The application requires in the U.S. Provisional Application 61/044 of submission on April 14th, 2008, No. 886, the U.S. Provisional Application 61/034 submitted on March 6th, 2008, No. 466 and the U.S. Provisional Application 61/034 submitted on March 6th, 2008, No. 464 priority, it intactly quotes adding herein separately.The application also requires in the U. S. application 11/830 of submission on July 30th, 2007, No. 733 priority, this application requires in the U.S. Provisional Application 60/833 of submission on July 28th, 2006, No. 886 rights and interests and International Application Serial No. PCT/US2006/028326 number the rights and interests of submitting on July 21st, 2006 as the part continuation application, it intactly quotes adding herein separately.Also require the priority of No. 60/701,814, the U.S. Provisional Application submitted on July 21st, 2005 for International Application Serial No. PCT/US2006/028326 number; 60/706,719 the priority of submitting on August 8th, 2005, and 60/731,633 the priority of submitting on October 28th, 2005, it intactly quotes adding herein separately.
Summary of the invention
Compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or the prodrug of formula I are provided herein:
Formula I
Wherein
Z is H or F;
X is F, Cl, CH
3, CH
2OH, CH
2F, CHF
2Or CF
3
Y is I, Br, Cl, CF
3, C
1-C
3Alkyl, C
2-C
3Thiazolinyl, C
2-C
3Alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, wherein Het is 5 to 10 yuan of monocyclic heterocycles groups or bicyclic heterocyclic groups that comprise 1-5 the ring hetero atom that is independently selected from N, O and S, described heterocyclic group be saturated, olefinic or aromatics; Wherein
Whole described phenyl or Het group are randomly by F, Cl, Br, I, acetyl group, methyl, CN, NO
2, CO
2H, C
1-C
3Alkyl, C
1-C
3Alkoxyl, C
1-C
3Alkyl-C (=O)-, C
1-C
3Alkyl-C (=S)-, C
1-C
3Alkoxy-C (=S)-, C
1-C
3Alkyl-C (=O) O-, C
1-C
3Alkyl-O-(C=O)-, C
1-C
3Alkyl-C (=O) NH-, C
1-C
3Alkyl-C (=NH) NH-, C
1-C
3Alkyl-NH-(C=O)-, two-C
1-C
3Alkyl N-(C=O)-, C
1-C
3Alkyl-C (=O) N (C
1-C
3Alkyl)-, C
1-C
3Alkyl-S (=O)
2NH-or trifluoromethyl replace;
Whole described methyl, ethyl, C
1-C
3Alkyl and cyclopropyl group are randomly replaced by OH;
Whole described methyl groups are randomly by 1,2 or 3 F atoms replacements;
R
0Be H, F, Cl, Br, I, CH
3NH-, (CH
3)
2N-, C
1-C
6Alkyl, C
1-C
4Alkoxyl, C
3-C
6Cycloalkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, phenyl, monosubstituted phenyl, O (C
1-C
4Alkyl), O-C (=O) (C
1-C
4Alkyl) or C (=O) O (C
1-C
4Alkyl); Wherein
1-3 the substituting group that described alkyl, alkoxyl, cycloalkyl, thiazolinyl, alkynyl and phenyl group randomly are independently selected from F, Cl, Br, I, OH, CN, cyanogen methyl, nitro, phenyl and trifluoromethyl replaces;
Described C
1-C
6Alkyl and C
1-C
4Alkoxy base is also randomly by OCH
3Or OCH
2CH
3Replace;
G is G
1, G
2, R
1a, R
1b, R
1c, R
1d, R
1e, Ar
1, Ar
2Or Ar
3Wherein
G
1Be randomly by an amino, C
1-C
3The C that alkyl amino or dialkyl amino group replace
1-C
6Alkyl, described dialkyl amino group comprise 2 can be identical or different C
1-C
4Alkyl group; Perhaps
G
1Be C
3-C
8The Diaminoalkyl group;
G
2Be 5 yuan of rings or the 6 yuan of rings that comprise saturated, the undersaturated or aromatics of 1-3 the ring hetero atom that is independently selected from N, O and S, it randomly is independently selected from F, Cl, OH, O (C
1-C
3Alkyl), OCH
3, OCH
2CH
3, CH
3C (=O) NH, CH
3C (=O) O, CN, CF
3Replace with 1-3 substituting group of 5 yuan of aromatic heterocyclic groups that comprise 1-4 the ring hetero atom that is independently selected from N, O and S;
R
1aBe methyl, it is randomly by 1-3 fluorine atom or 1-3 chlorine atom, perhaps OH, ring propoxyl group or C
1-C
3Alkoxyl replaces, wherein said ring propoxyl group group or described C
1-C
3The C of alkoxy base
1-C
3Moieties is randomly replaced by a hydroxyl or methoxy group, and described C
1-C
4All C in the alkoxyl
3-alkyl group is all randomly further replaced by another OH group;
R
1bBe CH (CH
3)-C
1-3Alkyl or C
3-C
6Cycloalkyl, described alkyl and group of naphthene base randomly are independently selected from F, Cl, Br, I, OH, OCH
3Replace with 1-3 the substituting group of CN;
R
1cBe (CH
2)
nO
mR '; Wherein
M is 0 or 1; And wherein
When m was 0, n was 1 or 2;
When m was 1, n was 2 or 3;
R ' is C
1-C
6Alkyl, it randomly is independently selected from F, Cl, OH, OCH
3, OCH
2CH
3And C
3-C
6The 1-3 of cycloalkyl substituting group replaces;
R
1dBe C (A) (A ') (B)-; Wherein
B is H or C
1-4Alkyl, it is randomly replaced by one or two OH group;
A and A ' are H or C independently
1-4Alkyl, it is randomly replaced by one or two OH group; Perhaps
The carbon atom that A and A ' are attached thereto with them forms 3-6 unit saturated rings;
R
1eBe
Wherein
Q is 1 or 2;
R
2And R
3Be H, F, Cl, Br, CH independently of one another
3, CH
2F, CHF
2, CF
3OCH
3, OCH
2F, OCHF
2, OCF
3, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group or mesyl;
R
4Be H, F, Cl, Br, CH
3, CH
2F, CHF
2, CF
3OCH
3, OCH
2F, OCHF
2, OCF
3, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, mesyl, nitro, acetylamino, amidino groups, cyano group, carbamyl, methyl carbamyl, dimethylamino formoxyl, 1,3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3,4-oxadiazole, 1,3,4-thiadiazoles, 5-methyl isophthalic acid, 3,4-thiadiazoles, 1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl and N-pyrrolidinyl carbonylamino;
R
5Be H, F, Cl or methyl;
R
6Be H, F, Cl or methyl;
Ar
1Be
Wherein
U and V are N, CR independently
2Or CR
3
R
2, R
3And R
4Be H, F, Cl, Br, CH independently
3, CH
2F, CHF
2, CF
3OCH
3, OCH
2F, OCHF
2, OCF
3, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, acetylamino, amidino groups, cyano group, carbamyl, methyl carbamyl, dimethylamino formoxyl, 1,3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3,4-oxadiazole base, 1,3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3,4-thiadiazolyl group, 1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl, N-pyrrolidinyl carbonylamino and mesyl;
R
5And R
6Be H, F, Cl or methyl independently;
Ar
2Be
Wherein
Dotted line represents the optional pro forma position of second two key of ring;
U is-S-,-O-or-N=, and wherein
When U be-O-or-during S-, V is-CH=,-CCl=or-N=;
When U be-during N=, V is-CH=,-CCl=, or-N=;
R
7Be H or methyl;
R
8Be H, acetylamino, methyl, F or Cl;
Ar
3Be
Wherein
U is-NH-,-NCH
3-or-O-;
R
7And R
8Be H, F, Cl or methyl independently.
In some embodiments, the invention provides the compound of the formula I that is selected from following compound:
In some embodiments, the invention provides the compound of formula I, described compound is selected from:
Wherein 2-OH carbon is in the R configuration.
In some embodiments, the invention provides the compound of formula I, described compound is selected from:
Wherein 2-OH carbon is in the S configuration.
In some embodiments, the invention provides and comprise the formula I compound compositions that is selected from compound shown below, wherein 2-OH carbon is in the R configuration, the essentially no S-isomer of described composition.
In some embodiments, the invention provides and comprise the formula I compound compositions that is selected from compound shown below, wherein 2-OH carbon is in the S configuration, the essentially no R-isomer of described composition.
In some embodiments, the invention provides the compound of formula I, wherein Y is phenyl, pyridine radicals or pyrazolyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein Y is phenyl, pyridine radicals or the pyrazolyl that replaces.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein Y is Br or I.In the embodiment of a subgenus, the invention provides the compound of formula I, wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is 1-piperazinyl or 2-piperazinyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is morpholinyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is N-methyl-2-amino-ethyl.In the embodiment of a subgenus, the invention provides the compound of formula I, wherein G is N-methyl-3-amino-n-pro-pyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is (CH
3)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n is 1,2 or 3.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is (CH
3CH
2)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n is 1 or 2.In the embodiment of subgenus more specifically, the invention provides the compound of formula I, wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl; R
oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is 1-piperazinyl or 2-piperazinyl; R
oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is morpholinyl; R
oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is N-methyl-2-amino-ethyl; R
oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is N-methyl-3-amino-n-pro-pyl; R
oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is (CH
3)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n is 1,2 or 3; R
oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is (CH
3CH
2)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n is 1 or 2; R
oBe H, halogen or methoxyl group; X is F; And Y is I.
In some embodiments, the invention provides the pharmaceutical composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition also comprises at least a pharmaceutically acceptable carrier.
In some embodiments, the invention provides to comprise and be selected from:
With
Compound or the pharmaceutical composition of the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition also comprises at least a pharmaceutically acceptable carrier.In some embodiments, described compound is in the R configuration.In some embodiments, described compound is in the R configuration, essentially no S-isomer.In some embodiments, described compound is in the S configuration.
In some embodiments, described compound is in the S configuration, essentially no R-isomer.In some embodiments, described compound is:
In some embodiments, described compound is:
The invention still further relates to N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (being also referred to as " compd A " and " N-(-)-(3; 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide " herein):
![Figure GPA00001070418800075](https://patentimages.storage.googleapis.com/b3/fa/74/fc3868e96d3324/GPA00001070418800075.png)
Crystalline polymorph A, it demonstrates specific x-ray diffractogram of powder.In some embodiments, described x-ray diffractogram of powder comprises the peak shown in Fig. 5 of at least 50%.In some embodiments, described x-ray diffractogram of powder comprises the peak shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.By R and S-MTPA ester and the contrast chemical shift of proton difference of preparation on secondary alcohol, compd A has been characterized as being " S " isomer.Referring to for example Dale, J.A.; Mosher, H.S., J.Am.Chem.Soc., 1973,95,512 and Ohtani etc., J.Am.Chem.Soc., 1991,113,4092.
The invention still further relates to N-(R)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (being also referred to as " compd B " and " N-(+)-(3; 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide " herein):
By R and S-MTPA ester and the contrast chemical shift of proton difference of preparation on secondary alcohol, compd B has been characterized as being " R " isomer.Referring to for example Dale, J.A.; Mosher, H.S., J.Am.Chem.Soc., 1973,95,512 and Ohtani etc., J.Am.Chem.Soc., 1991,113,4092.
The invention still further relates to the crystalline polymorph A of N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide:
It demonstrates specific differential scanning calorimetric figure.In some embodiments, the differential scanning calorimetric figure shown in described differential scanning calorimetric figure and Fig. 6 is basic identical.
The invention still further relates to pharmaceutical composition, it comprises the N-(S)-(3 of effective dose, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-crystalline polymorph A and pharmaceutically acceptable carrier or the carrier of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.
In some embodiments, the crystalline polymorph A of N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is used to treatment or pre-anti-cancer or inflammatory disease.The invention further relates to the method for the treatment of or pre-anti-cancer or inflammatory disease, it comprises the N-(S)-(3 to experimenter's effective dosage that these needs are arranged, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the crystalline polymorph A of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.
In other respects, the present invention relates to comprise the formula I compound of effective dose or the pharmaceutical composition of the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition also comprises pharmaceutically acceptable carrier.Reagent, filler, adhesive, adsorbent, buffer, disintegrant, solubilizer, other carriers that such composition can comprise assistant agent, excipient and preservative, be used for postponing absorption, and other inert fractions.The compound method of such composition is well known in the art.
In other respects, the present invention relates to comprise the pharmaceutical composition of formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition is for being fit to the form of oral administration.Further or in other the embodiment, described pharmaceutical composition is the form of tablet, capsule, pill, powder, sustained release preparation, solution, supensoid agent, be sterile solution agent, supensoid agent or emulsion for parenteral injection, being ointment or emulsifiable paste for topical, is suppository for rectally perhaps.Further or in other the embodiment, described pharmaceutical composition is the unit dosage forms that is suitable for accurate dosage single-dose.Further or the amount of other embodiment Chinese style I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or the amount of other embodiment Chinese style I compound in the scope of about 0.5 to about 50mg/kg/ day.Further or the amount of other embodiment Chinese style I compound be about 0.001 to about 7g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.002 to about 6g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.005 to about 5g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.01 to about 5g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.02 to about 5g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.05 to about 2.5g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.1 to about 1g/ day.
Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be essential.Further or in other the embodiment with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment every day twice Medicine-feeding type I compound.Further or in other the embodiment every day three Medicine-feeding type I compound.Compound at four times a day Medicine-feeding type I further or in other the embodiment.Every day further or in other the embodiment more than the compound of four Medicine-feeding type I.
In some embodiments, described pharmaceutical composition is used for to the mammal administration.Further or in other the embodiment, described mammal is human.
Further or in other the embodiment, described pharmaceutical composition also comprises pharmaceutical carrier, excipient and/or assistant agent.Further or in other the embodiment, described pharmaceutical composition also comprises at least a therapeutic agent.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin (epidophyllotoxins); Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is taxol, bortezomib or the two.Further or in other the embodiment, the described pharmaceutical composition of administration is with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, described pharmaceutical composition comprises the acceptable salt of pharmacy of formula I compound.
Provide herein to comprise and be selected from
Compound compositions and use comprise and be selected from
![Figure GPA00001070418800092](https://patentimages.storage.googleapis.com/46/97/ff/49bbca5fef79bf/GPA00001070418800092.png)
The method of compound compositions.In some embodiments, the 2-OH carbon on the described compound is in the R configuration.In some embodiments, the 2-OH carbon on the described compound is in the S configuration.In some embodiments, the S-isomer of the essentially no described compound of described composition.In some embodiments, the R-isomer of the essentially no described compound of described composition.In some embodiments, described compound comprises the S-isomer that is less than 10% described compound.In some embodiments, described compound comprises the R-isomer that is less than 10% described compound.In some embodiments, described compound comprises the S-isomer that is less than 5% described compound.In some embodiments, described compound comprises the R-isomer that is less than 5% described compound.In some embodiments, described compound comprises the S-isomer that is less than 1% described compound.In some embodiments, described compound comprises the R-isomer that is less than 1% described compound.
Also provide herein and comprise the compound that about 1-100mg has following structure:
Composition and with comprising the compound that about 1-100mg has following structure:
The combination treatment cancer or the method for inflammation.In some embodiments, described composition allows to improve the described compound of release.In some embodiments, described composition allows to continue to discharge described compound.In some embodiments, described composition allows to postpone to discharge described compound.In some embodiments, described compound exists with the amount of about 1-50mg.In some embodiments, described compound exists with the amount of about 1-10mg.In some embodiments, described compound exists with the amount of about 10-20mg.In some embodiments, described compound exists with the amount of about 20-40mg.In some embodiments, described compound exists with the amount of about 40-50mg.
Also provide herein and comprise the compound that about 1-50mg has following structure:
Composition and with comprising the compound that about 1-50mg has following structure:
The combination treatment cancer or the method for inflammation, wherein said composition allows to improve and discharges described medicine.In some embodiments, described composition also comprises microcrystalline cellulose.In some embodiments, described composition also comprises cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises lauryl sodium sulfate.In some embodiments, described composition also comprises dolomol.
Also provide herein and comprise the compound that about 1mg has following structure:
Composition.In some embodiments, described composition also comprises about 222.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.
Also provide herein and comprise the compound that about 10mg has following structure:
Composition and with comprising the compound that about 10mg has following structure:
The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 213.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.
