CN1863792A - Novel farnesyl protein transferase inhibitors as antitumor agents - Google Patents
Novel farnesyl protein transferase inhibitors as antitumor agents Download PDFInfo
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- CN1863792A CN1863792A CN 200480029384 CN200480029384A CN1863792A CN 1863792 A CN1863792 A CN 1863792A CN 200480029384 CN200480029384 CN 200480029384 CN 200480029384 A CN200480029384 A CN 200480029384A CN 1863792 A CN1863792 A CN 1863792A
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Abstract
Disclosed are novel tricyclic compounds of the formula (I) and a pharmaceutically acceptable salts or solvates thereof. The compounds are useful for inhibiting farnesyl protein transferase. Also disclosed are pharmaceutical compositions comprising the compounds of formula (I). Also disclosed are uses of the compounds of formula (I) for the manufacture of a medicament for the treatment of cancer.
Description
Background technology
The U.S.5 that disclosed WO in disclosed WO on disclosed WO on April 20 nineteen ninety-five July 3 in 95/10516,1997 on March 7, in 97/23478,2002 on December 26, in 02/18368,2002 disclosed U.S.2002/0198216 and on February 23rd, 1999 announce, 874,442 disclose the tricyclic compound that can be used for suppressing farnesyl-protein transferase.
On December 10th, 1998, disclosed WO 98/54966 disclosed the treatment method for cancer, comprise and give at least two kinds of medicines that are selected from antineoplastic agent compound and prenyl-protein transferase inhibitor (for example, farnesyl protein transferase inhibitor) compound.
The U.S.6 that on August 1st, 2000 announced, 096,757 discloses the treatment proliferative disease, and (for example, cancer) method comprises with antineoplastic agent and/or radiation giving fpt inhibitor.
Shih etc. " The farnesyl protein transferase inhibitor SCH66336synergizes with taxanes in vitro and enhances their antitumor activity invivo ", Cancer Chemother Pharmacol (2000) 46:387-393 have studied the combination of SCH66336 and taxol and SCH66336 and docetaxel on some cancerous cell line.
June 28 calendar year 2001, disclosed WO 01/45740 disclosed the method for treatment cancer (mammary cancer), comprised giving selective estrogen receptor modulators (SERM) and at least a farnesyl tranfering enzyme inhibitor (FTI) .FTI-277 is exemplary FTI.
Network address
Http:// www.osip.com/press/pr/07-25-01The news report of OSIPharmaceuticals is disclosed.This news report is announced to begin the IH clinical trial phase and is used its match watt (Tarceva) of egf inhibitor (TM) (OSI-774) and carboplatin (Paraplatin _) and taxol (safe element _) treatment nonsmall-cell lung cancer to estimate.
Network address
Http:// cancertrials.nci.nih.gov/types/lung/iressa12100.htmlIn the content of typing on the 14th December in 2000 the following open clinical trial of (Phase I HB and IV) nonsmall-cell lung cancer in late period is disclosed, in the clinical testing data storehouse from NCI:
(1) in the patient of IIIB that carries out chemotherapy first or IV stage nonsmall-cell lung cancer, carry out III stage randomised study that ZD 1839 (Iressa (Iressa), egf inhibitor) combines with gemcitabine and cis-platinum and
(2) in the patient of IIIB that carries out chemotherapy first or IV stage nonsmall-cell lung cancer, carry out the III stage randomised study that ZD 1839 (Iressa, egf inhibitor) combines with taxol and carboplatin.
The WO 01/56552 that announces August 9 calendar year 2001 has disclosed and has used fpt inhibitor to be used to prepare the pharmaceutical composition for the treatment of advanced breast cancer.Fpt inhibitor can be used for the therapeutic combination of advanced breast cancer with one or more other to be used, especially endocrine therapy such as estrogen antagonist medicament such as estrogen receptor antagon (for example, tamoxifen) or selective estrogen receptor modulators or aromatase inhibitor.Other operable carcinostatic agent comprises iridium-platinum complex (as cis-platinum or carboplatin), Taxan (as taxol or docetaxel), antitumor nucleoside derivates (as gemcitabine) and HER2 antibody (as trastzumab).
The WO 01/62234 that announces August 30 calendar year 2001 has disclosed a kind of methods of treatment and dosage regimen is used for the treatment of mammal tumor, by the discontinuous farnesyl tranfering enzyme inhibitor that gives in 1-5 days administration time tables that shorten.This patent documentation discloses a kind of dosage regimen, the administration in 1-5 days of wherein said farnesyl protein transferase inhibitor, the then not treatment of at least 2 weeks.This patent documentation also discloses: in research before, farnesyl protein transferase inhibitor shows, when the dosage timetable administration that is administered twice with every day, it suppresses the growth of mammal tumor.This patent documentation also discloses: farnesyl protein transferase inhibitor with every day single dose give 1-5 days, can produce significantly tumor growth at least 21 days time at 1-and suppress.This patent documentation also disclose FTI can with one or more other carcinostatic agents such as iridium-platinum complex (for example, cis-platinum or carboplatin), taxane compounds (for example, taxol or docetaxel), antitumor nucleoside derivates (for example, gemcitabine), HER2 antibody (for example, trastzumab) and estrogen receptor antagon or selective estrogen receptor modulators (for example, tamoxifen) be used in combination.
The combination that the WO 01/64199 that announces September 7 calendar year 2001 has disclosed specific fpt inhibitor and taxane compounds (for example, taxol or docetaxel) is used for the treatment of cancer.
To the interest of farnesyl protein transferase inhibitor, the compound that can be used for suppressing farnesyl-protein transferase will be made gratifying contribution to this area in view of at present.The invention provides this contribution.
Summary of the invention
The invention provides the compound (fpt inhibitor) of formula I:
And pharmacy acceptable salt or solvate, wherein said substituting group is as giving a definition.
The present invention also provides compound (fpt inhibitor) or its pharmacy acceptable salt or the solvate of formula 100-174 as described below.
The present invention also provides formula 100.1-102.2,103.1-135.2 as described below and compound (fpt inhibitor) or its pharmacy acceptable salt or the solvate of 136.1-174.1.
The present invention also provides at least a (normally a kind of) compound of the present invention that comprises significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier.
The present invention also provides a kind of method that suppresses farnesyl-protein transferase in the patient of this treatment of needs, comprises at least a (normally a kind of) compound of the present invention that gives described patient's significant quantity.
The present invention also provides a kind of treatment in the patient of this treatment of needs (or inhibition), and (that is, cancer) method comprises at least a (normally a kind of) compound of the present invention that gives described patient's significant quantity to tumour.
The present invention also provides a kind of treatment in the patient of this treatment of needs (or inhibition), and tumour (promptly, cancer) method, comprise at least a (normally a kind of) compound of the present invention that gives described patient's significant quantity and with its bonded at least a (for example, one or both) chemotherapeutics (being also referred to as antineoplastic agent or carcinostatic agent in the art).
The present invention also is provided at treatment among the patient who needs this treatment (or inhibition), and tumour (promptly, cancer) method, comprise at least a (normally a kind of) compound of the present invention that gives described patient's significant quantity and with at least a chemotherapeutics of its bonded (being also referred to as antineoplastic agent or carcinostatic agent in the art) and/or radiation.
The present invention also is provided at treatment among the patient who needs this treatment (or inhibition), and tumour (promptly, cancer) method, comprise at least a (normally a kind of) compound of the present invention that gives described patient's significant quantity and with at least a signal transduction inhibitor of its bonded.
The invention provides in the patient of this treatment of needs and treat mammary cancer (promptly, after the menopause and menopause before mammary cancer, hormonal dependent mammary cancer for example) method, wherein said treatment comprise give at least a (for example, a kind of) compound of formula 1.0 and with hormonotherapy (that is antihormone) combination.
Method of the present invention comprises the treatment of hormonal dependent transitivity and advanced breast cancer, the assisting therapy of hormonal dependent initial stage and breast carcinoma of early stage, the treatment of ductal carcinoma in situ, and the treatment of struvite original position mammary cancer.
Randomly, in the method for the invention, new assisting therapy (that is, using chemotherapeutics) is united use with the compound and the hormonotherapy of formula 1.0.
Method of the present invention can also be used for Breast Cancer Prevention in having the high-risk patient that forms mammary cancer.
In the method for the invention, compound of the present invention can with the administration simultaneously of chemotherapeutics or signal transduction inhibitor or (that is, continuously) administration successively.
Randomly, can give radiotherapy in the method for the invention.
Detailed description of the invention
As said, except as otherwise noted, in concrete period (for example, weekly, or per three weeks once, or the like) to use medicine or compound be every treatment cycle.
As used herein, except as otherwise noted, when relating to the number of employed compound or chemotherapeutics or medicine, " at least a " represent one or more (for example, 1-6), more preferably 1-4, most preferably 1,2 or 3.
As used herein, except as otherwise noted, following term has implication described below:
The anticancer effective chemotherapeutics of antineoplastic agent-expression;
Compound-, be included as the reagent of antibody about antineoplastic agent;
Simultaneously-expression (1) simultaneously (for example, at one time) in time; Or (2) different time during a common referral;
Continuously-be meant that one is followed another;
" difference " used in term " different antineoplastic agents " is meant the medicament of different compounds or structure; Preferably, " difference " used in term " different antineoplastic agents " is meant not to be antineoplastic agent from same kind; For example, a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex;
Significant quantity-expression treatment significant quantity; For example, the quantity of compound (or medicine) or radiation, its generation: (a) by the reduction of caused one or more symptoms of cancer, alleviate or disappear (b) minimizing of tumour size, (c) elimination of tumour, and/or (d) prolonged sickness stable (cessation of growth cessation) of tumour; For example, (for example, nonsmall-cell lung cancer in) the treatment, the treatment significant quantity is to alleviate or eliminate cough, breathe hard and/or the quantity of pain in lung cancer; Again for example, the treatment significant quantity of fpt inhibitor is meant the quantity that causes farnesylation to reduce; The farnesylation minimizing can use technology well known in the art to determine by analyzing drug effect mark such as Prelamin A and HDJ-2 (DNAJ-2).
Patient-expression animal, for example Mammals (for example, people);
In turn-after expression (1) gives a kind of component ((a) compound of the present invention or (b) chemotherapeutics, signal transduction inhibitor and/or radiotherapy) of described method, then give other one or more components; After giving first kind of component, can descend a kind of component immediately basically, or after through one period working lipe, can descend a kind of component; Described working lipe is for realizing giving the required time of largest benefit of first kind of component;
Alkenyl-expression has at least one carbon-to-carbon double bond and contains 2-12 carbon atom, preferred 2-6 carbon atom and the most preferably straight chain and the branch carbochain of 3-6 carbon atom;
Alkyl-expression contains 1-20 carbon atom, preferred 1-6 carbon atom, more preferably 1-4 carbon atom, the especially more preferably straight chain and the branch carbochain of 1-2 carbon atom;
Alkynyl-expression has at least one carbon-to-carbon triple bond and contains 2-12 carbon atom, preferred 2-6 carbon atom and the most preferably straight chain and the branch carbochain of 2-4 carbon atom;
Aryl-be illustrated in and contain 6-15 carbon atom in the unsubstituted carbon ring group and (for example have at least one aromatic ring, aryl is a phenyl ring) carbon ring group, the commutable carbon atom of all of this carbon ring group all is the possible tie point of described aryl, described aryl is unsubstituted or replaces, described substituted aryl have one or more (for example, 1-3) substituting group, described substituting group is independently selected from: halogen, alkyl, hydroxyl, alkoxyl group, phenoxy group, CF
3,-C (O) N (R
18)
2,-SO
2R
18,-SO
2N (R
18)
2, amino, alkylamino, dialkyl amido ,-COOR
23With-NO
2(preferably, described substituting group is independently selected from: alkyl (for example, C
1-C
6Alkyl), halogen (for example, Cl and Br) ,-CF
3With-OH), each R wherein
18Be independently selected from: H, alkyl, aryl, aralkyl, heteroaryl and cycloalkyl, and R wherein
23Be selected from: alkyl and aryl;
Aralkyl-expression quilt is the alkyl as defined above of aryl replacement as defined above;
The aryl following defined assorted alkyl that alkyl-expression is replaced by aryl as defined above of mixing;
Aryloxy-represent aryl moiety as defined above, covalently bound with adjacent structural unit by Sauerstoffatom, for example ,-O-phenyl (that is phenoxy group);
Cycloalkenyl group-be illustrated in contains the unsaturated carbocyclic of 3-20 carbon atom, preferred 3-7 carbon atom in the unsubstituted ring, described cyclenes basic ring comprises at least one (normally one) two key, and described cyclenes basic ring is unsubstituted or replaces, described substituted cycloalkenyl ring have one or more (for example, 1,2 or 3) substituting group, described substituting group is independently selected from: alkyl (for example, methyl and ethyl), halogen ,-CF
3With-OH;
Cycloalkyl-be illustrated in contains the saturated carbon ring of 3-20 carbon atom, preferred 3-7 carbon atom in the unsubstituted ring, described cycloalkyl ring is unsubstituted or replaces, described substituted cycloalkyl ring have one or more (for example, 1,2 or 3) substituting group, described substituting group is independently selected from: alkyl (for example, methyl and ethyl), halogen ,-CF
3With-OH; For example, the cycloalkyl ring that 1-replaces, for example,
Wherein said alkyl is C normally
1-C
6Alkyl usually is C
1-C
2Alkyl, and preferable methyl;
Therefore, in the 1-position by the example of methyl substituted cycloalkyl ring including, but not limited to:
Cycloalkylalkyl-expression quilt is the alkyl as defined above of cycloalkyl substituted as defined above;
Halo (or halogen)-expression fluorine, chlorine, bromine or iodine;
Heterochain thiazolinyl-expression have at least one carbon-to-carbon double bond and contain 2-20 carbon atom, preferred 2-6 carbon atom and by 1-3 be selected from-O-,-S-and-straight chain and the branch carbochain of the heteroatoms interruption of N-, condition is that described heteroatoms does not adjoin each other when having a more than heteroatoms;
Assorted alkyl-expression contain 1-20 carbon atom, preferred 1-6 carbon atom and by 1-3 is individual is selected from-O-,-S-and-straight chain and the branch carbochain of the heteroatoms interruption of N-, condition is that described heteroatoms does not adjoin each other when having a more than heteroatoms;
Assorted alkynyl-expression have at least one carbon triple bond and contain 2-20 carbon atom, preferred 2-6 carbon atom and by 1-3 is individual is selected from-O-,-S-and-straight chain and the branch carbochain of the heteroatoms interruption of N-, condition is that described heteroatoms does not adjoin each other when having a more than heteroatoms;
Unsubstituted or the cyclic group that replaces of heteroaryl-expression, has at least one heteroatoms that is selected from O, S or N (condition is that any O and S atom do not adjoin each other), described heteroaryl comprises O and S atom, the delocalized that described heteroatoms is interrupted the carbocyclic ring structure and has enough numbers is to provide aromaticity, wherein said not substituted heteroaryl preferably contains 2-14 carbon atom, wherein said substituted heteroaryl by one or more (for example, 1,2 or 3) identical or different substituting group replaces, and described substituting group is selected from:
(1) halogen; (2)-CF
3(3)-OR
30, R wherein
30Be selected from: H, alkyl, aryl and aralkyl; (4) COR
30, R wherein
30As defined above; (5)-SR
30, R wherein
30As defined above; (6)-S (O)
tR
35, R wherein
15Be selected from: aryl and alkyl; (7)-N (R
30)
2, R wherein
30As defined above; (8)-NO
2(9)-OC (O) R
30, R wherein
30As defined above; (10) CO
2R
30, R wherein
30As defined above; (11)-OCO
2R
35, R wherein
35As defined above; (12)-CN; (13)-NR
30COOR
35, R wherein
30And R
35As defined above; (14)-SR
35C (O) OR
35, R wherein
35As defined above; (15) benzotriazole-1-base oxygen base; (16) tetrazolium-5-base sulfenyl; (17) tetrazolium of Qu Daiing-5-base sulfenyl; (18) alkynyl; (19) alkenyl; (20) alkyl; (21) alkyl that is replaced by one or more (for example, 1,2 or 3) substituting group, described substituting group is independently selected from: halogen ,-OR
30With-CO
2R
30, R wherein
30As defined above; (22) alkenyl that is replaced by one or more (for example, 1,2 or 3) substituting group, described substituting group is independently selected from: halogen ,-OR
30With-CO
2R
30, R wherein
30As defined above; The example of heteroaryl including, but not limited to: for example, 2-or 3-furyl, 2-or 3-thienyl, 2-, 4-or 5-thiazolyl, 2-, 4-or 5-imidazolyl, 2-, 4-or 5-pyrimidyl, the 2-pyrazinyl, 3-or 4-pyridazinyl, 3-, 5-or 6-[1,2,4-triazinyl], 3-or 5-[1,2, the 4-thiadiazolyl group], 2-, 3-, 4-, 5-, 6-or 7-benzofuryl, 2-, 3-, 4-, 5-, 6-or 7-indyl, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-_ azoles base, triazolyl, 2-, 3-or 4-pyridyl, or 2-, 3-or 4-pyridyl N-oxide compound, wherein pyridyl N-oxide compound can be expressed as:
The alkenyl as defined above that heteroaryl alkenyl-expression is replaced by following defined heteroaryl;
Heteroarylalkyl-expression quilt is the alkyl as defined above of heteroaryl replacement as defined above;
The alkyl as defined above that Heterocyclylalkyl alkyl-expression is replaced by following defined Heterocyclylalkyl;
Heterocyclylalkyl-expression contains 3-15 carbon atom, the saturated carbon ring of preferred 4-6 carbon atom, wherein carbocyclic ring is selected from by 1-3 is individual :-O-,-S-or-NR
24Assorted group be interrupted R wherein
24Be selected from: H, alkyl, aryl and-C (O) N (R
18)
2, R wherein
18As above definition, the example of Heterocyclylalkyl be including, but not limited to 2-or 3-tetrahydrofuran base, 2-or 3-tetrahydro-thienyl, 2-, 3-or 4-piperidyl, 2-or 3-pyrrolidyl, 1-, 2-, 3-or 4-piperazinyl, 2-or 4-two _ alkyl, morpholinyl and
Heterocyclylalkyl alkyl-expression quilt is the alkyl as defined above of Heterocyclylalkyl replacement as defined above.
