4) phenyl that replaces of alkyl; Or
E) bridging or condensed bicyclic heterocycle, contain 6-12 carbon atom and contain at the most two be selected from-O-,-NH-,-N (C
1C
4Alkyl)-and-S (O)
m-hetero atom, wherein m is the integer of 0-2, described heterocycle is optional independently to be selected from following substituent group replacement by 1-3: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Acyloxy, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H-,-CN-,-CONHR
1-,-NH
2-, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2R
1,-NHCOR
1,-CONH (C
1-C
4) alkyl ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl ,-NO
2With optional by 1-3 (C
1-C
4) phenyl that replaces of alkyl;
And it is optional
Iii) one or more estrogen or its pharmaceutically acceptable salt.
2. the process of claim 1 wherein in described formula I or II chemical compound or its pharmaceutically acceptable salt:
R
1Be selected from H, OH or its C
1-C
12Ester or alkyl ether, benzyloxy or halogen;
R
2, R
3, R
5And R
6Independently be selected from H, OH or its C
1-C
12Ester or alkyl ether, halogen, cyano group, C
1-C
6Alkyl or trihalomethyl group; But work as R
1During for H, R
2Be not OH;
R
4Be selected from H, OH or its C
1-C
12Ester or alkyl ether, benzyloxy, halogen, cyano group, C
1-C
6Alkyl or trihalomethyl group;
X is selected from H, C
1-C
6Alkyl, cyano group, nitro, trifluoromethyl, halogen;
Y is with the lower part
R
7And R
8Independently be selected from H, C
1-C
6Alkyl or be combined into-(CH
2)
p-, wherein p is the integer of 2-6, make to form a ring, described ring optional by at the most 3 be selected from following substituent group and replace: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONH (C
1-C
4) alkyl ,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl and-NO
2
3. the method for claim 2, wherein in the chemical compound of described formula I or II, R
7And R
8By-(CH
2)
p-the ring that is connected to form is selected from aziridine, azetidine, pyrrolidine, piperidines, hexa-methylene amine or heptamethylene amine.
4. the method for claim 1, described method is used chemical compound or its pharmaceutically acceptable salt, the wherein R of described formula I or II
1Be OH; R
2-R
6Define with claim 1; X is selected from Cl, NO
2, CN, CF
3Or CH
3Y is with the lower part:
And R
7And R
8Link together and be-(CH
2)
r-, wherein r is the integer of 4-6, forms an optional quilt 3 rings that are selected from following substituent group replacement at the most: hydrogen, hydroxyl, halogen, C
1-C
4Alkyl, trihalomethyl group, C
1-C
4Alkoxyl, three halogenated methoxies, C
1-C
4Alkylthio group, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, hydroxyl (C
1-C
4) alkyl ,-CO
2H ,-CN ,-CONH (C
1-C
4) alkyl ,-NH
2, C
1-C
4Alkyl amino, two (C
1-C
4) alkyl amino ,-NHSO
2(C
1-C
4) alkyl ,-NHCO (C
1-C
4) alkyl and-NO
2
5. method for the treatment of the mammal osteopathia, described method comprise and give its bisphosphonates that needs the medicinal effective dose of mammal or its pharmaceutically acceptable salt; And choose any one kind of them or multiple estrogen or its pharmaceutically acceptable salt; And the chemical compound of the Formula Il I of medicinal effective dose or IV or its pharmaceutically acceptable salt:
Or
R wherein
1, R
2, R
3, R
4, R
5, R
6, n, X and Y define with claim 1.
6. method for the treatment of the mammal osteopathia, described method comprise and give its bisphosphonates that needs the medicinal effective dose of mammal or its pharmaceutically acceptable salt; And choose any one kind of them or multiple estrogen or its pharmaceutically acceptable salt; And the following formula V of medicinal effective dose or chemical compound (VI) or its pharmaceutically acceptable salt:
Or
R wherein
1, R
2, R
3, R
4, R
5, R
6, X and Y define with claim 1.
7. method for the treatment of the mammal osteopathia, described method comprise and give its bisphosphonates that needs the medicinal effective dose of mammal or its pharmaceutically acceptable salt; And choose any one kind of them or multiple estrogen or its pharmaceutically acceptable salt; And the following formula VII of medicinal effective dose and VIII chemical compound or its pharmaceutically acceptable salt:
Or
R wherein
1, R
2, R
3, R
4, R
5, R
6, n, X and Y define with claim 1.
8. the process of claim 1 wherein that described formula I or Ia chemical compound are 1-[4-(2-azepan-1 base-ethyoxyl)-benzyl]-2-(4-hydroxyl-phenyl)-3-Methyl-1H-indole-5-phenol or its pharmaceutically acceptable salt or 2-(4-hydroxyl-phenyl)-3-methyl isophthalic acid-(4-(2-piperidines-1-base-ethyoxyl)-benzyl)-1H-indole-5-phenol or its pharmaceutically acceptable salt.