Also provide herein and comprise the compound that about 20mg has following structure:
Composition and with comprising the compound that about 20mg has following structure:
The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 203.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.
Also provide herein and comprise the compound that about 40mg has following structure:
Composition and with comprising the compound that about 40mg has following structure:
The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 183.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.
The compound with following structure that comprises about 0.4 weight % also is provided herein:
With the composition of about 99.6 weight % pharmaceutically acceptable carriers or carrier and with the compound with following structure that comprises about 0.4 weight %:
With about 99.6 weight % pharmaceutically acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for the about 92.6 weight % of described composition.In some embodiments, described composition also comprises about 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 1 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 1 weight % dolomol.
The compound with following structure that comprises about 4.2 weight % also is provided herein:
With the composition of about 95.8 weight % pharmaceutically acceptable carriers or carrier and with the compound with following structure that comprises about 4.2 weight %:
With about 95.8 weight % pharmaceutically acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for the about 88.8 weight % of described composition.In some embodiments, described composition also comprises about 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 1 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 1 weight % dolomol.
Also provide herein and comprise the extremely compound with following structure of about 10 weight % of about 2 weight %:
With about 98 weight % to the composition of about 90 weight % pharmaceutically acceptable carriers or carrier and with comprising the extremely compound with following structure of about 10 weight % of about 2 weight %:
With about 98 weight % to about 90 weight % pharmaceutically acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier also comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.In some embodiments, described composition also comprises about 1 weight % to about 6 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 0.1 weight % to about 2 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 0.25 weight % to about 1.5 weight % dolomols.
Also provide herein and comprise the compound that about 1mg has following structure:
Composition and with comprising the compound that about 1mg has following structure:
The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 222.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.
Also provide herein and comprise the compound that about 10mg has following structure:
Composition and with comprising the compound that about 10mg has following structure:
The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 213.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.
Also provide herein and comprise the compound that about 20mg has following structure:
Composition and with comprising the compound that about 20mg has following structure:
The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 203.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.
Also provide herein and comprise the compound that about 40mg has following structure:
Composition and with comprising the compound that about 40mg has following structure:
The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 183.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.
The compound with following structure that comprises about 0.4 weight % also is provided herein:
With the composition of about 99.6 weight % pharmaceutical acceptable carriers or carrier and with the compound with following structure that comprises about 0.4 weight %
With about 99.6 weight % pharmaceutical acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for the about 92.6 weight % of described composition.In some embodiments, described composition also comprises about 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 1 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 1 weight % dolomol.
The compound with following structure that comprises about 4.2 weight % also is provided herein:
With the composition of about 95.8 weight % pharmaceutical acceptable carriers or carrier and with the compound with following structure that comprises about 4.2 weight %:
With about 95.8 weight % pharmaceutical acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for the about 88.8 weight % of described composition.In some embodiments, described composition also comprises about 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 1 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 1 weight % dolomol.
Also provide herein and comprise the extremely compound with following structure of about 10 weight % of about 2 weight %:
With about 98 weight % to the composition of about 90 weight % pharmaceutical acceptable carriers or carrier and with comprising the extremely compound with following structure of about 10 weight % of about 2 weight %:
With about 98 weight % to about 90 weight % pharmaceutical acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for the about 85 weight % of described composition to about 95 weight %.In some embodiments, described composition also comprises about 1 weight % to cross-linked carboxymethyl cellulose sodium of about 6 weight %.In some embodiments, described composition also comprises about 0.1 weight % to about 2 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 0.25 weight % to about 1.5 weight % dolomols.
N-(-)-(3 also is provided herein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide and comprise this compound compositions, described crystalline polymorph A demonstrate the x-ray diffractogram of powder that comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 50%.In some embodiments, described crystalline polymorph A, wherein said x-ray diffractogram of powder comprise the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point (melting point onset) of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.
N-(-)-(3 also is provided herein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide and comprise this compound compositions, described crystalline polymorph A demonstrates and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, claim 67 or 68 crystalline polymorph, wherein said crystalline polymorph is anhydrous basically.In some embodiments, each crystalline polymorph among the claim 67-69, the essentially no solvent of wherein said crystalline polymorph.
N-(3 also is provided herein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) polymorph of cyclopropane-1-sulfonamide and comprise this compound compositions, described polymorph makes unbodied N-(3 by comprising, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the method preparation of the step of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization.In some embodiments, described crystallisation step comprises crystallization from the mixture of ethyl acetate and heptane.In some embodiments, the ratio of the mixture of described ethyl acetate and heptane is that about 1-4 part ethyl acetate is than about 2-10 part heptane.In some embodiments, the ratio of the mixture of described ethyl acetate and heptane is that about 2 parts of ethyl acetate are than about 5 parts of heptane.
The method that suppresses the MEK enzyme also is provided herein, and it comprises makes described MEK enzyme contact with compound as herein described or composition, and there is the amount of described enzyme inhibition 25% in wherein said compound being enough at least.In some embodiments, described MEK enzyme is the MEK kinases.In some embodiments, described contact occurs in the cell.
The method of illness described in the individuality for the treatment of the illness of suffering from the MEK mediation also is provided herein, and it comprises compound as herein described or composition to described individual effective dosage.In some embodiments, the described mek inhibitor of administration is with other therapy couplings.In some embodiments, described other therapies are radiotherapy, non-MEK kinase inhibition agent therapy, chemotherapy, operation, glucocorticoid, methotrexate (MTX), biological response modifier or their any combination.In some embodiments, the illness of described MEK mediation is selected from inflammatory disease, infection, autoimmune disease, apoplexy, ischemic, cardiac conditions, neurological disorders, fibrillatable illness, proliferative disorders, excess proliferative illness, tumour, leukemia, knurl (neoplasms), cancer, cancer, metabolic disease and malignant diseases.In some embodiments, the illness of described MEK mediation is excess proliferative disease.In some embodiments, the illness of described MEK mediation is cancer, tumour, leukemia, knurl or cancer.In some embodiments, the illness of described MEK mediation is inflammatory disease.In some embodiments, described inflammatory disease is rheumatoid arthritis or multiple sclerosis.
The method of proliferative diseases in treatment or the prevention individuality also is provided herein, and it comprises compound as herein described or composition to described individual effective dosage.In some embodiments, described proliferative diseases is cancer, psoriasis, ISR, disease or atherosclerotic.In some embodiments, described proliferative diseases is cancer.In some embodiments, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer, leukemia, myeloid leukemia, glioblastoma, folliculus type lymphoma (follicular lymphoma), preceding B acute leukemia, chronic lymphocytic B leukemia, cancer of the stomach, celiothelioma or small-cell carcinoma of the lung.In some embodiments, described method also comprises at least a therapeutic agent of administration.In some embodiments, this step comprises and uses at least a other cancer therapies.In some embodiments, described other therapies are radiotherapy, non-MEK kinase inhibition agent therapy, chemotherapy, operation, glucocorticoid, methotrexate (MTX), biological response modifier or their any combination.
The method of inflammatory disease in treatment or the prevention individuality also is provided herein, and it comprises to comprising of described individual effective dosage of compound compositions described herein.In some embodiments, described inflammatory disease is rheumatoid arthritis or multiple sclerosis.
The method that makes cancer cell degenerate, suppress growth of cancer cells or kill cancer cell also is provided herein, and it comprises makes described cell contact with the compound as herein described or the composition that make cancer cell degenerate, suppress the amount of growth of cancer cells or kill cancer cell effectively.In some embodiments, described cancer cell comprises brain cancer cell, breast cancer cell, lung carcinoma cell, ovarian cancer cell, pancreatic cancer cell, prostate gland cancer cell, kidney cancer cell, stomach cancer cell or colorectal cancer cell.
Also be provided at herein in the individuality and suppress the method that the tumour size increases, reduces the tumour size, reduces tumor proliferation or prevention tumor proliferation, it comprises to the compound as herein described of described individual effective dosage or composition and increases, reduces the tumour size to suppress the tumour size, reduces tumor proliferation or prevention tumor proliferation.In some embodiments, described tumour comes across in brain, mammary gland, lung, ovary, pancreas, prostate, kidney, stomach, colon or the rectum.
The method for the treatment of or prevention ankylosing spondylitis, gout, myotenositis, bursal synovitis or sciatica also is provided herein, and it comprises formula (I) compound or pharmaceutically acceptable salt thereof to experimenter's effective dosage that these needs are arranged:
Wherein:
Z is H or F;
X is F, Cl, CH
3, CH
2OH, CH
2F, CHF
2Or CF
3
Y is I, Br, Cl, CF
3, C
1-C
3Alkyl, C
2-C
3Thiazolinyl, C
2-C
3Alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, wherein Het is 5 to 10 yuan of monocyclic heterocycles groups or bicyclic heterocyclic groups that comprise 1-5 the ring hetero atom that is independently selected from N, O and S, described heterocyclic group be saturated, olefinic or aromatics; Wherein
Whole described phenyl or Het group are randomly by F, Cl, Br, I, acetyl group, methyl, CN, NO
2, CO
2H, C
1-C
3Alkyl, C
1-C
3Alkoxyl, C
1-C
3Alkyl-C (=O)-, C
1-C
3Alkyl-C (=S)-, C
1-C
3Alkoxy-C (=S)-, C
1-C
3Alkyl-C (=O) O-, C
1-C
3Alkyl-O-(C=O)-, C
1-C
3Alkyl-C (=O) NH-, C
1-C
3Alkyl-C (=NH) NH-, C
1-C
3Alkyl-NH-(C=O)-, two-C
1-C
3Alkyl-N-(C=O)-, C
1-C
3Alkyl-C (=O) N (C
1-C
3Alkyl)-, C
1-C
3Alkyl-S (=O)
2NH-or trifluoromethyl replace;
Whole described methyl, ethyl, C
1-C
3Alkyl and cyclopropyl group are randomly replaced by OH;
Whole described methyl groups are randomly by 1,2 or 3 F atoms replacements;
R
0Be H, F, Cl, Br, I, CH
3NH-, (CH
3)
2N-, C
1-C
6Alkyl, C
1-C
4Alkoxyl, C
3-C
6Cycloalkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, phenyl, monosubstituted phenyl, O (C
1-C
4Alkyl), O-C (=O) (C
1-C
4Alkyl) or C (=O) O (C
1-C
4Alkyl); Wherein
1-3 the substituting group that described alkyl, alkoxyl, cycloalkyl, thiazolinyl, alkynyl and phenyl group randomly are independently selected from F, Cl, Br, I, OH, CN, cyanogen methyl, nitro, phenyl and trifluoromethyl replaces;
Described C
1-C
6Alkyl and C
1-C
4Alkoxy base is also randomly by OCH
3Or OCH
2CH
3Replace;
G is G
1, G
2, R
1a, R
1b, R
1c, R
1d, R
1e, Ar
1, Ar
2Or Ar
3Wherein
G
1Be randomly by an amino, C
1-C
3The C that alkyl amino or dialkyl amino group replace
1-C
6Alkyl, described dialkyl amino group comprise 2 can be identical or different C
1-C
4Alkyl group; Perhaps
G
1Be C
3-C
8The Diaminoalkyl group;
G
2Be 5 yuan of rings or the 6 yuan of rings that comprise saturated, the undersaturated or aromatics of 1-3 the ring hetero atom that is independently selected from N, O and S, it randomly is independently selected from F, Cl, OH, O (C
1-C
3Alkyl), OCH
3, OCH
2CH
3, CH
3C (=O) NH, CH
3C (=O) O, CN, CF
3Replace with 1-3 substituting group of 5 yuan of aromatic heterocyclic groups that comprise 1-4 the ring hetero atom that is independently selected from N, O and S;
R
1aBe methyl, it is randomly by 1-3 fluorine atom or 1-3 chlorine atom, perhaps OH, ring propoxyl group or C
1-C
3Alkoxyl replaces, wherein said ring propoxyl group group or described C
1-C
3The C of alkoxy base
1-C
3Moieties is randomly replaced by a hydroxyl or methoxy group, and described C
1-C
4All C in the alkoxyl
3-alkyl group is all randomly further replaced by another OH group;
R
1bBe CH (CH
3)-C
1-3Alkyl or C
3-C
6Cycloalkyl, described alkyl and group of naphthene base randomly are independently selected from F, Cl, Br, I, OH, OCH
3Replace with 1-3 the substituting group of CN;
R
1cBe (CH
2)
nO
mR '; Wherein
M is 0 or 1; And wherein
When m was 0, n was 1 or 2;
When m was 1, n was 2 or 3;
R ' is C
1-C
6Alkyl, it randomly is independently selected from F, Cl, OH, OCH
3, OCH
2CH
3And C
3-C
6The 1-3 of cycloalkyl substituting group replaces;
R
1dBe C (A) (A ') (B)-; Wherein
B is H or C
1-4Alkyl, it is randomly replaced by one or two OH group;
A and A ' are H or C independently
1-4Alkyl, it is randomly replaced by one or two OH group; Perhaps
The carbon atom that A and A ' are attached thereto with them forms 3-6 unit saturated rings;
R
1eBe
Wherein
Q is 1 or 2;
R
2And R
3Be H, F, Cl, Br, CH independently of one another
3, CH
2F, CHF
2, CF
3OCH
3, OCH
2F, OCHF
2, OCF
3, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group or mesyl;
R
4Be H, F, Cl, Br, CH
3, CH
2F, CHF
2, CF
3OCH
3, OCH
2F, OCHF
2, OCF
3, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, mesyl, nitro, acetylamino, amidino groups, cyano group, carbamyl, methyl carbamyl, dimethylamino formoxyl, 1,3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3,4-oxadiazole, 1,3,4-thiadiazoles, 5-methyl isophthalic acid, 3,4-thiadiazoles, 1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl and N-pyrrolidinyl carbonylamino;
R
5Be H, F, Cl or methyl;
R
6Be H, F, Cl or methyl;
Ar
1Be
Wherein
U and V are N, CR independently
2Or CR
3
R
2, R
3And R
4Be H, F, Cl, Br, CH independently
3, CH
2F, CHF
2, CF
3OCH
3, OCH
2F, OCHF
2, OCF
3, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, acetylamino, amidino groups, cyano group, carbamyl, methyl carbamyl, dimethylamino formoxyl, 1,3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3,4-oxadiazole base, 1,3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3,4-thiadiazolyl group, 1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl, N-pyrrolidinyl carbonylamino and mesyl;
R
5And R
6Be H, F, Cl or methyl independently;
Ar
2Be
Wherein
Dotted line represents the optional pro forma position of second two key of ring;
U is-S-,-O-or-N=, and wherein
When U be-O-or-during S-, V is-CH=,-CCl=or-N=;
When U be-during N=, V is-CH=,-CCl=, or-N=;
R
7Be H or methyl;
R
8Be H, acetylamino, methyl, F or Cl;
Ar
3Be
Wherein
U is-NH-,-NCH
3-or-O-;
R
7And R
8Be H, F, Cl or methyl independently.
In some embodiments, described compound is selected from:
In some embodiments, described compound is selected from
Wherein 2-OH carbon is in the R configuration.In some embodiments, the compound or pharmaceutically acceptable salt thereof of described formula (I) is selected from
With
Wherein 2-OH carbon is in the S configuration.In some embodiments, described compound is
In some embodiments, described compound is
Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment cancer of the stomach.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment leukemia melanoma (leukemiam melanoma) or hepatoma.
Method by compound as herein described or the combination treatment non-small cell lung cancer of drug treatment effective dose also is provided herein.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment colon cancer.Compound as herein described or combination treatment CNS method for cancer by the drug treatment effective dose also are provided herein.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment oophoroma.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment kidney.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment prostate cancer.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment breast cancer.In various embodiments, these methods also comprise at least a other treatment agent of administration.In some embodiments, use at least a other cancer therapies.In some embodiments, described other cancer therapies are radiotherapy, chemotherapy, operation or their any combination.
Also provide herein by with compound as herein described or the combination treatment of topical formulations drug treatment effective dose or prevent psoriatic method.
In various embodiments, the described composition of oral administration.In some embodiments, once a day or the described composition of twice administration every day.In some embodiments, the described composition of administration once a day continues at least one week.