Position in three-ring system is:
Also known in the art, of drawing from concrete atom is strong, does not wherein have the description scheme part at this strong end, and expression is by this strong methyl that is connected with described atom.For example:
Expression
Expression
Expression
Those skilled in the art will be understood that, following formula:
Can represent to be selected from one or more following isomer:
Preferred isomers is:
Therefore, a kind of embodiment of the present invention relates to the compound (fpt inhibitor) of formula I:
And pharmacy acceptable salt or solvate, wherein:
R
1Be selected from:
N is 1-6;
X is selected from O, S and N;
R
2, R
3, R
4And R
5Be independently selected from: H, Br, Cl and F;
R
5ABe selected from: H, C
1-C
6Alkyl and C
3-C
6Cycloalkyl;
For each n, R
6And R
7Be independently selected from: (1) H, (2) C
1-C
4Alkyl and (3) are by R
6And R
7The C that the carbon atom that links to each other with them forms
3-C
7Cycloalkyl ring;
R
8Be selected from:
H，
R
9Be selected from: C
1-C
6Alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkylalkyl, Heterocyclylalkyl alkyl, alkenyl, alkynyl, aralkyl, the assorted alkyl of aryl, cycloalkenyl group, heterochain thiazolinyl, assorted alkyl and assorted alkynyl; Or
R
9Be selected from: C
1-C
6Alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkylalkyl, Heterocyclylalkyl alkyl, alkenyl, alkynyl, aralkyl, the assorted alkyl of aryl, cycloalkenyl group, heterochain thiazolinyl, assorted alkyl and assorted alkynyl; (1) described R wherein
9Aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkylalkyl, Heterocyclylalkyl alkyl, alkenyl, alkynyl, aralkyl, the assorted alkyl of aryl, cycloalkenyl group, heterochain thiazolinyl, assorted alkyl and assorted alkynyl are replaced by 1-3 substituting group, described substituting group is independently selected from :-OH, halogen are (for example, Br, F or Cl), alkyl (for example, C
1-C
6Alkyl), cycloalkyl (for example, C
3-C
6, cyclopropyl for example) ,-NH
2,-NH (C
1-C
6Alkyl) (for example ,-NHCH
3) ,-N (C
1-C
6Alkyl)
2Wherein each alkyl select independently (for example-N (CH
3)
2), alkoxyl group (for example, methoxyl group) and-CO
2R
14R wherein
14Be selected from: H and alkyl (for example, C
1-C
6Alkyl, for example methyl and ethyl), condition is described R
9That carbon atom that links to each other with the X substituting group in the group not by-OH ,-NH
2,-NH (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2Group replaces; And (2) described R
9C
1-C
6Alkyl is replaced by 1-3 substituting group, and described substituting group is independently selected from :-OH, halogen (for example, Br, F or Cl), cycloalkyl (for example, C
3-C
6, cyclopropyl for example) ,-NH
2,-NH (C
1-C
6Alkyl) (for example ,-NHCH
3) ,-N (C
1-C
6Alkyl)
2Wherein each alkyl select independently (for example-N (CH
3)
2), alkoxyl group (for example, methoxyl group) and-CO
2R
14R wherein
14Be selected from: H and alkyl (for example, C
1-C
6Alkyl, for example methyl and ethyl); Condition is described R
9That carbon atom that links to each other with the X substituting group in the group not by-OH ,-NH
2,-NH (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2Group replaces;
R
9aBe selected from: alkyl and aralkyl;
R
10Be selected from: aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkylalkyl, Heterocyclylalkyl alkyl, alkenyl, alkynyl, the assorted alkyl of aryl, cycloalkenyl group, heterochain thiazolinyl, assorted alkyl and assorted alkynyl; Or
R
10Be selected from: aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkylalkyl, Heterocyclylalkyl alkyl, alkenyl, alkynyl, the assorted alkyl of aryl, cycloalkenyl group, heterochain thiazolinyl, assorted alkyl and assorted alkynyl; Wherein said R
10Group is replaced by 1-3 substituting group, and described substituting group is independently selected from :-OH, halogen (for example, Br, F or Cl), alkyl (for example, C
1-C
6Alkyl), cycloalkyl (for example, C
3-C
6, cyclopropyl for example) ,-NH
2,-NH (C
1-C
6Alkyl) (for example ,-NHCH
3) ,-N (C
1-C
6Alkyl)
2Wherein each alkyl select independently (for example-N (CH
3)
2), alkoxyl group (for example, methoxyl group) and-CO
2R
14R wherein
14Be selected from: H and alkyl (for example, C
1-C
6Alkyl, for example methyl and ethyl);
R
11Be selected from: (1) alkyl, (2) substituted alkyl, (3) unsubstituting aromatic yl, (4) substituted aryl, (5) unsubstituted ring alkyl, (6) substituted cycloalkyl, (7) are substituted heteroaryl not, (8) substituted heteroaryl, (9) Heterocyclylalkyl and (10) substituted heterocycle alkyl; Wherein said substituted alkyl, substituted cycloalkyl and substituted heterocycle alkyl R
11Group is replaced by one or more (for example 1,2 or 3) substituting group, described substituting group is independently selected from: (1)-OH, condition be when having more than one-OH group so each-the OH group be connected on the different carbon atoms (, only there is one-OH group to link to each other) with a carbon atom, (2) fluorine and (3) alkyl; And wherein said substituted aryl and substituted heteroaryl R
11Group is replaced by one or more (for example 1,2 or 3) substituting group, described substituting group is independently selected from: (1)-OH, condition be when having more than one-OH group so each-the OH group connect with different carbon atom (, only there is one-OH group to be connected) with a carbon atom, (2) halogen (for example Br, Cl or F) and (3) alkyl;
R
11aBe selected from: (1) H, (2) OH, (3) alkyl, (4) substituted alkyl, (5) aryl, (6) substituted aryl, (7) unsubstituted ring alkyl, (8) substituted cycloalkyl, (9) substituted heteroaryl not, (10) substituted heteroaryl, (11) Heterocyclylalkyl, (12) substituted heterocycle alkyl and (13)-OR
9aWherein said substituted alkyl, substituted cycloalkyl and substituted heterocycle alkyl R
11aGroup is replaced by one or more (for example 1,2 or 3) substituting group, described substituting group is independently selected from: (1)-OH, condition be when having more than one-OH group so each-the OH group connect with different carbon atom (, only there is one-OH group to be connected) with a carbon atom, (2)-and CN, (3)-CF
3, (4) fluorine, (5) alkyl, (6) cycloalkyl, (7) Heterocyclylalkyl, (8) aralkyl, (9) heteroarylalkyl, (10) alkenyl and (11) heterochain thiazolinyl; And wherein said substituted aryl and substituted heteroaryl R
11aGroup is replaced by one or more (for example 1,2 or 3) substituting group, described substituting group is independently selected from: (1)-OH, condition be when having more than one-OH group so each-the OH group connect with different carbon atom (, only there is one-OH group to be connected) with a carbon atom, (2)-and CN, (3)-CF
3, (4) halogen (for example Br, Cl or F), (5) alkyl, (6) cycloalkyl, (7) Heterocyclylalkyl, (8) aralkyl, (9) heteroarylalkyl, (10) alkenyl and (11) heterochain thiazolinyl;
R
12Be selected from: H, alkyl, piperidine ring V, cycloalkyl and-alkyl-(piperidine ring V), wherein piperidine ring V is
R wherein
44Definition below;
R
21, R
22And R
46Be independently selected from: (1)-H, (2) alkyl (for example, methyl, ethyl, propyl group, butyl or the tertiary butyl), (3) unsubstituting aromatic yl (for example phenyl), (4) substituted aryl that is replaced by one or more substituting groups, described substituting group is independently selected from: alkyl, halogen, CF
3And OH, (5) unsubstituted ring alkyl (for example cyclohexyl), the substituted cycloalkyl that (6) are replaced by one or more substituting groups, described substituting group is independently selected from: alkyl, halogen, CF
3And OH, the heteroaryl of (7) following formula:
(8) Heterocyclylalkyl of following formula:
(that is piperidine ring V) be R wherein
44Be selected from: (a)-H, (b) alkyl (for example, methyl, ethyl, propyl group, butyl or the tertiary butyl), (c) alkyl-carbonyl (for example, CH
3C (O)-), (d) carbalkoxy (for example ,-C (O) O-t-C
4H
9,-C (O) OC
2H
5With-C (O) OCH
3), (e) haloalkyl (for example, trifluoromethyl) and (f)-C (O) NH (R
51),
(9)-NH
2, condition is R
21, R
22And R
46Only having one in the group can be-NH
2And condition is to work as R
21, R
22And R
46One of be-NH
2The time so remaining group be not-OH, (10)-OH, condition is R
21, R
22And R
46Only have one in the group can be-OH and condition are to work as R
21, R
22And R
46One of be-during OH so remaining group be not-NH
2And (11) by one or more (for example, 1-3, or 1-2, and the preferred 1) alkyl that substituting group replaces, and described substituting group is selected from :-OH and-NH
2And condition is that one-OH or one-NH are only arranged
2Group on the carbon that replaces, or
R
21And R
22Form one with their continuous carbon and be selected from following ring: (1) unsubstituted ring alkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), (2) cycloalkyl that is replaced by one or more substituting groups, described substituting group is independently selected from: alkyl, halogen, CF
3And OH, (3) unsubstituted ring thiazolinyl:
(4) cycloalkenyl group that is replaced by one or more substituting groups, described substituting group is independently selected from: alkyl, halogen, CF
3And OH, (5) Heterocyclylalkyl, for example, the piperidine ring of following formula:
R wherein
44Be selected from: (a)-H, (b) alkyl (for example, methyl, ethyl, propyl group, butyl or the tertiary butyl), (c) alkyl-carbonyl (for example, CH
3C (O)-), (d) carbalkoxy (for example ,-C (O) O-t-C
4H
9,-C (O) OC
2H
5With-C (O) OCH
3), (e) haloalkyl (for example, trifluoromethyl) and (f)-C (O) NH (R
51),
(6) unsubstituting aromatic yl (for example, phenyl), the aryl that (7) are replaced by one or more substituting groups, described substituting group is independently selected from: alkyl (for example, methyl), halogen (for example, Cl, Br and F) ,-CN ,-CF
3, OH and alkoxyl group (for example, methoxyl group) and (8) are selected from following heteroaryl:
R
51Be selected from: H and alkyl (for example, methyl, ethyl, propyl group, butyl and the tertiary butyl).
For the compound of formula I, R
2, R
3, R
4And R
5Preferably select independently so that form unsubstituted (that is R,
2-R
5Be H), or single halogen, two halogens or the three plain ring systems that replace, wherein halogen is selected from: Br, Cl and F.The example that these halogens replace is: and the 8-halogen (for example, 8-Cl, 3,8-two halogens (for example, 3-Br-8-Cl), 3,7, (for example, 3-Br-7-Br-8-Cl) with 3,8,10-three halogens are (for example, 3-Br-8-Cl-10-Br) for 8-three halogens.The ring system that single halogen replaces is preferred, and wherein the 8-halogen is preferred, and 8-Cl is most preferred.
Therefore, the compound of the formula I compound of formula II preferably:
And most preferably be the compound of formula III:
The compound of formula I is more preferably the compound of formula IIA
And the compound that especially is more preferably formula IIA
The compound of formula I comprises the compound of formula IV:
And the compound that preferably includes formula V:
The compound of formula I comprises the compound of formula IVA
And preferably include the compound of formula VA:
The compound of formula I also comprises the compound of formula VI:
And preferably include the compound of formula VII:
The compound of formula I also comprises the compound of formula VIA:
And preferably include the compound of formula VIIA:
For the compound of formula I, R
5AExample include, but are not limited to: H, methyl, ethyl, sec.-propyl and cyclopropyl.
For the compound of formula I, R
5AC preferably
1-C
6Alkyl, wherein methyl is most preferred.
For the compound of formula I, X is O preferably.
For the compound of formula I, n preferably 1.
For the compound of formula I, R
6And R
7Preferably be independently selected from: H, methyl and R
6And R
7The carbon atom that links to each other with them forms cyclopropyl rings.More preferably, R
6And R
7Be independently selected from H and methyl.Most preferably, R
6And R
7Be H.
For the compound of formula I, R
9C preferably
1-C
6Alkyl is more preferably methyl.
For the compound of formula I, R
10Be preferably selected from: cycloalkyl and by C
1-C
6The cycloalkyl that alkyl replaces more preferably is selected from cycloalkyl and by methyl substituted cycloalkyl, most preferably is selected from: cyclopropyl and by methyl substituted cyclopropyl, and especially more preferably R
10Be:
For the compound of formula I, work as R
1Be
The time, R so
8Preferably
R wherein
11Substituting group and R
10Substituting group is identical.For example, work as R
1Be:
R so
8Preferably
For the compound of formula I, R
8Preferably
For the compound of formula I, R
8Be more preferably
R wherein
11Be selected from: alkyl, unsubstituted ring alkyl and substituted cycloalkyl.Most preferably, R
11Be selected from: alkyl and substituted cycloalkyl.Especially more preferably, R
11Be selected from: sec.-propyl and by methyl substituted cyclopropyl, that is, and group
For the compound of formula I, wherein R
1Be
X is O, and n is 1, R
6And R
7Be independently selected from H, methyl and R
6And R
7The cyclopropyl rings that the carbon atom that links to each other with their forms (R wherein
6And R
7Preferably be independently selected from H and methyl, R
6And R
7Be more preferably H), and R
9Be C
1-C
6Alkyl (preferable methyl), R
8Preferably
R wherein
11Alkyl (being more preferably sec.-propyl) preferably.
For the compound of formula I, wherein R
1Be
R
10Be selected from: cycloalkyl and by C
1-C
6Cycloalkyl (the R that alkyl replaces
10Be preferably selected from cycloalkyl and by methyl substituted cycloalkyl, R
10More preferably be selected from: cyclopropyl and by methyl substituted cyclopropyl, and R
10Most preferably be:
R
8Preferably
R wherein
11Be selected from: unsubstituted ring alkyl and substituted cycloalkyl (preferably, R
11Be substituted cycloalkyl, more preferably, R
11By methyl substituted cyclopropyl, that is, and group
The compound of formula 100-174 is:
The representative compounds of compound 100-174 includes, but are not limited to:
Be drawn into the line in the member ring systems, for example:
Be meant that described line (key) can be connected on any commutable ring carbon atom.
The carbon or the heteroatoms that it shall yet further be noted that any unsaturated valency in text, scheme, embodiment, structural formula and any table are considered to have hydrogen atom to satisfy valency.
Some compound of the present invention can exist with various isomeric form (for example, enantiomer, diastereomer, atropisomer).The present invention includes all these isomer of pure form or form of mixtures, comprise racemic mixture.The present invention also comprises enol form.
All steric isomers of The compounds of this invention (comprising salt, solvate and the prodrug of compound and the salt and the solvate of prodrug) (for example, confer structure body, optical isomer etc. how much), for example since various substituting groups on asymmetric carbon and may exist those, comprise enantiomerism form (even its do not have also may exist under the situation of asymmetric carbon), rotamerism form, atropisomer and diastereo-isomerism form, all comprise within the scope of the invention.The single steric isomer of The compounds of this invention for example can be substantially free of other isomer, perhaps can be mixture, for example with the form of racemic modification or as other or other mixtures of steric isomer through selecting with all.Chiral centre of the present invention can have as defined S of IUPAC 1974Recommendations or R configuration.Term " salt ", " solvate ", " prodrug " etc. are applicable to salt, solvate and the prodrug of enantiomer, steric isomer, rotational isomer, tautomer, racemic modification or the prodrug of The compounds of this invention equally.
The present invention also comprises the prodrug of The compounds of this invention.For example by hydrolysis in blood, be converted into the compound of following formula parent compound in this employed term " prodrug " expression in vivo rapidly.At T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14, A.C.S.Symposium Series and at Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, go through in 1987, these two pieces of documents are hereby incorporated by.
The present invention also comprises with the compound of the present invention that separates and purifying formation exists.
The polymorphic form of salt, solvate and the prodrug of formula I compound and formula I compound comprises within the scope of the invention.
Some tricyclic compound is tart in itself, for example has those compounds of carboxyl or phenolic hydroxyl group.These compounds can form pharmacy acceptable salt.The example of these salt can comprise sodium salt, sylvite, calcium salt, aluminium salt, golden salt and silver salt.The present invention also comprises and the pharmaceutically acceptable amine salt that forms such as ammonia, alkylamine, hydroxyalkyl amine, N-methylglucosamine for example.
Some alkaline tricyclic compound also forms pharmacy acceptable salt, for example, and acid salt.For example, pyrido-nitrogen-atoms can form salt with strong acid, and the compound with alkali subtituent such as amino can form salt with weak acid equally.The example that is used for salifiable appropriate acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetate, citric acid, oxalic acid, propanedioic acid, Whitfield's ointment, oxysuccinic acid, fumaric acid, succsinic acid, xitix, toxilic acid, methylsulfonic acid and other those mineral acids well known in the art and carboxylic acid.Described salt contacts generation salt by free alkali form and is prepared in a usual manner with the required acid of capacity.By described salt is handled with the dilute aqueous soln of suitable dilute alkaline aqueous solution such as sodium hydroxide, salt of wormwood, ammonia and sodium bicarbonate, can obtain free alkali form again.Some is different on some physical properties for free alkali form and their respective salt, the solubleness in polar solvent for example, but for purposes of the invention, described bronsted lowry acids and bases bronsted lowry salt and their corresponding free alkali forms are suitable.
The compound formation of formula I salt equally within the scope of the invention.Except as otherwise noted, be appreciated that at this when mentioning the compound of formula I, also comprise its salt.At expression of this employed term " salt " and acid salt inorganic and/or that organic acid forms, and with subsalt inorganic and/or that organic bases forms.In addition, during such as, but be not limited to carboxylic acid, can form zwitter-ion (" inner salt "), and be included in this employed term " salt " such as, but be not limited to pyridine or imidazoles and acidic moiety when the compound of formula I contains basic moiety.Pharmaceutically acceptable (that is, and nontoxic, acceptable salt on the physiology) be preferred.The salt of formula I compound for example can through type I compound and for example equivalent prepared in reaction or the then lyophilize preparation of reaction in water-bearing media in the medium that medium such as salt precipitation are separated out of quantitative acid or alkali.Usually be considered suitable for from alkalescence (or acid) medical compounds and form the acid (and alkali) of the salt of pharmaceutically useful, for example at S.Berge et al, Journal 0f Pharmaceutical Sciences (1977) 66 (1) 1-9; P.Gould, International J.of Pharmaceutics (1986) 33 201-217; Anderson etal, The Practice of Medicinal Chemistry (1996), Academic Press, NewYork; At The Orange Book (Food ﹠amp; Drug Administration, Washington, D.C. is on its website); With P.Heinrich Stahl, Camille G.Wermuth (Eds.), Handbook of Pharmaceutical Salts:Properties, Selection, andUse, (2002) Int ' l.Union of Pure and Applied Chemistry has argumentation among the pp.330-331.These contents are hereby incorporated by.
Exemplary acid salt comprises acetate, adipate, alginate, ascorbate salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, mesylate, methyl sulfate salt, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, embonate, pectate (pectinate), persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, salicylate, succinate, vitriol, sulfonate (for example referred in this those), tartrate, thiocyanate-, tosylate, undecane hydrochlorate etc.
Exemplary subsalt comprises ammonium salt, an alkali metal salt is sodium, lithium and sylvite for example, alkaline earth salt is calcium and magnesium salts for example, aluminium salt, zinc salt, organic bases (for example, organic amine) for example salt of benzyl star (benzathine), diethylamine, dicyclohexylamine, Kazakhstan amine (use N, N-two (dehydroabietic acid base) quadrol makes), N-methyl D-glycosamine, N-methyl D-glucamide, TERTIARY BUTYL AMINE, piperazine, benzyl ring hexyl amine, choline, Trometamol and the salt that forms with amino acid such as arginine, Methionin etc.The nitrogenous group of alkalescence can carry out quaternized with reagent, described reagent such as elementary alkyl halide (for example muriate of methyl, ethyl, propyl group and butyl, bromide and iodide), dialkylsulfates (for example sulfuric ester of dimethyl, diethyl, dibutyl and diamyl), long-chain halogenide (for example muriate of decyl, lauryl, myristyl and stearyl, bromide and iodide), aralkyl halide (for example bromide of benzyl and styroyl) or the like.
All these hydrochlorates and alkali salt are confirmed as pharmacy acceptable salt and comprise within the scope of the present invention, and for purposes of the invention, it is suitable with the free form of corresponding compounds that all these hydrochlorates and alkali salt are considered to.
The compound of formula 1.0 and salt thereof, solvate and prodrug can exist with their the tautomeric form form of acid amides or imino-ether (for example, with).All these tautomeric forms constitute a part of the present invention at this.
Compound of the present invention can exist with the form of non-solvent compound and the form of solvate (comprising hydrate forms such as semihydrate).Usually, for purposes of the invention, with pharmaceutically acceptable solvent for example the solvate form thereof that forms of water, ethanol or the like be of equal value with the solvent form of closing not.
Compound of the present invention: (i) suppress farnesyl-protein transferase, but do not suppress geranyl geranyl protein transferase I on external effective force ground; (ii) hinder by changing as a kind of Ras of conversion form inductive of farnesyl acceptor rather than by a kind of conversion Ras form inductive phenotype that is engineered to geranyl geranyl acceptor; (iii) hinder the interior processing of born of the same parents of Ras, it is a kind of farnesyl acceptor but is not the Ras that is engineered to geranyl geranyl acceptor; (iv) in cultivation, hinder by transforming Ras inductive abnormal cell growth.
Compound of the present invention suppresses the farnesylation of farnesyl-protein transferase and oncogene protein Ras.Therefore, the present invention further provides a kind of by (for example giving significant quantity, the treatment significant quantity) one or more (for example, a kind of) compounds of the present invention suppress the method for farnesyl-protein transferase (for example, ras farnesyl-protein transferase) in Mammals especially people.Compound of the present invention gives the patient and is used to treat cancer as described below to suppress farnesyl-protein transferase.
(for example, the treatment significant quantity) one or more (for example, a kind of) compounds of the present invention provide a kind of inhibition or the excrescent method of treatment cell (comprising transformant) by giving significant quantity in the present invention.Abnormal growth of cells is phalangeal cell growth and normal regulation mechanism irrelevant (for example, contact suppresses forfeiture).This comprises the misgrowth of following cell: (1) expresses the tumour cell (tumour) that activates the Ras oncogene; (2) tumour cell, wherein Ras albumen is owing to the sudden change of the oncogene in another gene is activated; (3) unusual Ras activation wherein appears in the optimum and malignant cell of other proliferative disease.
Mammals (for example, the people) significant quantity of the present invention by needing this treatment () one or more (for example, a kind of) compounds of the present invention for example, the treatment significant quantity, the method that also provides a kind of inhibitions or treatment tumour (that is cancer) to grow.Especially, the present invention provides a kind of method that suppresses or treat the tumor growth of expressing activation Ras oncogene by the above-claimed cpd that gives significant quantity (for example, treatment significant quantity).
The present invention also provides a kind of treatment proliferative disease, and especially cancer is (promptly, tumour) method, comprise need this treatment Mammals (for example, the people) significant quantity (for example, the treatment significant quantity) one or more (for example, a kind of) at least a anticarcinogen (that is chemotherapeutics) and/or the radiation of compound of the present invention and significant quantity.
Anticarcinogen (promptly, chemotherapeutics) example comprises and is selected from following anticarcinogen: (1) Taxan, (2) iridium-platinum complex, (3) be Urogastron (EGF) inhibitor of antibody, (4) be micromolecular EGF inhibitor, (5) be vascular endothelial growth factor (VEGF) inhibitor of antibody, (6) be micromolecular VEGF kinase inhibitor, (7) estrogen receptor antagon or selective estrogen receptor modulators (SERM), (8) antitumor nucleoside derivates, (9) ebormycine (epothilones), (10) topoisomerase enzyme inhibitor, (11) vinca alkaloids, (12) are the antibody of α V β 3 integrin inhibitors, and (13) are the small molecules of α V β 3 integrin inhibitors, (14) folate antagonist, (15) ribonucleotide reductase inhibitor, (16) anthracycline antibiotics (anthracylines), (17) biotechnological formulation; (18) Thalidomide (or relevant imines (imid)) and (19) imatinib mesylate (Gleevec).
The present invention also provides a kind of treatment proliferative disease, and especially cancer is (promptly, tumour) method, comprise need this treatment Mammals (for example, the people) significant quantity (for example, the treatment significant quantity) one or more (for example, a kind of) compounds of the present invention and at least a signal transduction inhibitor of significant quantity.
Proliferative disease (the tumour that can be suppressed or treat, promptly, cancer) example comprises, but be not limited to: (A) lung cancer (for example, adenocarcinoma of lung and nonsmall-cell lung cancer), (B) the carcinoma of the pancreas class (for example, carcinoma of the pancreas, for example, the exocrine pancreas cancer), (C) the colorectal carcinoma class (for example, colorectal carcinoma, for example, adenocarcinoma of colon and adenoma of colon), (D) myelogenous leukemia (for example, acute myeloid leukaemia (AML), CML and CMML), (E) thyroid follicle knurl, (F) myelodysplastic syndrome (MDS), (G) bladder cancer, (H) epidermal carcinoma, (I) melanoma, (J) mammary cancer, (K) prostate cancer, (L) head and neck cancer (for example, neck squamous cell cancer), (M) ovarian cancer, (N) cancer of the brain (for example, neurospongioma), (O) between matter source cancer (for example, knurl in fibrosarcoma and the voluntary muscle), (P) sarcoma, (Q) tetracarcinoma, (R) neuroblastoma (nuroblastoma), (S) kidney, (T) liver cancer, (U) non-Hodgkin lymphoma, (V) multiple myeloma and (W) anaplasia thyroid carcinoma.
For example, embodiment of the present invention are included among the patient who needs this treatment and treat method for cancer, wherein said cancer is selected from: carcinoma of the pancreas, lung cancer, myelogenous leukemia, thyroid follicle knurl, myelodysplastic syndrome, head and neck cancer, melanoma, mammary cancer, prostate cancer, ovarian cancer, bladder cancer, neurospongioma, epidermal carcinoma, colorectal carcinoma, non-Hodgkin lymphoma and multiple myeloma, this method comprise the compound of the present invention that gives described patient's significant quantity.
