CN1845741A - TRP-P8 active compounds and therapeutic treatment methods - Google Patents
TRP-P8 active compounds and therapeutic treatment methods Download PDFInfo
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- CN1845741A CN1845741A CN 200480025186 CN200480025186A CN1845741A CN 1845741 A CN1845741 A CN 1845741A CN 200480025186 CN200480025186 CN 200480025186 CN 200480025186 A CN200480025186 A CN 200480025186A CN 1845741 A CN1845741 A CN 1845741A
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Abstract
Compounds of the disclosure provide compositions, which are effective for prophylaxis and treatment of diseases or disorders, such as cell-proliferation, angiogenesis, or apoptosis mediated diseases. The disclosure encompasses compounds, analogs, prodrugs, metabolites, and pharmaceutically acceptable salts thereof, pharmaceutical compositions, and methods for prophylaxis and treatment of diseases and other maladies or conditions involving cancer, tumors, and like conditions. The disclosure also provides therapeutic methods including the administration of an effective amount of a compound of the disclosure.
Description
Background technology
The chemical compound that produces physiological creeping chill when being applied on the skin is known, for example referring to " New Compounds with the Menthol Cooling Effect, " H.R.Watson, et al., J.Soc.Cosmet.Chem., 1978,29,185-200.
Wei, E.T., et al., J.Pharm.Pharmacol, 1983,35 (2), 110-112 has described and has a kind ofly produced the chemical compound (being also referred to as AG-3-5) or 3-(2-the hydroxyphenyl)-6-(3-nitrobenzophenone)-3 of the performance called after " icilin " of creeping chill because of it, 4-dihydro-1H-pyrimid-2-one (3-(2-Hydroxy-phenyl)-6-(3-nitro-phenyl)-3,4-dihydro-1H-pyrimidin-2-one), its general formula is as follows:
Recently reported that other have the chemical compound of cooling effect, referring to H.Ottinger, et al., J.Agric.Food Chem., 2001,49,5383-5390.
U.S. Patent No. 4,150,052 discloses the chemical compound of menthane carbosamided (the menthene carboxamide) that for example have general formula I Ia3-1:
It is reported that this chemical compound has the physiology cooling effect to skin.
U.S. Patent No. 4,070,496 disclose concrete phosphine oxide (R
1R
2R
3P=O) chemical compound and compositions thereof it is reported, they have the physiology cooling effect to skin.
U.S. Patent No. 3,821,221 disclose concrete tetrahydropyrimidine-2-ketone, it is reported, and it has as tranquilizer or anti-depressant nervus centralis activity.
Recently, shown that specific T RP receptor has effect in hotness (thermosensation), referring to D.D.McKerny, et al., " Identification of a Cold Receptor Reveals a GeneralRole for TRP Channels in Thermosensation; " Nature, 2002, Mar 7; 416 (6876): 52-8.For the summary about " The TRP Ton Channel Family, " recently, referring to D.E.Clapham, et al., Nature Reviews, Neuroscience, 2001,2,387-396＜www.nature.com/reviews/neuro 〉.Okazawa et al Neuroscience letters (2004Apr 8)，359(1-2)：33-6；Nealen et al Journal of neurophysiology(2003 Jul)，90(1)：515-20；Thut et al.，Neuroscience(2003)，119(4)：1071-83。
(subtracted) cDNA storehouse of extraction by the screening prostate specific has had been found that gene Trp-p8.Precognition albumen has and Ca
2+The significant homology of instantaneous receptor potential (Trp) family of channel protein.The Northern engram analysis shows that the Trp-p8 in the health adult tissue expresses and is limited to prostate epithelial cell mostly.In situ hybridization the analysis showed that Trp-p8 mRNA is expressed in and is in medium level in the normal prostate tissue, shows rising in carcinoma of prostate.Trp-p8 mRNA also expresses in the many non-prostate primary tumor in thymus, colon, lung and skin source, and in corresponding health adult tissue, almost can't detect or not detect the transcript (Tsavaler of coding Trp-p8, et al CancerResearch (2001), 61 (9): 3760-3769).
The immunotherapy of carcinoma of prostate (PCa) mainly depends on the evaluation of the suitable target antigen in the tumor of prostate that is present in high percentage ratio.The calciphorin Trp-p8 that supposes does not have recurrence with the PSA of the expression of Trp-p 8mRNA loss and obvious shorter time and survives relevant.The evaluation of Trp-p8 is relevant with the result of carcinoma of prostate, shows that this receptor has integral body (integral) effect in the prostate carcinogenesis.Reported the immunogenicity peptide from the instantaneous receptor potential-p8 of the albumen of prostate specific (Trp-p8), it is by the identification of cytotoxin T lymphocyte (Kiessling, et al (2003) Prostate56 (4): 270-279 from PCa patient; Henshall, et al Cancer Research (2003), 63 (14): 4196-4203; Fuessel, et al International Journal of Oncology (2003), 23 (1): 221-228; US2003108963 A1).Evaluation in disease such as tumor, hypertrophy or treatment of conditions effectively therapeutic agent remain important research object.Recent work shows, can effectively treat angiogenesis relevant disease or diseases such as disease with the particular therapeutic agent of specific antibodies preparation combination, for example referring to U.S. Patent No. 6,582,959.
Need can be used for treating the disease relevant and treatment of conditions agent and method at present with regulating the Trp-p8 receptor.Also need cancerous cell is had specificity and selectivity and healthy cell had the therapeutic agent and the processing method of low cytotoxicity.Also need therapeutic agent and combination therapy thereof with other chemotherapeutants (comprising for example antibody preparation) combinations, described therapeutic agent can be used for the treatment of and relevant disease and the disease of adjusting Trp-p8 receptor with processing method.
Summary of the invention
Have been found that, comprise that some known particular compound that can produce physiology creeping chill (" refrigeration ") show useful biological activity, anti-tumor activity for example, described chemical compound for example are alkylamide chemical compound and the alpha-keto-enamines that tetrahydropyrimidine above-mentioned-2-ketone, phosphine oxide (phosphine oxide), menthane carbosamided chemical compound (methanecarboxamide compound), alkyl replace.
Therefore, the disclosure provides the chemical compound that can activate the Trp-p8 receptor in exemplary.In embodiments, the disclosure provides chemical compound and processing method, and its calcium ion that causes flowing into cancerous cell increases (that is " flow activated form " or " flow promoted type " chemical compound).In embodiments, the disclosure provides chemical compound, pharmaceutical composition and processing method, and it is by causing apoptosis and suppress or killing and wounding cancerous cell.
In embodiments, the disclosure also provides:
The pharmaceutical composition (said composition preferably comprises the described chemical compound or the salt for the treatment of effective dose) that comprises chemical compound of the present disclosure and pharmaceutically acceptable excipient;
The pharmaceutical composition that is used for the treatment of tumor, it comprises chemical compound of the present disclosure or its combination; Perhaps its officinal salt; And pharmaceutically suitable carrier.
The disease in the treatment mammal (for example people) or the method for disease wherein relate to Trp-p8 receptor and needs and regulate function of receptors, and this method comprises the chemical compound of the present disclosure of administration adjusting effective dose;
Treatment or prevention in the mammal disease or the relevant disease of Trp-p8 receptor () method for example, tumor comprises the chemical compound of the present disclosure of drug treatment effective dose;
The chemical compound of the present disclosure that is used for medical diagnosis or treatment (for example, treatment or prevention Trp-p8 receptor associated diseases or disease, for example tumor);
Chemical compound of the present disclosure preparation can be used for treating or the medicine of the disease (for example, treatment or relevant disease or the disease of prevention Trp-p8 receptor, for example tumor) that prevent disease or Trp-p8 receptor are relevant in purposes;
The treatment cancer is the method for tumor for example, comprises the chemical compound of the present disclosure to the mammal effective dosage of this treatment of needs;
Regulate the method for Trp-p8 function of receptors, comprise the chemical compound of the present disclosure of administration adjusting effective dose; And
Regulate the method for Trp-p8 function of receptors, comprise the chemical compound of the present disclosure that makes the contact of Trp-p8 receptor regulate effective dose.
The inventor also finds, particular compound of the present disclosure (for example known these chemical compounds that can produce physiological creeping chill (" cool-genic ") with structure on relevant chemical compound) has useful biological activity with other chemotherapeutants (comprising for example antibody) when being used in combination, anti-tumor activity for example, described chemical compound for example are alkylamide chemical compound and the alpha-keto-enamines that tetrahydropyrimidine above-mentioned-2-ketone, phosphine oxide, menthane carbosamided chemical compound, alkyl replace.
Therefore, the disclosure provides the combined therapy agent of chemical compound of the present disclosure (it can activate the Trp-p8 receptor) and other chemotherapeutants (comprising for example antibody) in embodiments.In embodiments, the disclosure provides the combined therapy agent that can effectively treat cancerous cell.In embodiments, the disclosure provides combined therapy agent and Therapeutic Method thereof, its can be for example by causing apoptosis, suppress angiogenesis or cause apoptosis and suppressing angiogenesis and effectively suppress or kill and wound cancerous cell.
In embodiments, the disclosure also provides:
Comprise compound compositions of the present disclosure with antibody and pharmaceutically suitable carrier combination;
Pharmaceutical composition, (said composition preferably comprises the described chemical compound for the treatment of effective dose or at least a other chemotherapeutants of salt and treatment effective dose to comprise the therapeutic combination of chemical compound of the present disclosure and antibody and pharmaceutically acceptable excipient, for example, angiogenesis inhibitor antibody);
The pharmaceutical composition that is used for the treatment of tumor, it comprises the compound or pharmaceutically acceptable salt thereof of the present disclosure of effective dose; At least a other chemotherapeutants (for example angiogenesis inhibitor antibody) of itself and effective antitumor amount and pharmaceutically suitable carrier combination;
The disease in the treatment mammal (for example people) or the method for disease, (for example wherein relate to the Trp-p8 receptor, wherein said disease or disease are characterised in that overexpression Trp-p8 receptor) and need to regulate function of receptors, this method comprises the chemical compound of the present disclosure of coupling administration adjusting effective dose and at least a other chemotherapeutants (for example angiogenesis inhibitor antibody) of effective antitumor amount;
(for example, tumor) method comprises the combination of chemical compound of the present disclosure and at least a other chemotherapeutants (for example angiogenesis inhibitor antibody) of drug treatment effective dose for disease in treatment or the prevention mammal or the relevant disease of Trp-p8 receptor;
With the chemical compound of the present disclosure of at least a other chemotherapeutants (for example angiogenesis inhibitor antibody of effective dose) combination, be used for pharmacy diagnosis or treatment (for example, treatment or prevention Trp-p8 receptor associated diseases or disease, for example tumor);
With the chemical compound of the present disclosure of at least a other chemotherapeutants (for example angiogenesis inhibitor antibody) of effective dose combination in preparation can be used for treating or prevent disease or Trp-p8 receptor are relevant disease (for example, treatment or relevant disease or the disease of prevention Trp-p8 receptor, for example tumor) medicine in purposes;
The treatment cancer is the method for tumor for example, comprises to the mammal administration of this treatment of needs and at least a other chemotherapeutants of effective dose (for example angiogenesis inhibitor antibody) chemical compound of the present disclosure combination, effective dose;
Regulate the method for Trp-p8 function of receptors, comprise the chemical compound of the present disclosure of regulating effective dose with at least a other chemotherapeutants (for example angiogenesis inhibitor antibody) administering drug combinations of effective dose; And
Regulate the method for Trp-p8 function of receptors, comprise making the contact of Trp-p8 receptor and at least a other chemotherapeutants (for example angiogenesis inhibitor antibody) of effective dose chemical compound of the present disclosure that make up, that regulate effective dose.
The inventor finds that also for example specific menthane carbosamided chemical compound of other specific chemical compounds that describes below is characterised in that they also show useful biological activity, for example the anti-tumor activity of killer cell.
Therefore, in embodiments, the disclosure also can provide the chemical compound with following general formula I Ia:
Wherein
R
1Be H or (C
1-C
6) alkyl;
R
2Be phenyl or have following general formula (PhR
3R
4R
5R
6R
7) substituted-phenyl
Wherein
R
3, R
4, R
6And R
7Be independently of one another-H, (C
1-C
6) alkyl, (C
1-C
6) alkoxy or halogen;
R
5Be halogen, (C
1-C
6) alkyl, (C
3-C
12) cycloalkyl, (C
1-C
6) alkoxyl ,-C (=O) (C
1-C
6) alkyl or (C
1-C
7) alkanoyl;
Or R
5Be-NR
8R
9, R wherein
8And R
9Be independently of one another-H, (C
1-C
6) alkyl, perhaps R
8And R
9Form morpholino (morpholino), ketopyrrolidine (pyrrolidino), piperidyl (piperzino), piperidines piperazine base (piperzino), indolinyl (indolino), benzimidazoline base (benzimidazolino), azetidinyl (azetidino), aziridinyl (aziridino), azepines base (azepino), 1 with the nitrogen that links to each other, 4-oxazinyl (oxazino) or thiomorpholine are for ring (thiomorpholino ring);
Or R
4And R
5Form the ring with 4-7 carbon atom with the phenyl that links to each other, this ring has the degree of unsaturation of 1-3; And
Stereoisomeric forms in any ratio, the mixture of stereoisomeric forms in any ratio;
Or its officinal salt;
Condition is to work as-PhR
3R
4R
5R
6R
7R
3, R
4, R
6And R
7Be-during H, R
5Be not-CH
3,-OCH
3,-OH ,-F, or-NO
2And
Condition is R
2It or not 3-hydroxy-4-methyl phenyl; And
Condition is R
2Not 2 hydroxy naphthalene base or pyridine radicals.