In some embodiments, when the described composition of oral administration, at the T that behind the described composition of fasted subjects administration, reaches described compound between 1 hour to 3 hours
MaxIn some embodiments, when to experimenter's administration, reach C at the 1st day described compound
MaxAbout 0.01 μ g/ml is to about 1.0 μ g/ml.In some embodiments, when to experimenter's administration, reach C at the 1st day described compound
MaxAbout 0.01 μ g/ml is to about 0.8 μ g/ml.In some embodiments, when to experimenter's administration, reach C at the 1st day described compound
MaxAbout 0.03 μ g/ml is to about 0.5 μ g/ml.In some embodiments, the AUC of described compound is that about 0.1 μ g hr/mL is to about 5.0 μ g hr/mL between 0-12 hour.In some embodiments, the AUC of described compound is that about 0.1 μ g hr/mL is to about 4.0 μ g hr/mL.In some embodiments, the AUC of described compound is that about 0.5 μ g hr/mL is to about 3.0 μ g hr/mL.In some embodiments, the T of described compound
MaxBetween 0.5 to 5.0 hour.In some embodiments, the T of described compound
MaxBetween 1.0 to 3.0 hours.In some embodiments, the T of described compound
MaxBetween 1.0 to 2.5 hours.In some embodiments, the plasma concentration at single-dose described compound after 5 hours is higher than about 0.01mg/mL.In some embodiments, the plasma concentration at single-dose described compound after 10 hours is higher than about 0.01mg/mL.In some embodiments, the plasma concentration at single-dose described compound after 15 hours is higher than about 0.01mg/mL.
In some embodiments, when to one group of 10 experimenter's administration, reach average C at the 1st day described compound
MaxAbout 0.01 μ g/ml is to about 1.0 μ g/ml.In some embodiments, when to one group of 10 experimenter's administration, reach average C at the 1st day described compound
MaxAbout 0.01 μ g/ml is to about 0.8 μ g/ml.In some embodiments, when to one group of 10 experimenter's administration, reach average C at the 1st day described compound
MaxAbout 0.03 μ g/ml is to about 0.5 μ g/ml.In some embodiments, the average A UC of described compound is that about 0.1 μ g hr/mL is to about 5.0 μ g hr/mL.In some embodiments, the average A UC of described compound is that about 0.1 μ g hr/mL is to about 4.0 μ g hr/mL.In some embodiments, the average A UC of described compound is that about 0.5 μ g hr/mL is to about 3.0 μ g hr/mL.In some embodiments, the average T of described compound
MaxBetween 0.5 to 5.0 hour.In some embodiments, the average T of described compound
MaxBetween 1.0 to 3.0 hours.In some embodiments, the average T of described compound
MaxBetween 1.0 to 2.5 hours.
The method that reduces gross tumor volume by administration compound as herein described and composition also is provided herein.In some embodiments, after 5 days, described gross tumor volume reduces at least about 25% at the described medicine of administration every day.In some embodiments, after 5 days, described gross tumor volume reduces at least about 50% at the described medicine of administration every day.In some embodiments, after 5 days, described gross tumor volume reduces at least about 20-70% at the described medicine of administration every day.In some embodiments, after 15 days, described gross tumor volume reduces at least about 25% at the described medicine of administration every day.In some embodiments, after 15 days, described gross tumor volume reduces at least about 50% at the described medicine of administration every day.In some embodiments, after 15 days, described gross tumor volume reduces at least about 20-70% at the described medicine of administration every day.In some embodiments, after 30 days, described gross tumor volume reduces at least about 25% at the described medicine of administration every day.In some embodiments, after 30 days, described gross tumor volume reduces at least about 50% at the described medicine of administration every day.In some embodiments, after 30 days, described gross tumor volume reduces at least about 20-70% at the described medicine of administration every day.
The method that suppresses tumor growth by administration compound as herein described and composition also is provided herein.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed at least about 20%.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed at least about 40%.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed at least about 60%.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed at least about 80%.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed about 20% to about 100%.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed substantially.
In some embodiments, the described composition of twice administration every day.In some embodiments, the described composition of administration once a day.
In some embodiments, described mek inhibitor does not disturb the administering drug combinations of another kind of tumor inhibitor.
In some embodiments, described composition is the form of tablet, capsule, soft capsule (gel cap), ingot, bolus or particle.In some embodiments, described composition is to have about 50mg to the capsule of about 1000mg gross weight or the form of Tabules.In some embodiments, described composition is the form with capsule or tablet of the gross weight that is selected from 50mg, 75mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg and 500mg.In some embodiments, described composition is the form with capsule or tablet of about 240mg gross weight.
In some embodiments, described composition also comprises at least a filler that is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sompressible sugar, xylitol, sorbierite, mannitol, pregelatinized starch, maltodextrin, calcium phosphate, calcium carbonate, starch and calcium silicates.
In some embodiments, described composition also comprises at least a disintegrant that is selected from cross-linked carboxymethyl cellulose sodium, primojel, Crospovidone, methylcellulose, alginic acid, mosanom, starch derivatives, bentonite (betonite) and aluminium-magnesium silicate.
In some embodiments, described composition also comprises at least a dolomol, metallic stearate, talcum, sodium stearyl fumarate and the stearic lubricant of being selected from.
In some embodiments, described composition also comprises at least a wetting agent or the surfactant that is selected from lauryl sodium sulfate, glycerine, sorbitan monooleate, Span60, polyoxyethylene anhydrous sorbitol laurate, palmitate, stearate, oleate or six oleates (hexaolate), the pure and mild sorbitan mono-laurate of polyoxyethylene stearyl.
It is the composition of capsule or tablet that form is provided herein, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged at least 60% described medicine in 30 minutes with 1% lauryl sodium sulfate in the water.In some embodiments, described composition is the form of capsule or tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged the described medicine of about 60-100% in 30 minutes with 1% lauryl sodium sulfate in the water.In some embodiments, described composition is the form of capsule or tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged the described medicine of about 60-90% in 30 minutes with 1% lauryl sodium sulfate in the water.In some embodiments, described composition is the form of capsule or tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged the described medicine of about 60-80% in 30 minutes with 1% lauryl sodium sulfate in the water.
In batch capsule or tablet also are provided herein, and it respectively comprises about 1 to about 50mg compound as herein described, and has and be lower than about 15 content uniformity USP admitted value (acceptance value).
Methods for the treatment of
The present invention relates to treatment or prevention method for cancer, it comprises the pharmaceutical composition that comprises formula as described herein (I) compound to experimenter's effective dosage that needs are arranged.In various embodiments, useful compound and composition are suc as formula the kind of (I) or as described in as an example any subgenus or kind in formula (I) scope that runs through the application in these methods.
The present invention relates to treat or prevent the method for inflammatory disease, it comprises the pharmaceutical composition that comprises formula as described herein (I) compound to experimenter's effective dosage that needs are arranged.In various embodiments, useful compound and composition are suc as formula the kind of (I) or as described in as an example any subgenus or kind in formula (I) scope that runs through the application in these methods.
In some embodiments, the present invention relates to treat or prevent the method for ankylosing spondylitis, gout, myotenositis, bursal synovitis or sciatica, it comprises to the pharmaceutical composition of comprising of the individual effective dosage that these needs are arranged of formula as described herein (I) compound.In various embodiments, useful compound and composition are suc as formula the kind of (I) or as described in as an example any subgenus or kind in formula (I) scope that runs through the application in these methods.
In some respects, the invention still further relates to treatment and suffer from the method for disease in the individuality of described disease, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.
In other respects, the present invention relates to treat the method for illness in the mammal, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.
In other respects, the present invention relates to treat the method for illness among the mankind, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.
In other respects, the present invention relates to treat the method that comprises excess proliferative illness in the human mammal, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.
In other respects, the present invention relates to treat the method that comprises inflammatory disease, the patient's condition or illness in the human mammal, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, ester, prodrug, solvate, hydrate or derivative.
In other respects, the present invention relates to treat and comprise the illness of being regulated by the MEK cascade in the human mammal or the method for the patient's condition, it comprises formula I compound or the acceptable salt of its pharmacy, ester, prodrug, solvate, hydrate or the derivative of regulating the amount of described cascade to described mammal administration effectively.In accordance with known methods, those skilled in the art can determine the suitable dosage of particular patient.
Suppress the MEK enzyme
In other respects, the present invention relates to suppress the method for MEK enzyme.In some embodiments, described method comprises makes described MEK enzyme contact with a certain amount of composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug that is enough to suppress described enzyme, and wherein said enzyme is suppressed.Further or in other the embodiment, described enzyme is suppressed at least about 1%.Further or in other the embodiment, described enzyme is suppressed at least about 2%.Further or in other the embodiment, described enzyme is suppressed at least about 3%.Further or in other the embodiment, described enzyme is suppressed at least about 4%.Further or in other the embodiment, described enzyme is suppressed at least about 5%.Further or in other the embodiment, described enzyme is suppressed at least about 10%.Further or in other the embodiment, described enzyme is suppressed at least about 20%.Further or in other the embodiment, described enzyme is suppressed at least about 25%.Further or in other the embodiment, described enzyme is suppressed at least about 30%.Further or in other the embodiment, described enzyme is suppressed at least about 40%.Further or in other the embodiment, described enzyme is suppressed at least about 50%.Further or in other the embodiment, described enzyme is suppressed at least about 60%.Further or in other the embodiment, described enzyme is suppressed at least about 70%.Further or in other the embodiment, described enzyme is suppressed at least about 75%.Further or in other the embodiment, described enzyme is suppressed at least about 80%.Further or in other the embodiment, described enzyme is suppressed at least about 90%.Further or in other the embodiment, described enzyme is suppressed basically fully.Further or in other the embodiment, described MEK enzyme is the MEK kinases.Further or in other the embodiment, described MEK enzyme is MEK1.Further or in other the embodiment, described MEK enzyme is MEK2.Further or in other the embodiment, described contact occurs in the cell.Further or in other the embodiment, described cell is mammalian cell.Further or in other the embodiment, described mammalian cell is the human cell.Further or in other the embodiment, suppress described MEK enzyme with the composition of the pharmaceutically acceptable salt that comprises formula I compound.
The illness of MEK mediation
In other respects, the present invention relates to treat the method for illness described in the individuality of the illness of suffering from MEK mediation, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or rectally comprise the described composition of formula I compound.In some embodiments, described pharmaceutical composition is the form that is suitable for oral administration.Further or in other the embodiment, described pharmaceutical composition is the form of tablet, capsule, pill, powder, sustained release preparation, solution, supensoid agent, be sterile solution agent, supensoid agent or emulsion for parenteral injection, being ointment or emulsifiable paste for topical, is suppository for rectally perhaps.Further or in other the embodiment, described pharmaceutical composition is the unit dosage forms that is suitable for accurate dosage single-dose.Further or in other the embodiment, described pharmaceutical composition also comprises pharmaceutical carriers, excipient and/or assistant agent.
Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality of suffering from the illness of MEK mediation is mammal.Further or in other the embodiment, described individuality is human.
In some embodiments, administration comprises the described composition of formula I compound, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.
In some embodiments, the illness of described MEK mediation is selected from inflammatory disease, infection, autoimmune disease, apoplexy, ischemic, cardiac conditions, neurological disorders, fibrillatable illness, proliferative disorders, excess proliferative illness, non-cancer excess proliferative illness, tumour, leukemia, knurl, cancer, cancer, metabolic disease, malignant diseases, reangiostenosis, psoriasis, atherosclerotic, rheumatoid arthritis, osteoarthritis, heart failure, chronic ache, neuropathic pain, dry eyes, angle-closure glaucoma and open-angle glaucoma.Further or in other the embodiment, the illness of described MEK mediation is inflammatory disease.Further or in other the embodiment, the illness of described MEK mediation is excess proliferative disease.Further or in other the embodiment, the illness of described MEK mediation is selected from tumour, leukemia, knurl, cancer, cancer and malignant diseases.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, cancer of the stomach, kidney, colorectal cancer or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
Obtain effect
In other respects, the present invention relates in the patient, obtain the method for effect, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to patient's effective dosage, and wherein said effect is selected from the inhibition to various cancers, immunological disease and inflammatory disease.In some embodiments, described effect is to suppress various cancers.Further or in other the embodiment, described effect is to suppress immunological disease.Further or in other the embodiment, described effect is to suppress inflammatory disease.
In some embodiments, administration comprises the described composition of formula I compound, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.
In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality of suffering from cancer is mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
In other respects, the present invention relates to make cancer cell to degenerate, suppress the method for growth of cancer cells or kill cancer cell, it comprises that the composition that makes described cell and make described cell degradation effectively, suppress described cell growth or kill the amount of described cell contacts, and described composition comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.In some embodiments, described cancer cell comprises brain cancer cell, breast cancer cell, lung carcinoma cell, ovarian cancer cell, pancreatic cancer cell, prostate gland cancer cell, kidney cancer cell or colorectal cancer cell.Further or in other the embodiment, described composition and at least a therapeutic agent administering drug combinations.Further or in other the embodiment, described therapeutic agent is taxol, bortezomib or the two.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.In some embodiments, described cancer cell is degenerated.Further or in other the embodiment, 1% described cancer cell is degenerated.Further or in other the embodiment, 2% described cancer cell is degenerated.Further or in other the embodiment, 3% described cancer cell is degenerated.Further or in other the embodiment, 4% described cancer cell is degenerated.Further or in other the embodiment, 5% described cancer cell is degenerated.Further or in other the embodiment, 10% described cancer cell is degenerated.Further or in other the embodiment, 20% described cancer cell is degenerated.Further or in other the embodiment, 25% described cancer cell is degenerated.Further or in other the embodiment, 30% described cancer cell is degenerated.Further or in other the embodiment, 40% described cancer cell is degenerated.Further or in other the embodiment, 50% described cancer cell is degenerated.Further or in other the embodiment, 60% described cancer cell is degenerated.Further or in other the embodiment, 70% described cancer cell is degenerated.Further or in other the embodiment, 75% described cancer cell is degenerated.Further or in other the embodiment, 80% described cancer cell is degenerated.Further or in other the embodiment, 90% described cancer cell is degenerated.Further or in other the embodiment, 100% described cancer cell is degenerated.Further or in other the embodiment, whole described cancer cells are degenerated.In various embodiments, above-mentioned degeneration occurs in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.
In some embodiments, described cancer cell is killed.Further or in other the embodiment, 1% described cancer cell is killed.Further or in other the embodiment, 2% described cancer cell is killed.Further or in other the embodiment, 3% described cancer cell is killed.Further or in other the embodiment, 4% described cancer cell is killed.Further or in other the embodiment, 5% described cancer cell is killed.Further or in other the embodiment, 10% described cancer cell is killed.Further or in other the embodiment, 20% described cancer cell is killed.Further or in other the embodiment, 25% described cancer cell is killed.Further or in other the embodiment, 30% described cancer cell is killed.Further or in other the embodiment, 40% described cancer cell is killed.Further or in other the embodiment, 50% described cancer cell is killed.Further or in other the embodiment, 60% described cancer cell is killed.Further or in other the embodiment, 70% described cancer cell is killed.Further or in other the embodiment, 75% described cancer cell is killed.Further or in other the embodiment, 80% described cancer cell is killed.Further or in other the embodiment, 90% described cancer cell is killed.Further or in other the embodiment, 100% described cancer cell is killed.Further or in other the embodiment, whole described cancer cells all are killed basically.In various embodiments, above-mentioned kill cancer cell occurs in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.
Further or in other the embodiment, the growth of described cancer cell is suppressed.Further or in other the embodiment, the growth of described cancer cell is suppressed about 1%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 2%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 3%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 4%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 5%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 10%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 20%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 25%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 30%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 40%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 50%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 60%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 70%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 75%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 80%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 90%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 100%.In various embodiments, above-mentioned inhibition occurs in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.