In addition, for example, embodiment of the present invention are included among the patient who needs this treatment and treat method for cancer, wherein said cancer is selected from: lung cancer (for example, nonsmall-cell lung cancer), head and neck cancer (for example, the neck squamous cell cancer), bladder cancer, mammary cancer, prostate cancer and myelogenous leukemia (for example, CML and AML), non-Hodgkin lymphoma and multiple myeloma.
The present invention also provides a kind of and treat method for cancer in the patient of this treatment of needs, comprise treat significant quantity one or more (for example, a kind of) compound of the present invention and the treatment significant quantity at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from: (1) Taxan, (2) iridium-platinum complex, (3) be Urogastron (EGF) inhibitor of antibody, (4) be micromolecular EGF inhibitor, (5) be vascular endothelial growth factor (VEGF) inhibitor of antibody, (6) be micromolecular VEGF kinase inhibitor, (7) estrogen receptor antagon or selective estrogen receptor modulators (SERM), (8) antitumor nucleoside derivates, (9) ebormycine, (10) topoisomerase enzyme inhibitor, (11) vinca alkaloids, (12) be the antibody of α V β 3 integrin inhibitors, (13) be the small molecules of α V β 3 integrin inhibitors, (14) folate antagonist, (15) ribonucleotide reductase inhibitor, (16) anthracycline antibiotics, (17) biotechnological formulation; (18) Thalidomide (or relevant imines) and (19) imatinib mesylate.
The present invention also provides a kind of and treat method for cancer in the patient of this treatment of needs, comprise treat significant quantity one or more (for example, a kind of) compound of the present invention and a kind of antineoplastic agent, described antineoplastic agent is selected from: (1) is the EGF inhibitor of antibody, (2) be micromolecular EGF inhibitor, (3) are that VEGF inhibitor and (4) of antibody are micromolecular VEGF inhibitor.Radiotherapy also can be used in combination with above-mentioned combination therapy, that is, the above-mentioned methods of treatment of using the combination of compound of the present invention and antineoplastic agent to carry out also can comprise the radiation for the treatment of significant quantity.
The present invention also provides a kind of and (for example treat leukemia in the patient of this treatment of needs, acute myeloid leukaemia (AML) and chronic myelogenous leukemia (CML)) method, comprise one or more (for example, a kind of) compounds of the present invention for the treatment of significant quantity and: (1) imatinib mesylate and Interferon, rabbit are with treatment CML; (2) Interferon, rabbit of imatinib mesylate and Pegylation is with treatment CML; (3) antitumor nucleoside derivates is (for example, Ara-C) with treatment AML; Or (4) antitumor nucleoside derivates (for example, Ara-C) combines with anthracycline antibiotics with treatment AML.
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment non-Hodgkin lymphoma, comprise one or more (for example, a kind of) compounds of the present invention for the treatment of significant quantity and: (1) biological products are (for example, Rituxan); (2) biological products (for example, Rituxan) and antitumor nucleoside derivates (for example, fludarabine); Or (3) Genasense (with the BCL-2 antisense).
The present invention also provides a kind of method for the treatment of multiple myeloma in the patient of this treatment of needs, comprise treat significant quantity one or more (for example, a kind of) compound of the present invention and: (1) proteoplast inhibitor (for example, from Millenium PS-341) or (2) Thalidomide (or relevant imines).
The present invention also provides a kind of treatment method for cancer, comprise and need the patient treatment of this treatment significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, and (b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from: (1) Taxan, (2) iridium-platinum complex, (3) be the EGF inhibitor of antibody, (4) are micromolecular EGF inhibitor, and (5) are the VEGF inhibitor of antibody, (6) be micromolecular VEGF kinase inhibitor, (7) estrogen receptor antagon or selective estrogen receptor modulators, (8) antitumor nucleoside derivates, (9) ebormycine, (10) topoisomerase enzyme inhibitor, (11) vinca alkaloids, (12) are the antibody of α V β 3 integrin inhibitors, and (13) are the small molecules of α V β 3 integrin inhibitors, (14) folate antagonist, (15) ribonucleotide reductase inhibitor, (16) anthracycline antibiotics, (17) biotechnological formulation; (18) Thalidomide (or relevant imines) and (19) imatinib mesylate.
The present invention also provides a kind of treatment method for cancer, comprise and need the patient treatment of this treatment significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, and (b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from: (1) Taxan, (2) iridium-platinum complex, (3) be the EGF inhibitor of antibody, (4) are micromolecular EGF inhibitor, and (5) are the VEGF inhibitor of antibody, (6) be micromolecular VEGF kinase inhibitor, (7) estrogen receptor antagon or selective estrogen receptor modulators, (8) antitumor nucleoside derivates, (9) ebormycine, (10) topoisomerase enzyme inhibitor, (11) vinca alkaloids, (12) are the antibody of α V β 3 integrin inhibitors, and (13) are the small molecules of α V β 3 integrin inhibitors, (14) folate antagonist, (15) ribonucleotide reductase inhibitor, (16) anthracycline antibiotics, (17) biotechnological formulation and (18) Thalidomide (or relevant imines).
The present invention also provides a kind of treatment method for cancer, comprise and need the patient treatment of this treatment significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, and (b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from: (1) Taxan, (2) iridium-platinum complex, (3) be the EGF inhibitor of antibody, (4) be micromolecular EGF inhibitor, (5) are the VEGF inhibitor of antibody, and (6) are micromolecular VEGF kinase inhibitor, (7) estrogen receptor antagon or selective estrogen receptor modulators, (8) antitumor nucleoside derivates, (9) ebormycine, (10) topoisomerase enzyme inhibitor, (11) vinca alkaloids, (12) be the antibody of α V β 3 integrin inhibitors, (13) are the small molecules of α V β 3 integrin inhibitors, (14) folate antagonist, (15) ribonucleotide reductase inhibitor, (16) anthracycline antibiotics and (17) biotechnological formulation.
The present invention also provides a kind of treatment method for cancer, comprise and need the patient treatment of this treatment significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, and (b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from: (1) Taxan, (2) iridium-platinum complex, (3) be the EGF inhibitor of antibody, (4) be micromolecular EGF inhibitor, (5) are the VEGF inhibitor of antibody, and (6) are micromolecular VEGF kinase inhibitor, (7) estrogen receptor antagon or selective estrogen receptor modulators, (8) antitumor nucleoside derivates, (9) ebormycine, (10) topoisomerase enzyme inhibitor, (11) vinca alkaloids, (12) are that antibody and (13) of α V β 3 integrin inhibitors are the small molecules of α V β 3 integrin inhibitors.
The present invention also provides a kind of method for the treatment of nonsmall-cell lung cancer, comprise and need the patient treatment of this treatment significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, and (b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from: (1) Taxan, (2) iridium-platinum complex, (3) be the EGF inhibitor of antibody, (4) be micromolecular EGF inhibitor, (5) are the VEGF inhibitor of antibody, and (6) are micromolecular VEGF kinase inhibitor, (7) estrogen receptor antagon or selective estrogen receptor modulators, (8) antitumor nucleoside derivates, (9) ebormycine, (10) topoisomerase enzyme inhibitor, (11) vinca alkaloids, (12) are that antibody and (13) of α V β 3 integrin inhibitors are the small molecules of α V β 3 integrin inhibitors.
The present invention also provides a kind of method for the treatment of nonsmall-cell lung cancer, comprise and need the patient treatment of this treatment significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, and (b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from: (1) Taxan, (2) iridium-platinum complex, (3) antitumor nucleoside derivates, (4) topoisomerase enzyme inhibitor and (5) vinca alkaloids.
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment nonsmall-cell lung cancer, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention, (b) carboplatin and (c) taxol.
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment nonsmall-cell lung cancer, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention, (b) cis-platinum and (c) gemcitabine.
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment nonsmall-cell lung cancer, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention, (b) carboplatin and (c) gemcitabine.
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment nonsmall-cell lung cancer, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention, (b) carboplatin and (c) docetaxel.
The present invention also provides a kind of and treat method for cancer in the patient of this treatment of needs, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, (b) antineoplastic agent, described antineoplastic agent is selected from: (1) is the EGF inhibitor of antibody, and (2) are micromolecular EGF inhibitor, and (3) are that VEGF inhibitor and (4) of antibody are micromolecular VEGF kinase inhibitor.
The present invention also provides a kind of method for the treatment of the neck squamous cell cancer in the patient of this treatment of needs, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, (b) one or more antineoplastic agents, described antineoplastic agent is selected from: (1) Taxan and (2) iridium-platinum complex.
The present invention also provides a kind of method for the treatment of the neck squamous cell cancer in the patient of this treatment of needs, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, (b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from: (1) Taxan, (2) iridium-platinum complex, (3) antitumor nucleoside derivates (for example, 5 FU 5 fluorouracil).
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment CML, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention, (b) imatinib mesylate and (c) Interferon, rabbit is (for example, Intron-A).
The present invention also provides a kind of method for the treatment of CML in the patient of this treatment of needs; Comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention, (b) imatinib mesylate and (c) Pegylation Interferon, rabbit (for example; Peg-Intron and Pegasys).
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment CML, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention and (b) imatinib mesylate.
The present invention also provides a kind of method for the treatment of CMML in the patient of this treatment of needs, comprises the fpt inhibitor of the present invention for the treatment of significant quantity, that is, and and compound of the present invention.
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment AML, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, (b) antitumor nucleoside derivates (for example, cytosine arabinoside (that is, Ara-C)).
The present invention also provides a kind of method for the treatment of AML in the patient of this treatment of needs, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, (b) antitumor nucleoside derivates (for example, cytosine arabinoside (that is, Ara-C)) and (c) anthracycline antibiotics.
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment non-Hodgkin lymphoma, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention and (b) Rituximab (Rituxan).
The present invention also provides a kind of method for the treatment of non-Hodgkin lymphoma in the patient of this treatment of needs, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, promptly, compound of the present invention, (b) Rituximab (Rituxan), (c) (for example, fludarabine (that is, F-ara-A) for antitumor nucleoside derivates.
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment non-Hodgkin lymphoma, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention and (b) Genasense (with the BCL-2 antisense).
The present invention also provides a kind of method for the treatment of multiple myeloma in the patient of this treatment of needs, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention, (b) proteoplast inhibitor (for example, PS-341 (Millenium)).
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment multiple myeloma, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, compound of the present invention is with (b) Thalidomide or relevant imines.
The present invention also provide a kind of in the patient of this treatment of needs the method for treatment multiple myeloma, comprise and treat significant quantity: (a) fpt inhibitor of the present invention, that is, and compound of the present invention and (b) Thalidomide.
The invention still further relates to treatment method for cancer described herein, particularly above-mentioned those cancers, wherein except that giving fpt inhibitor and antineoplastic agent, before the treatment cycle, during or afterwards, also give radiotherapy.
It is believed that, the present invention also provides a kind of and suppresses or treat optimum and the method malignant proliferation disease, wherein Ras albumen since other gene in Cancer-causing mutation by abnormal activation--promptly, described Ras gene itself is not activated into oncogenic forms by sudden change--and the Mammals by needing this treatment is (for example, the people) one or more of significant quantity (for example treating significant quantity) (for example, a kind of) compound of the present invention, carry out described inhibition or treatment.For example, optimum proliferative disease neurofibroma, or wherein Ras (tumour that is activated of) sudden change or overexpression for example, neu, src, abl, lck and fyn can suppress or treats by tricyclic compound described herein because the Tyrosylprotein kinase oncogene.
Employed in the method for the invention compound of the present invention suppresses or treats the misgrowth of cell.Be not wishing to be bound by theory, it is believed that these compounds can work by suppressing G-protein function such as Ras p21 by blocking-up G-albumen isoprenylation, make them can be used for treating proliferative disease such as tumor growth and cancer thus.Be not wishing to be bound by theory, it is believed that these compounds suppress the ras farnesyl-protein transferase, show the antiproliferative activity of anti-ras transformant thus.
Treatment proliferative disease (cancer of the present invention, promptly, tumour) method comprises: a kind of in the patient of this treatment of needs by simultaneously or give the compound of the present invention of significant quantity and the chemotherapeutics and/or the radiation of significant quantity continuously, treat the excrescent method of (inhibition) cell (comprising transformant).
In embodiments, method of the present invention is included in treatment among the patient who needs this treatment or suppresses the method for tumor growth, by simultaneously or give compound of the present invention of (1) significant quantity and at least a antineoplastic agent, microtubule-acting agent and/or the radiotherapy of (2) significant quantity continuously.For example, a kind of embodiment of these methods relates to a kind of treatment method for cancer, and described cancer is selected from: lung cancer, prostate cancer and myelogenous leukemia.
The method of treatment proliferative disease of the present invention also comprises the method for the optimum and malignant proliferation disease of a kind of treatment (inhibition), wherein ras albumen is owing to the Cancer-causing mutation in other gene causes by abnormal activation-promptly, described ras gene itself is not activated into carcinogenic form by sudden change.This method comprises simultaneously or needs continuously the compound of the present invention of patient's significant quantity of this treatment and the antineoplastic agent and/or the radiotherapy of significant quantity.The example of these proliferative disease that can be treated comprises: optimum proliferative disease neurofibroma, or wherein Ras because the sudden change of Tyrosylprotein kinase oncogene (for example, neu, src, abl, lck, lyn and fyn) or overexpression cause the tumour that is activated.
For radiotherapy, γ-radiation is preferred.
Treatment proliferative disease (cancer of the present invention, promptly, tumour) method also comprises: a kind of in the patient of this treatment of needs, by simultaneously or give the compound of the present invention of significant quantity and at least a signal transduction inhibitor of significant quantity successively, treat the excrescent method of (inhibition) cell (comprising transformant).
Typical signal transduction inhibitor including, but not limited to: (i) the Bcr/abl kinase inhibitor is for example, STI 571 (imatinib mesylate), (ii) Urogastron (EGF) acceptor inhibitor for example, kinase inhibitor (Iressa, OSI-774) and antibody (people (1995) such as Imclone:C225[Goldstein, Clin Cancer Res.1:1311-1318], and Abgenix:ABX-EGF) and (iii) the HER-2/neu acceptor inhibitor for example, Trastuzumab _ (trastuzumab).
The embodiment of methods of treatment of the present invention relates to uses the combination of medicine (compound) to be used for the treatment of cancer,, the present invention relates to be used for the treatment of the combination therapy of cancer that is.Those skilled in the art will be understood that, described medicine is usually respectively with the form administration of pharmaceutical composition.The pharmaceutical composition that use contains more than one medicines within the scope of the present invention.
The formulation administration that described antineoplastic agent obtains easily with skilled clinician usually, and usually (for example with their common prescribed dose administrations, described dosage is described in Physician ' s DeskReference, the 56th edition, 2002 (by Medical Economics company, Inc.Montvale, NJ 07645-1742 publishes) and be described in Physician ' s DeskReference, the 57th edition, 2003 (by Thompson PDR, Montvale, NJ 07645-1742 publishes, its content is hereby incorporated by), perhaps described dosage is described in manufacturer's operation instruction of medicament).
For example, fpt inhibitor of the present invention (that is, compound of the present invention) can be taken orally (for example, with capsular form), and described antineoplastic agent can intravenous administration (common form with IV solution).The pharmaceutical composition that use contains more than one medicines within the scope of the present invention.
Give described fpt inhibitor (that is, compound of the present invention) and described antineoplastic agent with the treatment effective dose, so that obtain acceptable result clinically, for example, the alleviating or eliminate of tumour symptom.Therefore, in treatment plan, described fpt inhibitor and antineoplastic agent can while or successive administrations.Described antineoplastic agent can carry out administration according to treatment plan known in the art.
Usually continue in the 1-7 week treatment plan a kind of, described fpt inhibitor of administration (that is, compound of the present invention) and antineoplastic agent, and typically repeat 6-12 time.Described treatment plan continues 1-4 week usually.Also can use the treatment plan that continues 1-3 week.Also can use the treatment plan that continues 1-2 week.At this treatment plan or during the cycle, described fpt inhibitor administration every day and described antineoplastic agent is administered once weekly or repeatedly.Usually, described fpt inhibitor can administration every day (that is, once a day), and every day twice in one embodiment, and described antineoplastic agent is administered once weekly or per three weeks are administered once.For example, described Taxan (for example, taxol (for example, safe plain _) or docetaxel (for example, taxotere _)) can be administered once weekly or per three weeks are administered once.
Yet those skilled in the art will be understood that treatment plan can change according to patient's needs.Therefore, the combination of employed in the methods of the invention compound (medicine) can administration in the version of such scheme.For example, during treatment cycle, described fpt inhibitor (that is, compound of the present invention) can discontinuous administration, rather than successive administration.Therefore, for example, during treatment cycle, described fpt inhibitor can administration every day continue a week, stops one week of administration then, repeats this dosage regimen during whole treatment cycle.Perhaps, described fpt inhibitor can administration every day continue for 2 weeks, stopped 1 week of administration then, repeated this dosage regimen during whole treatment cycle.Therefore, during treatment cycle, described fpt inhibitor can administration every day continue a week or how all, stops one week of administration or how all then during treatment cycle, repeats this dosage regimen during whole treatment cycle.This discontinuous treatment can also be based on many days rather than a whole week.For example, administration every day continues 1-6 days, and not administration continues 1-6 days, repeats this administering mode during treatment plan.The fate (or all numbers) that does not give fpt inhibitor needn't equal to give the fate (or all numbers) of fpt inhibitor.Usually, if use discontinuous dosage regimen, the fate or all numbers that give fpt inhibitor are equal to or greater than fate or all numbers that does not give fpt inhibitor at least.
Described antineoplastic agent can or continue transfusion by pill and give.During treatment cycle, described antineoplastic agent can be to be administered once every day to being administered once weekly, and perhaps whenever biweekly, or per three weeks are once, or whenever all around once.During treatment cycle, if administration every day, this administration every day can be discontinuous in all numbers of treatment cycle so.For example, one week of administration (or a couple of days), one week of not administration (or a couple of days), and during whole treatment cycle, repeat this mode.
Described fpt inhibitor (promptly, compound of the present invention) can be taken orally, preferably with the form administration of solid dosage, and in one embodiment with capsular form administration, and always treat effective per daily dose can with every day 1-4 time or 1-2 time divided dose form give, usually, described treatment effective dose is administered once or twice every day, and is administered twice every day in one embodiment.Described fpt inhibitor can be with the about 400mg of about 50-amount administration once a day, and can be with the about 300mg of about 50-amount administration once a day.Fpt inhibitor generally is administered twice with the amount of the about 350mg of about 50-every day, usually the amount with the about 200mg of 50mg-is administered twice every day, and in one embodiment, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and in another embodiment, fpt inhibitor is administered twice with the amount of about 100mg every day.
If the patient responds or be stable, after treatment cycle finishes, can repeat this treatment cycle so according to clinicist's judgement.When treatment cycle finishes, under the same dose that can in treatment plan, be used, continue to give patient's fpt inhibitor (promptly, compound of the present invention), perhaps, if dosage, can be promoted to this dosage twice of 200mg every day so less than 200mg every day twice.Can continue this maintenance dose, till the patient makes progress to some extent or can not stand this dosage again (in the case, can reduce dosage, the patient can proceed administration under the dosage that reduces).
During treatment cycle, the antineoplastic agent that uses together with fpt inhibitor (that is compound of the present invention) is with its normal prescribed dose administration (that is, described antineoplastic agent is according to the standard convention administration of these drug administrations).For example: (a) for taxanes, the about 300mg/m of about 30-
2(b) for cis-platinum, the about 100mg/m of about 30-
2(c) for carboplatin, about 8 AUC of about 2-; (d) for the EGF inhibitor that is antibody, the about 4mg/m of about 2-
2(e) for being micromolecular EGF inhibitor, the about 500mg/m of about 50-
2(f) for the VEGF kinase inhibitor that is antibody, the about 10mg/m of about 1-
2(g) for being micromolecular VEGF inhibitor, the about 2400mg/m of about 50-
2(h) for SERM, the about 20mg of about 1-; (i) for antitumor nucleosides 5 FU 5 fluorouracil, gemcitabine and capecitabine, the about 1250mg/m of about 500-
2(j) for antitumor nucleosides cytosine arabinoside (Ara-C), 100-200mg/m
2/ day, every 3-4 week administration 7-10 days, and be high dosage to intractable leukemia and lymphoma, that is, and 1-3gm/m
2, administration was 1 hour in per 12 hours, and every 3-4 week gives 4-8 dosage; (k) for antitumor nucleosides fludarabine (F-ara-A), 10-25mg/m
2/ day, every 3-4 week; (l) for antitumor nucleosides Decitabine, 30-75mg/m
2, per 6 all administrations three days, the highest 8 cycles; (m) (CdA 2-CdA), 0.05-0.1mg/kg/ days, to continue the form of transfusion, is administered to many 7 days every 3-4 week for antitumor nucleosides chlorine Desoxyadenosine; (n) for ebormycine, the about 100mg/m of about 1-
2(o) for topoisomerase enzyme inhibitor, the about 350mg/m of about 1-
2(p) for vinca alkaloids, the about 50mg/m of about 1-
2(q) for folate antagonist methotrexate (MTX), 20-60mg/m
2, oral, IV or IM, in every 3-4 week, middle dosage regimen is 80-250mg/m
2IV, every 3-4 week administration 60 minutes, the high dosage dosage regimen is 250-1000mg/m
2IV, every 3-4 week gives with formyl tetrahydrofolic acid; (r) for the general U.S.A of folate antagonist urge (Premetrexed) (Alimta), per 3 all 300-600mg/m
2(IV transfusion in first day 10 minutes); (s) for ribonucleotide reductase inhibitor hydroxyurea (HU), 20-50mg/kg/ days (causing that on demand blood counting reduces); (t) for iridium-platinum complex oxaliplatin (Eloxatin), 50-100mg/m
2Every 3-4 week (being preferred for solid tumor such as nonsmall-cell lung cancer, colorectal carcinoma and ovarian cancer); (u) for anthracycline antibiotics daunorubicin, 10-50mg/m
2/ day IV, every 3-4 week administration 3-5 days; (v) for anthracycline antibiotics Dx (Zorubicin), 50-100mg/m
2IV, every 3-4 week is carried out 1-4 days lasting transfusion, or 10-40mg/m
2IV weekly; (w) for anthracycline antibiotics idarubicin, 10-30mg/m
2Every day, in 10-20 minute to slow down the mode of IV transfusion, every 3-4 week administration 1-3 days; (x) for biological Interferon, rabbit (Intron-A, Roferon), 5-20 1,000,000 IU, on every Wendesdays time; (y) for biological Peg-Intron (Peg-intron, Pegasys), 3-4 microgram/kg/ days, chronic subcutaneous (up to the recurrence or loss of activity till); And (z) for biological Rituximab (Rituxan) (antibody that is used for non-Hodgkin lymphoma), 200-400mg/m
2IV weekly, 6 months administration 4-8 weeks.