9. each method of claim 1-8, wherein said bisphosphonates be selected from alendronic Acid ester, risedronic acid ester, Tiludronic acid, ibandronic acid ester, she for phosphonate ester, clodronic acid ester, minodronic acid ester, pamidronic acid ester, Zometa, she blocks phosphonate ester, Olpadronate or neridronic acid ester.
10. each method of claim 1-9, wherein said one or more estrogen are selected from estrone, estriol, 1,3,5,7-estratetraen-3-ol-17-one, female diene, (.+-.)-Equilenin., ethinyl estradiol, 17 beta estradiols, 17 'alpha '-dihydroequilenins, 17 β-dihydroequilenin, 17 α-dihydroequilin, 17 β-dihydroequilin, menstranol, conjugated estrogens, equol, enterolactone or their pharmaceutically acceptable salt.
11. each method of claim 1-10, wherein said osteopathia is an osteoporosis.
12. each method of claim 1-10, wherein said osteopathia is a Paget.
13. each method of claim 1-10, wherein said osteopathia is pernicious molten bone osteopathia.
The bone degraded that 14. each method of claim 1-10, wherein said osteopathia are cancerometastasis to be caused.
Give its 1-[4-that needs the medicinal effective dose of mammal (2-azepan-1 base-ethyoxyl)-benzyl 15. a method for the treatment of the mammal osteopathia, described method comprise]-bisphosphonates of 2-(4-hydroxyl-phenyl)-3-Methyl-1H-indole-5-phenol or its pharmaceutically acceptable salt and medicinal effective dose or its pharmaceutically acceptable salt and choose any one kind of them or multiple estrogen or its pharmaceutically acceptable salt.
16. a method for the treatment of the mammal osteopathia, described method comprise the bisphosphonates that gives its 2-that needs the medicinal effective dose of mammal (4-hydroxyl-phenyl)-3-methyl isophthalic acid-(4-(2-piperidines-1-base-ethyoxyl)-benzyl)-1H-indole-5-phenol or its pharmaceutically acceptable salt and medicinal effective dose or its pharmaceutically acceptable salt and choose any one kind of them or multiple estrogen or its pharmaceutically acceptable salt.
17. the method for claim 15 or 16, wherein said bisphosphonates be selected from alendronic Acid ester, risedronic acid ester, Tiludronic acid, ibandronic acid ester, she for phosphonate ester, clodronic acid ester, minodronic acid ester, pamidronic acid ester, Zometa, she blocks phosphonate ester, Olpadronate, neridronic acid ester or their pharmaceutically acceptable salt.
18. claim 15,16 or 17 method, wherein said one or more estrogen are conjugated estrogens.
19 1 kinds of products, this product comprises formula I or II chemical compound or its pharmaceutically acceptable salt and bisphosphonates or its pharmaceutically acceptable salt of each definition of claim 1-8, and choose any one kind of them or multiple estrogen or its pharmaceutically acceptable salt, described product as combination preparation simultaneously, separately or sequential administration be used for the treatment of the mammal osteopathia.
20. Pharmaceutical composition, said composition comprises formula I or II chemical compound or its pharmaceutically acceptable salt and bisphosphonates or its pharmaceutically acceptable salt of each definition of claim 1-8, and chooses any one kind of them or multiple estrogen or its acceptable salt pharmaceutically; And comprise pharmaceutically acceptable carrier.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21618800P | 2000-07-06 | 2000-07-06 | |
| US21606900P | 2000-07-06 | 2000-07-06 | |
| US60/216,188 | 2000-07-06 | ||
| US60/216,069 | 2000-07-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1450913A true CN1450913A (en) | 2003-10-22 |
Family
ID=26910620
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01815091A Pending CN1450913A (en) | 2000-07-06 | 2001-06-29 | Combination use of bisphosphonates, estrogenic agents and optionally estrogens |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1299093A2 (en) |
| JP (1) | JP2004502730A (en) |
| CN (1) | CN1450913A (en) |
| AU (1) | AU2001273125A1 (en) |
| BR (1) | BR0112364A (en) |
| CA (1) | CA2415052A1 (en) |
| MX (1) | MXPA02012897A (en) |
| WO (1) | WO2002003976A2 (en) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002003989A2 (en) * | 2000-07-06 | 2002-01-17 | Wyeth | Use of substituted indole compounds for treating sphincter incontinence |
| US6455568B2 (en) | 2000-07-06 | 2002-09-24 | Wyeth | Combination therapy for inhibiting sphincter incontinence |