In other respects, the present invention relates to reduce the tumour size in individuality, suppress the method that the tumour size increases, reduces tumor proliferation or prevention tumor proliferation, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.In some embodiments, the size of tumour is reduced.Further or in other the embodiment, the size of tumour is reduced at least 1%.Further or in other the embodiment, the size of tumour is reduced at least 2%.Further or in other the embodiment, the size of tumour is reduced at least 3%.Further or in other the embodiment, the size of tumour is reduced at least 4%.Further or in other the embodiment, the size of tumour is reduced at least 5%.Further or in other the embodiment, the size of tumour is reduced at least 10%.Further or in other the embodiment, the size of tumour is reduced at least 20%.Further or in other the embodiment, the size of tumour is reduced at least 25%.Further or in other the embodiment, the size of tumour is reduced at least 30%.Further or in other the embodiment, the size of tumour is reduced at least 40%.Further or in other the embodiment, the size of tumour is reduced at least 50%.Further or in other the embodiment, the size of tumour is reduced at least 60%.Further or in other the embodiment, the size of tumour is reduced at least 70%.Further or in other the embodiment, the size of tumour is reduced at least 75%.Further or in other the embodiment, the size of tumour is reduced at least 80%.Further or in other the embodiment, the size of tumour is reduced at least 85%.Further or in other the embodiment, the size of tumour is reduced at least 90%.Further or in other the embodiment, the size of tumour is reduced at least 95%.Further or in other the embodiment, described tumour is uprooted.In some embodiments, the size of tumour does not increase.In various embodiments, the above-mentioned effect of tumour size is occurred in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.
In some embodiments, tumor proliferation is reduced.In some embodiments, tumor proliferation is reduced at least 1%.In some embodiments, tumor proliferation is reduced at least 2%.In some embodiments, tumor proliferation is reduced at least 3%.In some embodiments, tumor proliferation is reduced at least 4%.In some embodiments, tumor proliferation is reduced at least 5%.In some embodiments, tumor proliferation is reduced at least 10%.In some embodiments, tumor proliferation is reduced at least 20%.In some embodiments, tumor proliferation is reduced at least 25%.In some embodiments, tumor proliferation is reduced at least 30%.In some embodiments, tumor proliferation is reduced at least 40%.In some embodiments, tumor proliferation is reduced at least 50%.In some embodiments, tumor proliferation is reduced at least 60%.In some embodiments, tumor proliferation is reduced at least 70%.In some embodiments, tumor proliferation is reduced at least 75%.In some embodiments, tumor proliferation is reduced at least 75%.In some embodiments, tumor proliferation is reduced at least 80%.In some embodiments, tumor proliferation is reduced at least 90%.In some embodiments, tumor proliferation is reduced at least 95%.In some embodiments, tumor proliferation is prevented from.In various embodiments, the above-mentioned effect of on cell proliferation occurs in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.
In some embodiments, administration comprises the described composition of formula I compound, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological respinse trim and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.
In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from cancer is mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
Proliferative diseases
In other respects, the present invention relates to increase in treatment or the prevention individuality
GrowThe method of property disease, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.In some embodiments, described increasing
GrowThe property disease is cancer, psoriasis, ISR, autoimmune disease or atherosclerotic.Further or in other the embodiment, described increasing
GrowThe property disease is excess proliferative disease.Further or in other the embodiment, described increasing
GrowThe property disease is selected from tumour, leukemia, knurl, cancer, cancer and malignant diseases.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer, cancer of the stomach, head and neck cancer or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, described cancer is cancer of the stomach, the cancer of the brain, breast cancer, lung cancer, non-small cell lung cancer, oophoroma, cancer of pancreas, liver cancer, prostate cancer, kidney, colorectal cancer or leukemia.Further or in other the embodiment, described cancer is the cancer of the brain or adrenocortical carcinoma.Further or in other the embodiment, described cancer is breast cancer.Further or in other the embodiment, described cancer is oophoroma.Further or in other the embodiment, described cancer is cancer of pancreas.Further or in other the embodiment, described cancer is prostate cancer.Further or in other the embodiment, described cancer is kidney.Further or in other the embodiment, described cancer is colorectal cancer.Further or in other the embodiment, described cancer is myeloid leukemia.Further or in other the embodiment, described cancer is glioblastoma.Further or in other the embodiment, described cancer is folliculus type lymphoma.Further or in other the embodiment, described cancer is preceding B acute leukemia.Further or in other the embodiment, described cancer is chronic lymphocytic B leukemia.Further or in other the embodiment, described cancer is celiothelioma.Further or in other the embodiment, described cancer is small-cell carcinoma of the lung.In other embodiments, described cancer is cancer of the stomach.
In some embodiments, administration comprises the described combination of formula I compound, thing and other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological respinse trim and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.
Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.
Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from proliferative diseases is mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
Inflammatory disease
In other respects, the present invention relates to treat or prevent the method for inflammatory disease in the individuality, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.Further or in other the embodiment, described inflammatory disease is selected from chronic inflammatory disease, rheumatoid arthritis, rheumatoid arthritis, spondyloarthropathy, urarthritis, osteoarthritis, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, pyogenic arthritis, atherosclerotic, systemic loupus erythematosus, inflammatory bowel disease, IBS, ulcerative colitis, reflux esophagitis, Crohn's disease, gastritis, asthma, anaphylaxis, Respiratory Distress Syndrome(RDS), pancreatitis, COPD, pulmonary fibrosis, psoriasis, eczema or chorionitis.
In some embodiments, administration comprises formula I compound compositions, with other therapy couplings.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.
In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from inflammatory disease is mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
Cancer
In other respects, the present invention relates to method for cancer in treatment or the prevention individuality, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, cancer of the stomach, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, cancer of the stomach, colorectal cancer or leukemia.Further or in other the embodiment, described cancer is the cancer of the brain or adrenocortical carcinoma.Further or in other the embodiment, described cancer is breast cancer.Further or in other the embodiment, described cancer is oophoroma.Further or in other the embodiment, described cancer is cancer of pancreas.Further or in other the embodiment, described cancer is prostate cancer.Further or in other the embodiment, described cancer is kidney.Further or in other the embodiment, described cancer is colorectal cancer.Further or in other the embodiment, described cancer is myeloid leukemia.Further or in other the embodiment, described cancer is glioblastoma.Further or in other the embodiment, described cancer is folliculus type lymphoma.Further or in other the embodiment, described cancer is preceding B acute leukemia.Further or in other the embodiment, described cancer is chronic lymphocytic B leukemia.Further or in other the embodiment, described cancer is celiothelioma.Further or in other the embodiment, described cancer is small-cell carcinoma of the lung.In some embodiments, described cancer is cancer of the stomach.
In some embodiments, administration comprises the described composition of formula I compound, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.
In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.
Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from cancer is mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
Quote adding
Whole publications and the patent application mentioned are in this manual quoted adding herein, and its degree is equal to each publication or patent application and specifically and individually is indicated as being and quotes adding.
The accompanying drawing summary
In additional claim in detail, novel feature of the present invention has been described in detail.Following detailed description and accompanying drawing thereof with reference to illustrating the exemplary of using the principle of the invention will be better appreciated by feature of the present invention and advantage.
Fig. 1 represents: have in the mouse of A375 melanoma, Colo205 colon tumor, A431 epiderm-like tumour or HT-29 colon tumor cell in implantation, mean tumour volume is to the chart of time (fate).To mouse oral administration (25mg/kg, 50mg/kg or 100mg/kg) once a day, continue 14 days.
Fig. 2 represents: in the A375 heterograft mouse of administration 50mg/kg QD, 25mg/kg BID, 50mg/kg QD and 12.5mg/kg BID, the % tumor growth suppresses (%TGI) chart.
Fig. 3 represents: the chart that plasma concentration (log nM) suppresses pERK% is arranged in the female nu/nu mouse of Colo205 tumour cell in implantation.To mouse administration 2.5,5,10 or the single dose of 25mg/kg.
Fig. 4 represents: among the mankind behind single dose administration 2mg (2x 1mg capsule), 4mg (4x1mg capsule) or 6mg (6x1mg capsule), plasma concentration (ng/mL) to the time (hour) chart.
Fig. 5 is to use powder x-ray diffraction (PXRD) figure of N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide A type of Inel XRG-3000 diffractometer generation.Use by the peak intensity of per second counting definition the angle of diffraction 2 θ (degree) are mapped.
The N-(S)-(3 that Fig. 6 is to use TA instrument differential scanning calorimetry (DSC) Q1000 to produce, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-modulation differential scanning calorimetry (DSC) thermal analysis curue of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide A type.Be the sample temperature ℃ mapping of normalized heat flow to recording of unit in order to watt/gram (W/g).
Fig. 7 is: the N-(S)-(3 that uses Inel XRG-3000 diffractometer to produce, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) PXRD of cyclopropane-1-sulfonamide A type figure (top) and N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-PXRD of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide amorphous substance figure (bottom).Use by the peak intensity of per second counting definition the angle of diffraction 2 θ (degree) are mapped.
Fig. 8 represents: the N-(S)-(3 that uses VTI SGA-100 steam adsorption analysis instrument to produce, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-dynamic steam absorption/desorption (DVS) isotherm of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide A type.
Fig. 9 represents: DTG (TG) thermal analysis curue that uses N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A) type of TA instrument 2950 thermogravimeters generation.
Figure 10 (a) and Figure 10 (b) expression: with the N-(S)-(3 of concentration increase, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-growth retardation of the A375 cell that the logarithmic phase of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide contact is dividing.Analysis of cells is measured ATP content.Use 1 μ M N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide to determine 100% growth retardation.
Figure 11 represents: the 48hr AK in the A375 cell measures.A375 cell and N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide that logarithmic phase is being divided contact 48hr with PD-325901, and analyze AK release.
Figure 12 A-12C represents: N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A) suppresses human colorectal cancer Colo205 cell growth (GI
50=11nM); (B) suppress A375 cell growth (GI
50=22nM), and (C) suppress the MDA-MB231 cell, it does not demonstrate N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) growth retardation that cyclopropane-the 1-sulfonamide causes in two-dimentional anchorage dependence test.
Figure 13 A represents to suppress human colorectal cancer Colo205 cell growth, GI
50Value is respectively 6nM and 11nM.
Figure 13 B represents to suppress the growth of A375 cell, GI
50Value is 5nM and 22nM.
Figure 14 A and Figure 14 B represent: N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) effect of cyclopropane-1-sulfonamide cell cycle process, this explanation makes A375 cell and N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) contact of cyclopropane-1-sulfonamide causes the G1 that is stagnated in the cell cycle in the phase, and it is all reduced by the cell that is in G2 phase and S phase and shows.
Figure 15 A and Figure 15 B represent: N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide to cancer of the stomach (sdenocarcinoma of stomach) cell-line AGS in (Figure 15 A) after 3 days and the effect of (Figure 15 B) after 6 days.The y axle is the cell number with respect to carrier, and the x axle is N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration uM.
Figure 16 represents: through N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (2mg/kg, once a day, oral; 10mg/kg, once a day, oral; And 50mg/kg, once a day, oral) treatment after, the average liver weight in tumor-bearing mice.
Figure 17 represents: through N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (2mg/kg, once a day, oral; 10mg/kg, once a day, oral; And 50mg/kg, once a day, oral) treatment after, the liver tumour weight in tumor-bearing mice.
Figure 18 represents: through N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (2mg/kg; 10mg/kg; And 50mg/kg) the average tumor weight after the treatment.
Figure 19 represents: in the figure of cell number (with respect to carrier) to N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration, and the inhibition of Hs746t cell proliferation.
Figure 20 A represents: handling the 5th day of non-small cell lung cancer (NSCLC) MV522 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases, and contrasts the chart of each level of apoptosis.
Figure 20 B represents: handling the 5th day of non-small cell lung cancer (NSCLC) H358 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.
Figure 20 C represents: handling the 6th day of non-small cell lung cancer (NSCLC) A549 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.
Figure 20 D represents: handling the 5th day of non-small cell lung cancer (NSCLC) H727 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.
Figure 20 E represents: handling the 5th day of colon HT29 cell, along with N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.
Figure 20 F represents: handling the 6th day of colon HCT116 cell, along with N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.
Figure 20 G represents: handling the 5th day of colon HUH7 hepatoma cells, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.
Figure 20 H represents: handling the 5th day of sarcoma U2-OS cell, along with N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.
Figure 20 I represents: handling the 5th day of glioma D37 cell, along with N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.
Figure 21 represents: under 10 μ M, compd A contrasts the selectivity of one group of 205 enzyme to MEK1 and MEK2.Cell-line is Colo205, A375, A431 and HT-29.
Figure 22 represents: in rat carrageenan pawl edema model, to rat administration 6,20,60 and the N-(S)-(3 of 200mg/kg, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) behind cyclopropane-1-sulfonamide, the chart that increases and reduce with respect to the vehicle Control oedema at each treatment group median claw volume.
Figure 23 A represents: with 2,6 and the N-(S)-(3 of 20mg/kg, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-acute stage of the rat of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment in, the inhibition of swelling in the arthritis model that adjuvant causes.
Figure 23 B represents: with 2,6 and the N-(S)-(3 of 20mg/kg, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) in the period of delay of the rat of cyclopropane-1-sulfonamide treatment, the inhibition of swelling in the arthritis model that adjuvant causes.
Figure 24 represents: with 1,3 ﹠amp; Average arthritis score in arthritis (CAIA) mouse that the collagen-antibody of 10mg/kg QD N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment causes.
Detailed Description Of The Invention
Chapter title used herein only should not be understood that to limit described theme for the logic purpose.All documents that include, but are not limited to patent, patent application, article, books, handbook and paper or the part document quoted among the application are intactly clearly quoted adding hereby with any purpose.
Some technical terms of chemistry
Unless otherwise defined, whole technology used herein has the implication identical with the theme one of ordinary skill in the art common sense of prescription with scientific terminology.Unless otherwise indicated, the material that runs through the whole disclosed whole patents that are cited, patent application, announcement is herein intactly quoted adding herein.If term herein has various definitions, to be defined as the master in these chapters and sections.Under the situation to URL or other such identifiers or address reference, understand that such identifier may change and the specifying information on the internet may constantly change, but can find the information that is equal to by search internet or other suitable reference sources.Availability and the public propagation of the information that its list of references proof is such.
It only is exemplary and indicative should understanding above-mentioned general introduction and following detailed description, is not any theme of requirement for restriction right.In this application, unless specifically describe in addition, the use of odd number comprises plural number.Clearly state in addition unless must be noted that context, the singulative that uses in this specification and the appended claims " a ", " an " and " should/this/described (the) " comprise the referent of plural number.Should also be noted that unless otherwise indicated, use " or " mean " and/or ".And term " comprises " and other forms of use is nonrestrictive.
(comprise Carey and Sundberg " A in reference works
DVANCEDO
RGANICC
HEMISTRYThe 4th edition " volume A (2000) and roll up B (2001), Plenum Press, New York) in can find the definition of standard chemical term.Unless otherwise indicated, use mass spectrum, NMR, HPLC, IR and UV/Vis spectroscopic methodology and pharmacological conventional method in the art technology.Unless concrete definition is provided, the name relevant with analytical chemistry as herein described, synthetic organic chemistry and pharmaceutical chemistry of use and laboratory method and the technology in these fields are known in the art.Standard technique can be used to chemosynthesis, chemical analysis, medication preparation, preparation and administration, and the treatment patient.For example, use manufacturer's kit specification, perhaps the mode of finishing usually according to this area is perhaps as described herein, can carry out reaction and purification technique.By conventional method well known in the art, and as run through various summaries that this specification quotes and discuss and more specifically as described in the list of references, can carry out above-mentioned technology and method usually.In whole specification, those skilled in the art can select its group and substituting group so that stable part and compound to be provided.
Illustrating under the substituted radical situation that by their the conventional chemical formula of writing from left to right they comprise equally writes the chemically identical substituting group that structure can produce from right to left.With-CH
2O-is equivalent to-OCH
2-as limiting examples.
Unless otherwise indicated, the generalization technics of use is equivalent to their randomly substituted form such as but not limited to " alkyl ", " amine ", " aryl ".For example, " alkyl " used herein comprises randomly substituted alkyl.