In embodiments, the disclosure also provides the chemical compound with above-mentioned general formula I Ia, it is characterized in that this chemical compound can effectively kill and wound the cell of expressing TRP-p8, but substantial variation needn't take place because of the existence of described chemical compound in the calcium ion flow of express cell.
In embodiments, the disclosure also provides:
Kill and wound the target cell of mammal expression in vivo Trp-p8 but can not change the method for the calcium current flow characteristic of mammiferous target cell (for example tumor) in fact, this method comprises the chemical compound of the present disclosure with general formula I Ia of drug treatment effective dose;
The disease in treatment mammal (for example people) or the method for disease comprise the chemical compound of the present disclosure with general formula I Ia of drug treatment effective dose, and this chemical compound is Cytotoxic to the Trp-p8 receptor and increases the calcium ion flow;
The method of the disease (for example tumor) that disease in treatment or the prevention mammal or Trp-p8 receptor are relevant, it comprises the chemical compound of the present disclosure with general formula I Ia of drug treatment effective dose, this chemical compound is Cytotoxic to the Trp-p8 receptor; And
Any above-mentioned killer cell, treatment disease or disease, perhaps treatment or prophylactic method all comprise chemical compound of the present disclosure and other chemical compounds of the present disclosure, angiogenesis inhibitor antibody or its mixture of administering drug combinations treatment effective dose.
Here set forth these and other embodiments.
Description of drawings
Figure 1A-D illustrates with the relative insensitivity of people's cell of not expressing Trp-p8 and compares, the effectiveness of selected refrigeration chemical compound of the present disclosure in killing and wounding people's cell of expressing Trp-p8.
Fig. 2 illustrates with the control cells system (PC3-Neo) of not expressing Trp-p8 and compares, the relative growth rate of the clone's of expression Trp-p8 cancerous cell line (PC3/Trp-p8).
The specific embodiment
The disclosure provides aforementioned pharmaceutical compositions and Therapeutic Method.The disclosure also provides above-mentioned chemical compound of the present disclosure with general formula I Ia, comprises the pharmaceutical composition of the chemical compound of the present disclosure of general formula I Ia, and using its method for the treatment of, described chemical compound and pharmaceutical composition are Cytotoxic to the Trp-p8 express cell.
The refrigeration examples for compounds is for example, to have the chemical compound of general formula (I-XIII):
R wherein
1And R
2Be H, alkyl, Het or aryl independently of one another, or as U.S. Patent No. 3,821,221 is disclosed;
R wherein
1And R
2Be H, alkyl or aryl independently of one another, perhaps as U.S. Patent No. 4,150,052 and J.Soc.Cosmet.Chem., 1978,29, disclosed among the 185-200;
R wherein
1, R
2And R
3Be H, alkyl or aryl independently of one another, perhaps as J Soc.Cosmet.Chem., 1978,29, disclosed among the 185-200 (and the document of wherein quoting, for example list of references 1);
R wherein
1, R
2And R
3Be the alkyl or cycloalkyl of straight chain or branching independently of one another, perhaps as U.S. Patent No. 4,070, disclosed in 496;
R wherein
3Be-OH-S (O) R
1,-P (=O) R
1R
2,-CO
2H ,-C (=O) NH
2,-OC (=O)-CH (OH) CH
3,-C (O) OC～H
2～-OH, wherein n be 1-4 ,-NR
1-C (=O) NR
1R
2-SO
2R
1,-SO
2NR
1R
2,-SONR
1R
2, and R wherein
1And R
2Be H, alkyl or aryl independently of one another, and R
4Be H, perhaps R
3And R
4With the carbon atom that links to each other is five yuan of ketal rings, and it is optional to have general formula and be-OCH
2-CH (CH
2-OH)-and the methylol substituent group of O-, perhaps as J.Soc.Cosmet.Chem., 1978,29, disclosed among the 185-200;
Be selected from VI group (X) nuclear of ring-type of Qu Daiing or branched hydrocarbon:
Wherein X be the N-alkyl formamides ,-C (=O) NR
1R
2, R wherein
1And R
2Be H, alkyl or aryl, perhaps R independently of one another
1And R
2With the nitrogen-atoms that links to each other is saturated or unsaturated heterocycle (Het) ring of 5-or 6-unit, its optional by oxygen (O-) ring hetero atom replaces, perhaps as J.Soc.Cosmet.Chem., 1978,29, disclosed among the 185-200;
Wherein X be the N-alkyl formamides ,-C (=O) NHR
1, R wherein
1Be the alkyl of alkyl or replacement, for example-C (=O) NHEt or-C (=O) NHCH
2CO
2Among the Et; Or the alkyl sulfone, for example at-SO
2Among the Bt, perhaps as J.Soc.Cosmet.Chem., 1978,29, disclosed among the 185-200;
The carbamide compound that alkyl replaces for example, has general formula VIII:
Perhaps as J.Soc.Cosmet.Chem., 1978,29, disclosed among the 185-200;
R wherein
1And R
2Be alkyl, perhaps R independently of one another
1And R
2With the nitrogen-atoms that links to each other is the saturated or unsaturated heterocycle (Het) of 5-or 6-unit, and it is optional, and (O-) ring hetero atom (for example morpholino ring) replaces, and this ring can be chosen wantonly by α-CO by oxygen
2H or α-CO
2CH
3Substituent group replaces, and
R
3, R
4And R
5Be H or alkyl independently of one another, perhaps as J.Agric.Food Chem., 2001,49, disclosed among the 5383-5390;
R wherein
1And R
2Be alkyl, perhaps R independently of one another
1And R
2With the nitrogen-atoms that links to each other is saturated or unsaturated heterocycle (Het) ring of 5-or 6-unit, R
3, R
4, R
5And R
6Be H or alkyl independently of one another, perhaps as J.Agric.Food Chem., 2001,49, disclosed among the 5383-5390;
R wherein
1And R
2Be alkyl independently of one another, or
R
1And R
2With the nitrogen-atoms that links to each other is saturated or unsaturated heterocycle (Het) ring of 5-or 6-unit, and R
3And R
4Be H or alkyl independently of one another, perhaps as J.Agric.Food Chem., 2001,49, disclosed among the 5383-5390;
R wherein
1And R
2Be alkyl independently of one another, or R
1And R
2Form the saturated or unsaturated ring of 5-or 6-unit together, and
R
3And R
4Be H or alkyl independently of one another, perhaps as J.Agric.Food Chem., 2001,49, disclosed among the 5383-5390; Perhaps
R wherein
1-R
5Be H, alkyl or aryl independently of one another, R
6Be-OH-S (O) R
8,-P (=O) R
8R
9,-CO
2H ,-C (=O) NH
2,-OC (=O)-CH (OH)-CH
3,-C (=O) OC
nH
2n-OH, wherein n is 1-4 ,-NR
8-C (=O) NR
8R
9,-SO
2R
8,-SO
2NR
8R
9, or-SONR
8R
9, and R wherein
6R
8And R
9Be H, alkyl or aryl independently of one another, and R
7Be H, or R
6And R
7With the carbon atom that links to each other is to have the substituent 5-of methylol unit ketal ring, and it has general formula-OCH
2-CH (CH
2-OH)-O-;
Or its officinal salt.
Unless otherwise noted, use to give a definition: halogen is fluorine, chlorine, bromine or iodine.Expression straight chain such as alkyl, alkoxyl and branching group; But mention separate base for example " propyl group " only comprise straight chain group, and specifically indicate branched chain isomer for example " isopropyl ".
" alkyl " be comprise primary, the C of secondary, uncle or ring-type carbon atom
1-C
18Hydrocarbon.Example is methyl (Me ,-CH
3), ethyl (Et ,-CH
2CH
3), 1-propyl group (n-Pr, n-propyl group ,-CH
2CH
2CH
3), 2-propyl group (i-Pr, i-propyl group ,-CH (CH
3)
2), 1-butyl (n-Bu, n-butyl ,-CH
2CH
2CH
2CH
3), 2-methyl isophthalic acid-propyl group (i-Bu, i-butyl ,-CH
2CH (CH
3)
2), 2-butyl (s-Bu, s-butyl ,-CH (CH
3) CH
2CH
3), 2-methyl-2-propyl group (t-Bu, t-butyl ,-C (CH
3)
3), 1-amyl group (n-amyl group ,-CH
2CH
2CH
2CH
2CH
3), 2-amyl group (CH (CH
3) CH
2CH
2CH
3), 3-amyl group (CH (CH
2CH
3)
2), 2-methyl-2-butyl (C (CH
3)
2CH
2CH
3), 3-methyl-2-butyl (CH (CH
3) CH (CH
3)
2), 3-methyl-i-butyl (CH
2CH
2CH (CH
3)
2), 2-methyl-1-butene base (CH
2CH (CH
3) CH
2CH
3), 1-hexyl (CH
2CH
2CH
2CH
2CH
2CH
3), 2-hexyl (CH (CH
3) CH
2CH
2CH
2CH
3), 3-hexyl (CH (CH
2CH
3) (CH
2CH
2CH
3)), 2-methyl-2-amyl group (C (CH
3)
2CH
2CH
2CH
3), 3-methyl-2-amyl group (CH (CH
3) CH (CH
3) CH
2CH
3), 4-methyl-2-amyl group (CH (CH
3) CH
2CH (CH
3)
2), 3-methyl-3-amyl group (C (CH
3) (CH
2CH
3)
2), 2-methyl-3-amyl group (CH (CH
2CH
3) CH (CH
3)
2), 2,3-dimethyl-2-butyl (C (CH
3)
2CH (CH
3)
2), 3,3-dimethyl-2-butyl (CH (CH
3) C (CH
3)
3
" aryl " represented phenyl or had the ortho-condensed bicyclic carbocyclic group of about 9-20 annular atoms, and wherein at least one ring is an aromatics.Aryl (Ar) can comprise the aryl of replacement, (for example for example have 1-5 substituent group, alkyl, substituent groups such as alkoxyl) phenyl, and described substituent group is consistent with described chemical compound and comprise about disclosed substituent group in the above-mentioned patent of chemical compound with general formula (I-XIII) or the document.
What the term here " antibody " used is the widest implication, and the multi-specificity antibody (for example bi-specific antibody) that specifically comprises complete monoclonal antibody, polyclonal antibody, forms by at least two complete antibodies, and antibody fragment, as long as they show required biological activity.Antibody is to discern the protein that produces with the antigenic immune system of binding specificity.Be described with regard to its structure, antibody is the Y shape protein of being made up of four amino acid chains (two heavy chains, two light chains).Be enough to support in the simplified model of this statement that each antibody all mainly has two districts: hypervariable region and constant region.Be positioned at Y the arm end the hypervariable region in conjunction with target antigen and with its interaction.The hypervariable region comprises complementary determining region (CDR), and its identification and combination are positioned at the specific binding site on the specific antigen.Be positioned at Y afterbody constant region by immune system recognition and with its interaction (Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immuno Biology, 5th Ed., Garland Publishing, NewYork).Target antigen has many binding sites usually, is also referred to as epi-position, and it is positioned at the CDR identification of multi-resistance on former.Each antibody in conjunction with different epi-positions all has different structures specifically.Therefore, an antigen can have more than one corresponding antibodies.
Term used herein " monoclonal antibody " is meant the antibody that obtains from consanguinity antibody population basically,, comprises that each antibody of described group is identical that is, except can exist on a small quantity can natural generation sudden change.Monoclonal antibody is a high degree of specificity, at single antigen site.In addition, compare with the polyclonal antibody preparation of the different antibodies that comprises the different determiners of guiding (epi-position), each monoclonal antibody is all at the single determiner on the described antigen.Except their specificity, the advantage of monoclonal antibody is and can synthesizes them under situation about not polluted by other antibody.Modifier " monoclonal " expression, not should be understood to and need prepare described antibody by any ad hoc approach as the antibody population acquisition of homogenizing basically from the characteristic of antibody.For example, monoclonal antibody used according to the invention can perhaps can prepare (referring to US 4816567) with the recombinant DNA method with the hybrid cell method preparation of describing first among Kohler etal (1975) the Nature 256:495.Can also use for example Clackson et al (1991) Nature, 352:624-628 and Marks et al (1991) J.Mol.Biol., the technology of describing among the 222:581-597 is separated " monoclonal antibody " from phage antibody library.
The monoclonal antibody here specifically comprises the fragment of " chimeric " antibody and these antibody, wherein part heavy chain and/or light chain with from specific species or belong to the identical or homology of corresponding sequence in the antibody of specific antibodies class or subclass, and the remainder of chain with from other species or belong to the identical or homology of corresponding sequence in the antibody of other antibody classes or subclass, as long as they show required biological activity (US4816567; With Morrison et al (1984) Proc.Natl.Acad.Sci.USA, 81:6851-6855).Here the chimeric antibody that receives publicity comprises (primatized) of sourceization " spirit long " antibody, and this antibody comprises hypervariable region antigen binding sequence from the non-human primate, and (e.g., Old World Monkey is Apeetc) with people's constant region sequence.