Imatinib mesylate can orally use with the about 800mg/ of about 200-days amount.
Thalidomide (and relevant imines) can orally use with the about 800mg/ of about 200-days amount, and can successive administration or use up to recur or toxicity till.For example referring to " Apoptotic signaling induced by immunomodulatory thalidomideanaloqs in human multiple myeloma cells such as Mitsiades; Therapeutic implications ", Blood, 99 (12): 4525-30, on June 15th, 2002, its content is hereby incorporated by.
For example, taxol (for example, safe plain _) can be with the about 100mg/m of about 50-
2Amount be administered once weekly, in another example, taxol (for example, safe plain _) is with the about 80mg/m of about 60-
2Amount be administered once weekly.In another example, taxol (for example, safe plain _) can be with the about 250mg/m of about 150-
2Be administered once in per three weeks of amount, in another example, taxol (for example, safe plain _) is with the about 225mg/m of about 175-
2Be administered once in per three weeks of amount.
In another example, docetaxel (for example, taxotere _) can be with the about 45mg/m of about 10-
2Amount be administered once weekly.In another example, docetaxel (for example, taxotere _) can be with the about 100mg/m of about 50-
2Be administered once in per three weeks of amount.
In another example, cis-platinum can be with the about 40mg/m of about 20-
2Amount be administered once weekly.In another example, cis-platinum can be with the about 100mg/m of about 60-
2Be administered once in per three weeks of amount.
In another example, carboplatin can be administered once weekly with the amount of AUC that about 2-about 3 is provided.In another example, carboplatin can being administered once with AUC that about 5-about 8 is provided in per three weeks of amount.
Therefore, in an example (for example, the treatment nonsmall-cell lung cancer): (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also have in another example, fpt inhibitor is administered twice with the amount of about 100mg every day, and (2) taxol (for example, safe plain _) is with the about 100mg/m of about 50-
2Amount be administered once weekly, and in another example, with the about 80mg/m of about 60-
2Amount be administered once weekly, and (3) carboplatin is administered once weekly with the amount of AUC that about 2-about 3 is provided.
In another example (for example, the treatment nonsmall-cell lung cancer): (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also has in another example, and fpt inhibitor is administered twice with the amount of about 100mg every day, (2) taxol (for example, safe plain _) is with the about 100mg/m of about 50-
2Amount be administered once weekly, and in another example, with the about 80mg/m of about 60-
2Amount be administered once weekly, and (3) cis-platinum is with the about 40mg/m of about 20-
2Amount be administered once weekly.
In another example (for example, the treatment nonsmall-cell lung cancer): (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also has in another example, and fpt inhibitor is administered twice with the amount of about 100mg every day, (2) docetaxel (for example, taxotere _) is with the about 45mg/m of about 10-
2Amount be administered once weekly, and (3) carboplatin is administered once weekly with the amount that the about 3AUC of about 2-is provided.
In another example (for example, the treatment nonsmall-cell lung cancer): (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also has in another example, and fpt inhibitor is administered twice with the amount of about 100mg every day, (2) docetaxel (for example, taxotere _) is with the about 45mg/m of about 10-
2Amount be administered once weekly, and (3) cis-platinum is with the about 40mg/m of about 20-
2Amount be administered once weekly.
Therefore, in an example (for example, the treatment nonsmall-cell lung cancer): (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also have in another example, fpt inhibitor is administered twice with the amount of about 100mg every day, and (2) taxol (for example, safe plain _) is with the about 250mg/m of about 150-
2Be administered once in per three weeks of amount, and in another example, with the about 225mg/m of about 175-
2Be administered once in per three weeks of amount, and also have in another example, with 175mg/m
2Be administered once in per three weeks of amount, and (3) carboplatin is with being administered once of AUC that about 5-about 8 is provided in per three weeks of amount, and in another embodiment 6.
In the example of another treatment nonsmall-cell lung cancer: (1) fpt inhibitor (that is, compound of the present invention) is with amount twice administration every day of 100mg, and (2) taxol (for example, safe plain _) is with 175mg/m
2Be administered once in per three weeks of amount, and (3) carboplatin was administered once with per three weeks of the amount that 6 AUC are provided.
In another example (for example, the treatment nonsmall-cell lung cancer): (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also has in another example, and fpt inhibitor is administered twice with the amount of about 100mg every day, (2) taxol (for example, safe plain _) is with the about 250mg/m of about 150-
2Be administered once in per three weeks of amount, and in another example, with the about 225mg/m of about 175-
2Be administered once in per three weeks of amount, and (3) cis-platinum is with the about 100mg/m of about 60-
2Be administered once in per three weeks of amount.
In another example (for example, the treatment nonsmall-cell lung cancer): (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also has in another example, and fpt inhibitor is administered twice with the amount of about 100mg every day, (2) docetaxel (for example, taxotere _) is with the about 100mg/m of about 50-
2Be administered once in per three weeks of amount, and (3) carboplatin was administered once with per three weeks of the amount that about 8 AUC of about 5-are provided.
In another example (for example, the treatment nonsmall-cell lung cancer): (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also has in another example, and fpt inhibitor is administered twice with the amount of about 100mg every day, (2) docetaxel (for example, taxotere _) is with the about 100mg/m of about 50-
2Be administered once in per three weeks of amount, and (3) cis-platinum is with the about 100mg/m of about 60-
2Be administered once in per three weeks of amount.
Use fpt inhibitor (promptly at another, compound of the present invention), among the embodiment of docetaxel and carboplatin treatment nonsmall-cell lung cancer: (1) fpt inhibitor is administered twice with the amount of the about 200mg of about 50-every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also have in another example, fpt inhibitor is administered twice with the amount of about 100mg every day, and (2) docetaxel (for example, taxotere _) is with about 75mg/m
2Be administered once in per three weeks of amount, and (3) carboplatin was administered once with per three weeks of the amount that about 6AUC is provided.
In the above among another embodiment of embodiment, docetaxel (for example, taxotere _) and cis-platinum, docetaxel (for example, taxotere _) and carboplatin, taxol (for example, safe plain _) and carboplatin or taxol (for example, safe element _) and cis-platinum are in administration on the same day.
At another embodiment (for example, CML) in: (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 10-is administered twice every day, (2) imatinib mesylate is with the about 800mg/ of about 400-days amount oral administration, and (3) Interferon, rabbit (Intron-A) is administered three times weekly with the amount of about 2,000 ten thousand IU of about 5-.
At another embodiment (for example, CML) in: (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 100-is administered twice every day, (2) imatinib mesylate is with the about 800mg/ of about 400-days amount oral administration, and the Interferon, rabbit of (3) Pegylation (Peg-Intron or Pegasys) was with about 6 micrograms of about 3-/Kg/ days amount administration.
At another embodiment (for example, non-Hodgkin lymphoma) in: (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also have in another example, fpt inhibitor is administered twice with the amount of about 100mg every day, and (2) Genasense (with the BCL-2 antisense) with the form that continues the IV transfusion with all administrations of the every 3-4 of the dosage of the about 5mg/kg/ of about 2-days (for example, 3mg/kg/ days) 5-7 days.
At another example (for example, multiple myeloma) in: (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also has in another example, and fpt inhibitor is administered twice with the amount of about 100mg every day, and (2) proteoplast inhibitor is (for example, PS-341-Millenium) with about 1.5mg/m
2Amount be administered twice weekly, two weeks stops a week.
At another example (for example, multiple myeloma) in: (1) fpt inhibitor (promptly, compound of the present invention) amount with the about 200mg of about 50-is administered twice every day, and in another example, fpt inhibitor is administered twice with the amount of the about 125mg of about 75mg-every day, and also have in another example, fpt inhibitor is administered twice with the amount of about 100mg every day, and (2) Thalidomide (or relevant imines) continues medication till recurrence or toxicity with the about 800mg/ of about 200-days amount oral administration.
In another example of example, taxotere and cis-platinum, taxotere and carboplatin, safe element and carboplatin or safe element and cis-platinum are in administration on the same day in the above.
Can with fpt inhibitor (promptly, compound of the present invention) antineoplastic agent of uniting use is: (1) taxanes such as taxol (safe plain _) and/or docetaxel (taxotere _), (2) iridium-platinum complex, as carboplatin, cis-platinum and oxaliplatin, (3) be the EGF inhibitor of antibody, for example: HER2 antibody (for example, trastuzumab (Trastuzumab _), Genentech, Inc.), Cetuximab (Erbitux, IMC-C225, ImClone Systems), EMD 72000 (Merck KGaA), anti--EFGR monoclonal antibody ABX (Abgenix), TheraCIM-h-R3 (Center ofMolecular Immunology), monoclonal antibody 425 (Merck KGaA), monoclonal antibody ICR-62 (ICR, Sutton, England); Herzyme (Elan PharmaceuticalTechnologies and Ribozyme Pharmaceuticals), PKI 166 (Novartis), EKB569 (Wyeth-Ayerst), GW 572016 (GlaxoSmithKline), CI 1033 (PfizerGlobal Research and Development), trastuzmab-maytansinoid conjugate (Genentech, Inc.), mitumomab (Imclone Systems and Merck KGaA) and Melvax II (Imclone Systems and Merck KgaA), (4) be micromolecular EGF inhibitor, for example, it matches watt (TM) (OSI-774, OSI Pharmaceuticals, Inc.) and Iressa (ZD 1839, Astra Zeneca), (5) be the VEGF inhibitor of antibody, for example: rhuMAb-VEGF (Genentech, Inc.) and IMC-1C11 (ImClone Systems), DC 101 (a kind of KDR vegf receptor 2) from ImClone Systems, (6) be micromolecular VEGF kinase inhibitor, for example SU 5416 is (from Sugen, Inc), SU 6688 is (from Sugen, Inc.), Bay 43-9006 (a kind of two VEGF and bRAF inhibitor) from Bayer Pharmaceuticals and OnyxPharmaceuticals, (7) estrogen receptor antagon or selective estrogen receptor modulators (SERM), tamoxifen for example, idoxifene, raloxifene, instead-2,3-dihydro raloxifene, Levormeloxifene, droloxifene, MDL 103,323 and acolbifene (Schering Corp.), (8) antitumor nucleoside derivates 5 FU 5 fluorouracil for example, gemcitabine or capecitabine, (9) for example BMS-247550 (Bristol-MyersSquibb) and EPO906 (Novartis Pharmaceuticals) of ebormycine, (10) for example Hycamtin (Glaxo SmithKline) and Camptosar (Pharmacia) of topoisomerase enzyme inhibitor, (11) vinca alkaloids, for example, nvelbine (Anvar and Fabre, France), vincristine(VCR) and vinealeucoblastine(VLB), (12) be the antibody of α V β 3 integrin inhibitors, for example, LM-609 (referring to, ClinicalCancer Research, Vol.6, the 3056-3061 page or leaf, in August, 2000, its content is hereby incorporated by).
In one embodiment, described antineoplastic agent is selected from: taxol, docetaxel, carboplatin, cis-platinum, gemcitabine, tamoxifen, Trastuzumab, Cetuximab, its match watt, Iressa, rhuMAb-VEGF, nvelbine, IMC-1C11, SU5416 and SU6688.In another embodiment, described antineoplastic agent is selected from: taxol, docetaxel, carboplatin, cis-platinum, nvelbine, gemcitabine and Trastuzumab.
Usually, when using more than a kind of antineoplastic agent in the method for the invention, described antineoplastic agent with their standard dosage forms simultaneously or continuously in administration on the same day.For example, the common intravenous administration of described antineoplastic agent preferably uses IV solution well known in the art (for example, isotonic saline solution (0.9%NaCl) or glucose solution (for example, 5% glucose)) by the IV dropleting medicine-feeding.
When using two or more antineoplastic agents, described antineoplastic agent is usually in administration on the same day; But those skilled in the art will be understood that, described antineoplastic agent can not on the same day with different all administrations.The clinicist can give this antineoplastic agent according to the dosage timetable that antineoplastic agent manufacturers is advised, and can for example, based on the reaction of patient to this treatment, regulate this dosage timetable according to patient's needs.For example, when gemcitabine and iridium-platinum complex such as cisplatin combined use treatment lung cancer, gemcitabine and cis-platinum in administration on the same day, gave gemcitabine first day of treatment cycle separately then at the 8th day, then gave one time gemcitabine more separately at the 15th day.
Therefore, a kind of specific embodiments of the present invention relates to a kind of treatment method for cancer, comprises the fpt inhibitor (that is compound of the present invention), Taxan and the iridium-platinum complex that need the patient treatment of this treatment significant quantity.
Another kind of specific embodiments of the present invention relates to a kind of treatment method for cancer, comprise need the patient treatment of this treatment significant quantity fpt inhibitor (promptly, compound of the present invention), Taxan and iridium-platinum complex, administration every day of wherein said fpt inhibitor, described Taxan weekly the phase be administered once weekly, and described iridium-platinum complex the phase is administered once weekly weekly.In another embodiment, described treatment is for the phase continues 1-4 week weekly.
Another kind of specific embodiments of the present invention relates to a kind of treatment method for cancer, comprise need the patient treatment of this treatment significant quantity fpt inhibitor (promptly, compound of the present invention), Taxan and iridium-platinum complex, administration every day of wherein said fpt inhibitor, described Taxan is administered once weekly in phase in per three weeks, and described iridium-platinum complex phase in per three weeks are administered once weekly.In another embodiment, described treatment is for the phase continues 1-3 week weekly.
Another kind of specific embodiments of the present invention relates to a kind of treatment method for cancer, comprises the fpt inhibitor (that is compound of the present invention), taxol and the carboplatin that need the patient treatment of this treatment significant quantity.In another embodiment, administration every day of described fpt inhibitor, described taxol weekly the phase be administered once weekly, and described carboplatin the phase is administered once weekly weekly.In another embodiment, described treatment is weekly the phase to continue 1-4 week.
Another embodiment of the present invention relates to a kind of treatment method for cancer, comprises the fpt inhibitor (that is compound of the present invention), taxol and the carboplatin that need the patient treatment of this treatment significant quantity.In another embodiment, administration every day of described fpt inhibitor, described taxol is administered once weekly in phase in per three weeks, and described carboplatin phase in per three weeks are administered once weekly.In another embodiment, described treatment is weekly the phase to continue 1-3 week.
Another embodiment of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of this treatment of needs, comprise treat significant quantity every day fpt inhibitor (promptly, compound of the present invention), phase is treated the carboplatin of significant quantity once in a week weekly, and weekly the phase treat the taxol of significant quantity once in a week, the phase continues 1-4 week weekly in wherein said treatment.In another embodiment, described fpt inhibitor is administered twice every day.In another embodiment, described carboplatin and described taxol be in administration on the same day, and in another embodiment, described carboplatin and described taxol successive administration, and in another embodiment, the administration behind described taxol of described carboplatin.
Another embodiment of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of this treatment of needs, comprise treat significant quantity every day fpt inhibitor (promptly, compound of the present invention), phase in per three weeks are once treated the carboplatin of significant quantity weekly, and the taxol of once treating significant quantity weekly phase in per three weeks, wherein should treatment continue 1-3 week.In another embodiment, described fpt inhibitor is administered twice every day.In another embodiment, described carboplatin and described taxol be in administration on the same day, and in another embodiment, described carboplatin and described taxol successive administration, and in another embodiment, the administration behind described taxol of described carboplatin.
Another embodiment of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of this treatment of needs, the fpt inhibitor that comprises twice about 200mg of about 50-every day (promptly, compound of the present invention), phase gives quantity once in a week for providing about 2-about 8 (and in another embodiment weekly, about 2-about 3) carboplatin of AUC, and the phase about 300mg/m of about 60-that is administered once weekly weekly
2(and in another embodiment, about 50-100mg/m
2, and also have in another embodiment the about 80mg/m of about 60-
2) taxol, wherein this is treated weekly the phase and continues 1-4 week.In another embodiment, described fpt inhibitor is administered twice with the amount of the about 125mg of about 75-every day, and in another embodiment, described fpt inhibitor is administered twice with the amount of about 100mg every day.In another embodiment, described carboplatin and described taxol be in administration on the same day, and in another embodiment, described carboplatin and described taxol successive administration, and in another embodiment, the administration behind described taxol of described carboplatin.
In another embodiment, the present invention relates to a kind of method of in the patient of this treatment of needs, treating nonsmall-cell lung cancer, the fpt inhibitor that comprises twice about 200mg of about 50-every day (promptly, compound of the present invention), once (about 5-about 8 in another embodiment so that about 2-about 8 to be provided phase in per three weeks weekly, and in another embodiment 6) amount of AUC gives carboplatin, and the about 250mg/m of once about 150-of phase in per three weeks weekly
2(and in another embodiment, the about 225mg/m of about 175-
2, and in another embodiment, 175mg/m
2) taxol, wherein should treatment continue 1-3 week.In another embodiment, described fpt inhibitor is administered twice with the amount of the about 125mg of about 75-every day, and in another embodiment, described fpt inhibitor is administered twice with the amount of about 100mg every day.In another embodiment, described carboplatin and described taxol be in administration on the same day, and in another embodiment, described carboplatin and described taxol successive administration, and in another embodiment, the administration behind described taxol of described carboplatin.
Other embodiment of the present invention relates to as described treatment method for cancer in the above-described embodiment, but in the method with following combination replacement taxol and carboplatin: (1) docetaxel (taxotere _) and cis-platinum; (2) taxol and cis-platinum; (3) docetaxel and carboplatin.In the another embodiment of the inventive method, the about 100mg/m of the about 30-of the consumption of cis-platinum
2In the another embodiment of the inventive method, the about 100mg/m of the about 30-of the consumption of docetaxel
2
Another embodiment of the present invention relates to a kind of treatment method for cancer, comprises fpt inhibitor (that is compound of the present invention), the Taxan that needs the patient treatment of this treatment significant quantity and is the EGF inhibitor of antibody.In another embodiment, employed Taxan is a taxol, and described EGF inhibitor is HER2 antibody (being Trastuzumab in one embodiment) or Cetuximab, and uses Trastuzumab in another embodiment.Described in treatment time length, consumption and the administration such as top embodiment of fpt inhibitor and Taxan.For the EGF inhibitor of antibody weekly the phase be administered once weekly, and in another embodiment, for the EGF inhibitor of antibody and Taxan in administration on the same day, and in another embodiment with the Taxan successive administration.For example, Trastuzumab is with the about 5mg/m of about 3-
2(in another embodiment, about 4mg/m
2) the loading dose administration, (this cycle is 1-4 week usually) is with about 2mg/m all the other times of treatment cycle then
2Maintenance dose weekly administration of phase weekly.In one embodiment, the cancer of being treated is a mammary cancer.
In another embodiment, the present invention relates to a kind of treatment method for cancer, comprise and need the patient treatment of this treatment significant quantity: (1) fpt inhibitor is (promptly, compound of the present invention), (2) Taxan, (3) antineoplastic agent, it is selected from: (a) for micromolecular EGF inhibitor, (b) be the VEGF inhibitor of antibody and (c) be micromolecular VEGF kinase inhibitor.In another embodiment, employed Taxan is taxol or docetaxel.In another embodiment, described antineoplastic agent is selected from: its match watt, Iressa, rhuMAb-VEGF, SU5416, SU6688 and BAY 43-9006.Described in treatment time length, consumption and the administration such as top embodiment of fpt inhibitor and Taxan.Usually the phase is administered once weekly weekly for the VEGF kinase inhibitor of antibody.Be micromolecular EGF and administration every day phase weekly usually of VEGF inhibitor.In another embodiment, for the VEGF inhibitor of antibody and Taxan in administration on the same day, and in another embodiment, be the VEGF inhibitor and the Taxan administration simultaneously of antibody.In another embodiment, when being micromolecular EGF inhibitor or for micromolecular VEGF inhibitor and Taxan during in administration on the same day, they and Taxan while administration.EGF or VEGF kinase inhibitor are usually with the about 500mg/m of about 10-
2Amount give.
In another embodiment, the present invention relates to a kind of treatment method for cancer, comprise the fpt inhibitor (that is compound of the present invention) that needs the patient treatment of this treatment significant quantity, antitumor nucleoside derivates and iridium-platinum complex.
Another embodiment of the present invention relates to a kind of treatment method for cancer, comprise need the patient treatment of this treatment significant quantity fpt inhibitor (promptly, compound of the present invention), antitumor nucleoside derivates and iridium-platinum complex, administration every day of wherein said fpt inhibitor, described antitumor nucleoside derivates weekly the phase be administered once weekly, and described iridium-platinum complex the phase is administered once weekly weekly.Can be 1-4 week though this treats weekly the phase, in one embodiment, this treats weekly the phase is 1-7 week.
Another embodiment of the present invention relates to a kind of treatment method for cancer, comprise need the patient treatment of this treatment significant quantity fpt inhibitor (promptly, compound of the present invention), antitumor nucleoside derivates and iridium-platinum complex, administration every day of wherein said fpt inhibitor, described antitumor nucleoside derivates weekly the phase be administered once weekly, and described iridium-platinum complex phase in per three weeks are administered once weekly.Can be 1-4 week though this treats weekly the phase, in one embodiment, this treats weekly the phase is 1-7 week.
Another embodiment of the present invention relates to a kind of treatment method for cancer, comprises the fpt inhibitor (that is compound of the present invention), gemcitabine and the cis-platinum that need the patient treatment of this treatment significant quantity.In another embodiment, administration every day of described fpt inhibitor, described gemcitabine weekly the phase be administered once weekly, and described cis-platinum the phase is administered once weekly weekly.In one embodiment, described treatment is weekly the phase to continue 1-7 week.
Another embodiment of the present invention relates to a kind of treatment method for cancer, comprises the fpt inhibitor (that is compound of the present invention), gemcitabine and the cis-platinum that need the patient treatment of this treatment significant quantity.In another embodiment, administration every day of described fpt inhibitor, described gemcitabine weekly the phase be administered once weekly, and described cis-platinum phase in per three weeks are administered once weekly.In another embodiment, described treatment is 1-7 week.
Another embodiment of the present invention relates to a kind of treatment method for cancer, comprises the fpt inhibitor (that is compound of the present invention), gemcitabine and the carboplatin that need the patient treatment of this treatment significant quantity.In another embodiment, administration every day of described fpt inhibitor, described gemcitabine weekly the phase be administered once weekly, and described carboplatin the phase is administered once weekly weekly.In another embodiment, described treatment is weekly the phase to continue 1-7 week.