Compound as herein described can have one or more stereocenters, and each center can be with R or S configuration, or their combination exists.Similarly, compound as herein described can have one or more pairs of keys, and each pair key can be with E (trans) or Z (cis) configuration, or their combination exists.The description that should understand a kind of specific stereoisomer, regional isomer (regioisomer), diastereomer, enantiomer or epimer comprises all possible stereoisomer, regional isomer, diastereomer, enantiomer or epimer and their mixture.Therefore, compound as herein described comprises all independent configuration stereoisomeric forms in any ratio, position isomerism form, diastereomer form, enantiomeric form and epimer form and their corresponding mixtures.Should understand comprising one or more chiral centres but do not specify a kind of particular chemical structure of concrete stereochemical compound or the description of chemical name to comprise all possible stereoisomer, it comprise might stereoisomer pure form or the pure form basically of mixture, a kind of particular stereoisomer, and the pure form of alternative stereoisomer or pure form basically.It is well known in the art making the technology of specific stereocenter upset or the technology that remains unchanged and fractionation stereoisomer, and selects suitable method fully within those skilled in the art's ability at particular case.Referring to for example, Furniss etc. (eds.), VOGEL ' S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991,809-816; And Heller, Acc.Chem.Res.1990,23,128.
Term used herein " part ", " chemical part ", " group " and " chemical group " mean specific part or the functional group of molecule.Chemical part is considered to be embedded in the molecule usually or is attached to chemical entities on the molecule.
Term " key " or " singly-bound " mean two chemical bonds between the atom, perhaps when the atom that is connected by described key is considered to the part of bigger minor structure, mean two chemical bonds between the part.
Term " optional " or " randomly " mean subsequently described event or situation may take place or may not take place, and this description comprises the situation that described event or situation take place and do not take place.For example, " randomly substituted alkyl " means " alkyl " or " substituted alkyl " as giving a definition.In addition, randomly substituted group can be unsubstituted (as-CH
2CH
3), replace fully (as-CF
2CF
3), mono-substituted (as-CH
2CH
2F), the perhaps replacement of any level between replacement and the single replacement fully (for example-CH
2CHF
2,-CH
2CF
3,-CF
2CH
3,-CFHCHF
2Deng).For comprising one or more substituent any groups, it will be understood by those skilled in the art that such group is not unactually and/or synthetic on the solid infeasible any replacement or substitute mode (comprises randomly substituted group of naphthene base as substituted alkyl in order to introduce, it is defined as comprising randomly substituted alkyl group successively, may be unlimited).Therefore, described any substituting group should be understood that to have highest weight about 1 usually, 000 dalton, more typically, up to about 500 dalton (except meaning big molecule substituting group clearly for example under those situations of polypeptide, polysaccharide, polyethylene glycol, DNA, RNA etc.).
Unless otherwise indicated, the generalization technics is unsubstituted such as but not limited to the use of " alkyl ", " amine ", " aryl ".
C used herein
1-C
xComprise C
1-C
2, C
1-C
3C
1-C
xOnly as example, be expressed as " C
1-C
4" group show and in this part, have 1-4 carbon atom, namely comprise 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, and scope C
1-C
2And C
1-C
3Group.Therefore, only as example, " C
1-C
4Alkyl " show and in alkyl group, have 1-4 carbon atom that namely described alkyl group is selected from methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group.Whenever number range for example " 1-10 " mean each integer in given range when occurring in this article; For example, " 1-10 carbon atom " means described group and can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
Term used herein " carbon atom that A and A ' are attached thereto with them forms 3-6 unit saturated rings " means the following array structure of formula I compound:
The term that is used alone or in combination herein " hetero atom " or " mixing " mean the atom except carbon or hydrogen.Hetero atom can be independently selected from oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin, but is not limited to these atoms.In having two or more heteroatomic embodiments, described two or more hetero atoms can be mutually the same, and perhaps some or all in described two or more hetero atom can be different with other hetero atoms separately.
The term that is used alone or in combination herein " alkyl " means and contains 1 to the straight or branched saturated hydrocarbon unit price base of about 10 carbon atoms or 1-6 carbon atom.Example includes but not limited to methyl, ethyl, n-pro-pyl, isopropyl, 2-methyl isophthalic acid-propyl group, 2-methyl-2-propyl group, the 2-methyl-1-butene base, 3-methyl isophthalic acid-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl group, 2-methyl-1-pentene base, 3-methyl-1-pentene base, 4-methyl-1-pentene base, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, tertiary pentyl and hexyl, and long alkyl group heptyl for example, octyl group etc.Whenever number range " C for example
1-C
6Alkyl " or " C
1-6Alkyl " when occurring in this article, meaning described alkyl group can be made up of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.In one embodiment, described " alkyl " is substituted.Unless otherwise indicated, described " alkyl " is unsubstituted.
The term that is used alone or in combination herein " thiazolinyl " means to have one or more carbon-carbon double bonds and has 2 to about 10 carbon atoms or 2 straight or branched hydrocarbon unit price bases to about 6 carbon atoms.Can be in cis or anti-configuration for the described group of two keys, and should understand described group and comprise two kinds of isomer.Example includes but not limited to vinyl (CH=CH
2), 1-acrylic (CH
2CH=CH
2), isopropenyl [C (CH
3)=CH
2], cyclobutenyl, 1,3-butadiene base etc.Whenever number range " C for example
2-C
6Thiazolinyl " or " C
2-6Thiazolinyl " when occurring in this article, meaning described alkenyl group can be made up of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.In one embodiment, described " thiazolinyl " is substituted.Unless otherwise indicated, described " thiazolinyl " is unsubstituted.
The term that is used alone or in combination herein " alkynyl " means to have one or more carbon-carbon triple bonds and has 2 to about 10 carbon atoms or 2 straight or branched hydrocarbon unit price bases to about 6 carbon atoms.Example includes but not limited to acetenyl, 2-propynyl, 2-butynyl, 1,3-diacetylene base etc.Whenever number range " C for example
2-C
6Alkynyl " or " C
2-6Alkynyl " when occurring in this article, meaning described alkynyl group can be made up of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.In one embodiment, described " alkynyl " is substituted.Unless otherwise indicated, described " alkynyl " is unsubstituted.
The term that is used alone or in combination herein " assorted alkyl ", " assorted thiazolinyl " and " assorted alkynyl " mean aforesaid alkyl, thiazolinyl and alkynyl structure respectively, wherein one or more skeletal chain carbon atoms (and any continuous suitable hydrogen atom) independently of one another by hetero atom (i.e. atom except carbon, such as but not limited to oxygen, nitrogen, sulphur, silicon, phosphorus, tin or their combination) or heteroatom group (such as but not limited to-O-O-,-S-S-,-O-S-,-S-O-,=N-N=,-N=N-,-N=N-NH-,-P (O)
2-,-O-P (O)
2-,-P (O)
2-O-,-S (O)-,-S (O)
2-,-SnH
2-etc.) substitute.
The term that is used alone or in combination herein " haloalkyl ", " haloalkenyl group " and " halo alkynyl " mean alkyl, thiazolinyl and alkynyl group as defined above respectively, and wherein one or more hydrogen atoms are replaced by fluorine atom, chlorine atom, bromine atoms or iodine atom or their combination.In some embodiments, two or more hydrogen atoms can be replaced (for example difluoromethyl) by mutually the same halogen atom; In other embodiments, two or more hydrogen atoms can be replaced (for example 1-chloro-1-fluoro-1-iodine ethyl) by incomplete same each other halogen atom.The limiting examples of halogenated alkyl group is methyl fluoride, chloromethyl and bromoethyl.The limiting examples of haloalkenyl group group is bromo vinyl.The limiting examples of halo alkynyl group is the chloroethene alkynyl.
The term that is used alone or in combination herein " carbochain " means any alkyl, thiazolinyl, alkynyl, assorted alkyl, assorted thiazolinyl or assorted alkynyl group, they be straight chain, ring-type or their any combination.If described chain is a part that connects base, and this connection base comprises the one or more rings as core main chain part, in order to calculate chain length, described " chain " only comprises the two those carbon atoms of the bottom that constitutes given ring or top rather than bottom and top, and under the long situation about not waiting in the top and bottom of ring, should use short distance to determine chain length.If described chain comprises the hetero atom as main chain part, in those atoms are not calculated in as the part of carbon chain length.
The term that is used alone or in combination herein " ring (cycle) ", " ring-type ", " ring (ring) and " unit's ring " mean any covalence closed structure, comprise alicyclic ring as described herein, heterocycle, aromatics, heteroaromatic and encircle more condensing or the ring system of non-condensed.Ring can randomly be substituted.Ring can form the part that condenses ring system.Term " unit " means the skeletal atom number that constitutes ring.Therefore, only as example, cyclohexane, pyridine, pyrans and pyrimidine are hexatomic rings, and pentamethylene, pyrroles, oxolane and thiophene are five-membered rings.
The term that is used alone or in combination herein " condenses " and means the ring structure that two or more rings share one or more keys.
The term that is used alone or in combination herein " cycloalkyl " means saturated hydrocarbon unit price basic ring, and it comprises 3 to about 15 ring carbon atoms or 3 to about 10 ring carbon atoms, but can comprise as substituent extra non-ring carbon atom (as the methyl cyclopropyl).Whenever number range " C for example
3-C
6Cycloalkyl " or " C
3-6Cycloalkyl " when occurring in this article; meaning described group of naphthene base can be made up of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; be cyclopropyl, cyclobutyl, cyclopenta or suberyl (cyclohepty), but the appearance of the term " cycloalkyl " of not specifying number range is also contained in this definition.This term comprise condense, non-condensed, bridge and tap bolt group.The fused rings alkyl can comprise 2-4 fused rings, and wherein connecting ring is cycloalkyl ring, and other each rings can be the ring of alicyclic ring, heterocycle, aromatics or heteroaromatic or their any combination.Example includes but not limited to cyclopropyl, cyclopenta, cyclohexyl, decahydronaphthalenes base and dicyclo [2.2.1] heptyl and adamantyl ring system.Illustrative examples includes but not limited to the lower part:
In one embodiment, described " cycloalkyl " is substituted.Unless otherwise indicated, described " cycloalkyl " is unsubstituted.
The term that is used alone or in combination herein " non-aromatic heterocycle " and " heterolipid cyclic group " mean comprise 3 to about 20 annular atomses saturated, part is undersaturated or the unit price base of undersaturated non-aromatic ring fully, one or more in the wherein said annular atoms are being independently selected from oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin but being not limited to the atom of these atoms except carbon.Exist in two or more heteroatomic embodiments in ring, described two or more hetero atoms can be mutually the same, and perhaps some or all in described two or more hetero atom can be different from other hetero atoms separately.These terms comprise condense, non-condensed, bridge and tap bolt group.The non-aromatic heterocycle group that condenses can comprise 2-4 fused rings, and wherein connecting ring is non-aromatic heterocyclic, and other each rings can be the ring of alicyclic ring, heterocycle, aromatics or heteroaromatic or their any combination.Condensing ring system can condense by singly-bound or two key, also can condense by carbon-carbon bond, carbon-heteroatom bond or hetero atom-heteroatomic bond.These terms also comprise have 3 to about 12 framework ring atoms and have 3 groups to about 10 framework ring atoms.Non-aromatic heterocyclidene can pass through hetero atom or carbon atom with being connected of its parent molecule.Similarly, other replacement can be passed through hetero atom or carbon atom.As limiting examples, the imidazolidine non-aromatic heterocyclic can be connected to parent molecule by its arbitrary N atom (imidazolidine-1-base or imidazolidine-3-yl) or its any carbon atom (imidazolidine-2-base, imidazolidine-4-base or imidazolidine-5-yl).In certain embodiments, non-aromatic heterocyclic comprises the group that one or more carbonyls or thiocarbonyl group for example contain oxo and contain sulfo-.Example includes but not limited to pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidino, morpholino, thiomorpholine generation, thioxane base, piperazinyl, azetidinyl, oxetanyl, Thietane base, homopiperidinyl, oxepane alkyl, thia cycloheptane base, oxygen azepine
![Figure GPA00001070418800352](https://patentimages.storage.googleapis.com/fd/8f/5f/2fbc4daa4dea03/GPA00001070418800352.png)
Base, diaza
Base, sulphur azepine
Base, 1,2,3,6-tetrahydro pyridyl, 2-pyrrolinyl, 3-pyrrolinyl, indoline base, 2H-pyranose, 4H-pyranose, alkyl dioxin, 1,3-dioxolanyl, pyrazolinyl, dithiane base, dithiolane base, dihydro pyranyl, dihydro-thiophene base, dihydrofuran base, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indyl and quinolizine base.The illustrative examples that heterocycloalkyl is also referred to as non-aromatic heterocycle comprises:
This term also comprises all loop types of carbohydrate, includes but not limited to monose, disaccharides and oligosaccharides.In one embodiment, described " non-aromatic heterocycle " or " heterolipid cyclic group " is substituted.Unless otherwise indicated, described " non-aromatic heterocycle " or " heterolipid cyclic group " is unsubstituted.
The term that is used alone or in combination herein " aryl " means 6 aromatic hydrocarbyls to about 20 ring carbon atoms, and comprises that condense and aryl rings non-condensed.The aryl rings group that condenses comprises 2-4 fused rings, and wherein connecting ring is aryl rings, and other each rings can be the ring of alicyclic ring, heterocycle, aromatics or heteroaromatic or their any combination.In addition, term aryl comprise comprise 6 to about 12 ring carbon atoms and comprise 6 condense and rings non-condensed to about 10 ring carbon atoms.The limiting examples of monocyclic aryl group comprises phenyl; The limiting examples of fused rings aromatic yl group comprises naphthyl, phenanthryl, anthryl, Azulene base; The limiting examples of the biaryl group of non-condensed comprises xenyl.In one embodiment, described " aryl " is substituted.Unless otherwise indicated, described " aryl " is unsubstituted.
The term that is used alone or in combination herein " heteroaryl " means and comprises about 5 aromatics unit price bases to about 20 framework ring atoms, wherein one or more in the annular atoms are independently selected from oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin but the hetero atom that is not limited to these atoms, and condition is that the ring of described group does not comprise two adjacent O or S atom.Exist in two or more heteroatomic embodiments in ring, described two or more hetero atoms can be mutually the same, and perhaps some or all in described two or more hetero atom can be different from other hetero atoms separately.The term heteroaryl comprises the heteroaryl groups with at least one heteroatomic that condense and non-condensed.The term heteroaryl also comprise have 5 to about 12 framework ring atoms and have 5 condense and heteroaryls non-condensed to about 10 framework ring atoms.Can pass through carbon atom or hetero atom and heteroaryl groups Cheng Jian.Therefore, as limiting examples, imidazole group can be by its any carbon atom (imidazoles-2-base, imidazol-4 yl or imidazoles-5-yl), and perhaps its any nitrogen-atoms (imidazoles-1-base or imidazo-3-yl) is connected with parent molecule.Similarly, heteroaryl groups can further be substituted by its any or all of carbon atom and/or its any or all of hetero atom.The heteroaryl groups that condenses can comprise 2-4 fused rings, and wherein connecting ring is heteroaromatic rings, and other each rings can be the ring of alicyclic ring, heterocycle, aromatics, heteroaromatic or their any combination.The limiting examples of bicyclic heteroaryl group comprises pyridine radicals; The limiting examples of fused ring heteroaryl group comprises benzimidazolyl, quinolyl, acridinyl; The limiting examples of non-condensed connection heteroaryl groups comprises bipyridyl.Other examples of heteroaryl comprise furyl without limitation, thienyl oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl benzoxazolyl, benzothiazolyl, the diazosulfide base, benzothienyl Ben Bing oxadiazole base, the BTA base, imidazole radicals, indyl isoxazolyl, isoquinolyl, the indolizine base, isothiazolyl, iso-indoles oxadiazole base, indazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrrole radicals, pyrazinyl, pyrazolyl, purine radicals, phthalazinyl, pteridyl, quinolyl, quinazolyl quinoxalinyl, triazolyl, tetrazole radical, thiazolyl, triazinyl, thiadiazolyl group etc., and their oxide, for example pyridine radicals-N-oxide.The illustrative examples of heteroaryl groups comprises with the lower part:
In one embodiment, described " heteroaryl " is substituted.Unless otherwise indicated, described " heteroaryl " is unsubstituted.