" chemotherapeutant " can be used for treating the chemical compound of cancer.The example of chemotherapeutant comprises alkylating reagent, for example thio-tepa (thiotepa) and CYTOXAN
TMCyclophosphamide (cyclosphosphamide); Alkyl sulfonic ester such as busulfan (busulfan), an improsulfan (improsulfan) and piposulfan (piposulfan); Aziridine such as benzcarbimine (bezodepa), carboquone (carboquone), meturedepa (meturedopa) and uredepa (uredopa); Aziridine (ethylenimine) and methylamelamine comprise altretamine (altretamine), triethylenemelamine (triethylenemelamine), triethylenephosphoramide (trietylenephosphoramide), triethylene thiophosphoramide (triethylenethiophosphoramide) and tri methylol melamine (trimethylolomelamine); Acetogenin (acetogenins) (specifically being bullatacin and bullatacinone); Delta9-tetrahydrocannabinol (dronabinol, MARINOL ); β-lapachol; Lapachol; Coichicines; Betulic acid; Camptothecine (camptothecin) (comprising synthetic analogues hycamtin (topotecan)); CPT-11 (irinotecan (irinotecan), CAMPTOSAR ), acetyl group camptothecine, scopolectin and 9-aminocamptothecin); Bryostatin (bryostatin); Callystatin; CC-1065 (comprising its adozelesin (adozelesin), carzelesin (carzelesin) and bizelesin (bizelesin) synthetic analogues); Podophyilotoxin; Rhizoma Dysosmae Versipellis tree acid (podophyllinic acid); Teniposide (teniposide); Cryptophycins (specifically being cryptophycin 1 and cryptophycin 8); Dolastatin (dolastatin); Duocarmycin (comprising synthetic analogues, KW-2189 and CB1-TM1); Eleutherobin; Pancratistatin; Sarcodictyin; Spongistatin; Chlormethine (nitrogen mustards) is as chlorambucil, chlornaphazine, gallbladder phosphamide (cholophosphamide), estramustine (estramustine), ifosfamide (ifosfamide), chlormethine (mechlorethamine), mustron; Melphalan, novoembichin (novembichin), phenesterine (phenesterine), prednimustine (prednimustine), trofosfamide (trofosfamide), uracil mustard; Nitroso ureas (nitrosureas) is as Carmustine (carmustine), chlorozotocin (chlorozotocin), fotemustine (fotemustine), lomustine (lomustine), nimustine (nimustine), Ranimustine (ranimustine); Antibiotic such as enediyne antibiotic (calicheamycin (calicheamicin) for example, specifically be calicheamycin γ 1 and calicheamycin ω 1 (see, for example, Agnew,
Chem Intl.Ed.Engl.,
33: 183-186 (1994)); Anthracycline antibiotics (dynemicin) comprises anthracycline antibiotics A; Esperamicin; And neocarzinostain NCS (neocarzinostatin) chromophore and related color fibroin enediyne antibiotic chromophore), aclacinomysins, actinomycin (actinomycin), authramycin, azaserine (azaserine), bleomycin (bleomycin), actinomycin C (cactinomycin), carabicin, Carubicin (carminomycin), cardinophyllin (carzinophilin), chromomycinis, dactinomycin (dactinomycin), daunorubicin, detorubicin (detorubicin), 6-diazonium-5-oxygen-L-nor-leucine, ADRIAMYCIN doxorubicin (doxorubicin) (comprises morpholino-doxorubicin, cyano group morpholino-doxorubicin, 2-pyrrolin-doxorubicin and deoxidation doxorubicin), epirubicin (epirubicin), esorubicin (esorubicin), idarubicin (idarubicin) is sent out ripple mycin (marcellomycin), and mitomycin is such as ametycin, mycophenolic acid, nogalamycin (nogalamycin), Olivomycin (olivomycin), peplomycin (peplomycin), potfiromycin, puromycin, triferricdoxorubicin (quelamycin), rodorubicin (rodorubicin), streptonigrin, streptozotocin (streptozocin), tubercidin, ubenimex (ubenimex), zinostatin (zinostatin), zorubicin (zorubicin); Antimetabolite such as methotrexate, 5-fluorouracil (5-FU); Folacin such as 9,10-dimethylpteroylglutamic acid (denopterin), methotrexate, teropterin (pteropterin), trimetrexate (trimetrexate); Purine analogue is fludarabine (fludarabine) for example, Ismipur, ITG, thioguanine; Pyrimidine analogue such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azauridine, carmofur (carmofur), cytosine arabinoside, two BrdUs, doxifluridine (doxifluridine), enocitabine (enocitabine), floxuridine; Androgens such as calusterone (calusterone), dromostanolone propionate (dromostanolong propionate), epitiostanol (epitiostanol), mepitiostane (mepitiostane), testolactone (testolactone); Anti-adrenal gland's class such as aminoglutethimide (aminoglutethimide), mitotane (mitotane), trilostane (trilostane); Folic acid supplement such as frolinic acid; 2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactone; Aldophosphamide glucosides (aldophosphamide glycoside); Amino-laevulic acid (aminolevulinic acid); Eniluracil (eniluracil); Amsacrine (amsacrine); Bestrabucil; Bisantrene (bisantrene); Edatrexate (edatraxate); Defofamine; Demecolcine; Diaziquone (diaziquone); Elfornithine; Elliptinium acetate; Epothilone; Etoglucid (etoglucid); Ganite (Fujisawa).; Hydroxyurea; Lentinan (lentinan); Lonidamine (lonidamine); CHROMATOGRAPHIC FRACTIONATION AND MASS (maytansinoids) such as maytansine (maytansine) and ansamitocin (ansamitocins); Mitoguazone (mitoguazone); Mitoxantrone (mitoxantrone); Mopidamol (mopidanmol); Nitraerine; Pentostatin (pentostatin); Phenamet (phenamet); Pirarubicin (pirarubicin); Losoxantrone (losoxantrone); 2-ethyl hydrazides; Procarbazine (procarbazine); PSK polysaccharide complex (JHS Natural Products, Eugene, OR); Razoxane (razoxane); Rhizomycin (rhizoxin); Sizofiran (sizofiran); Spirogermanium (spirogermanium); Tenuazonic acid (tenuazonic acid); Triaziquone; 2,2 ', 2 " RA3s (trichlorrotriethylamine); Trichothecene (trichothecene) (specifically being the T-2 toxin, verracurin A, roridin (roridin) A and anguidine); Urethane (urethan); Vindesine (ELDIS1NE , FILDESIN ); Dacarbazine (dacarbazine); Mannomustin; Mitobronitol (mitobronitol); Mitolactol (mitolactol); Pipobroman (pipobroman); Gacytosine; Galactoside (" Ara-C "); Tespamin (thiotepa); Taxane (taxoid), as TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE
TMNo cremophor (Cremophor-free), nano-particle preparaton (albumin-engineered nanoparticle formulation ofpaclitaxel) (the American Pharmaceutical Partners that the albumin of paclitaxel is transformed, Schaumberg, Illinois), with TAXOTERE doxetaxel (Rh ne-Poulenc Rorer, Antony, France); Chloranbucil; Gemcitabine (gemcitabine) (GEMZAR ); 6-thioguanine; Purinethol; Methotrexate; Platinum analogs such as cisplatin and carboplatin; Vinbiastine (VELBAN ); Platinum; Etoposide (etoposide) (VP-16); Ifosfamide; Mitoxantrone (mitoxantrone); Vincristine (ONCOVIN ); Oxaliplatin; Leucovovin; Vinorelbine (vinorelbine) (NAVELBINE ); Novantrone; Edatrexate (edatrexate); Daunorubicin; Aminopterin; Ibandronate (ibandronate); Topoisomerase enzyme inhibitor RFS 2000; Er Fujiajiniaoansuan (DMFO); Retinoid (retinoids) is such as retinoic acid; Capecitabine (XELODA ); And the officinal salt of above-mentioned any material, acid or derivant; And the combination of two or more above-mentioned substances, for example CHOP and FOLFOX, CHOP is the abbreviation of the combined therapy agent of cyclophosphamide, doxorubicin, vincristine and prednisolone (prednisolone), and FOLFOX is oxaliplatin (the oxaliplatin) (ELOXATIN that makes up with 5-FU and leucovovin
TM) the abbreviation of treatment prescription.
This definition also comprises energy adjusting, reduction, prevention or the inhibitory hormone hormone antagonist preparation to the effect of promotion cancer growth, and often uses with the form of system or whole body therapeutic.They can be hormones itself.The example comprises estrogen antagonist preparation and selective estrogen receptor instrumentality (SERM), comprise, tamoxifen (tamoxifen) (comprising NOLVADEX tamoxifen) for example, EVISTA raloxifene (raloxifene), droloxifene (droloxifene), the 4-trans-Hydroxytamoxifen, trioxifene (trioxifene), keoxifene, LY117018, onapristone (onapristone) and FARESTON toremifene (toremifene); Progesterone antagonist; Estrogen receptor is born regulator (ERDs); Be used to suppress or isolate the reagent of ovary, for example, discharge the hormone (LHRH) of lutropin; Agonist for example LUPRON and ELIGARD leuprorelin (leuprolide acetate) goserelin acetate (goserelin acetate) buserelin acetate (buserelin acetate) and tripterelin; Other androgen antagonist, for example Drogenil (flutamide), nilutamide (nilutamide) and bicalutamide (bicalutamide); The aromatase mortifier that suppresses aromatase, the estrogen that this enzyme is regulated among the adrenal gland generates, such as, 4 (5)-imidazoles for example, aminoglutethimide (aminoglutethimide), MEGASE megestrol acetate (megestrol acetate), AROMASIN exemestane (exemestane), formestanie, fadrozole (fadrozole), RIVISOR vorozole (vorozole), FEMARA letrozole (letrozole) and ARIMIDEX Anastrozole (anastrozole).And, this definition of chemotherapeutant comprises bisphosphonate (bisphosphonates), and for example clodronate is (for example, BONEFOS or OSTAC ), DIDROCAL 1-hydroxyl-ethylidene-1,1-di 2 ethylhexyl phosphonic acid (etidronate), NE-58095, ZOMETA zoledronic acid (zoledronic acid)/zoledronic acid salt (zoledronate), FOSAMAX alendronate (alendronate), AREDIA Pamidronate (pamidronate), SKELID tiludronic acid (tiludronate) or ACTONEL Risedronate (risedronate); And troxacitabine (troxacitabine) (1,3-dioxolane nucleoside cytosine analog); Antisense oligonucleotide specifically is those antisense oligonucleotides that suppress the gene expression in the related signal pathway of abnormal cell hypertrophy, such as, for example, PKC-α, Raf, H-Ras and egf inhibitor (EGF-R); Vaccine is such as THERATOPE vaccine and gene therapeutic vaccine, for example, and ALLOVECTIN vaccine, LEUVECTIN vaccine and VAXID vaccine; LURTOTECAN topoisomerase 1 mortifier; ABARELIX rmRH; Lapatinib ditosylate (the dual tyrosine kinase micromolecular inhibitor of ErbB-2 and EGFR is also referred to as GW572016); Antibody with antitumaous effect is particularly with officinal salt, acid or the derivant of bonded antibody such as VEGF-1, VEGF-2, VEGF-3, EGF-R, HER-2, CD20 and above-mentioned any material.
" Het " is the saturated or unsaturated heterocycles of four-(4), five-(5), six-(6) or seven-(7) units, and described ring has 1,2,3 or 4 hetero atom that is selected from oxygen, sulfo-, sulfinyl, sulfonyl and nitrogen, and described ring is optional to condense with phenyl ring.Het comprises " heteroaryl ", it comprises the group via the ring carbon connection of monocyclic aromatic rings, described aromatic ring contains five or six by carbon be selected from 1,2,3 or 4 annular atoms that hetero atom is formed of non-peroxide oxygen, sulfo-and N (X) respectively, and wherein X does not exist or H, O, C
1-4Alkyl, phenyl or benzyl, and from the group, particularly benzene derivative of the ortho-condensed bicyclic heterocycles of the about 8-10 of having of its annular atoms or by condensing propylidene, trimethylene or tetramethylene double-basis thereon deutero-group.
In embodiments, term " treatment " be meant alleviate, elimination, inhibition, improvement, change or prevent disease or disease, the chemical compound of the present disclosure of the effective dose that makes up of the chemical compound of the present disclosure by effective dosage or other chemotherapeutants (anti-angiogenic first antibody) by administration and effective dose for example, and term " treatment " can refer to medical therapy and prophylactic treatment.
In embodiments, term " adjusting " is meant that the chemical compound of the present disclosure of effective dose can optionally be regulated or multivalent ion (for example calcium ion) permeability of change cancerous cell on low relatively dosage level, described cancerous cell for example is the cell of expressing Trp-p8, and is opposite with the relative insensitivity of other cells (for example healthy or non-cancerous tumor cell and do not express the cell of Trp-p8).