Another embodiment of the present invention relates to a kind of treatment method for cancer, comprises the fpt inhibitor (that is compound of the present invention), gemcitabine and the carboplatin that need the patient treatment of this treatment significant quantity.In another embodiment, administration every day of described fpt inhibitor, described gemcitabine weekly the phase be administered once weekly, and described carboplatin phase in per three weeks are administered once weekly.In another embodiment, described treatment is weekly the phase to continue 1-7 week.
In the embodiment of above-mentioned use gemcitabine, fpt inhibitor (that is compound of the present invention) and iridium-platinum complex administration as the embodiment of top use Taxan is described.Gemcitabine is with the about 1250mg/m of about 500-
2The amount administration.In one embodiment, gemcitabine and iridium-platinum complex be in administration on the same day, and in another embodiment, gemcitabine and iridium-platinum complex successive administration, and in another embodiment, gemcitabine is administration behind iridium-platinum complex.
Another embodiment of the present invention relates to a kind ofly treats method for cancer in the patient of this treatment of needs, comprise and give described patient's fpt inhibitor (promptly, compound of the present invention) and antineoplastic agent, described antineoplastic agent is selected from all aforesaid: (1) is the EGF inhibitor of antibody, (2) be micromolecular EGF inhibitor, (3) are that VEGF inhibitor and (4) of antibody are micromolecular VEGF kinase inhibitor.This treats weekly the phase is 1-7 week, and usually this to treat weekly the phase be 1-4 week.Fpt inhibitor with other embodiment of the invention described above in identical mode administration.Common administration every day of described small molecules antineoplastic agent, the phase is administered once weekly described antibody antineoplastic agent weekly usually.In one embodiment, described antineoplastic agent is selected from: Trastuzumab, Cetuximab, its match watt, Iressa, rhuMAb-VEGF, IMC-1C11, SU5416, SU6688 and BAY 43-9006.
Iridium-platinum complex uses with at least a other antineoplastic agent therein, and in embodiment of the present invention of these medicine successive administrations, described iridium-platinum complex is administration after giving other antineoplastic agent usually.
Other embodiment of the present invention comprises, except that giving also to treat the radiotherapy of significant quantity outside the antineoplastic agent described in patient's fpt inhibitor (that is, compound of the present invention) and the top embodiment.Give radiotherapy according to those skilled in the art's technique known and scheme.
Another embodiment of the present invention relates to a kind of pharmaceutical composition, comprises at least two kinds of different antineoplastic agents and the pharmaceutically acceptable carrier that is used for intravenous administration.Described pharmaceutically acceptable carrier preferably waits and oozes salts solution (0.9% NaCl) or glucose solution (for example, 5% glucose).
Another embodiment of the present invention relates to a kind of pharmaceutical composition, comprises fpt inhibitor (that is compound of the present invention) antineoplastic agent and the pharmaceutically acceptable carrier that be used for intravenous administration different with at least two kinds.Described pharmaceutically acceptable carrier preferably waits and oozes salts solution (0.9%NaCl) or glucose solution (for example, 5% glucose).
Another embodiment of the present invention relates to a kind of pharmaceutical composition, comprises fpt inhibitor (that is compound of the present invention) and at least one antineoplastic agent and the pharmaceutically acceptable carrier that is used for intravenous administration.Described pharmaceutically acceptable carrier preferably waits and oozes salts solution (0.9%NaCl) or glucose solution (for example, 5% glucose).
It will be appreciated by those skilled in the art that employed in the method for the invention compound (medicine) to the clinicist be can from the pharmaceutical composition (formulation) of producer, obtain and in those compositions, use.Therefore, the kind of cited compound or compound can be replaced with the pharmaceutical composition of enumerating that contains particular compound or classes of compounds in aforesaid method.For example, relate to comprise need the patient treatment of this treatment significant quantity fpt inhibitor (promptly, compound of the present invention), the embodiment of the treatment cancer method of Taxan and iridium-platinum complex, comprise the treatment method for cancer in its scope, this method comprises the pharmaceutical composition that contains fpt inhibitor that needs the patient treatment of this treatment significant quantity, contain the pharmaceutical composition of Taxan and contain the pharmaceutical composition of iridium-platinum complex.
Actual using dosage can change with patient's needs and sanatory severity.For a kind of particular case, those skilled in the art can determine suitable dosage.
Fpt inhibitor (promptly, compound of the present invention) and the consumption of antineoplastic agent and frequency of utilization can be according to the judgement that cures mainly clinicist (doctor), consider these factors such as age, patient's situation and size and regulate after the severity of treatment cancer.
Described antineoplastic agent can be according to treatment plan administration well known in the art.The administration of antineoplastic agent can change with the cancer of being treated and this antineoplastic agent known action to this disease, and this point is conspicuous to those skilled in the art.In addition, according to clinicist's knowledge, treatment plan (for example, dosage and administration number of times) can according to give observed effect behind patient's medicine and according to the observation to cancer the reaction of giving medicine is changed.
Initial administration can be carried out according to definite scheme known in the art, and then, with the observed basis that act as, the clinicist can change dosage, administering mode and administration number of times.
The concrete selection of antineoplastic agent will depend on attending doctor's diagnosis and they are to the judgement of patient's illness and suitable treatment plan.
During treatment plan, after the cancer of being treated and patient's situation was made an appraisal, skilled practitioners can be determined the order of administration and the administration multiplicity of antineoplastic agent with knowledge.
Therefore, rule of thumb and knowledge, holding the industry doctor can change each scheme of antineoplastic agent administration according to independent patient's needs when treating.All these change all within the scope of the present invention.
Cure mainly the clinicist, judging that treatment is under the dosage of being used whether effectively the time, the extenuating of patient's general health situation and clearer and more definite symptom such as cancer related symptoms (for example, pain, cough (for lung cancer) and breathe hard (for lung cancer)), the inhibition of tumor growth, the actual contraction of tumour or the inhibition of transfer will be will consider.The size of tumour can be measured by standard method, for example radioactivity research, for example, CAT or MRI scanning, and can use serial testing whether to be delayed or even reverse to judge growth of tumor.Extenuating of symptom relevant with disease such as pain, and the improvement on integral status also can be with the validity of helping judge treatment.
Other embodiment of the present invention relates to uses at least a (for example, a kind of) compound of formula I and the combination of medicine to be used for the treatment of mammary cancer,, the present invention relates to be used for the treatment of the conjoint therapy of mammary cancer that is.Those skilled in the art will be understood that the compound of described formula I and medicine are usually respectively as the administration of drug alone composition.The pharmaceutical composition that use contains more than one medicines within the scope of the present invention.
Therefore, another embodiment of the present invention relates to a kind of treatment in the patient of this treatment of needs (or prevention), and mammary cancer (promptly, after the menopause and menopause before mammary cancer, for example, hormonal dependent mammary cancer) method comprises the compound of at least a (for example, a kind of) the formula I that gives described patient treatment significant quantity and at least a antihormone of treatment significant quantity, described antihormone is selected from: (a) aromatase inhibitor, (b) antiestrogen and (c) LHRH analogue; And the optional at least a chemotherapeutics of administration that comprises of described treatment.
The compound preferred oral administration of formula I, and in one embodiment, the compound of formula I is with the capsule form administration.
Examples of aromatase inhibitors is including, but not limited to Anastrozole (for example, Arimidex), letrozole (for example, furlong), Exemestane (Arnold is new), fadrozole and formestane (for example, Lentaron).
(for example, Faslodex), raloxifene (for example, Yi Weite) and Acolbifene including, but not limited to: tamoxifen (for example, Nolvadex/Nolvadex-D), fulvestrant for the example of antiestrogen.
The example of LHRH analogue is including, but not limited to goserelin (for example, Zoladex) and leuproside (for example, acetic acid leuproside, for example Lupron or Lupron Depot).
The example of chemotherapeutics including, but not limited to: trastuzumab is (for example, Trastuzumab), Gefitinib (for example, Iressa), erlotinib (Erlotinib) (for example, Erlotinib hydrochloride, for example its match watt), rhuMAb-VEGF (for example, Avastin), Cetuximab (for example, Erbitux) and Bao Tezuomi (for example, Velcade).
Preferably, when using more than a kind of antihormone, every kind of medicament is selected from different sorts.For example, a kind of medicament is that aromatase inhibitor (for example, Anastrozole, letrozole or Exemestane) and a kind of medicament are antiestrogen (for example, tamoxifen or fulvestrants).
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, the compound that wherein said treatment comprises at least a formula I that treats significant quantity (for example, a kind of) and at least a being selected from: (a) aromatase inhibitor, (b) antiestrogen and (c) antihormone of LHRH analogue; And give at least a chemotherapeutics of significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, the compound that wherein said treatment comprises at least a formula I that treats significant quantity (for example, a kind of) and at least a being selected from: (a) aromatase inhibitor, (b) antiestrogen and (c) antihormone of LHRH analogue.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of) and at least a being selected from of at least a formula I that treats significant quantity: (a) aromatase inhibitor and (b) antihormone of antiestrogen.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, the compound that wherein said treatment comprises at least a formula I that treats significant quantity (for example, a kind of), at least a being selected from: (a) aromatase inhibitor and (b) antihormone of antiestrogen; And at least a chemotherapeutics.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of) and at least a aromatase inhibitor of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, the compound that wherein said treatment comprises at least a formula I that treats significant quantity (for example, a kind of), at least a aromatase inhibitor, and at least a chemotherapeutics.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises treats significant quantity: the compound of (1) at least a formula I (for example, a kind of); And (2) at least a antihormone, be selected from: (a) aromatase inhibitor, be selected from Anastrozole, letrozole, Exemestane, fadrozole and formestane, (b) antiestrogen, be selected from: tamoxifen, fulvestrant, raloxifene and Acolbifene, (c) LHRH analogue is selected from: goserelin and leuproside; And give at least a of significant quantity and be selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises treats significant quantity: the compound of (1) at least a formula I (for example, a kind of); And (2) at least a antihormone, be selected from: (a) aromatase inhibitor, be selected from Anastrozole, letrozole, Exemestane, fadrozole and formestane, (b) antiestrogen, be selected from: tamoxifen, fulvestrant, raloxifene and Acolbifene, (c) LHRH analogue is selected from: goserelin and leuproside.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises treats significant quantity: the compound of (1) at least a formula I (for example, a kind of); And (2) at least a antihormone, be selected from: (a) aromatase inhibitor, be selected from Anastrozole, letrozole, Exemestane, fadrozole and formestane and (b) antiestrogen, be selected from: tamoxifen, fulvestrant, raloxifene and Acolbifene.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises treats significant quantity: the compound of (1) at least a formula I (for example, a kind of); And (2) at least a antihormone, be selected from: (a) aromatase inhibitor, be selected from Anastrozole, letrozole, Exemestane, fadrozole and formestane, (b) antiestrogen is selected from: tamoxifen, fulvestrant, raloxifene and Acolbifene; And give at least a of significant quantity and be selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises treats significant quantity: the compound of (1) at least a formula I (for example, a kind of); And (2) at least a aromatase inhibitor, be selected from Anastrozole, letrozole, Exemestane, fadrozole and formestane.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises treats significant quantity: the compound of (1) at least a formula I (for example, a kind of); (2) at least a aromatase inhibitor is selected from Anastrozole, letrozole, Exemestane, fadrozole and formestane; And (3) give at least a of significant quantity and are selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises treats significant quantity: the compound of (1) at least a formula I (for example; A kind of); (2) at least a aromatase inhibitor; And (3) at least a LHRH analogue.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises treats significant quantity: the compound of (1) at least a formula I (for example, a kind of); (2) at least a antiestrogen; And (3) at least a LHRH analogue.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises treats significant quantity: the compound of (1) at least a formula I (for example, a kind of); (2) at least a aromatase inhibitor is selected from: Anastrozole, letrozole, Exemestane, fadrozole and formestane; And (3) at least a LHRH analogue is selected from: goserelin and leuproside.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises treats significant quantity: the compound of (1) at least a formula I (for example, a kind of); (2) at least a antiestrogen is selected from: tamoxifen, fulvestrant, raloxifene and Acolbifene; And (3) at least a LHRH analogue is selected from: goserelin and leuproside.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the Anastrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the letrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the Exemestane of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the fadrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the formestane of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the raloxifene of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the Acolbifene of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the goserelin of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of) and the leuproside of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the Anastrozole of at least a formula I that treats significant quantity and is selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the letrozole of at least a formula I that treats significant quantity and is selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the Exemestane of at least a formula I that treats significant quantity and is selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the fadrozole of at least a formula I that treats significant quantity and is selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the formestane of at least a formula I that treats significant quantity and is selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), Anastrozole and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), letrozole and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), Exemestane and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), fadrozole and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), formestane and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), Anastrozole and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), letrozole and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), Exemestane and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), fadrozole and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), formestane and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the Anastrozole of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the letrozole of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the Exemestane of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the fadrozole of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the formestane of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the tamoxifen of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the fulvestrant of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the raloxifene of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the Acolbifene of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the goserelin of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), the Leuprolein of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprise at least a formula I that treats significant quantity compound (for example, a kind of), Anastrozole, be selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene and being selected from: the chemotherapeutics of tamoxifen, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprise at least a formula I that treats significant quantity compound (for example, a kind of), letrozole, be selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene and being selected from: the chemotherapeutics of tamoxifen, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprise at least a formula I that treats significant quantity compound (for example, a kind of), Exemestane, be selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene and being selected from: the chemotherapeutics of tamoxifen, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprise at least a formula I that treats significant quantity compound (for example, a kind of), fadrozole, be selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene and being selected from: the chemotherapeutics of tamoxifen, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprise at least a formula I that treats significant quantity compound (for example, a kind of), formestane, be selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene and being selected from: the chemotherapeutics of tamoxifen, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), Anastrozole, the tamoxifen of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), letrozole, the tamoxifen of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), Exemestane, the tamoxifen of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), fadrozole, the tamoxifen of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Te position rice.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), formestane, the tamoxifen of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), Anastrozole, the fulvestrant of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), letrozole, the fulvestrant of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), Exemestane, the fulvestrant of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), fadrozole, the fulvestrant of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, wherein said treatment comprises compound (for example, a kind of), formestane, the fulvestrant of at least a formula I that treats significant quantity and is selected from: the chemotherapeutics of trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), goserelin and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), goserelin and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), goserelin and the raloxifene of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), goserelin and the Acolbifene of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), leuproside and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), leuproside and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), leuproside and the raloxifene of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), leuproside and the Acolbifene of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), goserelin and the Anastrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), goserelin and the letrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), goserelin and the Exemestane of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), goserelin and the fadrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), goserelin and the formestane of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), leuproside and the Anastrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of .), leuproside and the letrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), leuproside and the Exemestane of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), leuproside and the fadrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates in the patient of this treatment of needs the method for treatment or Breast Cancer Prevention, and wherein said treatment comprises compound (for example, a kind of), leuproside and the formestane of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of) and the Anastrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of) and the letrozole of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of) and the Exemestane of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of) and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of) and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of), Anastrozole and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of), letrozole and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of), Exemestane and the fulvestrant of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of), Anastrozole and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of), letrozole and the tamoxifen of at least a formula I that treats significant quantity.
Another embodiment of the present invention relates to treatment or Breast Cancer Prevention in the patient of this treatment of needs, and described treatment comprises compound (for example, a kind of), Exemestane and the tamoxifen of at least a formula I that treats significant quantity.
Other embodiment of the present invention relates to any above-mentioned embodiment that is used for the treatment of mammary cancer, and wherein said chemotherapeutics is a trastuzumab.
Other embodiment of the present invention relates to any above-mentioned embodiment that is used for the treatment of mammary cancer, and wherein said method relates to a kind of method for the treatment of mammary cancer.
Administration simultaneously of the compound of formula I, antihormone and chemotherapeutics or administration successively.
Described antihormone and optional chemotherapeutics are according to the known scheme of their those skilled in the art, dosage and formulation administration (for example, Physician ' s Desk Reference or disclosed document).For example, for tamoxifen, fulvestrant, raloxifene, Anastrozole, letrozole, Exemestane, leuproside and goserelin, referring to Physician ' s DeskReference, the 57th edition, 2003, publish Montvale by Thomas PDR, N.J.07645-1742, its content is hereby incorporated by.
Usually, in the embodiment that relates to the breast cancer treatment method: the compound of (1) formula I can administration every day (for example, once a day, and twice of every day in one embodiment), (2) aromatase inhibitor can be according to the known arrangement administration of employed aromatase inhibitor (for example, once a day), (3) antiestrogen can be according to the known arrangement administration of employed antiestrogen (for example, from once a day to January once), (4) the LHRH analogue can be according to the known arrangement administration of employed LHRH analogue (for example, January once to per March once), and (5) chemotherapeutics can be according to the known arrangement administration of employed chemotherapeutics (for example, from once a day to weekly).
Radiotherapy, if give, it gave according to known arrangement before the compound of giving construction I, antihormone and optional chemotherapeutics usually.
The treatment of carrying out according to the breast cancer treatment method is successive (that is, abideing by continuous dosing regimens).Treatment continuously till have a response fully, or up to skilled clinician determine the patient not from this treatment benefited till (for example, when having disease progression).
If according to the judgement of skilled clinician, this patient will obtain advantage from use one or more discontinuous treatment plans that give medicine, and the continuous treatment plan of mammary cancer can change discontinuous treatment plan into so.For example, the compound of formula I can use discontinuous treatment plan to give, and employed all the other medicines can mode as described herein give in treatment.An example of the discontinuous treatment plan of formula I compound is a kind of repeat cycle, in this repeat cycle, three all giving construction I compounds, then a week giving construction I compound not.
After breast cancer treatment obtains response fully, use the dosage described in the inventive method to continue to keep treatment with the compound of formula I.Keep treatment and can also comprise the antihormone that gives dosage described in the inventive method.Keep treatment and can only use antihormone.For example, after obtaining response fully, can continue to give aromatase inhibitor (for example, Anastrozole, letrozole or Exemestane) up to 5 years.Perhaps, for example, after obtaining response fully, can use antiestrogen such as tamoxifen up to 5 years.Perhaps, for example, after obtaining response fully, can use antiestrogen (for example, tamoxifen), then use aromatase inhibitor (for example, Anastrozole, letrozole or Exemestane) up to 5 years up to 5 years.
Relate in the embodiment for the treatment of mammary cancer above-mentioned, the compound of formula I can be with total per daily dose successive administration of the about 600mg of about 100mg-.Usually, total per daily dose gives with the form of divided dose, and in one embodiment, and total per daily dose is to give for twice every day.In one embodiment, the compound of formula I gives with the amount of the about 300mg of about 50mg-at every turn, and be administered twice every day.In another embodiment, the compound of formula I gives with the amount of the about 200mg of about 100mg-at every turn, and be administered twice every day.Example comprises each compound with 100mg giving construction I, and be administered twice every day.Example also comprises each compound with 200mg giving construction I, and be administered twice every day.
Anastrozole is by the p.o. administration and once a day with the each quantity administration of the about 10mg of about 0.5-, in one embodiment, each amount is about 1.0mg.
Letrozole is by the p.o. administration and once a day with the each quantity administration of the about 10mg of about 1.0-, in one embodiment, each amount is about 2.5mg.
Exemestane is by the p.o. administration and once a day with the each quantity administration of the about 50mg of about 10-, in one embodiment, each amount is about 25mg.
Fadrozole by twice of p.o. administration and every day with the each quantity administration of the about 10mg of about 0.5-, in one embodiment, each amount is about 2.0mg.
Formestane is by i.m. administration and every biweekly with the each quantity administration of the about 500mg of about 100-, and in one embodiment, each amount is about 250mg.
Tamoxifen is by the p.o. administration and once a day with the each quantity administration of the about 100mg of about 10-, in one embodiment, each amount is about 20mg.
Fulvestrant by i.m. administration and January once with the each quantity administration of the about 1000mg of about 100-, in one embodiment, each amount is about 250mg.
Raloxifene is by the p.o. administration and once a day with the each quantity administration of the about 120mg of about 10-, in one embodiment, each amount is about 60mg.
Acolbifene is by the p.o. administration and once a day with the each quantity administration of the about 20mg of about 5-, in one embodiment, each amount is about 20mg.
Goserelin by s.c. administration and January once or per March once with the each quantity administration of the about 20mg of about 2-, in one embodiment when January during single administration, the quantity of administration is each for about 3.6mg, when per March during single administration, each quantity is about 10.8mg in another embodiment.
Leuproside by s.c. administration and January once or per March once with the each quantity administration of the about 20mg of about 2-, in one embodiment when January during single administration, the quantity of administration is each for about 3.75mg, when per March during single administration, each quantity is about 11.25mg in another embodiment.
Trastuzumab is by i.v. administration and weekly with the each quantity administration of the about 20mpk of about 2-, in one embodiment, each amount be about 2mpk. trastuzumab usually at first with the loading dose administration, loading dose is the twice of dosage weekly normally.Therefore, for example, give 4mpk loading dose, give 2mpk then weekly at every turn.
Gefitinib is by the p.o. administration and once a day with the each quantity administration of the about 1000mg of about 100-, in one embodiment, each amount is about 250mg.
Erlotinib is by the p.o. administration and once a day with the each quantity administration of the about 500mg of about 100-, in one embodiment, each amount is about 150mg.
RhuMAb-VEGF is by i.v. administration and every biweekly with the each quantity administration of the about 15mg per kilogram of body weight of about 2.5-, and in one embodiment, each amount is about 10mg per kilogram.
Cetuximab is by i.v. administration and weekly with every square metre of each quantity administration of the about 500mg of about 200-, and in one embodiment, each amount is every square metre of about 250mg.
The Bao Tezuo rice grain pattern is crossed the i.v. administration, and twice weekly, two weeks, follow 10 days time of having a rest (21 days treatment cycle), maximum eight treatment cycle, each amount administration with every square metre of the about 2.5mg of about 1.0-, in one embodiment, each quantity administration with every square metre of about 1.3mg.