| US6376486B1 (en) | 2000-07-06 | 2002-04-23 | American Home Products Corporation | Methods of inhibiting sphincter incontinence |
| WO2004009035A2 (en) | 2002-07-24 | 2004-01-29 | Children's Hospital Medical Center | Compositions and products containing enantiomeric equol, and methods for their making |
| US8668914B2 (en) | 2002-07-24 | 2014-03-11 | Brigham Young University | Use of equol for treating skin diseases |
| JP4889944B2 (en) | 2002-10-29 | 2012-03-07 | コロラド ステート ユニバーシティー リサーチ ファウンデーション | Use of equol to treat androgen-mediated diseases |
| US8580846B2 (en) | 2002-10-29 | 2013-11-12 | Brigham Young University | Use of equol for ameliorating or preventing neuropsychiatric and neurodegenerative diseases or disorders |
| NZ536273A (en) | 2002-12-20 | 2007-08-31 | Hoffmann La Roche | High dose ibandronate formulation |
| US7781478B2 (en) | 2004-07-14 | 2010-08-24 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| US10292971B2 (en) | 2015-10-01 | 2019-05-21 | Olema Pharmaceuticals, Inc. | Tetrahydro-1H-pyrido[3,4-b]indole anti-estrogenic drugs |
| CA3008020C (en) | 2015-12-09 | 2024-02-20 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
| CN109562107A (en) | 2016-05-10 | 2019-04-02 | C4医药公司 | Heterocycle degron body for target protein degradation |
| EP3454862B1 (en) | 2016-05-10 | 2024-09-11 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
| CN109641874A (en) | 2016-05-10 | 2019-04-16 | C4医药公司 | C for target protein degradation3The glutarimide degron body of carbon connection |
| CN109789143A (en) | 2016-07-01 | 2019-05-21 | G1治疗公司 | Antiproliferative based on pyrimidine |
| WO2018081168A2 (en) | 2016-10-24 | 2018-05-03 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective mixed estrogen receptor downregulators |
| EP3565558B1 (en) | 2017-01-06 | 2023-12-06 | G1 Therapeutics, Inc. | Combination therapy with a serd compound and a cdk4/6 inhibitor for the treatment of cancer |
| WO2018148576A1 (en) | 2017-02-10 | 2018-08-16 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators |
| EP4455146A2 (en) | 2017-06-29 | 2024-10-30 | G1 Therapeutics, Inc. | Morphic forms of git38 and methods of manufacture thereof |
| CN113453679A (en) | 2018-12-20 | 2021-09-28 | C4医药公司 | Targeted protein degradation |
| EP4076450A4 (en) | 2019-12-20 | 2024-01-10 | C4 Therapeutics, Inc. | Isoindolinone and indazole compounds for the degradation of egfr |
| CA3165309A1 (en) | 2020-03-05 | 2021-09-10 | Christopher G. Nasveschuk | Compounds for targeted degradation of brd9 |
| WO2024030968A1 (en) | 2022-08-03 | 2024-02-08 | Brystol-Myers Squibb Company | Compounds for modulating ret protein |
| WO2024097980A1 (en) | 2022-11-04 | 2024-05-10 | Bristol-Myers Squibb Company | Ret-ldd protein inhibitors |
| WO2024097989A1 (en) | 2022-11-04 | 2024-05-10 | Bristol-Myers Squibb Company | Ret-ldd protein degraders |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| NZ508200A (en) * | 1998-05-15 | 2003-09-26 | Wyeth Corp | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole in combination with estrogens |
| AU3894299A (en) * | 1998-05-15 | 1999-12-06 | American Home Products Corporation | Compositions comprising 2-phenyl-indole compounds and estrogen formulations |
| US6465445B1 (en) * | 1998-06-11 | 2002-10-15 | Endorecherche, Inc. | Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors |
-
2001
- 2001-06-29 JP JP2002508431A patent/JP2004502730A/en active Pending
- 2001-06-29 EP EP01952365A patent/EP1299093A2/en not_active Withdrawn
- 2001-06-29 WO PCT/US2001/020970 patent/WO2002003976A2/en not_active Application Discontinuation
- 2001-06-29 AU AU2001273125A patent/AU2001273125A1/en not_active Abandoned
- 2001-06-29 CN CN01815091A patent/CN1450913A/en active Pending
- 2001-06-29 BR BR0112364-5A patent/BR0112364A/en not_active Application Discontinuation
- 2001-06-29 MX MXPA02012897A patent/MXPA02012897A/en unknown
- 2001-06-29 CA CA002415052A patent/CA2415052A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002003976A2 (en) | 2002-01-17 |
| JP2004502730A (en) | 2004-01-29 |
| AU2001273125A1 (en) | 2002-01-21 |
| MXPA02012897A (en) | 2003-10-24 |
| WO2002003976A3 (en) | 2003-01-03 |
| BR0112364A (en) | 2003-07-29 |
| CA2415052A1 (en) | 2002-01-17 |
| EP1299093A2 (en) | 2003-04-09 |
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