In embodiments, be purpose of the present disclosure, term such as " treatment of cancer ", " treatment cancer " is meant the treatment method for cancer, it comprises makes cancerous cell contact chemical compound of the present disclosure, thereby the growth of anticancer, the time-to-live or its combination that kill and wound cancerous cell, prolongation patient, perhaps make the chemical compound of the present disclosure of cancerous cell contact and the combination of angiogenesis inhibitor antibody, thereby the growth of anticancer, kill and wound cancerous cell, prolong patient's time-to-live or its combination.Also comprise by method of the present disclosure treatment cancer and to make described cells contacting chemical compound of the present disclosure, to activate the Trp-p8 receptor in the cancerous cell (for example tumor), the flow that causes flowing to the multivalent ion of described cell increases, thereby causes that cell smoulders or cell death.Cancer can comprise that wherein abnormal cell carries out splitted disease uncontrollably.Cancerous cell can also be attacked contiguous tissue and is distributed to other positions of body through blood flow and lymphsystem.The main type of cancer is cancer, sarcoma, leukemia and lymphoma.Have many subgroups in these main types, described subgroup is described the organ of cancer origin, for example oat-cell carcinoma of adenocarcinoma of stomach or lung usually.
" tumor " for example is meant the unusual optimum or pernicious material of tissue, and described tissue may not have inflammation, from the cell of the tissue that is pre-existing in and may not have physiological function.Benign tumor comprises, for example, cyst, wart, nevus and polyp are not dispersed to other positions of body usually.Malignant tumor is made up of the cell of growing rapidly usually, has to be different from Normocellular other anomalous performances, and often attacks other normal structures.
" vascular endothelial cell growth factor " or " VEGF " is meant the mammal somatomedin, and for example U.S. Patent No. 5,332, and be defined in 671.The biological activity of natural VE GF is that its any analog or its variant are total, and described analog or its variant promote vascular endothelial cell rather than bovine corneal inner skin cell, lens epithelial cell, adrenal gland's cortical cell, BHK-21 fibroblast or Keratinocytic selection growth.
" angiogenic disease " or " angiogenic defective " is meant the unusual disease of the reagent that need to use suppresses angiogenesis (for example antiotasis chemical compound or compositions, chemical compound for example of the present disclosure and angiogenesis inhibitor antibody) treatment.These imbalances comprise, for example, cancer types, vascular tumor for example, as hemangioma (blood capillary and sponge sample), glomus tumor (glomus tumor), telangiectasis, bacillus cereus angiomatosis (bacillary angiomatosis), hemangioendothelioma, angiosarcoma, hemanyiopericytoma (haemangiopericytoma), Ka Boqi (Kaposi ' s) sarcoma, lymphangioma and lymphangiosarcoma, and tumor-blood-vessel growth.
Comprise (walking abreast) administration simultaneously with one or more other treatment agent " combination " administrations and with any order successive administration.
The refrigeration chemical compound is applicable to mammal.As used herein, " mammal " is meant the level vertebrate animals of their the follow-on any kind of milk nurture that uses mammary gland secretion, for example, and people, horse, cattle, pig, sheep, Canis familiaris L., rabbit and monkey.
Terms such as " accent die cell death ", " programmed cell death ", " apoptosis " are meant any cell death that the complicated cascade by the cell incident that produces in the moment of cell differentiation and reaction particular stimulation causes.Apoptotic cell death is characterised in that, the Cytoplasm of cell that will be dead and nuclear concentrate (condensation).Apoptosis is the active process that needs synthetic novel protein.Usually, this process need ATP relates to synthetic new RNA and protein, and finishes in the activation process of the interior living endonuclease of degradation of cell DNA, thereby destroys the required gene template of cell dynamic equilibrium.Change in (general cell turnover) in form generation, differentiation and whole cell, in the controlled disappearance of cell, observe apoptosis, and be subjected to the adjusting of receptor coupling incident usually.For this reason, apoptosis is known as " programmed cell death " or " cell suicide ".Although each cell all has the gene program of committing suiside, they are suppressed usually.Under normal circumstances, those cells that have only organism no longer to need could activate and be somebody's turn to do from the destruction program.
In embodiments, " treatment effective dose " is meant the dosage of the combination (being with or without excipient) of the dosage of chemical compound of the present disclosure or chemical compound of the present disclosure and other voltinism therapeutic agents, described chemical compound and combination for example by activation Trp-p8, irritation cell apoptosis or by both in vivo external or simultaneously in vivo with vitro inhibition, reduce or eliminate the cell growth.Precise dosage depends on therapeutic purposes, and can be determined by the those of ordinary skill that uses known technology in this area.
In an embodiment of the present disclosure, chemical compound of the present disclosure with for example use the therapy of other Antybody therapy agent to be used in combination.In one embodiment, chemical compound of the present disclosure and known cancer treatment antibody is used in combination.Usually referring to for example: PCT/US02/19592; PCT/US01/20118; PCT/US01/25464; PCT/US01/26626; PCT/US02/28859; PCT/US02/41798; PCT/US02/12206; PCT/US03/11148; PCT/US02/12619; And PCT/US02/33050.In another embodiment, chemical compound of the present disclosure is used in combination with the antibody such as anti-VEGF antibodies that comprise people, inhuman, mice, heterozygote and chimeric form.For example referring to U.S. Patent No. 6,582,959 (VEGF) and U.S. Patent application No.2002/0122797A1 (people VEGF).
In embodiment of the present disclosure, chemical compound of the present disclosure can be used in combination with other treatment agent (for example above-mentioned antibody), with treatment immunological diseases or disease, described disease or disease for example relate to for example cells such as B-cell (bone-marrow-derived lymphocyte), T-cell (T lymphocyte), accessory cell (macrophage and other antigens provide cell), killer cell (NK and K cell), mastocyte of immunoreactive cell.
In preferred embodiments, can be used for the chemical compound that chemical compound of the present disclosure comprises the non-radioactive labelling that is used for the treatment of non-central nervous system cell or disease.In embodiments, chemical compound of the present disclosure does not contain radio-labeled and is not radioactivity.Nonlabelled compound of the present disclosure can be used to kill and wound cancerous cell described here, for example expresses the cell of Trp-p8, for example prostate gland cancer cell and hepatoma carcinoma cell.
In the disclosure " experimenter ' comprise people and other animals, particularly mammal.Like this, described method is applicable to human therapy and veterinary treatment.In preferred embodiments, the experimenter is a mammal, and in the most preferred embodiment, the experimenter is the people.
" improved therapeutic outcome " or " reducing the number of tumor cell " or " reducing the tumor size " are meant that tumor size or volume reduce 50%, preferably reduce 80%, more preferably reduce 90%, further preferably reduce 100%, by checking patient before or after the treatment and take from that patient's sample measures, the decreased number of the detected circulating cancer cells in blood, infected tissue or the organ.
Terms such as " chemical compound ", " molecule ", " polypeptide " comprise the chemical compound by synthesizing the chemical compound for preparing, the chemical compound (for example, the protein of recombinant dna expression) of genetic modification, naturally occurring chemical compound and producing in vivo after the different chemical compounds of administration.Described chemical compound may not be realized effect in the body of chemical compound of administration described herein, but for example biotransformation such as metabolite, conjugate, complex, ion complex, chelate, hydrate, solvate or combination can realize described effect to one or more catabolites of the chemical compound of described administration or molecule.Except above-mentioned salt, " officinal salt " can also comprise the subclass of the salt that exists in the body or form.
The disclosure provide with TRP (instantaneous receptor potential) ion channel family in the bonded chemical compound of special receptor.More specifically, the disclosure provides the chemical compound of the subclass of combination long TRP (or TIRPM) passage specifically, and the most particularly, the disclosure provides specifically in conjunction with the chemical compound that is called the TRP passage of " Trp-p8 " (or TRP-M8).The Trp-p8 receptor is present in cancer for example in the carcinoma of prostate with high level usually.Chemical compound of the present disclosure is endowed Trp-p8 receptor activation activity.The activation of Trp-p8 receptor causes flowing into the calcium ionic current increase in the cancerous cell and finally causes cell death.Chemical compound of the present disclosure can be used for but is not limited to treat cell breeding disease or disease, and the irritation cell apoptosis.As described herein, how for example to use code test described herein or to use other similar tests to measure the Trp-p8 receptor active be known in the field.
Those of ordinary skill in the art should be appreciated that the chemical compound of the present disclosure with chiral centre can exist and separates with optical activity and racemic form.Some chemical compound can show pleomorphism.Be to be understood that, the disclosure contains any raceme, optical activity, pleomorphism, tautomerism or stereoisomeric forms in any ratio or its mixture of disclosure chemical compound, described mixture has useful performance described herein, (for example how to prepare the optical activity form, by using recrystallization technology dissolving (resolution) racemic form, by synthesizing by the optical activity raw material, synthetic by chirality, perhaps by using chiral stationary phase to carry out chromatographic isolation) be known in the field.Especially, should be appreciated that chemical compound of the present disclosure (for example general formula is the chemical compound of (I-XIII)) can contain chiral centre, for example, at the R of general formula (I)
1In the substituent group, the R of logical formula V
3In the substituent group, and the R of general formula (XIII)
1-R
6Contain chiral centre in the substituent group.It is also understood that chemical compound of the present disclosure for example general formula can exist with the form of " enol " or corresponding tautomer " ketone " for the chemical compound of (I), and all these tautomers all are included in the chemical compound scope of the present disclosure.
The carbon content of various hydrocarbonaceous parts is by lower limit and the prefix designates of the upper limit, for example the prefix C of the carbon number in the described part of expression
I-jExpression integer " i " is to the part of the individual carbon atom of integer " j " (comprising end points).Therefore, for example, C
1-6Alkyl or (C
1-C
6) alkyl represents to have the alkyl of 1-6 carbon atom (comprising end points).
Usually name chemical compound of the present disclosure according to the IUPAC nomenclature.Can use abbreviation known to a person of ordinary skill in the art (for example, " Ph " represents phenyl, and " Me " represents methyl, and " Et " represents ethyl, " h " expression hour, and " rt " expression room temperature).
Concrete and the preferred value of the group of listing below, substituent group and scope only is for illustration purpose; These values are not got rid of for other limit values in group and the substituent limited range or other values.Chemical compound of the present disclosure comprise have value described herein, occurrence, the chemical compound of the general formula (I-XIII) of the combination in any of value and preferred value more specifically.
Particularly, aryl can be phenyl, naphthyl, anthraquinonyl, phenanthryl, fluorenyl, tetralyl or indanyl.
Particularly, alkyl (C for example
1-6) alkyl can be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, 3-amyl group, hexyl, or heptyl; (C
2-C
6) alkyl can be ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, 3-amyl group, or hexyl; (C
3-12) cycloalkyl can be cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, bicyclo-or multi-ring substituent group, for example has the substituent group of following general formula:
C
1-6Alkoxyl can be methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, amoxy, 3-amoxy, or hexyloxy;-C (=O) alkyl or (C
2-C
7) alkanoyl can be acetyl group, propiono, bytyry, valeryl, 4-methylpent acyl group, caproyl or heptanoyl group; Aryl can be phenyl, indenyl or naphthyl; Het can be pyrrolidinyl, piperidyl, morpholinyl, thio-morpholinyl or heteroaryl; Heteroaryl can be furyl, imidazole radicals, triazolyl, triazine radical, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrole radicals, pyrazinyl, tetrazole radical, pyridine radicals (or its N-oxide), thienyl, pyrimidine radicals (or its N-oxide), indyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
The occurrence of Het is the saturated or unsaturated rings of five-(5), six-(6) or seven-(7) units, and it contains 1,2,3 or 4 hetero atom, for example non-peroxide oxygen, sulfo-, sulfinyl, sulfonyl and nitrogen; And from the group, particularly benzene derivative of the ortho-condensed bicyclic heterocycles of the about 8-12 of having of its annular atoms or by condensing propylidene, trimethylene, tetramethylene or another monocycle Het double-basis thereon deutero-group.
The particular compound of general formula (I) is the chemical compound of general formula (A)
A (Icilin is also referred to as AG-3-5).
The particular compound of general formula (II) is the chemical compound of general formula (B)
Another particular compound of general formula (II) is the preferred stereochemical chemical compound of general formula (C) performance:
Another particular compound of general formula (II) is the chemical compound of general formula (D):
The particular compound of general formula (III) is the chemical compound of general formula (E):
The particular compound of general formula (IV) is the chemical compound of general formula (F):
The particular compound of logical formula V is the chemical compound of general formula (G):
G (menthol).
The particular compound of general formula (VI) is the chemical compound of general formula (H):
The particular compound of general formula (VII) is the chemical compound of general formula (I '):
The particular compound of general formula (IX) is the chemical compound of general formula (J):
The particular compound of general formula (X) is the chemical compound of general formula (K):
The particular compound of general formula (XI) is the chemical compound of general formula (L):
The particular compound of general formula (XII) is the chemical compound of general formula (M):
The particular compound of general formula (XIII) is the chemical compound of general formula (N):
Should be appreciated that the particular compound of above-mentioned general formula (A-N) and every other chemical compound of the present disclosure can be or comprise its officinal salt.
Particular compound is 3-(2-hydroxyphenyl)-6-(3-nitrobenzophenone)-3,4-dihydro-1H-pyrimid-2-one or its officinal salt.
Another particular compound is 2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (4-methoxyl group-phenyl)-amide (2-isopropyl-5-methyl-yclohexanecarboxylic acid (4-methoxy-phenyl)-amide) or its officinal salt.
Another particular compound is a 2-isopropyl-2,3, and-N-trimethyl-butyramide (2-isopropyl-2,3, N-trimethyl-butyramide) or its officinal salt.