Therefore, In one embodiment of the present invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) is at every turn with the compound of the amount orally give formula I of the about 300mg of about 50mg-, wherein be administered twice every day, and (2) Anastrozole by p.o. with the each quantity administration of the about 10mg of about 0.5-, wherein be administered once in one day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) is at every turn with the compound of the amount orally give formula I of the about 200mg of about 100-, wherein be administered twice every day, and (2) Anastrozole wherein was administered once with the each quantity administration of about 1.0mg in one day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) is at every turn with the compound of the amount orally give formula I of the about 300mg of about 50mg-, wherein be administered twice every day, and (2) letrozole by p.o. with the each quantity administration of the about 10mg of about 1.0-, wherein be administered once in one day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) is at every turn with the compound of the amount giving construction I of the about 200mg of about 100-, wherein be administered twice every day, and (2) letrozole by p.o. with the each quantity administration of about 2.5mg, wherein be administered once in one day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) is at every turn with the compound of the amount orally give formula I of the about 300mg of about 50mg-, wherein be administered twice every day, and (2) Exemestane by p.o. with the each quantity administration of the about 50mg of about 10-, wherein be administered once in one day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) is at every turn with the compound of the amount giving construction I of the about 200mg of about 100-, wherein be administered twice every day, and (2) Exemestane wherein was administered once with the each quantity administration of about 25mg in one day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) is at every turn with the compound of the amount orally give formula I of the about 300mg of about 50mg-, wherein be administered twice every day, and (2) fulvestrant by i.m. with the each quantity administration of the about 1000mg of about 100-, wherein be administered once in every month.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) is at every turn with the compound of the amount orally give formula I of the about 200mg of about 100-, wherein be administered twice every day, and (2) fulvestrant by i.m. with the each quantity administration of about 250mg, wherein be administered once in every month.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) is at every turn with the compound of the amount giving construction I of the about 300mg of about 50mg-, wherein be administered twice every day, and (2) tamoxifen by p.o. with the each quantity administration of the about 100mg of about 10-, wherein be administered once in one day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) is at every turn with the compound of the amount giving construction I of the about 200mg of about 100-, wherein be administered twice every day, and (2) tamoxifen by p.o. with the each quantity administration of about 20mg, wherein be administered once in one day.
In other embodiments of the present invention, in the patient of this treatment of needs, treat mammary cancer, wherein said treatment (for example comprises the compound of giving construction I, a kind of aromatase inhibitor, Anastrozole, letrozole or Exemestane, and be Anastrozole in one embodiment) and a kind of antiestrogen is (for example, fulvestrant or tamoxifen), compound, aromatase inhibitor and the antiestrogen of its Chinese style I are with above-mentioned dosed administration.
Therefore, for example in another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: the compound of (1) formula I gives with the amount of the about 300mg of each about 50mg-by p.o., wherein be administered twice every day, (2) Anastrozole gives with the amount of the about 10mg of each about 0.5-by p.o., wherein be administered once every day, (3) fulvestrant gives with the amount of the about 1000mg of about 100-by i.m. at every turn, wherein is administered once in every month.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) passes through compound of p.o giving construction I at every turn with the amount of the about 200mg of about 100-, wherein be administered twice every day, (2) each amount with about 1.0mg gives Anastrozole by p.o., wherein be administered once every day and (3) fulvestrant by i.m. at every turn with the quantity administration of about 250mg, wherein be administered once in every month.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) by p.o. at every turn with the compound of the amount giving construction I of the about 300mg of about 50mg-, wherein be administered twice every day, (2) give letrozole with the amount of the about 10mg of about 1.0-by p.o. at every turn, wherein be administered once every day and (3) at every turn give fulvestrant with amount of the about 1000mg of about 100-, wherein be administered once in every month.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) passes through compound of p.o giving construction I at every turn with the amount of the about 200mg of about 100-, wherein be administered twice every day, (2) each amount with about 2.5mg gives letrozole by p.o., wherein be administered once every day and (3) give fulvestrant with the quantity of about 250mg by i.m. at every turn, wherein be administered once in every month.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) by p.o. at every turn with the compound of the amount giving construction I of the about 300mg of about 50mg-, wherein be administered twice every day, (2) give Exemestane with the amount of the about 50mg of about 10-by p.o. at every turn, wherein be administered once every day, (3) give fulvestrant with the amount of the about 1000mg of about 100-by i.m. at every turn, wherein be administered once in every month.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) passes through compound of p.o giving construction I at every turn with the amount of the about 200mg of about 100-, wherein be administered twice every day, (2) each amount with about 25mg gives Exemestane by p.o., wherein be administered once every day and (3) give fulvestrant with the quantity of about 250mg by i.m. at every turn, wherein be administered once in every month.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) by p.o. at every turn with the compound of the amount giving construction I of the about 300mg of about 50mg-, wherein be administered twice every day, (2) give Anastrozole with the amount of the about 10mg of about 0.5-by p.o. at every turn, wherein be administered once every day, (3) give tamoxifen with the amount of the about 100mg of about 10-by p.o. at every turn, wherein be administered once every day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) passes through compound of p.o giving construction I at every turn with the amount of the about 200mg of about 100-, wherein be administered twice every day, (2) each amount with about 1.0mg gives Anastrozole by p.o., wherein be administered once every day and (3) give tamoxifen with the quantity of about 20mg by p.o. at every turn, wherein be administered once every day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) by p.o. at every turn with the compound of the amount giving construction I of the about 300mg of about 50mg-, wherein be administered twice every day, (2) give letrozole with the amount of the about 10mg of about 1.0-by p.o. at every turn, wherein be administered once every day and (3) give tamoxifen with the amount of the about 100mg of about 10-by p.o. at every turn, wherein be administered once every day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) passes through compound of p.o giving construction I at every turn with the amount of the about 200mg of about 100-, wherein be administered twice every day, (2) each amount with about 2.5mg gives letrozole by p.o., wherein be administered once every day and (3) give tamoxifen with the quantity of about 20mg by p.o. at every turn, wherein be administered once every day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) by p.o. at every turn with the compound of the amount giving construction I of the about 300mg of about 50mg-, wherein be administered twice every day, (2) give Exemestane with the amount of the about 50mg of about 10-by p.o. at every turn, wherein be administered once every day, (3) give tamoxifen with the amount of the about 100mg of about 10-by p.o. at every turn, wherein be administered once every day.
In another embodiment of the invention, treatment in the patient of this treatment of needs (or prevention) mammary cancer, wherein said treatment comprises and gives described patient: (1) passes through compound of p.o giving construction I at every turn with the amount of the about 200mg of about 100-, wherein be administered twice every day, (2) each amount with about 25mg gives Exemestane by p.o., wherein be administered once every day and (3) give tamoxifen with the quantity of about 20mg by p.o. at every turn, wherein be administered once every day.
Those skilled in the art will be understood that, when using other combination of antihormone, antihormone is with the quantity use of top specified this independent antihormone separately.
Other embodiment of treatment mammary cancer relates to the method for above-mentioned treatment mammary cancer, and the compound of its Chinese style I is administered twice with about 100mg/ time amount every day.
Other embodiment of treatment mammary cancer relates to the method for above-mentioned treatment mammary cancer, and the compound of its Chinese style I is administered twice with about 200mg/ time amount every day.
Other embodiment of treatment mammary cancer relates to the method for above-mentioned treatment mammary cancer, wherein except that the compound and antihormone (or multiple antihormone) of giving construction I, also gives chemotherapeutics.In these embodiments, described in the compound of formula I and the dosage range of antihormone such as the top combination therapy those, or as top independent formula I compound and antihormone described those, and the dosage of this chemotherapeutics such as top independent chemotherapeutics described those.The dosage of chemotherapeutics is known in the art.
Other embodiment of the present invention relates to the compound that contains formula I and the pharmaceutical composition of at least a antihormone and pharmaceutically acceptable carrier.
Other embodiment of the present invention relates to the pharmaceutical composition of the compound that contains formula I, at least a antihormone, at least a chemotherapeutics and pharmaceutically acceptable carrier.
Other embodiment of the present invention relates to the pharmaceutical composition of the compound that contains formula I, at least a chemotherapeutics and pharmaceutically acceptable carrier.
Those skilled in the art will recognize that the dosage of employed reality and scheme can change according to the judgement of skilled clinician in the methods of the invention.Skilled clinician considered following factor such as patient's age, situation and size, after the severity of treatment cancer and the reaction of patient to treatment, can make decision changes the dosage and the scheme of administration.
The diagnosis that antihormone, optional chemotherapeutics and optional radiotherapeutic concrete selection will be depended on the attending doctor and they are to the judgement of patient's illness and suitable treatment plan.
During treatment plan, after mammary cancer to be treated and patient's illness was made an appraisal, skilled practitioners can be determined order of administration, antihormone, optional chemotherapeutics and the optional radiotherapeutic number of times that gives with knowledge.
Therefore, rule of thumb and knowledge, holding the industry doctor can be according to the needs of individual patient, changes each scheme of antihormone, optional chemotherapeutics and optional radiotherapy administration when treating.All these change all within the scope of the present invention.
Be responsible for the clinicist, in whether judgement treats under the dosage of being used effectively, patient's general health situation and clearer and more definite symptom such as cancer related symptoms (for example, pain), the inhibition of tumor growth, the actual contraction of tumour or the inhibition of transfer will be will consider.The size of tumour can be measured by standard method, for example radioactivity research, for example, CAT or MRI scanning, and can use serial testing whether to be delayed or even reverse to judge growth of tumor.Extenuating of symptom relevant with disease such as pain, and the improvement on whole illness also can be with the validity of helping judge treatment.
Chemotherapeutics
The kind of compound that can be used as chemotherapeutics (antineoplastic agent/microtubule effect reagent) is including, but not limited to alkylating reagent, metabolic antagonist, natural product and their derivative, hormone and steroide (comprising synthetic analogues) and synthetics.The examples for compounds of these types is as follows.
Alkylating reagent (comprising nitrogen mustards, aziridine derivative, alkylsulfonate, nitrosourea inflammation and triazene class): Uramustine, mustargen, endoxan (Cytoxan_), ifosfamide, Mo Falun, Chlorambucil, pipobroman, Tretamine, plug are for group, busulfan, carmustine, lomustine, streptozocin, Dacarbazine and Temozolomide.
Metabolic antagonist (comprising folic acid antagonist, pyrimidine analogue, purine analogue and adenosine deaminase inhibitors): Rheumatrex, 5 FU 5 fluorouracil, floxuridine, cytosine arabinoside, Ismipur, 6-thioguanine, fludarabine phosphate, pentostatin and gemcitabine.
Natural product and their derivative (comprise vinca alkaloids, antitumor antibiotics, enzyme, lymphokine and epipodophyllotoxin): vinealeucoblastine(VLB), vincristine(VCR), desacetyl vinblastine amide, bleomycin, dactinomycin, daunorubicin, Dx, epirubicin, idarubicin, taxol (taxol be with safe plain _ form commercially available and be described in greater detail in following title in the trifle of " microtubule effect reagent "), D51-7059 (for example taxotere), Plicamycin, deoxycoformycin, ametycin, leunase, Interferon, rabbit (especially IFN-α), Etoposide and teniposide.
Hormone and steroide (comprising synthetic analogues): 17 α-lynoral, stilboestrol, testosterone, prednisone, Fluoxymesterone, dromostanolone propionate, testolactone, Magace, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, Chlortrianisoestrol, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuproside, flutamide, toremifene, Zoladex.
Synthetics (comprising inorganic complex such as platinum coordination complex): cis-platinum, carboplatin, hydroxyurea, amsacrine, Procarbazine, mitotane, mitoxantrone, LEVAMISOLE HCL and hexamethylmelamine.
Other chemotherapeutics comprises nvelbine, CPT-11, Anastrozole, letrozole, capecitabine, Reloxafine and Droloxafine.
In one embodiment, described antineoplastic agent is selected from endoxan, 5 FU 5 fluorouracil, Temozolomide, vincristine(VCR), cis-platinum, carboplatin and gemcitabine.In another embodiment, described antineoplastic agent is selected from gemcitabine, cis-platinum and carboplatin.
The method of most safety in these chemotherapeutics and effectively administration is known to those skilled in the art.In addition, their administration is described in the normative document.For example, the administration of many chemotherapeutics be described in " Physicion ' s Desk Reference " (PDR) in, for example 1996 editions (Medical Economics Company, Montvale, NJ 07645-1742, USA), the Physician ' s Desk Reference, 56
ThEdition, 2002 (by MedicalEconomics company, Inc.Montvale, NJ 07645-1742 publishes), and thePhysician ' s Desk Reference, 57
ThEdition, 2003 (by Thompson PDR, Montvale, NJ 07645-1742 publishes); Its content is hereby incorporated by.
Microtubule effect reagent
As used in this, microtubule effect reagent (for example, the compound of taxol, D51-7059 or similar taxol) is a kind of by influencing microtubule formation and/or the mitotic compound of effect interference cell,, has the antimitotic effect that is.These reagent for example can be microtubule stabilizers or destroy the reagent that microtubule forms.
The microtubule effect reagent of Shi Yonging is known to those skilled in the art and comprises in the present invention, but be not limited to, other colchicine (NSC 406042), halichondrin B (NSC609395), colchicine (NSC 757), colchicine derivative (for example, NSC 33410), dolastatin 10 (NSC 376128), maytenin (NSC 153858), agile new (NSC332598), taxol (safe element _, NSC 125973), D51-7059 (for example, taxotere, NSC 608832), thio-colchicine (NSC 361792), trityl halfcystine (NSC83265), Vinblastine sulphate (NSC 49842), vincristine sulphate (NSC 67574), ebomycin A, ebormycine and discodermolide are (referring to Service, (1996) Science, 274:2009) estramustine, R 17934, MAP4 etc.The example of these reagent also is described in academic and the patent documentation, for example, and referring to BulinsKi (1997) J.Cell Sci.110:3055-3064; Panda (1997) Proc.Natl.Acad.Sci.USA 94:10560-10564; Muhlradt (1997) Cancer Res.57:3344-3346; Nicolaou (1997) Nature387:268-272; Vasquez (1997) Mol.Biol.Cell.8:973-985; Panda (1996) J.Biol.Chem.271:29807-29812.
In one embodiment, described reagent is to have the active compound of similar taxol.These include, but are not limited to taxol and D51-7059 (compound of similar taxol) and analogue.Taxol and derivative thereof (for example safe element and taxotere) can have been bought from the market.In addition, the method for preparing taxol and D51-7059 and analogue is known (for example, referring to United States Patent (USP): 5,569,729 to those skilled in the art; 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589; 5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769; 5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; With 5,296,506).
More particularly, be meant the medicine (NSC number: 125973) of commercially available safe element _ form at this employed term " taxol ".Partly become the polymerization of stabilize microtubules bundle (it can not reorganize and be mitotic suitable construction) by strengthening tubulin, safe element _ inhibition eukaryotic cell duplicates.In the middle of numerous existing chemotherapeutics, because the effectiveness of taxol in the clinical trial for the treatment of tumour (comprising ovarian cancer and mammary cancer) at the medicine refractory, therefore it is to make interested (Hawkins (1992) Oncology of people, 6:17-23, Horwitz (1992) TrendsPharmacol.Sci.13:134-146, Rowinsky (1990) J.Natl.Canc.Inst.82:1247-1259).
Additional microtubule effect reagent can use a kind of evaluation the in many these tests known in the art, for example, measure the semi-automatic test of the tubulin-polymerization activity of paclitaxel analogs, it combines with test cell line to determine the potentiality (referring to Lopes (1997) Cancer Chemother.Pharmacol.41:37-47) of the cell of these compounds block in mitotic division.
Usually whether, it is destroyed to contact and measure the cell cycle with compound by cell, particularly by suppressing the mitotic division phenomenon, determines the activity of test compounds.This inhibition can be regulated by destroying the mitotic division organ, for example, destroys normal spindle body and forms.The interrupted cell of mitotic division is characterised in that form change (for example, microtubule compression, chromosome number increases or the like).
The active compound of tubulin polymerization with possibility can screen external.For example, with cultivating WR21 cell (deriving from is 69-2 wap-ras mouse) SCREENED COMPOUND, at suppressing propagation and/or, particularly compressing at microtubule at changing cellular form.Then, use the nude mice of band WR21 tumour cell to carry out the interior screening of body of the positive-test compounds.The detailed protocol of this sieve method is by Porter (1995) Lab.Anim.Sci., and 45 (2): 145-150 describes.
SCREENED COMPOUND is known to obtain required active other method to those skilled in the art.Typically, these tests comprise the test that suppresses the microtubule assembling and/or break.The test of microtubule assembling for example by Gaskin etc. at (1974) J.Molec.Biol., describe among the 89:737-758.United States Patent (USP) 5,569,720 also provide the external and in vivo test with the active compound of similar taxol.
The method of the safety of above-mentioned microtubule effect reagent and effectively administration is known to those skilled in the art.In addition, their administration is described in the normative document.For example, the administration of many chemotherapeutics is described in " Physician ' s Desk Reference " (quoting in the above).
Compound of the present invention can use according to the method described in U. S. application sequence number of submitting on November 25th, 2,002 10/303259 and on June 12nd, the 2003 disclosed WO 03/047697, and the content of these documents is hereby incorporated by.
Compound of the present invention is illustrated in the following embodiments, but these embodiment should be interpreted as limitation of the scope of the invention.Alternative mechanicalness path within the scope of the present invention and similar structures are conspicuous to those skilled in the art.
Compound of the present invention can use methods known in the art to be prepared according to following reaction scheme, for example, referring on March 7th, 2002 disclosed WO 02/18368 and U.S.5,874,442, the content of these documents is hereby incorporated by.
Scheme 1A
Scheme 2A
Embodiment 1
Scheme 1
Steps A
With tricycle kentones base-compound (at United States Patent (USP) 5,151,423 in open) (30.0g; 123.2mmol) and NBS (48.2g; 271.0mmol) and benzoyl peroxide (0.42g) at CCl
4Mix (210mL).With reaction be heated to 80 ℃ 10 hours.With the mixture cooling, allow it leave standstill 8 hours.Filtration gained precipitation.Add MeOH (200ml), then mixture was stirred 2 days.Cross filter solid, be dried to constant weight in a vacuum, obtain compound 8.
Step B
Dibromo compound (8) (35.72g with top steps A acquisition; 88.97mmol) be dissolved in CH
2Cl
2(1.5L), then be cooled to 0 ℃.Be added dropwise to DBU (15.96ml), then suspension stirred 3 hours.Reaction mixture concentrates, and is dissolved in CH again
2Cl
2(1.5L), filter, use 5%EtOAc/CH then by the silica gel bed
2Cl
2(4L) rinsing.The rinsing liquid that merges is concentrated, purify, follow 3%EtOAc/CH with 10-30% EtOAc/ hexane with quick silica gel column chromatography
2Cl
2Wash-out obtains the compound that 5 pure (compounds 9) and 6 (compound 10) list-bromine replace.
Step C
In nitrogen, under 0 ℃, (10.0g 35.07mmol) adds NaBH in the solution in MeOH (200ml) to list-bromine compounds (10) that the step B under stirring obtains
4(1.94g, 51.2mmol).Gained solution stirred 1.5 hours down at 0 ℃, and CH is then used in evaporation then
2Cl
2-H
2The O extraction.The organic layer MgSO that merges
4Drying is filtered, be evaporated to dried, obtain white solid (11) (10.3g, 100%, M=287).
Step D
Under 0 ℃, (10.0g is 34.8mmol) at CH for the alcohol (11) that the step C under stirring obtains
2Cl
2Add 2 in the solution (200ml), the 6-lutidine (14.9g, 139.3mmol) and thionyl chloride (8.28g, 69.66mmol).Gained solution is warming up to room temperature, stirs then and spend the night.Then, described solution is poured in the 0.5N NaOH solution, then uses CH
2Cl
2Extraction.The water layer Na that merges
2SO
4Drying is filtered, and is concentrated into driedly then, obtains thick brown oil (15.5g).In this thick oil (15.5g) solution in acetonitrile (200ml), add 2, two (the dimethyl)-1-methyl piperidines of 6-(10.81g, 69.66mmol) and the N-Boc piperidines (6.49g, 34.83mmol).The gained mixture is warming up to 65 ℃ and spends the night.Mixture is evaporated to dried, then uses CH
2Cl
2/ saturated NaHCO
3Extraction.The organic layer Na that merges
2SO
4Drying concentrates, purifies by silica gel column chromatography, and with 5% EtOAc/95% hexane wash-out, the N-Boc compound (12) (5.68g, 36% yield, the MH that are protected
+=455).
Step e
By chirality HPLC, use Chiralpak AD post and carry out wash-out with IPA (20%) hexane (80%)+0.2%DEA, finish enantiomer 13 and 14 separate.
Isomer 13: retention time=7.65min; MH
+=492.
Isomer 14: retention time=12.16min; MH
+=492, m.p.95-100 ℃.
Step F
(0.9g 1.83mmol) is dissolved in the dry THF (15ml), then is cooled to-75 ℃ (dry ice/acetone batch) with 13.Drip n-Butyl Lithium (hexane solution of 2.5N) down at-75 ℃; 1.5ml, 3.74mmol), then stirred～20 minutes.Add 5-formyl radical-1-Methylimidazole (0.3g, 2.75mmol is in 2ml THF) fast, stirred 3 hours down at-75 ℃ then.By adding 10mlH
2O, with ethyl acetate extraction, with the salt water washing, use MgSO
4Drying, filtration and evaporation are handled, and obtain crude product.Crude product is purified (silicagel column) by flash chromatography, uses CH
2Cl
2/ 5% CH
3OH (15%NH
4OH) wash-out obtains 0.54g compound 15,56% yields.
Step G
At room temperature, to (15) (6.2g, add in toluene solution 11.9mm0l) (100mL) DPPA (8.5g, 30.9mmol), then add DBU (6.5mL, 43.5mmol).Mixture was stirred 4 hours, use ethyl acetate (300mL) dilution then, wash twice with water, then once with the salt water washing.Dry organic layer, then steaming desolventizes.(1%-10%MeOH is at CH with gradient column for resistates
2Cl
2In) purify, obtain product (16) (5.6g, MH+547.1).
Step H
To 16 (13.26gm, 24.7mmol) adding 24ml trifluoroacetic acids in the solution in the 88ml methylene dichloride.Reaction mixture stirred 3 hours, was evaporated to driedly, then evaporated from toluene.Crude product is dissolved in 19ml pyridine and the 137ml methylene dichloride.Add isopropyl chlorocarbonate (dichloromethane solution of 29ml 1N), reaction mixture was stirred 1 hour.Reaction mixture is joined in the salt solution, use ethyl acetate extraction three times, use dried over mgso, filter, evaporation obtains 14.66gm compound 17 (MH+=533).