The term that is used alone or in combination herein " heterocyclic radical " jointly means heterolipid cyclic group and heteroaryl groups.Herein, (the C for example of the carbon number in specifying heterocycle
1-C
6Heterocycle), must there be at least one non-carbon atom (hetero atom) in the ring.Title is " C for example
1-C
6Heterocycle " only mean the ring in carbon number and be not mean the ring in total atom number.Title for example " 4-6 unit heterocycle " means the total atom number that comprises in the ring (namely 4 yuan of rings, 5 yuan encircle or 6 yuan of rings, and wherein at least one atom is carbon atom, and at least one atom is hetero atom, and a remaining 2-4 atom is carbon atom or hetero atom).For having two or more heteroatomic heterocycles, those two or more hetero atoms can be same to each other or different to each other.The non-aromatic heterocyclic group comprises the group that only has 3 atoms in the ring, and aromatic heterocyclic group must have at least 5 atoms in ring.Can be by hetero atom or carbon atom and heterocycle Cheng Jian (namely being connected to parent molecule or further replacement).It is in one embodiment, described that " heterocyclic radical " is substituted.It is unless otherwise indicated, described that " heterocyclic radical " is unsubstituted.
The term that is used alone or in combination herein " halogen ", " halo " or " halide " mean fluorine, chlorine, bromine and/or iodine.
The term that is used alone or in combination herein " amino " means unit price base-NH
2
The term that is used alone or in combination herein " alkyl amino " means unit price base-NH (alkyl), and wherein alkyl as defined herein.
The term that is used alone or in combination herein " dialkyl amido " means unit price base-N (alkyl) (alkyl), and wherein each alkyl can be identical or different and as defined herein.
The term that is used alone or in combination herein " Diaminoalkyl " means the alkyl group that comprises two amine groups, wherein said amine groups can be the substituting group on the alkyl group, it can be amino, alkyl amino or dialkyl amino group, perhaps one or two in the wherein said amine groups can the component part alkyl chain with formation-alkylidene-N (H or alkyl)-alkylidene-N (H or alkyl or alkylidene-) (H or alkyl or alkylidene-).
The term that is used alone or in combination herein " hydroxyl " means unit price base-OH.
The term that is used alone or in combination herein " cyano group " means unit price base-CN.
The term that is used alone or in combination herein " cyanogen methyl " means unit price base-CH
2CN.
The term that is used alone or in combination herein " nitro " means unit price base-NO
2
The term that is used alone or in combination herein " oxygen base " means bilvalent radical-O-.
The term that is used alone or in combination herein " oxo " means bilvalent radical=O.
The term that is used alone or in combination herein " carbonyl " mean bilvalent radical-C (=O)-, also can write-C (O)-.
The term that is used alone or in combination herein " carboxyl " means-C (O) OH part, and it also can be write-COOH.
The term that is used alone or in combination herein " alkoxyl " means alkyl ether groups,-O-alkyl, it comprise group-O-aliphatic group and-the O-carbocylic radical, wherein said alkyl, aliphatic group and carbocylic radical group can randomly be substituted, and wherein term alkyl, aliphatic group and carbocylic radical be as defined herein.The limiting examples of alkoxyl comprises: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.
The term that is used alone or in combination herein " sulfinyl " mean bilvalent radical-S (=O)-.
The term that is used alone or in combination herein " sulfonyl " mean bilvalent radical-S (=O)
2-.
The term that is used alone or in combination herein " sulfonamide ", " sulfonamido " and " amino-sulfonyl (sulfonamidyl) " mean diradical group-S (=O)
2-NH-and-NH-S (=O)
2-.
Herein individually or the term that is used in combination " sulphamide (sulfamide) " and " aminosulfonyl amino (sulfamido, sulfamidyl) " mean diradical group-NH-S (=O)
2-NH-.
Term used herein " reactant " means for generation of the nucleophile of covalent bond or close electric body.
Should understand and use two or more groups to define under the substituent situation that is connected with structure continuously, it is terminal that first group of being named is considered to, and the group of being named at last is considered to be connected to the structure of being discussed.Therefore, for example, the group aryl alkyl is connected to the structure of discussing by alkyl group.
Some technical term of pharmacology
Term used herein " mek inhibitor " means with the Mek1 kinase assay of general introduction herein and measures, and demonstrates about 100 μ M at the most or is no more than the IC of about 50 μ M for the MEK activity
50Compound." IC
50" be to make the activity of enzyme (as MEK) be reduced to the inhibitor concentration of maximum half level.Found that compound exhibits as herein described goes out the inhibitory action to MEK.Measure with Mek1 kinase assay as herein described, compound of the present invention preferably demonstrates the IC of about 10 μ M at the most for MEK
50, more preferably about 5 μ M at the most, even more preferably no more than about 1 μ M, and be most preferably not exceeding about 200nM.
Term about ill disease individuality used herein " experimenter ", " patient " or " individuality " etc. comprise mammal and nonmammalian.Mammiferous example includes but not limited to any member of class of mammals: human, such as non-human primate and other ape kinds and the monkey kind of chimpanzee; Domestic animal such as ox, horse, sheep, goat, pig; Domestic animal such as rabbit, dog and cat; Comprise for example laboratory animal etc. of rat, mouse and cavy of rodent.The example of nonmammalian includes, but not limited to bird, fish etc.In the embodiment of the method and composition that provides in this article, described mammal is human.
The word of equivalence on term used herein " treatment " and other grammers, comprise alleviation, alleviate or improve the symptom of disease or the patient's condition, prevent other symptoms, improve or prevent the potential metabolism cause of symptom, suppress disease or the patient's condition, for example contain the development of disease or the patient's condition, palliate a disease or the patient's condition, cause disappearing of disease or the patient's condition, palliate a disease or the caused situation of the patient's condition, perhaps stop the symptom of disease or the patient's condition, and in order to comprise prevention.This term also comprises obtains treatment benefit and/or prevention benefit.The treatment benefit means elimination or improves the potential illness of just receiving treatment.In addition, in the patient, observe improvement thereby reach the treatment benefit by elimination or improvement one or more physiological signs relevant with potential illness, but the patient may be tormented by potential illness still.For the prevention benefit, to the patient that the specified disease risk takes place is arranged, or to the patient of one or more physiological signs of report disease, even do not make the diagnosis of this disease as yet, also can the described composition of administration.
Term used herein " effective dose ", " treatment effective dose " or " pharmacy effective dose " means is enough to treat or prevent at least a reagent of specified disease or the patient's condition or the dosage of compound.Its result reduces and/or alleviates sign, symptom or the cause of disease of disease, the perhaps change of any other hope of biosystem.For example, " effective dose " for the treatment of use provides the required amount that comprises compound compositions disclosed herein that significantly palliates a disease clinically.Operation technique for example dose escalation study can be determined " effectively " amount suitable in any individual case.
Term used herein " anhydrous basically " and " essentially no solvent " mean crystalline polymorph and comprise water or the solvent that is less than 0.01,0.1,0.2,0.3,0.4,0.5,1 or 2 weight % respectively.
Term used herein " basic identical " means and may not be equal to described figure herein, but the x-ray diffractogram of powder in the experimental error limit that those skilled in the art consider or differential scanning calorimetric figure.
Term used herein " administration " etc. means and can be used for making compound or composition can be delivered to the method in the biological agent site of expectation.These methods include but not limited to oral route, intraduodenal route, parenteral injection (comprising administration in intravenous administration, subcutaneous administration, the peritonaeum, intramuscular administration, intravascular administration or infusion administration), topical and rectally.Those skilled in the art know the operable medicine-feeding technology of Compounds and methods for as herein described, for example, as Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; And Remington ' s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton discusses among the Pa.In preferred embodiments, oral administration compound as herein described and composition.
Term used herein " acceptable ", with regard to preparation, composition or composition, meaning the general health that aligns the experimenter who receives treatment does not have lasting adverse effect.
Term used herein " pharmacy is acceptable " means biologically active or character and the avirulent relatively material such as carrier or thinner of not eliminating compound described herein, namely can not cause bad biological effect to the described material of individual administration, perhaps not with any component interaction in the mode that is harmful to and the composition that comprises described material.
Term used herein " pharmaceutical composition " means bioactive compound, it randomly mixes with the acceptable chemical composition of at least a pharmacy (such as, but not limited to carrier, stabilizing agent, thinner, dispersant, suspending agent, thickener and/or excipient).
Term used herein " carrier " means avirulent relatively chemical compound or the reagent that promotes cell or tissue to include compound in.
Term used herein " activator " means the molecule such as compound, medicine, zymoexciter or hormone regulator that strengthens another molecular activity or acceptor site activity.
Term used herein " antagonist " means the molecule such as compound, medicine, enzyme inhibitor or hormone regulator that weakens or stop another molecular action or acceptor site activity.
Term used herein " adjusting " means the activity that interacts to change target spot directly or indirectly with target spot, comprises that (only as an example) strengthens the activity of target spot, suppresses the activity of target spot, the activity of restriction target spot, the activity that perhaps prolongs target spot.
Term used herein " conditioning agent " means directly or indirectly and the interactional molecule of target spot.Described interaction includes, but are not limited to the interaction of activator and antagonist.
Term used herein " pharmacy acceptable derivates or prodrug " means the acceptable salt of any pharmacy, the ester of formula I compound, salt or other derivatives of ester, when to recipient's administration, it can provide compound of the present invention or its pharmaceutical active metabolite or residue directly or indirectly.Shou Xuan derivative or prodrug are when to the such compound of patient's administration especially, improve derivative or the prodrug (for example more easily being absorbed in the blood by the compound that makes oral administration) of the bioavilability of compound of the present invention, perhaps improve derivative or prodrug that parent compound is sent to biological compartment (as brain or lymphatic system).
" prodrug " used herein is can be under physiological condition or change into the compound of the acceptable salt of pharmacy of appointed compound or such compound by lyolysis.Prodrug comprises such compound, and wherein the polypeptide chain of amino acid residue or two or more amino acid residues is by amido link or the covalently bound free amine group to formula I compound of ester bond, hydroxyl or hydroxy-acid group.The amino acid residue that relates to includes but not limited to 20 kinds of naturally occurring amino acid.Other amino acid that are fit to comprise 4-hydroxy-proline, oxylysine, desmosine (demosine), isodensmosine (isodemosine), 3-Methyl histidine, norvaline, Beta-alanine, γ-An Jidingsuan, citrulling (cirtulline), homocysteine, homoserine, ornithine and methionine sulfone.The prodrug of other types is well known in the art.
The pharmacy acceptable prodrugs of compound as herein described includes but not limited to quaternary ammonium derivative, N-Mannich base, schiff bases, amino acid conjugate, phosphate, slaine and the sulphonic acid ester of ester, carbonic ester, sulfocarbonate, N-acyl derivative, N-acyloxy alkyl derivative, tertiary amine.Various forms of prodrugs are known in this field.Referring to for example, Designof Drugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. etc., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. " Design and Application of Prodrugs " be at ATextbook of Drug Design and Development, Krosgaard-Larsen and H.Bundgaard, and Ed., 1991, the 5 chapters, p.113-191; And Bundgaard, H., Advanced Drug Delivery Review, 1992,8,1-38, it quotes adding herein.Prodrug as herein described includes but not limited to the combination of following group and these groups; The prodrug that amine is derived:
The hydroxyl prodrug includes but not limited to acyloxy Arrcostab, alkoxy-carbonyl oxy Arrcostab, Arrcostab, aryl ester and comprises the disulphide of ester.
Term used herein " the acceptable salt of pharmacy " comprises the biological effectiveness of the free acid that keeps appointed compound and free alkali and abiology is not optimum or other not optimum salt.Described compound can have acidity or basic group, and therefore can be with some inorganic or organic base and inorganic or organic acid reaction form the acceptable salt of pharmacy.The example of the acceptable salt of pharmacy comprises those salt by compound as herein described and inorganic acid or organic acid or inorganic base prepared in reaction, such salt comprises acetate, acrylates, adipate, alginates, aspartate, benzoate, benzene sulfonate, disulfate, bisulfites, bromide, butyrate, butine-1, the 4-diacid salt, camphorate, camsilate, caproate, caprylate, chloride, chloro benzoate, chloride, citrate, cyclopentane propionate, caprate, digluconate, dihydric phosphate, dinitro-benzoate, lauryl sulfate, esilate, formates, fumarate, gluceptate (glucoheptanoate), glycerophosphate, glycollate, Hemisulphate, enanthate, caproate, hexin-1, the 6-diacid salt, hydroxy benzoate, gamma hydroxybutyrate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, iodide, isobutyrate, lactate, maleate, malonate, mesylate, mandelate, metaphosphate, mesylate, methoxy benzoic acid salt, methyl benzoic acid salt, hydrophosphate, 1-naphthalene sulfonic aicd salt, the 2-naphthalene sulfonate, the nicotinic acid cigarette, nitrate, oxalate, pamoate (palmoate), pectate (pectinate), persulfate, phenylacetate, phenpropionate, the 3-phenpropionate, phosphate, picrate, Pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, propionate, phthalate, benzenebutanoic acid salt, the propane sulfonic acid ester, pyrophosphate, salicylate, succinate, sulphate, sulphite, succinate, suberate, sebacate, sulfonate, tartrate, rhodanate, toluene fulfonate, hendecane hydrochlorate (undeconate) and xylenesulfonate.Other acid are oxalic acid for example, though they itself are not that pharmacy is acceptable, can for the preparation of be used as the salt that obtains the intermediate in compound of the present invention and the acceptable acid-addition salts process of their pharmacy (referring to for example Berge etc., J.Pharm.Sci.1977,66,1-19.).In addition, those compounds that can comprise free acid group as herein described can with suitable for example hydroxide, carbonate, the bicarbonate reaction of the acceptable metal cation of pharmacy of alkali, with ammonia react, perhaps with the acceptable organic primary amine of pharmacy, secondary amine or reactive tertiary amine.Representational alkali metal salt or alkali salt comprise lithium salts, sodium salt, sylvite, calcium salt, magnesium salts and aluminium salt etc.The illustrative example of alkali comprises sodium hydroxide, potassium hydroxide, bursine, sodium carbonate, N
+(C
1-4Alkyl)
4Deng.The representative organic amine that is used to form base addition salts comprises ethamine, diethylamine, ethylenediamine, monoethanolamine, diethanol amine, piperazine etc.Should understand the quaternized of any alkaline nitrogen-containing group that compound as herein described comprises that also they may comprise.Quaternizedly can obtain water-soluble or oil-soluble or water dispersible or oil-dispersing property product by such.Referring to for example, Berge etc. are on seeing.During the final separation of compound of the present invention and purifying, can prepare these salt on the spot, the perhaps purified compound by making free alkali form respectively and suitable organic or inorganic acid reaction, and separate the salt that forms thus and prepare these salt.
Term used herein " enhancing " means effectiveness or the continuation that improves or prolong predictive role.Therefore, about strengthening the therapeutic agent effect, term " enhancing " means in effectiveness or continuation and improves or prolong the other treatment agent to the ability of the effect of system." synergy amount " used herein means the amount that is enough to strengthen the effect of another therapeutic agent in required system.
Term used herein " drug regimen ", " using other therapies ", " administration other therapeutic agent " etc. mean by mixing or merge the pharmacotherapy that produces more than a kind of active component, and comprise fixing and revocable combination of active component.Term " fixed Combination " means at least a compound as herein described and at least a auxiliary agent with the form of single entities or dosage simultaneously to patient's administration.Term " on-fixed combination " means with at least a compound as herein described and at least a auxiliary agent with the entity that separates to the patient side by side and deposit ground or in turn to limit administration variable blanking time, and wherein such administration provides the level of significance of two or more compounds in patient's body.These also are applicable to conjoint therapy, for example three kinds of administrations or more kinds of active component.
Term used herein " administering drug combinations ", " with ... administering drug combinations " and their grammer word of equal value etc., intention comprises to the selected therapeutic agent of single patient administration, and intention comprises by identical or different administration path or at the therapeutic scheme of the described medicament of identical or different time administration.In some embodiments, compound as herein described can with the administration simultaneously of other medicaments.These terms comprise to two or more medicaments of animals administer so that medicament and/or their metabolite are present in the animal simultaneously.The administration simultaneously of composition that they comprise separating, in the composition administration of different time to separate, and/or all be present in wherein composition administration with two kinds of medicaments.Therefore, in some embodiments, with single composition administration compound of the present invention and other medicaments.In some embodiments, compound of the present invention and other medicaments are mixed in the described composition.
Term used herein " metabolite " means the derivative of the compound that forms during by metabolism when compound.
Term used herein " active metabolite " means the biologically active derivatives of the compound that forms during by metabolism when compound.