Another particular compound is 1-(sec-butyl-isobutyl group-phosphino-(phosphinoyl))-heptane or its officinal salt.
Another particular compound is 2-isopropyl-5-methyl-cyclohexyl alcohol (2-isopropyl-5-methyl-cyclohexanol) or its officinal salt.
The particular compound of general formula I Ia is the compound or pharmaceutically acceptable salt thereof of general formula I Ia1:
R wherein
1, R
3, R
4, R
5, R
6And R
7Definition as above.
Other particular compound of general formula lIa are each compound or pharmaceutically acceptable salt thereofs of general formula I Ia2-IIa12, and wherein the R substituent group is as defined herein:
And
The particular compound of general formula I Ia comprises:
2-isopropyl (isopropyl)-5-methyl (methyl)-cyclohexane-carboxylic acid (cyclohexanecarboxylicacid) (4-morpholine (morpholin)-4-base (yl)-phenyl (phenyl))-amide (amide) or its officinal salt;
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (3-chlorine (chloro)-4-methoxyl group (methoxy)-phenyl)-amide or its officinal salt;
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (4-sec-butyl (sec-butyl)-phenyl)-amide or its officinal salt,
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid indenes (cylclohexanecarboxylic acid indan)-5-base amide (ylamide) or its officinal salt,
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (the 4-tert-butyl group (tert-butyl)-phenyl)-amide or its officinal salt;
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (4-propyl group (propyl)-phenyl)-amide or its officinal salt; And
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (4-isopropyl-3-methyl-phenyl)-amide or its officinal salt.
Information such as the preparation process of the chemical compound of general formula (I-XIII) and the particular compound of above-mentioned general formula A-N, sign, refrigeration performance, foul smell (odor) property, structure-refrigeration activity relationship, design principle have report at corresponding above-mentioned document or patent.
Can be as described in the following scheme for example, by method similar,, perhaps known or may be obvious that the method for learning and prepare for example Formula B of chemical compound of the present disclosure by those of ordinary skills by the method in above-mentioned document or the patent with it, C, the chemical compound of D or N.All variablees that use in this programme all below or the definition of other parts of this paper.The scheme 1 for example preparation of amide compound 3 (IIa4-1) of expression representative compounds of the present disclosure.Chlorinated compound 1 by carboxylation, obtains carboxylic acid 2 through the Grignard intermediate, and carboxylic acid 2 is converted into amide 3, as described in embodiment 1.
Scheme 1
Other preparation methoies of chemical compound 3 (IIa4-1) and relevant amide compound are used the corresponding acid chloride (acid chloride) of above-mentioned carboxylic acid compound 2.The acid chloride of carboxylic acid compound 2 (easily by with SOCl
2Make Deng reagent reacting) can react with multiple primary amine or secondary amine compound, form and amide 3 similar corresponding amides.Can similarly prepare other and amide 3 or the relevant chemical compound of general formula I I, as described herein.
About the synthetic method of preparation methane carboxylic acid compound 2 (raw materials of IIa4-1), referring to the D.G.Rowsell in the following tabulation, Wilkinson Sword Ltd., U.K.Patent (1975).About another synthetic method of preparation methane carboxylic acid, referring to D.Cunningham, et.al., J.Chem.Soc., Perkin Trans.I, 2002,2692-2698.
For preparation J.Soc.Cosmet.Chem., 1978,29, other preparation details of the refrigeration chemical compound described in the 185-200 referring to the 199th page list of references 1, have been listed 17 British patent.
Other are applicable to that the condition that forms chemical compound of the present disclosure by multiple intermediate described herein is well known in the art.For example referring to Feiser and Feiser, " Reagents for Organic Synthesis, " Vol.1,1967; March, J. " Advanced Organic Chemistry, " 4
ThEd., John Wiley ﹠amp; Sons, 1992; House, H.O., " Modern Synthetic Reactions ", 2
NdEd., W.A.Benjamin, New York, 1972; And Laroek, R.C., " Comprehensive Organic Transformations, " 2
NdEd., Wiley-VCH Publishers, New York, 1999.
The raw material that uses in the synthetic method described herein can buy, and reports in scientific literature, perhaps can use the feedstock production of methods known in the art by easy acquisition.It is optional in above-mentioned or other synthetic methods in all or part that to use protecting group be ideal.These protecting groups and introducing thereof and the method for removing are well known in the art.Referring to Greene, T.W.; Wutz, P.G.M. " ProtectingGroups In Organic Synthesis " 2
NdEd., New York, John Wiley ﹠amp; Sons, Inc., 1991.
Chemical compound have enough alkalescence or acid with the situation that forms stable non-toxicity acid salt or basic salt under, be suitable with the form administration of salt chemical compound of the present disclosure.The example of officinal salt is the organic acid addition salt that is formed by acid, it forms physiologically acceptable anion, and described salt for example is toluene fulfonate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoate, Ascorbate, alpha-ketoglutarate and α-glycerophosphate.Also suitable inorganic salt be can form, hydrochlorate, hydrobromate, sulfate, nitrate, bicarbonate and carbonate comprised.
Can use standard method well known in the art to obtain officinal salt, for example by make have enough alkalescence chemical compound for example amine with provide physiology can accept anionic suitable acid reaction.The alkali metal salt that can also prepare carboxylic acid, for example sodium salt, potassium salt or lithium salts, or alkali salt, for example calcium salt.
Can be to contain and the form of the pharmaceutical composition of the disclosure chemical compound of suitable excipient composition administration chemical compound of the present invention easily, described compositions can be used for treating tumor.Preparation contains the pharmaceutical composition of the chemical compound that is applicable to anticancer usage by means commonly known in the art, and described compositions contains excipient well known in the art.The known summary of these methods and composition is Remington ' s Pharmaceutical Science (Mark PubI.Co., 15 of E.W.Martin
ThEd., 1975).According to the deposition or the propagation of for example tumor cell, can for example pass through by the mode of parenteral through intravenous injection, through intraperitoneal injection or through intramuscular injection, oral or per rectum administration chemical compound of the present disclosure and compositions.
In embodiments, the antibody contained of disclosure scope comprises hybrid antibody and recombinant antibodies (for example, " humanization " and " people " antibody), and do not consider to originate from species or immunoglobulins or subclass name, and antibody fragment (for example, Fab, F (ab ')
2, and Fv).Referring to U.S. Patent No. 4,816,567; Mageand Lamoyi, in Monoclonal Antibody Production Techniques and Applications, 79-97, Marcel Dekker, Inc., New York, (1987).
Like this, modifier " monoclonal " expression should not be construed as and need prepare antibody by any ad hoc approach from the feature of the antibody of the antibody population acquisition of this homogenizing basically.For example, monoclonal antibody of the present disclosure can be used the ﹠amp at Kohler; Milstein, Nature, the hybrid cell method of describing first among the 256:495 (1975) preparation perhaps can prepare by recombinant DNA method.Referring to U.S. Patent No. 4,816,567.For example at Goding, Monoclonal Antibodies:Principles and Practice, 59-103, Academic Press (1986); Kozbor, J.Immunol., 133:3001 (1984), Brodeur, et al., Monoclonal Antibody Production Techniques and Applications, 51-63, Marcel Dekker, Inc. has described other known methods that prepare antibody among the New York (1987).
Used several different methods to prepare monoclonal antibody (MAb).Hybridoma technology (being meant clone's the cell line of antibody of the single type of generation) is used the cell of various species, comprises mice (murine), hamster, rat and people's cell.The another kind of method for preparing MAb is used genetic engineering, comprises recombinant DNA technology.Monoclonal antibody by these technology preparations comprises chimeric antibody and humanized antibody.The chimeric antibody combination is from the dna encoding district of more than one type species.For example, chimeric antibody can be derived from from the hypervariable region of mice with from people's constant region.Humanized antibody is mainly from the people, even it contains inhuman part.As chimeric antibody, humanized antibody can contain human constant region completely.But unlike chimeric antibody, the hypervariable region can be partly from the people.The inhuman composite part of humanized antibody is often from the CDR in the mouse antibodies.Under any circumstance, these districts are for making antibody recognition and being crucial in conjunction with specific antigen.
As noted, murine antibody has important function in these technology.Although murine antibody can be used for diagnosis and short term therapy, can not the long term administration the pure man, this administration process can increase the risk that is harmful to immunogenic response.When human immune system identification mouse antibodies be foreign body and attack it the time, this reaction appears, be called human anti-mouse antibody (HAMA).The HAMA reaction can cause toxic shock or even dead.
Chimeric and humanized antibody reduces the probability of HAMA reaction by the inhuman part that minimizes administration antibody.In addition, chimeric and humanized antibody has the immunoreactive additional advantage of the secondary people of activation, for example antibody dependent cellular cytotoxicity.
" antibody fragment " comprises the part of complete antibody, the antigen binding domain or the variable region of preferred complete antibody.The example of antibody fragment comprises Fab, Fab ', F (ab ')
2And Fv fragment; Bivalent antibody (diabodies); Linear antibody; The single-chain antibody molecule; With the multi-specificity antibody that forms by antibody fragment.
" complete " antibody is to comprise antigen in conjunction with hypervariable region and light chain constant domain (CL) and heavy chain constant domain at least, C
H1, C
H2 and C
H3 antibody.Described constant domain can be native sequences constant domain (for example natural sequence constant domain of people) or its aminoacid sequence variant.
Described complete antibody has one or more effector function, and described function is meant the biological activity in the Fc district (the aminoacid sequence variant in the native sequences in Fc district or Fc district) owing to antibody.The example of antibody mediated effect subfunction comprises the Clq combination; CDC; The Fc receptors bind; The cytotoxicity (ADCC) of antibody dependent cellular mediation; Phagocytosis; Cell surface receptor (for example, B-cell receptor; BCR) downward modulation etc.
According to its heavy chain constant domain (C
H) aminoacid sequence, complete antibody can be divided into dissimilar.Have the complete antibody of five main types: IgA, IgD, IgE, IgG and IgM, wherein several can be further divided into subclass (isotype), for example IgG1, IgG2, IgG3, IgG4, IgA and IgA2.Heavy chain constant domain corresponding to dissimilar antibody is called α, δ, ε, γ and μ respectively.The subgroup structure and the 3-d modelling of inhomogeneity immunoglobulin are known.
When combined therapy is carried out in use in vivo, can be with treatment effective dose (that is, eliminating or alleviate the amount of patient's tumor load) administration antibody.The combination of administration chemical compound of the present disclosure and antibody simultaneously or sequentially.They are parenteral normally, if possible, and in the administration of target cell site or through intravenously administrable.Dosage and dosage regimen depend on, for example, the type of cancer (primary or shift), its colony, antibody at site, specific antitoxic characteristic (during use), for example, therapeutic index, patient and patient's medical history.The amount of administration antibody is generally the about 10mg/kg weight in patients of about 0.1-.Be generally for example about 5-1 of weight in patients with the amount of the chemical compound of the present disclosure of antibody combination medicine-feeding, 000mg/kg or about 0.1-300mg/kg, and can depend on above-mentioned many factors and consideration
The disclosure is also imagined the combination of using chemical compound of the present disclosure and anti--TRP-P8 antibody in diagnostic application.For diagnostic application, but use test section labelling antibody of the present disclosure usually.But the test section can be any material that can produce direct or indirect detectable signal.For example, but the test section can be a radiosiotope, for example
3H,
14C,
32P,
35S or
125I; Fluorescence or chemiluminescence compound, for example fluorescein isothiocyanate, rhodamine or luciferin; Or enzyme, for example alkaline phosphatase, β-nougat or horseradish peroxidase.
But can use the known in the art any method that is used for antibody is coupled to separately the test section, comprise Hunter, et al., Nature, 144:945 (1962); David, et al., Biochemistiy, 13:1014 (1974); Pain, et al., J.Immunol.Meth., 40:219 (1981); And Nygren, J.Histochem.And Cytochem, the method described in the 30:407 (1982).
Use for treatment, can be with pharmaceutically acceptable dosage form with antibody administration to mammal, preferred people, comprising can be with pill form through vein or long-time continuous infusion, through the dosage form of muscle, subcutaneous, intraarticular or inhalation route administration the pure man.Antibody also is fit to by in tumor, around the tumor, in the damage or the mode administration around the damage, to bring into play part and whole body therapeutic effect.
Described dosage form comprises the pharmaceutically suitable carrier or the excipient of known avirulence own and no therapeutical effect.Usually the concentration with about 0.1mg/ml-100mg/ml is formulated in antibody in the described excipient.
In order to prevent or treat disease, whether the suitable dose of combination of compounds of the present disclosure depends on type (definition as above), severity of disease and the process of disease to be treated, is prevention or the described chemical compound of therapeutic purposes administration, former treatment, patient's clinical medical history and to the reaction of chemical compound, and attending doctor's judgment.Described chemical compound is suitable for disposable or is administered to the patient in serial therapy.
The type and the seriousness that depend on disease, the chemical compound of about 0.015-15mg/kg are the initial candidate dosage to patient's administration, for example pass through once or a plurality of individually dosed or continuous infusion.For lasting several days or the longer time repetitively administered, according to circumstances, repetitive therapy is until the required inhibition effect that occurs disease symptoms.But, can use other dosage regimens.