Step I
In 17 (24.7mmol) solution in the 230ml tetrahydrofuran (THF), add sodium hydride (60% oil dispersion, 1.5gm, 39.9mmol).Reaction mixture stirred 2 hours down at 60 ℃.After 2 hours, reaction mixture is cooled to room temperature, then it is joined in the salt solution lentamente.Dried over mgso is used in ethyl acetate extraction three times of this salt solution, filters, and evaporation obtains 13.84gm compound 18 (MH+=505).
Step J
Under 0 ℃, in 15 minutes, under the ice bath refrigerative stirs 18 (13.84gm ,～24.7mmol) add in the solution in 250ml methyl alcohol sodium borohydride (4.13gm, 100mmol).Reaction mixture was stirred 1 hour.Reaction mixture is joined among the cold 1NHCl (330ml) under stirring lentamente.This mixture is joined in the 385ml1N sodium hydroxide, and dried over mgso is used in aqueous mixture ethyl acetate extraction four times, filters, and evaporation obtains 11.94gm compound 19 (MH+=507)
Step K
Under ice-cooled 19 (～24.7mmol) add in the solution in the 217ml methylene dichloride triethylamine (10.3ml, 74mmol).(2.7ml 29mmol) also stirs to drip methoxyacetyl chloride.After 2 hours, dried over mgso is used in reaction mixture salt water washing, then filters.Crude product is purified by silica gel column chromatography, uses the 20% hexane/acetone wash-out that contains 0.2% ammonium hydroxide, obtains the 7.9gm compound, and it is further purified by silica gel column chromatography, with 2% ethanol/methylene wash-out, obtains 7gm 20 (MH+=579).
Embodiment 2
Scheme 2
Steps A
(7.98gm 14.6mmol) adds the 15ml trifluoroacetic acid in the solution in the 150ml methylene dichloride to 16 (embodiment 1 step G).Reaction mixture was stirred 3 hours, be evaporated to driedly, then from toluene, evaporate.Crude product is dissolved in the 100ml methylene dichloride, then add triethylamine (20.35ml, 146mmol).Add carbonic acid 2,5-dioxo-tetramethyleneimine-1-base ester 1-methyl-cyclopropyl ester (3.89gm, 18.25mmol)), reaction mixture stirred 1 hour.Reaction mixture is joined in the salt solution, use ethyl acetate extraction three times, use dried over mgso, filter, evaporation obtains a kind of solid.Crude product separates by silica gel chromatography, uses the 2-5% ethanol/methylene as eluent, obtains 7.44gm compound 21 (MH+=545).
Step B
To 21 (7.24gm, 13.3mmol) add in the solution in the 150ml tetrahydrofuran (THF) sodium hydride (60% oil dispersion, 1.5gm, 39.9mmol).Reaction mixture stirred 2 hours down at 60 ℃.After 3-4 hour, reaction mixture is cooled to room temperature, then it is joined in the salt solution lentamente.Dried over mgso is used in ethyl acetate extraction three times of this salt solution, filters, and evaporation obtains 7.54gm crude compound 22.
Step C
Under 0 ℃, in 15 minutes, under the ice bath refrigerative stirs 22 (7.34gm, 12.94mmol) add in the solution in 150ml methyl alcohol sodium borohydride (1.47gm, 38.82mmol).Reaction mixture was stirred 1 hour.Reaction mixture is joined among the cold 1NHCl (150ml) under stirring lentamente.Mixture is joined in the 175ml 1N sodium hydroxide, and dried over mgso is used in aqueous mixture ethyl acetate extraction four times, filters, and evaporation obtains 7.15gm compound 23, and it is used for next step.
Step D
23 (7.15gm under the ice bath cooling, 12.94mmol) add triethylamine (5.41ml in the solution in the 100ml methylene dichloride, 38.82mmol) and 4-dimethylaminopyridine (0.1gm, 0.82mmol). add carbonic acid 2,5-two-oxo-tetramethyleneimine-1-base ester 1-methyl-cyclopropyl ester (4.138gm, 19.41mmol)), reaction mixture stirs after .18 hour under refluxing, reaction mixture salt water washing, use dried over mgso, then filtering. crude product is purified by silica gel column chromatography, uses the 0.5%-5% ethanol/methylene as eluent, obtains 6.0gm compound 24 (MH+=617).
Embodiment 3
4-{8-chloro-6-[[(1-methoxyl group-cyclopropane carbonyl)-amino]-(3-methyl-3H-imidazol-4 yl)-methyl]-11H-benzo [5,6] ring [1,2-b] pyridine in heptan-11-yl }-piperazine-1-carboxylic acid isopropyl
Steps A: 1-methoxyl group-methyl cyclopropanecarboxylate
(1.16gm 10mmol) is dissolved in the 10ml tetrahydrofuran (THF), then is cooled to 0 ℃ in nitrogen atmosphere with 1-hydroxyl-methyl cyclopropanecarboxylate.Add sodium hydride (0.52gm, 60% oil dispersion) in batches, then add methyl iodide (1ml), stirred 18 hours.Ethyl acetate extraction is used in reaction mixture ammonium chloride cancellation, obtains the 2gm title product.(MH+＝130)
Step B:1-methoxyl group-cyclopropane-carboxylic acid
Above-mentioned 1-methoxyl group-methyl cyclopropanecarboxylate is dissolved in the 10ml tetrahydrofuran (THF), then adds 7ml 5M sodium hydroxide.Stir after 18 hours, ethyl acetate extraction is used in reaction mixture concentrated hydrochloric acid acidifying, uses dried over mgso then.Filtrate is evaporated, and obtains the title product of 0.72gm light yellow oil form.
Step C:4-{8-chloro-6-[[(1-methoxyl group-cyclopropane carbonyl)-amino]-(3-methyl-3H-imidazol-4 yl)-methyl]-11H-benzo [5,6] ring [1,2-b] pyridine in heptan-11-yl }-piperazine-1-carboxylic acid isopropyl
(52mg 0.1mmol) is dissolved in the 5ml methylene dichloride with compound 19 (embodiment 1 step J).When stirring, add 1-methoxyl group-cyclopropane-carboxylic acid (21mg, 0.18mmol), I-hydroxybenzotriazole (16gm, 0.12mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (46mg, 0.24mmol) and N-methylmorpholine (0.15ml).In nitrogen atmosphere, reaction mixture is stirred at ambient temperature.After 18 hours, reaction mixture salt water washing is concentrated into yellow solid with organic layer.The final product that obtains is purified with preparation property thin layer of silicon dioxide chromatogram, as eluent, obtains 45mg title product (MH+=605) with 10% ethanol/methylene.
Embodiment 4
4-{8-chloro-6-[[(1-hydroxyl-cyclopropane carbonyl)-amino]-(3-methyl-3H-imidazol-4 yl)-methyl]-11H-benzo [5,6] ring [1,2-b] pyridine in heptan-11-yl }-piperazine-1-counts isopropyl propionate
Except that using 1-hydroxyl cyclopropane carboxylic acid acid substitution 1-methoxyl group cyclopropane-carboxylic acid, compound 151.1 obtains according to the method that is similar to embodiment 3.
Embodiment 5
Introduce the general method of amide group
The acid amides of above compound is prepared according to the method that is similar to embodiment 3 and 4, perhaps by commercially available carboxylic acid and I-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and N-methylmorpholine prepared in reaction, or by compound 19 (embodiment 1 step J) and suitable commercially available carboxylic acid chloride prepared in reaction in the presence of triethylamine alkali.
Embodiment 6
Carbonic acid di-cyclopropyl-1-base ester 2,5-dioxo-tetramethyleneimine-1-base ester
Di-cyclopropyl-1-alcohol is according to O.G.Kulinkovich, et.al.Synthesis, 3,1991, p.234 preparation.Di-cyclopropyl-1-alcohol (2gm) is dissolved in the 100ml acetonitrile, adds 7.7gm two-succinimidyl carbonate in the presence of the 9ml triethylamine.Reaction mixture stirred 18 hours at ambient temperature.Reaction mixture washs with saturated sodium bicarbonate solution, then uses the salt water washing, uses dried over mgso then.Steaming desolventizes, and obtains the 1.6gm title compound.
Embodiment 7
Introduce the general method of carbamate groups
Carbamate is prepared according to the method that is similar to embodiment 6 by the N-hydroxy-succinamide carbonic ether of the corresponding alcohol of preparation.Suitable alcohol and two-succinimidyl carbonate react in the presence of triethylamine.After stirring 18 hours at ambient temperature, reaction mixture washs with saturated sodium bicarbonate solution, then uses the salt water washing, uses dried over mgso then.Steaming desolventizes, and obtains required product.
Embodiment 8
Steps A: 4-{6-[amino-(3-methyl-3H-imidazol-4 yl)-methyl]-8-chloro-11H-benzo [5,6] ring heptan-[1,2-b] pyridine-11-yl }-piperazine-1-carboxylic acid ring pentyl ester
4-{6-[amino-(3-methyl-3H-imidazol-4 yl)-methyl]-8-chloro-11H-benzo [5,6] encircle heptan [1,2-b] pyridine-11-yl-piperazine-1-carboxylic acid ring pentyl ester by compound 16 according to the method that is similar to embodiment 1 step I and J, by replacing isopropyl chlorocarbonate to be prepared with chloroformate cyclopentyl ester.
Step B:4-{6-[(di-cyclopropyl-1-base oxygen base carbonylamino)-(3-methyl-3H-imidazol-4 yl)-methyl]-8-chloro-11H-benzo [5,6] ring [1,2-b] pyridine in heptan-11-yl }-piperazine-1-carboxylic acid ring pentyl ester
With 4-{6-[amino-(3-methyl-3H-imidazol-4 yl)-methyl]-8-chloro-11H-benzo [5,6] encircle heptan [1,2-b] pyridine-11-yl }-piperazine-1 carboxylic acid ring pentyl ester (60mg, 0.11mmol) be dissolved in 5ml methylene dichloride and the 0.2 ml triethylamine. add carbonic acid di-cyclopropyl-1-base ester 2,5-dioxo-tetramethyleneimine-1-base ester (45mg, 0.19mmol), under dry nitrogen atmosphere, reaction mixture was stirred 18 hours at ambient temperature.Reaction mixture salt water washing is evaporated to solid.Solid is purified by silica gel chromatography, as eluent, obtains the 49mg title product with 5% ethanol/methylene.
Residue compound of the present invention can be prepared according to the method that is similar to embodiment 1-8.
The mass-spectrometric data of The compounds of this invention
| Compound | MS MH+ | Compound | MS MH+ | Compound | MS MH+ |
| 100.1 | 589 | 101.1 | 575 | 102.1 | 633 |
| 102.2 | 633 | 103.1 | 619 | 104.1 | 619 |
| 105.1 | 605 | 106.1 | 605 | 109 | 631 |
| 108.1 | 617 | 109.1 | 671 | 110.1 | 603 |
| 111.1 | 633 | 112.1 | 657 | 113.1 | 659 |
| 114.1 | 633 | 115.1 | 619 | 116.1 | 633 |
| 117.1 | 631 | 118.1 | 645 | 119.1 | 633 |
| 120.1 | 630 | 121.1 | 646 | 122.1 | 689 |
| 123.1 | 754 | 124.1 | 647 | 125.1 | 724 |
| 126.1 | 617 | 127.1 | 617 | 128.1 | 724 |
| 129.1 | 663 | 130.1 | 746 | 131.1 | 593 |
| 132.1 | 633 | 133.1 | 621 | 134.1 | 605 |
| 135.1 | 607 | 135.2 | 607 | 136.1 | 579 |
| 137.1 | 565 | 138.1 | 563 | 139.1 | 593 |
| 140.1 | 619 | 141.1 | 600 | 142.1 | 593 |
| 143.1 | 606 | 144.1 | 622 | 145.1 | 635 |
| 146.1 | 593 | 147.1 | 607 | 148.1 | 574 |
| 149.1 | 593 | 150.1 | 593 | 151.1 | 591 |
| 152.1 | 605 | 153.1 | 619 | 154.1 | 605 |
| 155.1 | 591 | 156.1 | 607 | 157.1 | 577 |
| 158.1 | 591 | 159.1 | 617 | 160.1 | 621 |
| 161.1 | 635 | 162.1 | 579 | 163.1 | 720 |
| 164.1 | 620 | 165.1 | 606 | 166.1 | 651 |
| 167.1 | 605 | 168.1 | 605 | 169.1 | 619 |
| 170.1 | 585 | 171.1 | 681 | 173.1 | 607 |
| 174.1 | 621 | ------ | ------ | ------ | ------ |
Test
FPT is active to be passed through to measure [
3H] farnesyl from [
3H] (determine by the transfer of vitamin H-CVLS) to the biotinylation peptide that derives from H-ras C-end for farnesyl pyrophosphate.Reaction mixture contains: 50mM Tris pH7.7,5mM MgCl
2, 5 μ M Zn
++, 5mM DTT, 0.1%Triton-X, 0.05 μ M peptide, people's farnesyl-protein transferase of 0.03nM purifying, 0.180 μ M[
3H] farnesyl pyrophosphate, tricyclic compound of concentration shown in adding or vehicle contrast, cumulative volume are 100 μ l.Be reflected in the Vortemp wave and culture case and cultivated 60 minutes at 37 ℃ of 45 RPM, the 0.25M EDTA that contains 0.5%BSA and 1.3mg/ml streptavidin SPA pearl with 150 μ l stops.In Wallach 1450 Microbeta liquid scintillation counters, measure radioactivity.Calculate inhibition per-cent with respect to the vehicle contrast.
COS cell IC
50(based on the test of cell) can be measured according to the testing sequence described in the April 20 nineteen ninety-five disclosed WO 95/10516.GGPT IC
50(suppress geranyl geranyl protein transferase, vitro enzyme is measured), cell Mat biochemical test and anti-tumor activity (anti-tumor in vivo research) can be measured by the test procedure described in the WO 95/10516.The content of WO 95/10516 is hereby incorporated by.
The soft agar test:
The growth of pool point (Anchorage) dependent/non-dependent is a feature of tumorigenic cell system.Human tumor cells can be suspended in contain 0.3% agarose and shown in the growth medium of farnesyl tranfering enzyme inhibitor of concentration.Solution is covered on the 0.6% agarose solidified growth medium of using the farnesyl tranfering enzyme inhibitor that contains same concentrations as the top layer.After solidify on the top layer, dull and stereotyped at 37 ℃ at 5% CO
2In cultivate 10-16 days to allow bacterium colony grow.After the cultivation, bacterium colony can dye by covering agar with MTT (3-[4,5-dimethyl-thiazol-2-yl]-2,5-phenylbenzene tetrazolium _ bromide, tetrazolium bromide) (1mg/mL is in PBS) solution.To enumeration and measure IC
50
Compound of the present invention has the FPT IC the in＞20nM scope at＜0.5nM
50And at＜0.5nM soft agar the IC the in＞100nM scope
50
Formula 100.1,101.1,102.1,102.2,103.1,104.1,105.1,106.1,107.1,108.1,109.1,110.1,111.1,112.1,113.1,114.1,115.1,116.1,117.1,118.1,119.1,120.1,124.1,125.1,127.1,131.1,133.1,134.1,135.1,135.2,136.1,139.1,140.1,143.1,147.1,150.1,152.1,153.1,154.1,155.1,156.1,157.1,158.1,160.1,161.1,167.1 168.1,169.1,173.1 and 174.1 compound has the FPT IC in the 5nM scope at＜0.5nM
50And at＜0.5nM soft agar the IC the in＞5nM scope
50
The compound of formula 108.1 has the FPT IC of 1.5nM
50And＜the soft agar IC of 0.5nM
50The compound of formula 136.1 has the FPT IC of 0.6nM
50And the soft agar IC of 0.6nM
50
In order to prepare the pharmaceutical composition of The compounds of this invention, inert, pharmaceutically acceptable carrier can be solid or liquid.But solid formulation comprises pulvis, tablet dispersible granule, capsule, cachet and suppository.Described pulvis and tablet can contain the active ingredient of the 5-that has an appointment about 95%.The solid carrier that is fit to is well known in the art, for example magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar or lactose.Tablet, pulvis, bolt for fastening a door from outside wafer and capsule can be as the solid dosages that is applicable to oral administration.The example of pharmaceutically acceptable carrier and various preparation of compositions methods can be at A.Gennaro (ed.), Remington:The Science and Practice ofPharmacy, 20
ThEdition, (2000), Lippincott Williams ﹠amp; Wilkins, Baltimore finds among the MD.
Liquid form preparation comprises solution, suspension and emulsion.What can mention as an example is water or the water-propylene glycol solution that is used for parenteral injection, perhaps for oral liquid, suspension and emulsion, can add sweeting agent and opalizer.Liquid form preparation can also comprise the solution that is used for intranasal administration.
The aerosol that be fit to suck can comprise the solid of solution and powder type, and it can combine with pharmaceutically acceptable carrier such as inertia pressurized gas such as nitrogen.
In addition, the present invention also is included in the solid formulation that faces with before being translated into liquid form preparation, is used for oral administration or administered parenterally.These liquid form preparations comprise solution, suspension and emulsion.
Compound of the present invention can also percutaneous dosing.Transdermal composition can be taked the form of emulsifiable paste, washing lotion, aerosol and/or emulsion, for this reason, it can be included in the transdermal patch or the container of the matrix of this area routine that is used for this purpose.
Compound preferred oral of the present invention administration.
Preferably, described pharmaceutical preparation is a unit dosage.In this formulation, preparation is divided into the unitary dose of suitable size again, and its active ingredient that contains suitable quantity is significant quantity for example, to realize required purpose.
In the unitary dose of preparation, the quantity of active compound can be between the about 1000mg of about 0.01mg-, preferably at the about 750mg of about 0.01mg-,, most preferably between the about 250mg of about 0.01mg-, change or regulate according to concrete application more preferably at the about 500mg of about 0.01mg-.
Actual using dosage can change with patient's needs and sanatory severity.For particular case, those skilled in the art can determine suitable dosage range.For simplicity, can be separately with total per daily dose, administration in batches in a day as required.
The administration quantity of The compounds of this invention and/or its pharmacy acceptable salt and frequency will be adjusted with doctor in charge's judgement, consider usually these factors such as patient's age, physical qualification and size and the severity of treatment symptom.The oral administration that the typical case recommends the per daily dose scope can be from about 0.04mg/ days-Yue 4000mg/ days, with 2-4 divided dose administration.
Though invention has been described in conjunction with top specific embodiments, many alternativess, change and the variation of described embodiment is conspicuous to the common those of skill in the art in this area.All these alternativess, change and variation all fall within the spirit and scope of the present invention.
Claims (120)
1. the compound of following formula:
And pharmacy acceptable salt or solvate, wherein:
R
1Be selected from:
N is 1-6;
X is selected from O, S and N;
R
2, R
3, R
4And R
5Be independently selected from: H, Br, Cl and F;
R
5ABe selected from: H, C
1-C
6Alkyl and C
3-C
6Cycloalkyl;
For each n, R
6And R
7Be independently selected from: (1) H, (2) C
1-C
4Alkyl and (3) are by R
6And R
7The C that the carbon atom that links to each other with them forms
3-C
7Cycloalkyl ring;
R
8Be selected from:
H，
R
9Be selected from: C
1-C
6Alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkylalkyl, Heterocyclylalkyl alkyl, alkenyl, alkynyl, aralkyl, the assorted alkyl of aryl, cycloalkenyl group, heterochain thiazolinyl, assorted alkyl and assorted alkynyl; Or
R
9Be selected from: C
1-C
6Alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkylalkyl, Heterocyclylalkyl alkyl, alkenyl, alkynyl, aralkyl, the assorted alkyl of aryl, cycloalkenyl group, heterochain thiazolinyl, assorted alkyl and assorted alkynyl; (1) described R wherein
9The assorted alkyl of aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkylalkyl, Heterocyclylalkyl alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkenyl group, heterochain thiazolinyl, assorted alkyl and assorted alkynyl are replaced by 1-3 substituting group, and described substituting group is independently selected from :-OH, halogen, alkyl, cycloalkyl ,-NH
2,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2Wherein each alkyl selection independently, alkoxyl group and-CO
2R
14R wherein
14Be selected from: H and alkyl, condition are described R
9That carbon atom that links to each other with the X substituting group in the group not by-OH ,-NH
2,-NH (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2Group replaces; And (2) described R
9C
1-C
6Alkyl is replaced by 1-3 substituting group, and described substituting group is independently selected from :-OH, halogen, cycloalkyl ,-NH
2,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2Wherein each alkyl selection independently, alkoxyl group and-CO
2R
14R wherein
14Be selected from: H and alkyl; Condition is described R
9That carbon atom that links to each other with the X substituting group in the group not by-OH ,-NH
2,-NH (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2Group replaces;
R
9aBe selected from: alkyl and aralkyl;
R
10Be selected from: aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkylalkyl, Heterocyclylalkyl alkyl, alkenyl, alkynyl, the assorted alkyl of aryl, cycloalkenyl group, heterochain thiazolinyl, assorted alkyl and assorted alkynyl; Or
R
10Be selected from: aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkylalkyl, Heterocyclylalkyl alkyl, alkenyl, alkynyl, the assorted alkyl of aryl, cycloalkenyl group, heterochain thiazolinyl, assorted alkyl and assorted alkynyl; Wherein said R
10Group is replaced by 1-3 substituting group, and described substituting group is independently selected from :-OH, halogen, alkyl, cycloalkyl ,-NH
2,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2Wherein each alkyl selection independently, alkoxyl group and-CO
2R
14R wherein
14Be selected from: H and alkyl;
R
11Be selected from: (1) alkyl, (2) substituted alkyl, (3) unsubstituting aromatic yl, (4) substituted aryl, (5) unsubstituted ring alkyl, (6) substituted cycloalkyl, (7) are substituted heteroaryl not, (8) substituted heteroaryl, (9) Heterocyclylalkyl and (10) substituted heterocycle alkyl; Wherein said substituted alkyl, substituted cycloalkyl and substituted heterocycle alkyl R
11Group is replaced by one or more substituting group, and described substituting group is independently selected from: (1)-OH, condition be when having more than one-OH group so each-the OH group is connected on the different carbon atoms (2) fluorine and (3) alkyl; And wherein said substituted aryl and substituted heteroaryl R
11Group is replaced by one or more substituting group, and described substituting group is independently selected from: (1)-OH, condition be when having more than one-OH group so each-OH group and different carbon atom connect (2) halogen and (3) alkyl;
R
11aBe selected from: (1) H, (2) OH, (3) alkyl, (4) substituted alkyl, (5) aryl, (6) substituted aryl, (7) unsubstituted ring alkyl, (8) substituted cycloalkyl, (9) are substituted heteroaryl not, (10) substituted heteroaryl, (11) Heterocyclylalkyl, (12) substituted heterocycle alkyl and (13)-OR
9aWherein said substituted alkyl, substituted cycloalkyl and substituted heterocycle alkyl R
11aGroup is replaced by one or more substituting group, and described substituting group is independently selected from: (1)-OH, condition be when having more than one-OH group so each-OH group and different carbon atom connect (2)-CN, (3)-CF
3, (4) fluorine, (5) alkyl, (6) cycloalkyl, (7) Heterocyclylalkyl, (8) aralkyl, (9) heteroarylalkyl, (10) alkenyl and (11) heterochain thiazolinyl; And wherein said substituted aryl and substituted heteroaryl R
11aGroup has one or more substituting groups, and described substituting group is independently selected from: (1)-OH, condition be when having more than one-OH group so each-OH group and different carbon atom connect (2)-CN, (3)-CF
3, (4) halogen, (5) alkyl, (6) cycloalkyl, (7) Heterocyclylalkyl, (8) aralkyl, (9) heteroarylalkyl, (10) alkenyl and (11) heterochain thiazolinyl;
R
12Be selected from: H, alkyl, piperidine ring V, cycloalkyl and-alkyl-(piperidine ring V), wherein piperidine ring V is
R wherein
44Be selected from: (a)-H, (b) alkyl, (c) alkyl-carbonyl, (d) carbalkoxy,
(e) haloalkyl and (f)-C (O) NH (R
51);
R
21, R
22And R
46Be independently selected from: (1)-H, (2) alkyl (for example, methyl, ethyl, propyl group, butyl or the tertiary butyl), (3) unsubstituting aromatic yl, the aryl that (4) are replaced by one or more substituting groups, described substituting group is independently selected from: alkyl, halogen, CF
3And OH, (5) unsubstituted ring alkyl, the cycloalkyl that (6) are replaced by one or more substituting groups, described substituting group is independently selected from: alkyl, halogen, CF
3And OH, the heteroaryl of (7) following formula:
(8) Heterocyclylalkyl of following formula:
R wherein
44Be selected from: (a)-H, (b) alkyl, (c) alkyl-carbonyl, (d) carbalkoxy,
(e) haloalkyl and (f)-C (O) NH (R
51), (9)-NH
2, condition is R
21, R
22And R
46Only having one in the group can be-NH
2And condition is to work as R
21, R
22And R
46One of be-NH
2The time so remaining group be not-OH, (10)-OH, condition is R
21, R
22And R
46Only have one in the group can be-OH and condition are to work as R
21, R
22And R
46One of be-during OH so remaining group be not-NH
2And (11) alkyl of being replaced by one or more substituting groups, described substituting group is selected from :-OH and-NH
2And condition is that one-OH or one-NH are only arranged
2Group on the carbon that replaces, or
R
21And R
22Form one with their continuous carbon and be selected from following ring: (1) unsubstituted ring alkyl, the cycloalkyl that (2) are replaced by one or more substituting groups, described substituting group is independently selected from: alkyl, halogen, CF
3And OH, (3) unsubstituted ring thiazolinyl, the cycloalkenyl group that (4) are replaced by one or more substituting groups, described substituting group is independently selected from: alkyl, halogen, CF
3And OH, (5) Heterocyclylalkyl, (6) unsubstituting aromatic yl, the aryl that (7) are replaced by one or more substituting groups, described substituting group is independently selected from: alkyl, halogen ,-CN ,-CF
3, OH and alkoxyl group and (8) are selected from following heteroaryl:
R
51Be selected from: H and alkyl.