For oral therapeutic administration, reactive compound of the present disclosure can use with forms such as digestible tablet, buccal tablet, tablet, capsule, elixir, suspension, syrup, thin slices with one or more vehicle group merging.This compositions and preparation contain the reactive compound at least about 0.1% usually.The percentage rate of compositions and preparation can change, and can be about 2-about 60% of given unit dosage forms weight easily.These are treated, and the amount that goes up the reactive compound in the useful compositions is feasible can to obtain effective dosage level.
Tablet, tablet, pill, capsule etc. can also contain following material: binding agent, for example tragakanta, Radix Acaciae senegalis, corn starch or gelatin; Excipient, for example dicalcium phosphate; Disintegrating agent, for example corn starch, potato starch, alginic acid etc.; Lubricant, for example magnesium stearate; And sweeting agent, for example sucrose, fructose, lactose or aspartame sugar; Or flavoring agent, for example green pepper Oleum menthae, Herba pyrolae japonicae (wintergreen) oil or Fructus Pruni pseudocerasi flavouring agent etc.When unit dosage forms was capsule, it can also contain liquid-carrier except that the material of the above-mentioned type, for example vegetable oil or Polyethylene Glycol.Other multiple materials can be used as the physical form that there is or is used to change solid unit dosage form in coating.For example, tablet, pill, capsule etc. can be coated with gelatin, wax, lacca or sugar etc.Syrup or elixir can contain described reactive compound, as the sucrose of sweeting agent or fructose, as the methyl parabens and the propyl para-hydroxybenzoate class of antiseptic, and dyestuff and flavoring agent, for example Fructus Pruni pseudocerasi or Fructus Citri junoris flavoring agent.Certainly, to prepare the employed any material of any unit dosage forms should be pharmaceutically useful and be avirulent on used water gaging is flat basically.And, reactive compound can be mixed in slow releasing preparation and the device.
Chemical compound of the present disclosure or compositions can also be by infusion or injection and through intravenously administrables or through intraperitoneal administration.The solution that can prepare reactive compound or its salt in water is chosen wantonly and is mixed with nontoxic surfactants.Can also and in oil, prepare dispersion liquid at glycerol, liquid macrogol, glycerol triacetate and composition thereof.Under the storage and service condition of routine, these preparations contain antiseptic, to prevent growth of microorganism.
Be suitable for injecting or the pharmaceutical dosage form of infusion can comprise aseptic aqueous solution or dispersion liquid or the sterilized powder that contains active component, but they are applicable to the sterile solution or the dispersion liquid of interim preparation injectable or infusion, and they are chosen wantonly by coating in liposome or implantable seed (seed) or granule (pellet).In all cases, final dosage form should be sterile fluid and be stable under production and condition of storage.Liquid-carrier or excipient can be to comprise for example solvent or the liquid dispersion medium of water, ethanol, polyhydric alcohol (for example glycerol, propylene glycol, liquid macrogol etc.), vegetable oil, nontoxic glyceride and suitable mixture thereof.For example by forming liposome, pass through under the situation of dispersion liquid, to keep required particle size or, can keeping suitable flowability by using surfactant.For example p-Hydroxybenzoate, methaform, phenol, sorbic acid, thiomersalate etc. can prevent action of microorganisms by various antibacterial and antifungal.In many cases, preferably include isotonic agent for example sugar, cushion or sodium chloride.By the reagent that in compositions, use to postpone absorbs for example aluminum monostearate and gelatin, the absorption that can prolong Injectable composition.
Can in various above-mentioned other compositions (as required) introducing suitable solvent, carry out filter sterilised then by reactive compound and prepare aseptic parenteral solution aequum.For the sterilized powder that is used to prepare aseptic parenteral solution, preferred manufacturing procedure is vacuum drying and Freeze Drying Technique, the powder of any extra required composition before described method generation active component adds and is present in the solution of aseptic filtration.
Available solid carrier comprises finely divided solid for example Talcum, clay, microcrystalline Cellulose, Silicon stone, Alumina etc.Available liquid-carrier comprises water, alcohol or glycerol or water-alcohol/glycerol blend, wherein can choose the chemical compound of the present disclosure that dissolves or disperse effective dose under the help of nontoxic surfactants wantonly.For example essence and extra antimicrobial are used for the performance of given purposes with optimization can to add adjuvant.The doses available of chemical compound of the present disclosure can be by relatively their activity in vivo and external activity are determined in animal model.Be used for mice and other animals for example the method for people's administration effective dose be known in the art, for example referring to U.S. Patent No. 4,938,949.
With the unit dosage forms described chemical compound of administration easily; For example described dosage form contains 5-1000mg active component/unit dosage forms, advantageously contains 10-750mg, the most advantageously contains 50-500mg.Required dosage can be present in the single dose or easily as with the appropriate interval separate dose of every day twice, three times, four times or more times low dose of administration for example.Described low dose itself can further be divided into for example with repeatedly concrete discrete interval administration; For example repeatedly suck from inhaler.
For inner administration, can be with about 0.1-300mg/kg the weight of animals, the dosage level of preferred 1.0-30mg/kg the weight of animals (calculating as free benchmark) is oral or through the described compositions of parenteral, can in human body, use described compositions, be administered once to four times every day with the amount of 1-1000mg/ unit dose with unit dosage forms.
For through parenteral or drop form administration, as be used for the treatment of the situation of eyes, described chemical compound is about 10% with about 0.1-, and more preferably from about the concentration of 0.1-about 7% is present in the aqueous solution.Described solution can contain other compositions, for example emulsifying agent, antioxidant or cushion.
Usually, the chemical compound of general formula (I-XIll) fluid composition for example the concentration in IV (intravenous) compositions to be generally about 0.1-about 25%, the about 10 weight % of preferably about 0.5-.Concentration in semisolid or solid composite example gel or powder is the about 5 weight % of about 0.1-, the about 2.5 weight % of preferably about 0.5-.
The definite prescription that is used for administration chemical compound disclosed herein and compositions must depend on by the patient's of straight chain needs, treat type, and in the nature of things, the doctor's of participation judgement.
Chemical compound of the present disclosure in conjunction with active and be the excellent prediction index of the anti-tumor activity of chemical compound of the present disclosure in conjunction with selectivity.Can use drug model well known in the art or use the following analysis method to determine in conjunction with activity with in conjunction with selectivity.The example results of biologic test is summarised in the following table 1.
The assessment biological activity
Be used to assess and measure calcium ion flow or cell absorption and inducing cell and transfer common method and the R.Skyryrna that dies, et al., I Physiology, 2000,527.1, disclosed method is applicable to the disclosure among the 71-83, as described here.It is conspicuous that other test methods and for example following method that comprises that the interior and external tumor growth of cell line cultivation, transfection and body suppresses are understood the disclosure for those of ordinary skill in the art.
Activity analysis
In order to treat cancer, the multiple animal model of knowing can be used for further understanding gene in the effect of tumor development and pathogeny and be used to check the effect of candidate therapeutic agent, and described therapeutic agent comprises the combination of chemical compound of the present disclosure and angiogenesis inhibitor antibody.The body internal characteristic of these models makes their specifically reactions among the predict human patient.The animal model of tumor and cancer (for example, breast carcinoma, colon cancer, carcinoma of prostate, pulmonary carcinoma etc.) comprises non-reorganization and reorganization (transgenic) animal.Non-recombinant animal model comprises, for example rodent, for example mouse model.These models can be introduced tumor cell by implantation under for example percutaneous injection down of use standard technique, terminal intravascular injection, spleen implantation, intraperitoneal implantation, the scrotum or normal (orthopin) implantation and make in the homogenic mice, for example implant the colon cancer cell in the colon.For example referring to JIUYUE in 1997 open No.WO97/33551 of disclosed PCT on the 18th.
Possibly, the most frequently used animal species is an immunodeficient mouse in the oncology studies, particularly nude mouse.Thymus function is low/and undergrown nude mouse can successfully serve as the host of people's tumor xenogeneic graft, and this observed result causes nude mouse to be widely used in this purpose.A large amount of uniquenesses that autosomal recessive nu gene is introduced nude mouse are different is in the homogenic bacterial strain, for example ASW, A/He, AKR, BALB/c, B10.LP, C17, C3H, C57BL, C57, CBA, DBA, DDD, I/st, NC, NFR, NFS, NFS/N, NZB, NZC, NZW, P, RIII and SJL.In addition, other the multiple animals with the heredoimmunity defective that is different from nude mouse have been cultivated and as the receptor of tumor xenogeneic graft.For more details, referring to for example The Nude Mouse in OncologyResearch, E.Boven and B.Winograd, eds. (CRC Press, Inc., 1991).
The cell of introducing in these animals can be from known lesion/cancer cell line, for example any above-mentioned tumor cell line, and B104-1-1 cell line (stable NIH-3T3 cell line, transfection neu proto-oncogene) for example; The N1H-3T3 cell of ras-transfection; Caco-2 (ATCC HTB-37); Or the II level human colon adenocarcinoma cell line of appropriate good discrimination, HT29 (ATCC HTB-38); Or from tumor and cancer.Use is included in the freezing and standard conditions that store in the liquid nitrogen, can obtain the sample of tumor or cancerous cell in the patient's body the operation.Karmali et al.，Br.J.Cancer；48：689-696(1983)。Can use several different methods that tumor cell is introduced animal for example in the nude mouse body.Subcutaneous (s.c.) space in the mice is very suitable for tumor and implants.Tumor can subcutaneous transplantation, as solid block, by using the trocar as needle biopsy, perhaps as cell suspension.Implant for the solid block or the trocar, the tumor tissues fragment of suitable dimension is introduced subcutaneous space.By primary tumor or stable tumor cell line prepared fresh cell suspension and subcutaneous injection.Tumor cell can also be with the form injection of hypodermic implant.In this position, inoculum is deposited between corium connective tissue bottom and the subcutaneous tissue.
Can for example pass through basically as Drebin, et al., Proc.Nat.Acad.Sci.USA, 83:9129-9133 (1986) is described, is implanted into the NIH-3T3 cell that rat neuroblast oncocyte (by its initially-separate neu oncogene) or neu-transform and produces the animal model of breast carcinoma to the nude mouse body.
Similarly, can cause in these animals, tumor occurring by at animal nude mouse interior generation colon cancer cell for example, thus the animal model of preparation colon cancer.Wang for example, et al., CancerResearch, 54:4726-4728 (1994) and Too, et al., Cancer Research, the Chang Weiyi that 55:681-684 (1995) has described the human colon carcinoma in the nude mouse plants model.This model is based on so-called " METAMOUSE
TM", it is by AntiCancer, and (San Diego Calif.) sells Inc..
Can take out intravital tumor of animal and In vitro culture.Cell from the In vitro culture thing can go down to posterity to animal then.This tumor can be with the target that acts on further test or drug screening.Perhaps, can separate the tumor that obtains by going down to posterity, and analyze from the cell before going down to posterity with one and take turns or take turns more the RNA of isolated cells afterwards that goes down to posterity, be used for the differential expression of interested gene.Can use any known tumor or cancerous cell line to implement this technology that goes down to posterity.The following examples are used for describing in more detail uses above-mentioned disclosed mode, and is used to set forth the best mode that is used to implement various aspects of the present disclosure.Should be appreciated that these embodiment are used to limit true scope of the present disclosure, but provide for the example purpose.
Embodiment 1
Prepare Compound I Ia4-1 by (-) menthyl chloride.Be placed on 1.39g magnesium metal (57mmol) in the 100mL flask and add 4mL and do THF to cover the magnesium metal.In metal-THF mixture, add iodine crystal and stir a few minutes, add about 1/3 part of 10g (57mmol) (-) menthyl chloride (Aldrich) then.Heat this mixture and form, and will also stir until the reaction end among the dried THF of remaining menthyl chloride (2/3 part) adding 50mL to induce Grignard.In nitrogen, Grignard solution is transferred in the container that contains excessive dry ice with intubation way.The mixture of dry ice cancellation is turned round and round, be poured in the 300mL ice that contains the dense HCl of 2mL.Add diethyl ether and separating mixture.Merge isolated organic layer and washing, use the NaOH aqueous solution extraction then.Use HCl acidified aqueous solution (and oil) until forming solid, add diethyl ether, acid extraction in organic facies, is used the salt water washing, use dried over sodium sulfate, concentrate and obtain 4.18g (40%) white needles body.
(0.57g 3.1mmol) is dissolved in the 1.5mL-dimethyl acetylamide (DMA) with acid.Add PyBOP (2.1g, 4.0mmol), P-nethoxyaniline (0.58g, 4.7mmol, Aldrich) and DiPEA (2.7mL, 15.5mmol).After 2 hours and 5 hours, add the 0.25g P-nethoxyaniline respectively in addition.With ethyl acetate (EtOAc) diluted reaction mixture,, use the sodium bicarbonate aqueous solution washed twice after 7 hours, use the salt water washing then with the HCl washed twice of 1N.Merge isolated organic layer, and use dried over sodium sulfate, be concentrated into brown solid.The silica gel thromboembolism (plug) that this solid is passed have the 30%EtOAc/ hexane is with decolouring.Product begins crystallization when concentrating, and therefore allows crystallization to carry out, and uses pipette to remove and desolvates, and uses cold EtOAc washing white needles body, and vacuum drying obtains first product of 0.365g (1.26mmol, 40% productive rate).Recrystallization mother liquor additionally produces the white needles body of 0.346g (1.2mmol, 39% productive rate).