2. the compound of claim 1, wherein R
2To R
5Be H.
3. the compound of claim 1, wherein R
2To R
4Be H, and R
5It is halogen.
4. the compound of claim 1, wherein R
2Be H, R
3Be halogen, R
4Be H, and R
5It is halogen.
5. the compound of claim 1, wherein R
2Be H, R
3Be halogen, R
4Be halogen, and R
5It is halogen.
6. the compound of claim 3, wherein R
5Be 8-Cl.
7. the compound of claim 4, wherein R
3Be 3-Br and R
5Be 8-Cl.
8. the compound of claim 5, wherein R
3Be Br, R
4Be 10-Br and R
5Be 8-Cl.
9. the compound of claim 5, wherein R
3Be Br, R
4Be 7-Br and R
5Be 8-Cl.
10. the compound of claim 1, wherein said compound has structure
11. the compound of claim 10, wherein R
5Be Cl.
12. the compound of claim 1 has structure:
13. the compound of claim 12, wherein R
5Be Cl.
14. the compound of claim 1 has formula:
15. the compound of claim 1 has formula:
16. the compound of claim 1 has formula:
17. the compound of claim 1 has formula:
18. the compound of claim 1 has formula:
19. the compound of claim 1 has formula:
20. the compound of claim 1 has formula:
21. the compound of claim 1 has formula:
22. the compound of claim 1, wherein R
5ABe selected from: H, methyl, ethyl, sec.-propyl and cyclopropyl.
23. the compound of claim 1, wherein R
5AIt is methyl.
24. the compound of claim 1, wherein X is O.
25. the compound of claim 1, wherein n is 1.
26. the compound of claim 1, wherein each R
6And R
7Be independently selected from: H, methyl and R
6And R
7The cyclopropyl rings that the carbon atom that links to each other with them forms.
27. the compound of claim 1, wherein R
6And R
7Be independently selected from H and methyl.
28. the compound of claim 1, wherein R
6And R
7Be H.
29. the compound of claim 1, wherein R
9Be C
1-C
6Alkyl.
30. the compound of claim 1, wherein R
9It is methyl.
31. the compound of claim 1, wherein R
10Be selected from: cycloalkyl and by C
1-C
6The cycloalkyl that alkyl replaces.
32. the compound of claim 1, wherein R
10Be selected from: cycloalkyl and by methyl substituted cycloalkyl.
33. the compound of claim 1, wherein R
10Be:
34. the compound of claim 1, wherein R
8Be:
35. the compound of claim 1, wherein R
1Be
And R
8Be
36. the compound of claim 35, wherein R
10And R
11Be identical.
37. the compound of claim 35, wherein R
10And R
11Be identical and be selected from: the cycloalkyl of unsubstituted cycloalkyl and replacement.
38. the compound of claim 37, wherein R
10And R
11Be:
39. the compound of claim 1, wherein R
1Be
X is O, and n is 1, R
6And R
7Be independently selected from H, methyl and R
6And R
7The cyclopropyl rings that the carbon atom that links to each other with them forms, and R
9Be C
1-C
6Alkyl, R
8Be
R wherein
11It is alkyl.
40. the compound of claim 1, wherein R
1Be
R
10Be selected from: cycloalkyl and by C
1-C
6The cycloalkyl that alkyl replaces, and R
8Be
R wherein
11Be selected from: the cycloalkyl of unsubstituted cycloalkyl and replacement.
41. the compound of claim 1, wherein: (A) (1) R
2To R
5Be H, or (2) R
2To R
4Be H, and R
5Be Br, or (3) R
2Be H, R
3Be 3-Br, R
4Be H, and R
5Be 8-Cl, perhaps (4) R
2Be H, R
3Be 3-Br, R
4Be 10-Br and R
5Be 8-Cl, perhaps (5) R
2Be H, R
3Be 3-Br, R
4Be 7-Br and R
5Be 8-Cl, (B) R
5ABe selected from: H, methyl, ethyl, sec.-propyl and cyclopropyl, (C) X is O, (D) n is 1, (E) R
6And R
7Be independently selected from: H, methyl and R
6And R
7The cyclopropyl rings that the carbon atom that links to each other with them forms, (F) R
9Be C
1-C
6Alkyl, (G) R
10Be selected from: cycloalkyl and by C
1-C
6The cycloalkyl that alkyl replaces, (H) R
8Be
(I) R
11Be selected from: the cycloalkyl of alkyl, unsubstituted cycloalkyl and replacement.
42. the compound of claim 1 has formula:
Wherein: (1) R
5ABe selected from: H, methyl, ethyl, sec.-propyl and cyclopropyl, (2) X is O, (3) n is 1, (4) R
6And R
7Be independently selected from: H, methyl and R
6And R
7The cyclopropyl rings that the carbon atom that links to each other with them forms, (5) R
9Be C
1-C
6Alkyl, and (6) R
8Be
43. the compound of claim 42, wherein R
11It is alkyl.
44. the compound of claim 1 has formula:
Wherein: (1) R
5ABe selected from: H, methyl, ethyl, sec.-propyl and cyclopropyl, (2) R
10Be selected from: cycloalkyl and by C
1-C
6The cycloalkyl that alkyl replaces, and R
8Be
45. the compound of claim 44, wherein R
11Be selected from: the cycloalkyl of unsubstituted cycloalkyl and replacement.
46. the compound of claim 45, wherein R
10And R
11Be identical.
47. the compound of claim 46, wherein R
10And R
11Be
48. the compound of claim 1, it is a form separated and that purify.
49. be selected from compound or its pharmacy acceptable salt or the solvate of formula 100-173 and 174 compounds.
50. the compound of claim 49 or its pharmacy acceptable salt or solvate, described compound are selected from the compound of formula 100.1-102.2,103.1-135.2,136.1-173.1 and 174.1.
51. the compound of claim 49, or its pharmacy acceptable salt or solvate, described compound is selected from formula 100.1,101.1,102.1,102.2,103.1,104.1,105.1,106.1,107.1,108.1,109.1,110.1,111.1,112.1,113.1,114.1,115.1,116.1,117.1,118.1,119.1,120.1,124.1,125.1,127.1,131.1,133.1,134.1,135.1,135.2,136.1,139.1,140.1,143.1,147.1,150.1,152.1,153.1,154.1,155.1,156.1,157.1,158.1,160.1,161.1,167.1,168.1,169.1,173.1 and 174.1 compound.
52. the compound of claim 51, it has the structure of formula 101.1.
53. the compound of claim 51, it has the structure of formula 102.1.
54. the compound of claim 51, it has the structure of formula 102.2.
55. the compound of claim 51, it has the structure of formula 105.1.
56. the compound of claim 51, it has the structure of formula 108.1.
57. the compound of claim 51, it has the structure of formula 114.1.
58. the compound of claim 51, it has the structure of formula 118.1.
59. the compound of claim 51, it has the structure of formula 124.1.
60. the compound of claim 51, it has the structure of formula 136.1.
61. the compound of claim 51, it has the structure of formula 139.1.
62. the compound of claim 51, it has the structure of formula 158.1.
63. the compound of claim 51, it has the structure of formula 168.1.1.
64. each compound of claim 1-63 is used for the treatment of purposes in the medicine of abnormal cell growth in preparation.
65. each compound of claim 1-63 is used for the treatment of purposes in the medicine of cancer in preparation.
66. at least aly be used for the treatment of purposes in the medicine of the tumour that express to activate the ras oncogene in preparation according to each compound of claim 1-63.
67. at least aly be used for the treatment of purposes in the medicine of cancer according to each compound of claim 1-63 in preparation, wherein said cancer is selected from: carcinoma of the pancreas, lung cancer, myelogenous leukemia, thyroid follicle knurl, myelodysplastic syndrome, head and neck cancer, melanoma, mammary cancer, prostate cancer, ovarian cancer, bladder cancer, neurospongioma, epidermal carcinoma, colorectal carcinoma, non-Hodgkin lymphoma and multiple myeloma.
68. at least a purposes that is used for suppressing the medicine of ras farnesyl-protein transferase according to each compound of claim 1-63 in preparation.
69. at least aly be used for the treatment of purposes in the medicine of cancer in preparation according to each compound of claim 1-63, wherein said Ras albumen since the Cancer-causing mutation in the gene beyond the Ras gene be activated.
70. at least aly be used for the treatment of purposes in the medicine of cancer according to each compound of claim 1-63 in preparation, described medicine and at least a antineoplastic agent and/or radiation are used simultaneously or successively.
71. the purposes of claim 70, wherein the cancer of being treated is that lung cancer and described antineoplastic agent are selected from: carboplatin, safe element and taxotere.
72. the purposes of claim 70, wherein the cancer of being treated is that lung cancer and described antineoplastic agent are selected from: gemcitabine and cis-platinum.
73. the purposes of claim 70, wherein said antineoplastic agent are safe plain.
74. at least aly be used for the treatment of purposes in the medicine of cancer according to each compound of claim 1-63 in preparation, described medicine and at least a signal transduction inhibitor use simultaneously or successively.
75. the purposes of claim 74, wherein said signal transduction inhibitor is selected from: imatinib mesylate, Iressa, OSI-774, Imclone C225, Abgenix ABX-EGF and Trastuzumab.
76. at least aly be used for the treatment of purposes in the medicine of cancer in preparation according to each compound of claim 1-63, the described medicine antineoplastic agent different with at least two kinds united use, these two kinds of different antineoplastic agents are selected from: (1) Taxan, (2) iridium-platinum complex, (3) be the EGF inhibitor of antibody, (4) be micromolecular EGF inhibitor, (5) be the VEGF inhibitor of antibody, (6) be micromolecular VEGF kinase inhibitor, (7) estrogen receptor antagon or selective estrogen receptor modulators, (8) antitumor nucleoside derivates, (9) ebormycine, (10) topoisomerase enzyme inhibitor, (11) vinca alkaloids, (12) be the antibody of α V β 3 integrin inhibitors, the micromolecular inhibitor of (13) α V β 3 integrins, (14) folate antagonist; (15) ribonucleotide reductase inhibitor, (16) anthracycline antibiotics, (17) biotechnological formulation, (18) Thalidomide (or relevant imines) and (19) imatinib mesylate.
77. the purposes of claim 76 is wherein used two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is that Taxan and another kind of antineoplastic agent are iridium-platinum complexes.
78. the purposes of claim 77, wherein: (a) described Taxan is that taxol and described iridium-platinum complex are carboplatins, or (b) described Taxan is that taxol and described iridium-platinum complex are cis-platinums, or (c) described Taxan is that docetaxel and described iridium-platinum complex are cis-platinums, or (d) described Taxan is that docetaxel and described iridium-platinum complex are carboplatins.
79. the purposes of claim 76 is wherein used two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is that Taxan and another kind of antineoplastic agent are the EGF inhibitor for antibody.
80. the purposes of claim 76, wherein using two kinds of antineoplastic agents and wherein a kind of antineoplastic agent is that anti-nucleoside derivates and another kind of antineoplastic agent are iridium-platinum complexes.
81. the purposes of claim 76, wherein said medicine is used for the treatment of nonsmall-cell lung cancer with carboplatin and taxol.
82. the purposes of claim 76, wherein said medicine is used for the treatment of nonsmall-cell lung cancer with cis-platinum and gemcitabine.
83. the purposes of claim 76, wherein said medicine is used for the treatment of nonsmall-cell lung cancer with carboplatin and gemcitabine.
84. at least aly be used for the treatment of purposes in the medicine of cancer in preparation according to each compound of claim 1-63, the compound and the antineoplastic agent of wherein said medicine and at least a claim 1 are united use, described antineoplastic agent is selected from: (1) is the EGF inhibitor of antibody, (2) be micromolecular EGF inhibitor, (3) be the VEGF inhibitor of antibody, or (4) are micromolecular VEGF kinase inhibitor.
85. the purposes of claim 84, wherein said antineoplastic agent is selected from: Trastuzumab, Cetuximab, its match watt, Iressa, rhuMAb-VEGF, IMC-1C11, SU5416, SU6688 and BAY 43-9006.
86. the purposes of claim 70, wherein said medicine and carboplatin and docetaxel are united and are used for the treatment of nonsmall-cell lung cancer.
87. the purposes of claim 70, wherein said medicine is used for the treatment of the squamous cell cancer of neck with one or more antineoplastic agents that are selected from (1) Taxan and (2) iridium-platinum complex.
88. the purposes of claim 70, the wherein said medicine antineoplastic agent different with at least two kinds is used for the treatment of the squamous cell cancer of neck together, and described antineoplastic agent is selected from: (1) Taxan, (2) iridium-platinum complex and (3) antitumor nucleoside derivates.
89. the purposes of claim 70, wherein said medicine is used for the treatment of CML with imatinib mesylate and Interferon, rabbit.
90. the purposes of claim 70, wherein said medicine is used for the treatment of CML with the Interferon, rabbit of imatinib mesylate and Pegylation.
91. the purposes of claim 70, wherein said medicine is used for the treatment of AML with antitumor nucleoside derivates.
92. the purposes of claim 70, wherein said medicine is used for the treatment of AML with antitumor nucleoside derivates and anthracycline antibiotics.
93. the purposes of claim 70, wherein said medicine is used for the treatment of non-Hodgkin lymphoma with Rituximab.
94. the purposes of claim 70, wherein said medicine is used for the treatment of non-Hodgkin lymphoma with Rituximab and antitumor nucleoside derivates.
95. the purposes of claim 70, wherein said medicine is used for the treatment of non-Hodgkin lymphoma with Genasense.
96. the purposes of claim 70, wherein said medicine is used for the treatment of multiple myeloma with the proteoplast inhibitor.
97. the purposes of claim 70, wherein said medicine is used for the treatment of multiple myeloma together with Thalidomide or relevant imines.
98. the purposes of claim 70, wherein said medicine is used for the treatment of multiple myeloma with Thalidomide.
99. at least aly be used for the treatment of purposes in the medicine of mammary cancer in preparation according to each compound of claim 1-63, described medicine uses with at least a hormone antagonist reagent, wherein said at least a hormone antagonist reagent is selected from: (a) aromatase inhibitor, (b) antiestrogen and (c) LHRH analogue; Wherein antineoplastic agent is optional uses with described medicine and hormone antagonist reagent.
100. the purposes of claim 99, wherein said medicine uses with at least a hormone antagonist reagent, and described hormone antagonist reagent is selected from: (a) aromatase inhibitor, (b) antiestrogen and (c) LHRH analogue.
101. the purposes of claim 99, wherein said medicine uses with at least a aromatase inhibitor.
102. the purposes of claim 99, wherein said medicine uses with at least a antiestrogen.
103. the purposes of claim 99, wherein said medicine uses with at least a aromatase inhibitor and at least a antiestrogen.
104. the purposes of claim 99, wherein said medicine uses with at least a aromatase inhibitor and at least a antineoplastic agent.
105. the purposes of claim 99, wherein said medicine uses with at least a antiestrogen and at least a antineoplastic agent.
106. the purposes of claim 99, wherein said medicine uses with at least a aromatase inhibitor, at least a antiestrogen and at least a chemotherapeutics.
107. the purposes of claim 99, wherein said: (a) aromatase inhibitor is selected from: Anastrozole, letrozole, Exemestane, fadrozole and formestane, (b) antiestrogen is selected from: tamoxifen, fulvestrant, raloxifene and Acolbifene, (c) the LHRH analogue is selected from: goserelin and Leuprolide (Leuproelin) and (d) antineoplastic agent be selected from: trastuzumab, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi.
108. the purposes of claim 99, wherein said medicine is selected from (1): the aromatase inhibitor of Anastrozole, cause azoles, Exemestane, fadrozole and formestane, and (2) are selected from: the antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifene uses together.
109. the purposes of claim 99, wherein said medicine and (1) Anastrozole and tamoxifen, or (2) letrozole and tamoxifen, or (3) Exemestane and tamoxifen, or (4) fadrozole and tamoxifen, or (5) formestane and tamoxifen, or (6) Anastrozole and fulvestrant, or (7) letrozole and fulvestrant, or (8) Exemestane and fulvestrant, or (9) fadrozole and fulvestrant, or (10) formestane and fulvestrant use together.
110. the purposes of claim 99, wherein said medicine is with being selected from: song wants the antineoplastic agent of monoclonal antibody, Gefitinib, erlotinib, rhuMAb-VEGF, Cetuximab and Bao Tezuomi to use.
111. the purposes of claim 99, wherein said medicine uses with at least a aromatase inhibitor and at least a LHRH analogue.
112. the purposes of claim 99, wherein said medicine uses with at least a antiestrogen and at least a LHRH analogue.
113. the purposes of claim 99, wherein said medicine and (1) are selected from least a aromatase inhibitor of Anastrozole, letrozole, Exemestane, fadrozole and formestane, and at least a LHRH analogue that (2) are selected from goserelin and leuproside uses together.
114. the purposes of claim 99, wherein said medicine and (1) are selected from least a antiestrogen of tamoxifen, fulvestrant, raloxifene and Acolbifen, and at least a LHRH analogue that (2) are selected from goserelin and leuproside uses together.
115. at least aly be used for the treatment of purposes in the medicine of CML according to each compound of claim 1-63 in preparation, described medicine uses with imatinib mesylate.
116. at least aly be used for the treatment of purposes in the medicine of CMML in preparation according to each compound of claim 1-63.
117. pharmaceutical composition comprises the compound and the pharmaceutically acceptable carrier of at least a claim 1.
118. pharmaceutical composition comprises the compound of at least a claim 1, at least a hormone antagonist reagent and pharmaceutically acceptable carrier.
119. pharmaceutical composition comprises the compound of at least a claim 1, at least a hormone antagonist reagent, at least a chemotherapeutics and pharmaceutically acceptable carrier.
120. pharmaceutical composition comprises compound, at least a antineoplastic agent and the pharmaceutically acceptable carrier of at least a claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49326903P | 2003-08-07 | 2003-08-07 | |
| US60/493,269 | 2003-08-07 | ||
| US60/498,509 | 2003-08-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1863792A true CN1863792A (en) | 2006-11-15 |
Family
ID=36587432
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480029384 Pending CN1863792A (en) | 2003-08-07 | 2004-08-04 | Novel farnesyl protein transferase inhibitors as antitumor agents |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1863792A (en) |
| NO (1) | NO20061077L (en) |
| ZA (1) | ZA200601052B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108276328A (en) * | 2018-03-31 | 2018-07-13 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of Sorafenib |
-
2004
- 2004-08-04 CN CN 200480029384 patent/CN1863792A/en active Pending
-
2006
- 2006-02-06 ZA ZA200601052A patent/ZA200601052B/en unknown
- 2006-03-06 NO NO20061077A patent/NO20061077L/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108276328A (en) * | 2018-03-31 | 2018-07-13 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of Sorafenib |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20061077L (en) | 2006-05-05 |
| ZA200601052B (en) | 2007-05-30 |
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Open date: 20061115 |