LCMS shows that the molecular weight of product is 289, meets the desired molecule amount, and the NMR spectrogram shows that product has desired structure.
Embodiment 2
Ion channel activity-assessment the calcium ion that confirms the selected refrigeration chemical compound of reaction absorbs.The following calcium ion absorption experiment of carrying out.For the cell of expressing the Trp-p8 tumor antigen with do not express the cell of Trp-p8 tumor antigen, after every kind of cell line contacts refrigeration chemical compound of the present disclosure, measurement calcium absorption amount.The result shows that the cell of expressing the Trp-p8 tumor antigen has the calcium absorption amount that increases gradually along with the refrigeration compound concentrations reaches about 10mM from about five concentration levels of about 0.0001 increase.Under all refrigeration compound concentrations, chemical compound (IIa4-1) has extra high unexpectedly calcium absorption amount.The antigenic cell of expressing tumor does not have observable calcium absorption amount basically in all refrigeration compound concentration scopes.Expressing and not in the express cell system, non-refrigeration chemical compound dimethyl sulfoxide (DMSO) is as control compound, the cell that DMSO exposes does not show tangible calcium absorption amount under any concentration.Cell line comprises that non-expression is: 293, PC3 and PC3/neo and tumor antigen are expressed system: 293, PC3 and PC3/neo.
Embodiment 3
The chemical compound that uses activation Trp-p8 is at the external people's cell that kills and wounds.Referring to accompanying drawing, in Fig. 1, assessed the effectiveness of selected refrigeration chemical compound in killing and wounding people's cell.In two relevant human cell lines, compare the magnitude (order) and the effectiveness of refrigeration chemical compound, a cell line is 293 cells of expressing Trp-p8, second cell line is to use coupling 293 cells of shortage (the not expressing) Trp-p8 that compares.In plating, they are about 50000 cells/well.When plating, add the refrigeration chemical compound.By handling cell under the varied concentration of the about 1000mM of about 0.1-cellular exposure being reached 72 hours in each chemical compound.X-axis indicated concentration increment, but the y axle is illustrated in 72 hours when finishing survival cells (having arbitrary unit).Figure 1A and 1C illustrate express Trp-p8 and apparatus have shown in the reaction of cell of refrigeration compound treatment of numbering or name.Figure 1B and 1D illustrate do not have (not expression type) Trp-p8 and also use shown in the reaction of cell of refrigeration compound treatment.The result of Figure 1A and 1C shows that the refrigeration chemical compound has killing and wounding of certain limit to the cell with Trp-p8 and reacts or effectiveness.Compound I Ia4-1 has best fragmentation effect (IC for the cell of expressing Trp-p8
50＜ImM).The comparing result of Figure 1B and 1D shows, the cell that does not have Trp-p8 is to identical refrigeration chemical compound, particularly has lower under refrigeration chemical compound (for example, the being lower than 100mM) situation of low concentration or do not kill and wound reaction basically.
Use the chemical compound that activates Trp-p8 to suppress the method for tumor growth in vivo.The method of cancerous cell that the cancerous cell of preparation transfection is for example expressed the transfection of Trp-p8 is conspicuous for the ordinary skill in the art, referring to for example J.M.Schallhorn, and et al., Nucleic Acids Res., 1996, Feb 15; 24 (4): 596-601.Referring to Fig. 2, this illustrates transfected with antigenic PC3 clone cell of expressing tumor (PC3/Trp-p8.c8 and .c9) and the not growth of the antigenic PC3 clone cell of expressing tumor (PC3-Neo) in athymic nude mouse (500 ten thousand cell/mices).Non-Trp-p8 expression type tumor PC3-Neo 200 (--) that form the PC-3 show the exponential type growth of tumour cell speed of expection.On the contrary, form PC-3's Trp-p8 expression type (i.e. " overexpression type ") tumor PC3/Trp-p8:.c8 (clone 8) 220 (■-); And .c9 (clone 9) 230 (▲-) slower in fact growth rate and the static growth rate of expression respectively.
Inoculate about 5 * 10 in flank portion for athymic mouse (8 every group)
6PC3 clone cell (cl.8) or the vehicle Control cell line (PC3-Neo) of stably express Trp-p8.Make the size of each tumor growth to about 200mg, be administered once or twice refrigeration chemical compound every day this moment, and dosage is about 1-30mg/kg body weight.Use per three days I.V. of caliper or P.O. to measure gross tumor volume, and calculate average external volume.
With for example above-mentioned cell of Trp-p8 expression type cancerous cell with have appropriateness to the of the present disclosure specific refrigeration chemical compound of efficient and carry out contacting in the body, as mentioned above, expection is expressed cancerous cell to Trp-p8 and is caused strong cell killing effect, and healthy or non-Trp-p8 express cell are not caused the cell killing effect or cause low cell killing effect.This expected results is consistent with the result of the above-mentioned vitro human cell killing shown in the embodiment 3.
Table 1 has been summed up exemplary ion channel activity and to the cell killing reaction of above-mentioned or the selected refrigeration chemical compound that illustrates below, and the comparable or relative active grade of these chemical compounds is provided.
The ion channel activity and the cell killing of table 1 pair selected refrigeration chemical compound reaction
| Active grade | Compound I D# | Peak value (FLIPR) 1 | The 293/Trp-p8 cell killing | The PC3/Trp-p8 cell killing |
| 1 | IIa4-1 | 31,000 | Be | Be |
| 2 | TV-1 | 31,000 | Be | |
| 3 | XIII-1 | 29,000 | Be | Be |
| 4 | IV-2 | 29,000 | ||
| 5 | IIb-2 | 25,100 | Be | Be |
| 6 | IIb-3 | 25,100 | Be | Be |
| 7 | IIb-4 | 25,100 | Be | |
| 8 | IIb-1 | 25,000 | ||
| 9 | XIII-2 | 25,000 | ||
| 10 | IIb-5 | 23,300 | ||
| 11 | IV-3 | 22,000 | ||
| 12 | Icilin | 20,000 | ||
| 13 | V-4 | 17,500 | ||
| 14 | V-2 | 17,000 | ||
| 15 | V-1 | 9,600 | ||
| 16 | III-1 | 5,000 | ||
| 17 | The DMSO reference | 1,400 |
1. peak value (FLIPR) is the measuring of maximum calcium ion flow under 10mM.FLIPR is meant exometer imaging plate reader; Can buy from for example Molecular Devices Corp..
C
11H
20O
2 C
13H
25NO C
13H
24O
3 C
15H
27NO
3
Mol.Wt.：184.28 Mol.Wt.：211.34 Mol.Wt.：228.33 Mol.Wt.：269.38
C
14H
27NO C
15H
29NO
2 C
18H
27NO
2 C
15H
29NO
Mol.Wt.：225.37 Mol.Wt.：255.40 Mol.Wt.：289.41 Mol.Wt.：239.40
C
10H
21NO C
14H
25NO
3 C
15H
29NO C
15H
28O
4
Mol.Wt.：171.28 Mol.Wt.：255.35 Mol.Wt.：239.40 Mol.Wt.：272.38
C
15H
33OP C
13H
29OP C
14H
31OP
Mol.Wt.：260.40 Mol.Wt.：232.34 Mol.Wt.：246.37
Embodiment 5
Preparation has other selected compounds of general formula I Ia.Each compound embodiment for following repeats embodiment 1 substantially, and difference is to use amine (P-nethoxyaniline) co-reactant of corresponding amine replacement embodiment 1, the primary product the when chemical compound of structure is as purification shown in having with preparation.For example by the primary product of following each embodiment of mass spectral characteristi, described product has parent peak at the place of molecular weight shown in the pact.
C
18H
27NO
2 C
17H
25NO C
17H
25NO
2
Mol.Wt.：289.41 Mol.Wt.：259.39 Mol.Wt.：275.39
C
20H
31NO C
17H
24ClNO C
17H
24FNO
Mol.Wt.：301.47 Mol.Wt.：293.83 Mol.Wt.：277.38
C
18H
27NO C
19H
29NO
Mol.Wt.：273.41 Mol.Wt.：287.44
C
18H
26FNO
2 C
18H
27NO
2
Mol.Wt.：307.40 Mol.Wt.：289.41
C
18H
27NO
2 C
17H
24FNO
Mol.Wt.：289.41 Mol.Wt.：277.38
C
19H
29NO
2
Mol.Wt.：303.44
C
21H
32N
2O
2 C
21H
33NO
Mol.Wt.：344.49 Mol.Wt.：315.49
C
91H
33NO C
20H
31NO
Mol.Wt.：315.49 Mol.Wt.：301.47
C
18H
26ClNO
2 C
20H
29NO C
21H
33NO
Mol.Wt.：323.86 Mol.Wt.：299.45 Mol.Wt.：315.49
Table 2 has been summed up for 293/Trp-p8. clone 18 and 293/Trp-p8. clone 10, shown in the right IC of menthane carbosamided chemical compound
50The result.
Table 2 is for 293/Trp-p8. clone 18 and 293/Trp-p8. clone 10, menthane carbosamided IC
50Data.
| Compound I Ia2, wherein R 1=H and R 2＝-PhRR 4R 5R 6R 7Be | Compound I D# | 293/Trp-p8.c18 | 293/Trp-p8.c10 |
| 4-MeO-Ph- | IIa4-1 | 0.58/0.45 | 0.42 |
| Ph- | IIa4-2 | 3.38 | 3.21 |
| 4-HO-Ph- | IIa4-3 | 1.05 | 1.23 |
| 3-MeO-Ph- | IIa10-1 | 3.69 | 3.80 |
| 4-iPr-Ph- | IIa4-4 | 0.98 | 0.76 |
| 2-MeO-Ph- | IIa8-1 | 17.57 | 16.74 |
| 4-Cl-Ph- | IIa4-5 | 17.57 | 1.99 |
| 4-F-Ph- | IIa4-6 | 3.78 | 3.58 |
| 3-F，4-MeO-Ph- | IIa6-1 | 0.60 | 0.79 |
| 4-Me-Ph- | IIa4-7 | 1.14 | 1.21 |
| 4-Et-Ph- | IIa4-8 | 0.68 | 0.73 |
| 2-Me，4-MeO-Ph- | IIa12-1 | 0.93 | 1.14 |
| 3-F-Ph- | IIa10-2 | 2.91 | 6.31 |
| 4-morpholino-Ph- | IIa4-9 | 1.45 | 1.28 |
| 3-Cl，4-Me-Ph- | IIa6-2 | 2.57 | 3.10 |
| 4-secBu-Ph- | IIa4-10 | 1.08 | 3.59 |
| 3,4-propylidene-Ph-(that is indanyl) | IIa6-3 | 1.71 | 1.35 |
| 4-tBuPh- | IIa4-11 | 1.41 | 1.23 |
| 4-nPrPh- | IIa4-12 | 4.93 | 5.65 |
| 3-Me，4-iPrPh- | IIa6-4 | 4.37 | 5.05 |
| Icilin (reference) | -- | -- | 79.24 |
Embodiment 6
Table 3 has been summed up for 293/Trp-p8. clone 21, shown in the IC of menthane carbosamided chemical compound
50The result of a-type double.
Table 3 is for PC3/Trp-p8. clone 21, menthane carbosamided IC
50Data (in duplicate).
| Compound I Ia4, wherein R5-is | Compound I D# | IC 50 |
| 4-MeO-Ph- | IIa4-1 | 1.642 |
| 4-HO-Ph- | IIa4-3 | 4.2696 |
| 4-iPr-Ph- | IIa4-4 | 3.2082 |
| 4-secBu-Ph- | IIa4-10 | 8.4937 |
| 4-nPr-Ph- | IIa4-12 | 12.857 |
| Compound I Ia4, wherein R5-is | Compound I D# | IC 50 |
| 4-MeO-Ph- | IIa4-1 | 1.5938 |
| 4-HO-Ph- | IIa4-3 | 3.7606 |
| 4-iPr-Ph- | IIa4-4 | 3.1039 |
| 4-secBu-Ph- | IIa4-10 | 48.613 |
| 4-nPr-Ph- | IIa4-12 | 16.473 |
Embodiment 7
The implantable seed of production that carrier products for example can be bought or conventional or spherolite can with the formulated in combination of independent one or more chemical compounds of the present disclosure or itself and other chemotherapeutant or other drug or excipient together, perhaps described carrier products can comprise the described material in back.Preferred preparation can have the selectable timing release characteristics of refrigeration chemical compound for example or other compositions, for example is used for the treatment of carcinoma of prostate.For at the therapeutic treatment of cancer example of the nonradioactive sustained release implants in the carcinoma of prostate for example, referring to U.S. Patent No. 5,633,274, its full content is incorporated this paper by reference into.
Following example contains for example representative drugs dosage form of the chemical compound of general formula I or II of chemical compound of the present disclosure (" chemical compound x "), and it is used for the treatment of in human body or preventive use.
(i) tablet 1
The mg/ sheet
' chemical compound x ' 100.0
Lactose 77.5
Polyvidon 15.0
Cross-linked carboxymethyl cellulose sodium 12.0
Microcrystalline Cellulose 92.5
Magnesium stearate
3.0
300.0
(ii) tablet 2
The mg/ sheet
' chemical compound x ' 20.0
Microcrystalline Cellulose 410.0
Starch 50.0
Sodium starch glycollate 15.0
Magnesium stearate
5.0
500.0
(iii) capsule
The mg/ capsule
' chemical compound x ' 10.0
Colloidal silica 1 .5
Lactose 465.5
The starch 120.0 of gel in advance
Magnesium stearate
3.0
600.0
(v) injection 1 (mg/ml)
Mg/ml
' chemical compound x ' 1.0
Sodium hydrogen phosphate 12.0
Dibastic sodium phosphate 0.7
Sodium chloride 4.5
1.0N sodium hydroxide solution
(with pH regulator to 7.0-7.5) capacity
Water for injection capacity ad 1mL
(v) injection 2 (10mg/ml)
Mg/ml
' chemical compound x ' 10.0
Dibastic sodium phosphate 0.3
Sodium hydrogen phosphate 1.1
PEG400 200.0
The 01N sodium hydroxide solution
(with pH regulator to 7.0-7.5) capacity
Water for injection capacity ad 1mL
(vi) aerosol
The mg/ jar
' chemical compound x ' 20.0
Oleic acid 10.0
Trichlorine methyl fluoride 5,000.0
Dichlorodifluoromethane 10,000.0
The Dichlorotetrafluoromethane 5,000.0
Can obtain above-mentioned preparation by the conventional method that drug world is known.
Embodiment 9
Coupling treatment-administration altogether.Following example contains the representative drugs dosage form (" compositions y ") of the disclosure chemical compound that directly makes up (mixture) with antibody, is used for the treatment of in human body or preventive use.For example, with for example chemical compound and for example anti-VEGF antibodies combination of antibody of general formula I or II of chemical compound of the present disclosure.One or more ' chemical compound x ' in the injection formulation of the combination preparation that obtains ' compositions y ' replacement the foregoing description 8.Can obtain above-mentioned preparation by the conventional method that drug world is known.
Coupling treatment-administration successively.Following example contains the representative drugs dosage form with the disclosure chemical compound of antibody (' antibody z ') sequential combination (mixture) (' chemical compound x '), is used for the treatment of in human body or preventive use.For example, with for example chemical compound and for example anti-VEGF antibodies administration successively of antibody of general formula I or II of chemical compound of the present disclosure.For example, the combination of administration can comprise successively: the administration first time of disclosure chemical compound (' chemical compound x ') is any in the above-mentioned preparation of embodiment 7 or 8, is the drug administration by injection second time of antibody (' antibody z ') then.Perhaps, at first administration ' antibody z ', ' the chemical compound x ' of administration then.Can obtain above-mentioned preparation by the conventional method that drug world is known.
Embodiment 11
It is open in above-mentioned U.S. Patent No. 6,582,959 with the method, example and other lists of references that characterize antibody (comprising antigenic specificity, epi-position drawing, isotype, binding affinity) to be used to prepare antibody.
All periodicals, patent and patent documentation are all incorporated this paper into by introducing, as incorporating this paper by reference respectively into.With reference to various concrete and preferred embodiment and technical descriptions the disclosure.But, should be appreciated that in spirit and scope of the present disclosure and can make many changes and improvements it.
Claims (20)
1. treatment method for cancer comprises the refrigeration chemical compound that makes cancerous cell contact effective dose.
2. the process of claim 1 wherein that the refrigeration chemical compound is selected from the combination of the compound or pharmaceutically acceptable salt thereof of the have general formula chemical compound of (I-XIII) or two or more general formulas (I-XIII):
R wherein
1And R
2Be H, alkyl, Het or aryl independently of one another;
R wherein
1And R
2Be H, alkyl or aryl independently of one another;
R wherein
1, R
2And R
3Be H, alkyl or aryl independently of one another;
R wherein
1, R
2And R
3Be the alkyl or cycloalkyl of straight chain or branching independently of one another;
R wherein
3Be-OH;-S (O) R
1-P (=O) R
1R
2-CO
2H;-C (=O) NH
2-OC (=O)-CH (OH)-CH
3-C (=O) OC
nH
2n-OH, wherein n is 1-4;-NR
1-C (=O) NR
1R
2,-SO
2R
1,-SO
2NR
1R
2,-SONR
1R
2, and R wherein
1And R
2Be H, alkyl or aryl independently of one another, and R
4Be H, or R
3And R
4With the carbon atom that links to each other is 5 yuan of ketal rings, and it is chosen wantonly has the following methylol substituent group of general formula:
-OCH
2-CH(CH
2-OH)-O-；
Be selected from IV group (X) nuclear of ring-type of Qu Daiing or branched hydrocarbon:
Wherein X be the N-alkyl formamides ,-C (=O) NR
1R
2, R wherein
1And R
2Be H, alkyl or aryl, perhaps R independently of one another
1And R
2With the nitrogen-atoms that links to each other is the saturated or unsaturated heterocycle (Het) of 5-unit or 6-unit, and it is optional, and (O-) ring hetero atom replaces by oxygen;
Wherein X be the N-alkyl formamides ,-C (=O) NHR
1, R wherein
1Be alkyl or substituted alkyl or alkyl sulfone;
The urea that the alkyl of general formula VIII replaces:
The cyclopentenone chemical compound of general formula I X:
R wherein
1And R
2Be alkyl independently of one another, or R
1And R
2With the nitrogen-atoms that links to each other is 5 yuan or 6 yuan of saturated or unsaturated heterocycles (Het), and it is optional, and (O-) ring hetero atom replaces, and such as morpholino-ring, and described ring can be chosen wantonly by α-CO by oxygen
2H or α-CO
2CH
3Substituent group replaces, and R
3, R
4, and R
5Be H or alkyl independently of one another;
The cyclonene chemical compound of general formula X:
R wherein
1And R
2Be alkyl independently of one another, or R
1And R
2With the nitrogen-atoms that links to each other is 5 yuan or 6 yuan of saturated or unsaturated heterocycles (Het), and R
3, R
4, R
5And R
6Be H or alkyl independently of one another;
The unsaturated lactone chemical compound of general formula X I:
R wherein
1And R
2Be alkyl independently of one another, or R
1And R
2With the nitrogen-atoms that links to each other is 5 yuan or 6 yuan of saturated or unsaturated heterocycles (Het), and R
3And R
4Be H or alkyl independently of one another;
The chemical compound of general formula X II:
R wherein
1And R
2Be alkyl independently of one another, or R
1And R
2Form 5 yuan or 6 yuan of saturated or unsaturated rings together, and R
3And R
1Be H or alkyl independently of one another; Or
The chemical compound of general formula X III:
R wherein
1-R
5Be H, alkyl or aryl independently of one another, R
6Be-OH;-S (O) R
8-P (O) R
8R
9-CO
2H;-C (=O) NH
2-OC (=O)-CH (OH)-CH
3-C (=O) OC
nH
2n-OH, wherein n is 1-4;-NR
8-C (=O) NR
8R
9-SO
2R
8-SO
2NR
8R
9Or-SONR
3R
9, and R wherein
6R
8And R
9Be H, alkyl or aryl independently of one another, and R
7Be H, or R
6And R
7With the carbon atom that links to each other is 5 yuan of ketal rings, and it has general formula-OCH
2-CH (CH
2-OH)-the methylol substituent group of O-.
3. suppress or kill and wound the method for cancerous cell, this method comprises the chemical compound to the general formula of cell drug treatment effective dose (I-XII1), or its combination, or its officinal salt.
4. cause the apoptotic method in the cancerous cell, this method comprises the chemical compound of the general formula (I-XIII) that makes described cells contacting effective dose, or its combination, or its officinal salt.
5. the disease in the treatment mammal or the method for disease wherein relate to Trp-p-8 receptor and needs and regulate function of receptors, and this method comprises the chemical compound of the general formula (I-XIII) of administration adjusting effective dose, or its combination, or its officinal salt.
6. treat or prevent the method for disease relevant with the Trp-p-8 receptor in the mammal, this method comprises the chemical compound of the general formula (I-XIII) of drug treatment effective dose, or its combination, or its officinal salt.
7. pharmaceutical composition comprises the chemical compound of general formula (I-XIII), or its combination, or its officinal salt, and pharmaceutically acceptable excipient.
8. the chemical compound of general formula (I-XIII), or its combination, or its officinal salt, it is used for medical diagnosis or treatment.
9. the chemical compound of claim 8, wherein medical diagnosis or treatment are treatment or relevant disease or the disease of prevention Trp-p-8 receptor.
10. the purposes of the chemical compound of general formula (I-XIII) is used to prepare and can be used for treating or the medicine of the disease that prevent disease or Trp-p-8 receptor are relevant.
11. the treatment method for cancer comprises the chemical compound to the general formula (I-XIII) of the mammal effective dosage of this treatment of needs, or its combination, or its officinal salt.
12. regulate the method for Trp-p-8 function of receptors, comprise the chemical compound of the general formula (I-XIII) of administration adjusting effective dose, or its combination, or its officinal salt.
13. regulate the method for Trp-p-8 function of receptors, comprise the chemical compound that makes the contact of Trp-p-8 receptor regulate the general formula (I-XIII) of effective dose, or its combination, or its officinal salt.
14. the method for trigger cell apoptosis in cancerous cell comprises the chemical compound to the general formula (I-XIII) of patient's effective dosage, or its combination, or its officinal salt, thereby causes apoptosis in described cell.
15. the process of claim 1 wherein that described cancer comprises that expressing tumor is antigenic, the human prostate cell of formation tumor.
16. the method for claim 2 further comprises the refrigeration chemical compound that administration and antibody make up, described antibody causes apoptosis and/or suppresses angiogenesis.
17. the compound or pharmaceutically acceptable salt thereof of general formula (I-XIII), at least a extra chemotherapeutant combination of itself and effective dose is used for the treatment of or prevent disease or the relevant disease of Trp-p8 receptor.
18. the chemical compound of claim 17, wherein said chemotherapeutant are VEGF antibody.
19. the method for claim 2, the chemical compound of its formula of (I-XIII) is:
3-(2-hydroxyphenyl)-6-(3-nitrobenzophenone)-3,4-dihydro-1H-pyrimid-2-one;
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (4-methoxyl group-phenyl)-amide;
2-isopropyl-2,3, N-trimethyl-butyramide;
1-(sec-butyl-isobutyl group-phosphino-)-heptane; And
2-isopropyl-5-methyl-cyclohexyl alcohol;
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (4-morpholine-4-base-phenyl)-amide;
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (3-chloro-4-methoxyl group-phenyl)-amide;
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (4-sec-butyl-phenyl)-amide;
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid indane-5-base amide;
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (the 4-tert-butyl group-phenyl)-amide;
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (4-propyl group-phenyl)-amide, and
2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid (4-isopropyl-3-methyl-phenyl)-amide,
Or its officinal salt.
20. the chemical compound of general formula I Ia:
Wherein
R
1Be H, or (C
1-C
6) alkyl;
R
2Be phenyl or have general formula (PhR
3R
4R
5R
6R
7) substituted-phenyl
Wherein
R
3, R
4, R
6And R
7Be independently of one another-H, (C
1-C
6) alkyl, (C
1-C
6) alkoxy or halogen;
R
5Be halogen, (C
1-C
6) alkyl, (C
3-C
12) cycloalkyl, (C
1-C
6) alkoxyl ,-C (=O) (C
1-C
6) alkyl or (C
1-C
7) alkanoyl;
Or R
5Be-NR
8R
9, R wherein
8And R
9Be-H (C independently of one another
1-C
6) alkyl, or R
5And R
9Form morpholino, ketopyrrolidine, piperidyl, piperidines piperazine base, indolinyl, benzimidazoline base, azetidinyl, aziridinyl, azepines base, 1 with the nitrogen-atoms that links to each other, the 4-oxazinyl, or thiomorpholine is for ring;
Or R
4And R
5Form the ring with 4-7 atom with the phenyl that links to each other, this ring has 1-3 degree of unsaturation; And
Stereoisomeric forms in any ratio, the mixture of stereoisomeric forms in any ratio;
Or its officinal salt,
Condition is to work as-PhR
3R
4R
5R
6R
7R
3, R
4, R
6And R
7Be-during H, R
5Be not-CH
3,-OCH
3,-OH ,-F, or-NO
2And
Condition is R
2It or not 3-hydroxy-4-methyl-phenyl; And another condition is R
2Not 2-hydroxyl-naphthyl, or pyridine radicals.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US48452603P | 2003-07-02 | 2003-07-02 | |
| US60/484,526 | 2003-07-02 | ||
| US60/491,616 | 2003-07-31 |
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|---|---|---|---|
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ID=37064583
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100582089C (en) * | 2003-11-21 | 2010-01-20 | 吉万奥丹股份有限公司 | N-substituted p-menthane carbosamided |
| CN102241646A (en) * | 2010-05-14 | 2011-11-16 | 中国人民解放军军事医学科学院毒物药物研究所 | Hexenone compound, and medical purpose thereof |
-
2004
- 2004-07-02 CN CN 200480025186 patent/CN1845741A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100582089C (en) * | 2003-11-21 | 2010-01-20 | 吉万奥丹股份有限公司 | N-substituted p-menthane carbosamided |
| CN102241646A (en) * | 2010-05-14 | 2011-11-16 | 中国人民解放军军事医学科学院毒物药物研究所 | Hexenone compound, and medical purpose thereof |
| CN102241646B (en) * | 2010-05-14 | 2014-04-09 | 中国人民解放军军事医学科学院毒物药物研究所 | Hexenone compound, and medical purpose thereof |
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