Term used herein " by metabolism " means the biological summation (including but not limited to hydrolysis and enzymatic reaction) that changes the process of predetermined substance.Therefore, enzyme can make compound produce specific structural change.For example, the various oxidations of Cytochrome P450 catalysis and reduction reaction, and the glucuronic acid molecule of uridine diphosphate glucuronate transferase catalytic activation is to the transfer of aromatic alcohol, fatty alcohol, carboxylic acid, amine and free thiohydroxy group.From The PharmacologicalBasis of Therapeutics, the 9th edition, McGraw-Hill (1996) can obtain other about metabolic information.
Compound
Compound and the acceptable salt of pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or the prodrug of formula I have been described herein:
Formula I
Wherein
Z is H or F;
X is F, Cl, CH
3, CH
2OH, CH
2F, CHF
2Or CF
3
Y is I, Br, Cl, CF
3, C
1-C
3Alkyl, C
2-C
3Thiazolinyl, C
2-C
3Alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, wherein Het is 5 to 10 yuan of monocyclic heterocycles groups or bicyclic heterocyclic groups that comprise 1-5 the ring hetero atom that is independently selected from N, O and S, and described heterocyclic group is saturated, olefinic or aromatic; Wherein
Whole described phenyl or Het group are randomly by F, Cl, Br, I, acetyl group, methyl, CN, NO
2, CO
2H, C
1-C
3Alkyl, C
1-C
3Alkoxyl, C
1-C
3Alkyl-C (=O)-, C
1-C
3Alkyl-C (=S)-, C
1-C
3Alkoxy-C (=S)-, C
1-C
3Alkyl-C (=O) O-, C
1-C
3Alkyl-O-(C=O)-, C
1-C
3Alkyl-C (=O) NH-, C
1-C
3Alkyl-C (=NH) NH-, C
1-C
3Alkyl-NH-(C=O)-, two-C
1-C
3Alkyl-N-(C=O)-, C
1-C
3Alkyl-C (=O) N (C
1-C
3Alkyl)-, C
1-C
3Alkyl-S (=O)
2NH-or trifluoromethyl replace;
Whole described methyl, ethyl, C
1-C
3Alkyl and cyclopropyl group are randomly replaced by OH;
Whole described methyl groups are randomly by 1,2 or 3 F atoms replacements;
R
0Be: H, F, Cl, Br, I, CH
3NH-, (CH
3)
2N-, C
1-C
6Alkyl, C
1-C
4Alkoxyl, C
3-C
6Cycloalkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, phenyl, mono-substituted phenyl, O (C
1-C
4Alkyl), O-C (=O) (C
1-C
4Alkyl) or C (=O) O (C
1-C
4Alkyl); Wherein
1-3 the substituting group that described alkyl, alkoxyl, cycloalkyl, thiazolinyl, alkynyl and phenyl group randomly are independently selected from F, Cl, Br, I, OH, CN, cyano methyl, nitro, phenyl and trifluoromethyl replaces;
Described C
1-C
6Alkyl and C
1-C
4Alkoxy base is also randomly by OCH
3Or OCH
2CH
3Replace;
G is G
1, G
2, R
1a, R
1b, R
1c, R
1d, R
1e, Ar
1, Ar
2Or Ar
3Wherein
G
1Be randomly by an amino, C
1-C
3The C that alkyl amino or dialkyl amino group replace
1-C
6Alkyl, described dialkyl amino group comprise 2 can be identical or different C
1-C
4Alkyl group; Perhaps
G
1Be C
3-C
8The Diaminoalkyl group;
G
2Be saturated, undersaturated or aromatic 5-or the 6-unit ring that comprises 1-3 the ring hetero atom that is independently selected from N, O and S, it randomly is independently selected from F, Cl, OH, O (C
1-C
3Alkyl), OCH
3, OCH
2CH
3, CH
3C (=O) NH, CH
3C (=O) O, CN, CF
3Replace with 1-3 substituting group of the 5 membered aromatic heterocycle groups that comprise 1-4 the ring hetero atom that is independently selected from N, O and S;
R
1aBe methyl, randomly by 1-3 fluorine atom or 1-3 chlorine atom, perhaps OH, ring propoxyl group or C
1-C
3Alkoxyl replaces, wherein said ring propoxyl group group or described C
1-C
3The C of alkoxy base
1-C
3Moieties is randomly replaced by a hydroxyl or methoxy group, and wherein said C
1-C
4Whole C in the alkoxyl
3-alkyl group is randomly further replaced by another OH group;
R
1bBe CH (CH
3)-C
1-3Alkyl or C
3-C
6Cycloalkyl, described alkyl and group of naphthene base randomly are independently selected from F, Cl, Br, I, OH, OCH
3Replace with 1-3 the substituting group of CN;
R
1cBe (CH
2)
nO
mR '; Wherein
M is 0 or 1; And wherein
When m was 0, n was 1 or 2;
When m was 1, n was 2 or 3;
R ' is C
1-C
6Alkyl, it randomly is independently selected from F, Cl, OH, OCH
3, OCH
2CH
3And C
3-C
6The 1-3 of cycloalkyl substituting group replaces;
R
1dBe C (A) (A ') (B)-; Wherein
B is H or C
1-4Alkyl is randomly replaced by one or two OH group;
A and A ' are H or C independently
1-4Alkyl is randomly replaced by one or two OH group; Perhaps
A forms 3 yuan of-6 yuan of saturated rings with A ' with the carbon atom that links to each other with them;
R
1eBe
Wherein
Q is 1 or 2;
R
2And R
3Be independently of one another: H, F, Cl, Br, CH
3, CH
2F, CHF
2, CF
3OCH
3, OCH
2F, OCHF
2, OCF
3, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group or mesyl;
R
4Be: H, F, Cl, Br, CH
3, CH
2F, CHF
2, CF
3OCH
3, OCH
2F, OCHF
2, OCF
3, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, mesyl, nitro, acetylamino, amidino groups, cyano group, carbamoyl, methylamino formoxyl, formyl-dimethylamino, 1,3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3,4-oxadiazole, 1,3,4-thiadiazoles, 5-methyl isophthalic acid, 3,4-thiadiazoles, 1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl and N-pyrrolidinyl carbonylamino;
R
5Be H, F, Cl or methyl;
R
6Be H, F, Cl or methyl;
Ar
1Be
Wherein
U and V are N, CR independently
2Or CR
3
R
2, R
3And R
4Be independently: H, F, Cl, Br, CH
3, CH
2F, CHF
2, CF
3OCH
3, OCH
2F, OCHF
2, OCF
3, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, acetylamino, amidino groups, cyano group, carbamoyl, methylamino formoxyl, formyl-dimethylamino, 1,3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3,4-oxadiazole base, 1,3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3,4-thiadiazolyl group, 1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl, N-pyrrolidinyl carbonylamino, and mesyl;
R
5And R
6Be H, F, Cl or methyl independently;
Ar
2Be
Wherein
Dotted line represents the optional pro forma position of second two key of ring;
U is-S-,-O-or-N=, and wherein
When U be-O-or-during S-, V is-CH=,-CCl=or-N=;
When U be-during N=, V is-CH=,-CCl=, or-N=;
R
7Be H or methyl;
R
8Be H, acetylamino, methyl, F or Cl;
Ar
3Be
Wherein
U is-NH-,-NCH
3-or-O-;
R
7And R
8Be H, F, Cl or methyl independently.
Except herein to group G, R
0, outside the definition that provides of X, Y and Z, comprise that chemistry and pharmaceutical field technical staff can thinkable other replacements.
In some embodiments, the invention provides the compound of formula I, wherein G is G
1Or G
2In other embodiments, G is G
1Further or in other the embodiment, G is G
2
In some embodiments, the invention provides the compound of formula I, wherein G is R
1a, R
1b, R
1c, R
1d, R
1e, Ar
1, Ar
2Or Ar
3Further or in other the embodiment, G is R
1a, R
1b, R
1c, R
1dOr R
1eFurther or in other the embodiment, G is R
1aFurther or in other the embodiment, G is R
1bFurther or in other the embodiment, G is R
1cFurther or in other the embodiment, G is R
1dFurther or in other the embodiment, G is R
1eFurther or in other the embodiment, G is Ar
1, Ar
2Or Ar
3Further or in other the embodiment, G is Ar
1Further or in other the embodiment, G is Ar
2Further or in other the embodiment, G is Ar
3
Compound or the acceptable salt of their pharmacy of formula I are provided in some embodiments.Further or in other the embodiment, provide the compound of formula I or their solvate herein.Further or in other the embodiment, provide the compound of formula I or their polymorphs body herein.Further or in other the embodiment, provide the compound of formula I or their ester herein.Further or in other the embodiment, provide the compound of formula I or their acid amides herein.Further or in other the embodiment, provide the compound of formula I or their dynamic isomer herein.Further or in other the embodiment, provide the compound of formula I or their prodrug herein.
In some embodiments, Z is H.In some embodiments, Z is F.In some embodiments, X is F.In some embodiments, X is Cl.In some embodiments, X is CH
3In some embodiments, X is CH
2OH.In some embodiments, X is CH
2F.In some embodiments, X is CHF
2In some embodiments, X is CF
3In some embodiments, X is F, Cl or CH
3
In some embodiments, G is G
1Or G
2, X is F, Cl or CH
3Y is I, Br, Cl, CF
3, C
1-C
3Alkyl, phenyl, pyridine radicals, pyrrole radicals, pyrazolyl, described phenyl, pyridine radicals, pyrrole radicals and pyrazolyl groups are randomly by F, Cl, Br, I, acetyl group, methyl, CN, NO
2, CO
2H, C
1-C
3Alkyl, C
1-C
3Alkoxyl, C
1-C
3Alkyl-C (=O)-, C
1-C
3Alkyl-C (=S)-, C
1-C
3Alkoxy-C (=S)-, C
1-C
3Alkyl-C (=O) O-, C
1-C
3Alkyl-O-(C=O)-, C
1-C
3Alkyl-C (=O) NH-, C
1-C
3Alkyl-C (=NH) NH-, C
1-C
3Alkyl-NH-(C=O)-, two-C
1-C
3Alkyl-N-(C=O)-, C
1-C
3Alkyl-C (=O) N (C
1-C
3Alkyl)-, C
1-C
3Alkyl-S (=O)
2NH-or trifluoromethyl replace; And Z is H or F.Further or in other the embodiment, G is G
1Or G
2, and R
0Be F, Cl, C
1-C
4Alkyl or C
1-C
4Alkoxyl, described C
1-C
4Alkyl group and described C
1-C
4The C of alkoxy base
1-C
4Moieties is randomly by F, Cl, OCH
3Or OCH
2CH
3Replace.Further or in other the embodiment, G is G
1Or G
2, and R
0Be H, F, Cl, C
1-C
4Alkyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl.
In some embodiments, G
1It is N-methyl-2-amino-ethyl.Further or in other the embodiment, G
1Be (CH
3)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n is 1,2 or 3.Further or in other the embodiment, G
1Be (CH
3)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n is 1,2 or 3, and X is F.Further or in other the embodiment, G
1Be (CH
3)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n be 1,2 or 3, X be F, and Z is F.
In some embodiments, G
2Be 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl.Further or in other the embodiment, G
2Be morpholinyl, 1-piperazinyl or 2-piperazinyl.
In some embodiments, G is R
1a, R
1b, R
1c, R
1d, R
1e, Ar
1, Ar
2Or Ar
3, and X is F, Cl or CH
3Further or in other the embodiment, G is R
1a, R
1b, R
1c, R
1d, R
1e, Ar
1, Ar
2Or Ar
3, X is F, Cl or CH
3, and Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl.Further or in other the embodiment, G is R
1a, R
1b, R
1c, R
1d, R
1e, Ar
1, Ar
2Or Ar
3, X is F, Cl or CH
3, Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl, and Z is H or F.
Further or in other the embodiment, G is R
1a, R
1b, R
1c, R
1d, R
1e, Ar
1, Ar
2Or Ar
3, and R
0Be F, Cl, C
1-C
4Alkyl or C
1-C
4Alkoxyl, described C
1-C
4Alkyl group and described C
1-C
4The C of alkoxy base
1-C
4Moieties is randomly by F, Cl, OCH
3Or OCH
2CH
3Replace.Further or in other the embodiment, G is R
1a, R
1b, R
1c, R
1d, R
1e, Ar
1, Ar
2Or Ar
3, and R
0Be H, F, Cl, C
1-C
4Alkyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl.
In some embodiments, G is R
1aAnd Z is F.Further or in other the embodiment, G is R
1a, R wherein
1aBe CH
3, R
0Be H; And Y is Br, I, CF
3Or CH
3In some embodiments, G is R
1bAnd Z is F.Further or in other the embodiment, G is R
1b, Z is F, and R
0Be H, F or OCH
3Further or in other the embodiment, G is R
1b, Z is F, R
0Be H, F or OCH
3, and X is F or CH
3Further or in other the embodiment, G is R
1b, Z is F, R
0Be H, F or OCH
3, X is F or CH
3, and Y is Br, I or CH
3Further or in other the embodiment, G is R
1b, R wherein
1bBe C
3-C
6Cycloalkyl.Further or in other the embodiment, G is R
1b, R wherein
1bBe substituted C
3-C
6Cycloalkyl.Further or in other the embodiment, G is R
1b, R wherein
1bBe unsubstituted C
3-C
6Cycloalkyl.Further or in other the embodiment, G is R
1b, R wherein
1bBe unsubstituted C
3-C
6Cycloalkyl and R
0Be H.Further or in other the embodiment, G is R
1b, R wherein
1bBe isopropyl or cyclopropyl.
In some embodiments, G is R
1c, and Y is I, Br, CH
3Or CF
3Further or in other the embodiment, G is R
1c, Y is I, Br, CH
3Or CF
3, and Z is F.Further or in other the embodiment, G is R
1c, Y is I, Br, CH
3Or CF
3, Z is that F and m are 0.
In some embodiments, G is R
1d, and R
0Be fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino.Further or in other the embodiment, G is R
1d, R
0Be fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino, and X is F, Cl, CH
3Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl.Further or in other the embodiment, G is R
1d, R
0Be fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino, X is F, Cl, CH
3Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl, and Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl.Further or in other the embodiment, G is R
1d, R
0Be fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino, X is F, Cl, CH
3Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl, Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl, and Z is H or F.Further or in other the embodiment, G is R
1dAnd R
0Be F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl.
Further or in other the embodiment, G is R
1d, R
0Be F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl, and X is F, Cl or CH
3Further or in other the embodiment, G is R
1d, R
0Be F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl, X is F, Cl or CH
3, and Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl.Further or in other the embodiment, G is R
1d, R
0Be F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl, X is F, Cl or CH
3, Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl, and Z is H or F.Further or in other the embodiment, G is R
1dAnd R
0Be H; X is F, Cl, CH
3Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl.Further or in other the embodiment, G is R
1d, R
0Be H; X is F, Cl, CH
3Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl, and Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl.Further or in other the embodiment, G is R
1d, R
0Be H; X is F, Cl, CH
3Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl, Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl, and Z is H or F.
Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6The group of cycloalkyl.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the group of H.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are methyl, ethyl, 2-hydroxyethyl, n-pro-pyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3, the group of 4-dihydroxy butyl, isopropyl, 1-methyl-2-hydroxyethyl, normal-butyl, sec-butyl, isobutyl group or 2-hydroxymethyl-3-hydroxypropyl.
Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the group of 2,3-dihydroxypropyl or 3,4-dihydroxy butyl.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the group of 2,3-dihydroxypropyl or 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the R configuration.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the group of 2,3-dihydroxypropyl or 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the S configuration.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the methyl that is randomly replaced by an OH group, perhaps the C that is randomly replaced by one or two OH group
2-C
4The group of alkyl.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6The group of cycloalkyl and R
0Be fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6The group of cycloalkyl and R
0Be F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6The group of cycloalkyl and R
0Be H; X is F, Cl, CH
3Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl.
Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the group of 2,3-dihydroxypropyl or 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the R configuration, the essentially no S isomer of described composition.Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the group of 2,3-dihydroxypropyl, and wherein the chiral carbon among the B is in the R configuration, the essentially no S isomer of described composition.Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the group of 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the R configuration, the essentially no S isomer of described composition.Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the group of 2,3-dihydroxypropyl or 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the S configuration, the essentially no R isomer of described composition.Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the group of 2,3-dihydroxypropyl, and wherein the chiral carbon among the B is in the S configuration, the essentially no R isomer of described composition.Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is C
1-C
6Cycloalkyl and B are the group of 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the S configuration, the essentially no R isomer of described composition.
Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is the group of cyclopropyl.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are the group of H.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are methyl, ethyl, 2-hydroxyethyl, n-pro-pyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3, the group of 4-dihydroxy butyl, isopropyl, 1-methyl-2-hydroxyethyl, normal-butyl, sec-butyl, isobutyl group or 2-hydroxymethyl-3-hydroxypropyl.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the R configuration.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the S configuration.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is cyclopropyl and the methyl of B for randomly being replaced by an OH group, the perhaps C that is randomly replaced by one or two OH group
2-C
4The group of alkyl.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is the group of cyclopropyl and R
0It is the group of fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is the group of cyclopropyl and R
0Be F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl.Further or in other the embodiment, G is R
1d, R wherein
1dBe that C (A) (A ') is the group of cyclopropyl and R
0Be H; X is F, Cl, CH
3Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl.
Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the R configuration, the essentially no S isomer of described composition.Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are 2, the group of 3-dihydroxypropyl, wherein the chiral carbon among the B is in the R configuration, the essentially no S isomer of described composition.Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the R configuration, the essentially no S isomer of described composition.Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the S configuration, the essentially no R isomer of described composition.Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are 2, the group of 3-dihydroxypropyl, wherein the chiral carbon among the B is in the S configuration, the essentially no R isomer of described composition.Further or in other the embodiment, the invention provides and comprise formula I compound compositions, wherein G is R
1d, R wherein
1dBe that C (A) (A ') is that cyclopropyl and B are 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the S configuration, the essentially no R isomer of described composition.
In some embodiments, G is R
1eAnd n is 1.Further or in other the embodiment, G is R
1e, R
0Be H, R
4-6Be H, R
2And R
3Be H, F, Cl, Br, CH independently
3, CH
2F, CHF
2, CF
3, OCH
3, OCH
2F, OCHF
2, OCF
3, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group and mesyl, X is that F and Y are I.
In some embodiments, G is Ar
1, Ar wherein
1It is phenyl; described phenyl randomly is selected from acetylamino, amidino groups, cyano group, carbamyl, methyl carbamyl, dimethylamino formoxyl, 1; 3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3; 4-oxadiazole base, 1; 3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3; a group of 4-thiadiazolyl group, 1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl, N-pyrrolidinyl carbonylamino and mesyl replaces, and randomly is independently selected from F, Cl and CH
31-3 substituting group replace.Further or in other the embodiment, G is Ar
1, Ar wherein
1It is phenyl; described phenyl randomly is selected from acetylamino, amidino groups, cyano group, carbamyl, methyl carbamyl, dimethylamino formoxyl, 1; 3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3; 4-oxadiazole base, 1; 3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3; a group of 4-thiadiazolyl group, 1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl, N-pyrrolidinyl carbonylamino and mesyl replaces, and randomly is independently selected from F, Cl and CH
31-3 substituting group replace R
0Be H, X is that F, Cl or methyl and Y are Br, I, CF
3, C
1-C
3Alkyl, C
2-C
3Thiazolinyl, C
2-C
3Alkynyl, cyclopropyl, OCH
3, OCH
2CH
3Or SCH
3In some embodiments, G is Ar
1, Ar wherein
1Be
And R wherein
2And R
3Be H, F, Cl, CH independently
3, CF
3, OCH
3Further or in other the embodiment, G is Ar
1, Ar wherein
1Be
And R wherein
2And R
3Be H, F, Cl, CH independently
3, CF
3, OCH
3, X is F or CH
3, Y is I, Br or Cl; And Z is F.Further or in other the embodiment, G is Ar
1, Ar wherein
1Be phenyl or monosubstituted phenyl.Further or in other the embodiment, G is Ar
1, Ar wherein
1Be phenyl or monosubstituted phenyl, X is F or CH
3, Y is I, Br or Cl, Z is F; And R
0Be F, methyl, ethyl, methoxyl group or 2-methoxyl group-ethyoxyl.Further or in other the embodiment, G is Ar
1, wherein U is N or CR
2And V is N.Further or in other the embodiment, G is Ar
1, wherein U is N or CR
2And V is CR.Further or in other the embodiment, G is Ar
1, wherein U is N or CR
2, V is CR, R
0Be H, X is that F, Cl or methyl and Y are Br, I, CF
3, C
1-C
3Alkyl, C
2-C
3Thiazolinyl, C
2-C
3Alkynyl, cyclopropyl, OCH
3, OCH
2CH
3Or SCH
3
In some embodiments, G is Ar
2, Ar wherein
2Be
R wherein
7Be H or methyl and R
8Be H, acetylamino, methyl, F or Cl.Further or in other the embodiment, G is Ar
2, Ar wherein
2Be
R wherein
7Be H or methyl, R
8Be H, acetylamino, methyl, F or Cl, R
0Be H, X is F, Cl or methyl, and Y is Br, I, CF
3, C
1-C
3Alkyl, C
2-C
3Thiazolinyl, C
2-C
3Alkynyl, cyclopropyl, OCH
3, OCH
2CH
3Or SCH
3, and Z is F.Further or in other the embodiment, G is Ar
2, Ar wherein
2Be
Wherein U is S or O, and V is CH=, and R
8Be H or CH
3, R
7Be H or methyl, R
8Be H, acetylamino, methyl, F or Cl, R
0Be H, X is F, Cl or methyl, and Y is Br, I, CF
3, C
1-C
3Alkyl, C
2-C
3Thiazolinyl, C
2-C
3Alkynyl, cyclopropyl, OCH
3, OCH
2CH
3Or SCH
3And Z is F.Further or in other the embodiment, R
0Be H.Further or in other the embodiment, R
0Be H, X is that F or Cl and Y are Br, I, CH
2CH
3Or SCH
3
In some embodiments, G is Ar
3, wherein U is-O-.
Further or in other the embodiment, G is R
1a, R wherein
1aAs above definition.Further or in other the embodiment, G is R
1a, and R
0Be H, R wherein
1aAs above definition.Further or in other the embodiment, G is R
1aAnd R
0As above definition except H, and R
1aAs above definition.Further or in other the embodiment, G is R
1a, R wherein
1aBe methyl, single halogenated methyl, C
1-C
3Alkoxy methyl or ring propoxyl group methyl.Further or in other the embodiment, G is R
1a, R wherein
1aBe methyl, single halogenated methyl, C
1-C
3Alkoxy methyl or ring propoxyl group methyl and R wherein
0Be F, Cl, C
1-C
3Alkyl, monochloro are for C
1-C
3Alkyl, C
1-C
3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
Further or in other the embodiment, G is R
1b, R wherein
1bAs above definition.Further or in other the embodiment, G is R
1b, and R
0Be H, R wherein
1bAs above definition.Further or in other the embodiment, G is R
1b, R
0Be that H and Z are F, R wherein
1bAs above definition.Further or in other the embodiment, G is R
1bAnd R
0As above definition except H, and R
1bAs above definition.Further or in other the embodiment, G is R
1b, R wherein
1bBe isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, all randomly be independently selected from F, Cl, OH and OCH
31 or 2 substituting groups replace; Y is Br, I, methyl or trifluoromethyl.Further or in other the embodiment, G is R
1b, R wherein
1bBe isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, randomly be independently selected from F, Cl, OH and OCH
31 or 2 substituting groups replace; Y is Br, I, methyl or trifluoromethyl; And R
0Be: F, Cl, C
1-C
3Alkyl, monochloro are for C
1-C
3Alkyl, C
1-C
3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.Further or in other the embodiment, G is R
1b, R wherein
1bBe isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, all randomly by 1 Cl or by 1 or 2 OH groups replacements; And Y is Br, I, methyl or trifluoromethyl.Further or in other the embodiment, G is R
1b, R wherein
1bBe isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, all randomly by 1 Cl or by 1 or 2 OH groups replacements; Y is Br, I, methyl or trifluoromethyl; And R
0Be F, Cl, C
1-C
3Alkyl, monochloro are for C
1-C
3Alkyl, C
1-C
3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
Further or in other the embodiment, G is R
1c, R wherein
1cAs above definition.Further or in other the embodiment, G is R
1c, and R
0Be H, R wherein
1cAs above definition.Further or in other the embodiment, G is R
1cAnd R
0As above definition except H, and R
1cAs above definition.Further or in other the embodiment, G is R
1c, and R
0Be H, R wherein
1cBe (CH
2)
nO
mR ', wherein m is 0 or 1, and when m was 1, n was 2 or 3, and when m was 0, n was 1 or 2, and R ' is C
1-C
6Alkyl, it randomly is independently selected from F, Cl, OH, OCH
3, OCH
2CH
3And C
3-C
6The 1-3 of cycloalkyl substituting group replaces.More specifically in the embodiment of subgenus, m is that 0, n is 1 or 2, and R ' is C at another
1-C
4Alkyl, it randomly is substituted as mentioned above.More specifically in the embodiment of subgenus, m is that 1, n is 2 or 3, and R ' is C at another
1-C
4Alkyl, it randomly is substituted as mentioned above.At one also more specifically in the embodiment of subgenus, m is that 0, n is 1 or 2, and R ' is C
1-C
4Alkyl, it randomly is selected from OH, OCH
3, Cl and cyclopropyl 1-3 group replace.
Further or in other the embodiment, G is R
1d, R wherein
1dAs above definition.Further or in other the embodiment, G is R
1d, and R
0Be H, R wherein
1dAs above definition.Further or in other the embodiment, G is R
1dAnd R
0As above definition except H, and R
1dAs above definition.Further or in other the embodiment, G is R
1d, and R
0Be H, R wherein
1dBe C (A) (A ') (B)-, wherein B, A and A ' are H or the C that randomly replaced by one or two OH group or halogen atom independently
1-4Alkyl, perhaps the carbon atom that is attached thereto with them of A and A ' forms 3-6 unit saturated rings, described ring randomly comprises one or two hetero atom that is independently selected from O, N and S, and randomly is independently selected from one or two group replacement of methyl, ethyl, fluorine, chlorine, bromine and iodine.
Further or in other the embodiment, G is R
1e, R wherein
1eAs above definition.Further or in other the embodiment, G is R
1e, and R
0Be H, R wherein
1eAs above definition.Further or in other the embodiment, G is R
1eAnd R
0As above definition except H, and R
1eAs above definition.
Further or in other the embodiment, G is Ar
1, Ar wherein
1As above definition.Further or in other the embodiment, G is Ar
1, and R
0Be H, Ar wherein
1As above definition.Further or in other the embodiment, G is Ar
1And R
0As above definition except H, and Ar
1As above definition.
Further or in other the embodiment, G is Ar
2, Ar wherein
2As above definition.Further or in other the embodiment, G is Ar
2, and R
0Be H, Ar wherein
2As above definition.Further or in other the embodiment, G is Ar
2And R
0As above definition except H, and Ar
2As above definition.
Further or in other the embodiment, X is F, Cl or CH
3Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl, and Z is H or F.Further or in other the embodiment, X is F, Cl or CH
3Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl, Z are H or F, and R
0Be halogen, C
1-C
6Alkyl, single halo C
1-C
6Alkyl, C
3-C
6Cycloalkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, phenyl, monosubstituted phenyl, OR
3, O-C (=O) R
4Or C (=O) OR
5Further or in other the embodiment, X is F, Cl or CH
3Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl, Z are H or F, and R
0Be furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl.Further or in other the embodiment, X is F, Cl or CH
3Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl, Z are H or F, and R
0Be F, Cl, C
1-C
4Alkyl, C
1-C
3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
At another more specifically in the embodiment of subgenus, R
1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group randomly replaces by one or two OH group or by one or two halogen atom.
At another more specifically in the embodiment of subgenus, R
0Be halogen, C
1-C
6Alkyl, single halo C
1-C
6Alkyl, C
3-C
6Cycloalkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, phenyl, monosubstituted phenyl, OR
3, O-C (=O) R
4Or C (=O) OR
5And R
1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group randomly replaces by one or two OH group or by one or two halogen atom.
At another more specifically in the embodiment of subgenus, R
0Be furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl; And R
1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group randomly replaces by one or two OH group or by one or two halogen atom.
At another more specifically in the embodiment of subgenus, R
1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group is randomly replaced by one or two OH group, and wherein Y is Br, I, methyl or trifluoromethyl.At another more specifically in the embodiment of subgenus, R
1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group is randomly replaced by one or two fluorine atom or chlorine atom, and wherein Y is Br, I, methyl or trifluoromethyl.At another more specifically in the embodiment of subgenus, R
1dBe cycloalkyl or (1-alkyl (alleyl))-cycloalkyl, wherein said 1-alkyl group is randomly replaced by one or two OH group, and R wherein
0' be: F, Cl, C
1-C
3Alkyl, monochloro are for C
1-C
3Alkyl, C
1-C
3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.At another more specifically in the embodiment of subgenus, R
1dBe tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl, randomly be substituted as mentioned above separately, and wherein Y is Br, I, methyl or trifluoromethyl.At another more specifically in the embodiment of subgenus, R
1dBe oxazole alkyl, thiazolidinyl, isoxazole alkyl, isothiazole alkyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl, randomly be substituted as mentioned above separately, and wherein Y is Br, I, methyl or trifluoromethyl.At another more specifically in the embodiment of subgenus, R
1dBe cyclopropyl or 1-alkyl-cyclopropyl, wherein said 1-alkyl group is randomly replaced by one or two OH group, and R wherein
0' be F, Cl, methyl, ethyl, chloromethyl, C
1-C
2Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.In one even more particular embodiment, R
1dIt is 1-(monohydroxy alkyl) cycloalkyl.In another more particular embodiment, R
1dBe 1-(monohydroxy alkyl) cycloalkyl, wherein R
0' be F, Cl, methyl, ethyl, chloromethyl, C
1-C
2Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.In one even more particular embodiment, R
1dIt is 1-(dihydroxy alkyl) cycloalkyl.In another more particular embodiment, R
1dBe 1-(dihydroxy alkyl) cycloalkyl, wherein R
0' be F, Cl, methyl, ethyl, chloromethyl, C
1-C
2Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
At one more specifically in the embodiment of subgenus, U is CR
2And V is N.More specifically in the embodiment of subgenus, U and V are N at another.At one more specifically in the embodiment of subgenus, U is CR
2And V is CR
3
The invention provides the compound of formula I at one also more specifically in the embodiment of subgenus, wherein G is Ar
1And Ar
1Be phenyl or monosubstituted phenyl, R
0Be F, methyl, ethyl, C
1-C
3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl; X is F, Cl or CH
3Y is I; And Z is F.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is Ar
1, Ar wherein
1Be phenyl or monosubstituted phenyl, R
0Be halogen, C
1-C
6Alkyl, C
3-C
6Cycloalkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, all such alkyl, cycloalkyl, thiazolinyl and alkynyl group randomly is independently selected from 1-3 substituting group replacement of halogen, OH, CN, cyanogen methyl, nitro, phenyl and trifluoromethyl; Perhaps R
0Be phenyl, OR
3, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl.The invention provides the compound of formula I at one more specifically in the embodiment of subgenus, wherein A is Ar
1, Ar wherein
1Be phenyl or monosubstituted phenyl, R
0Be F, Cl, C
1-C
3Alkyl, C
1-C
3Alkoxyl, 2-methoxy ethoxy, C
2-C
3Thiazolinyl, C
2-C
3Alkynyl, trifluoromethyl, phenyl, furyl or thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl; X is F, Cl or methyl; Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl; And Z is F.
Also more specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is Ar
1, Ar wherein
1Be phenyl or monosubstituted phenyl, R
0Be H; X is F, Cl or CH
3Y is Br or I; And Z is F.
In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is Ar
2, Ar wherein
2Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all randomly replaced by methoxycarbonyl, methyl carbamyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen.The invention provides the compound of formula I at one more specifically in the embodiment of subgenus, wherein G is Ar
2, Ar wherein
2Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all randomly replaced by methoxycarbonyl, methyl carbamyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen; R
0Not H; X is F, Cl or CH
3Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl, and Z is H or F.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is Ar
2, Ar wherein
2Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all randomly replaced by methoxycarbonyl, methyl carbamyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen; R
0Be F, Cl, C
1-C
3Alkyl, monochloro are for C
1-C
3Alkyl, C
1-C
3Alkoxyl, trifluoromethoxy, methoxyl group-methoxyl group or 2-methoxyl group-ethyoxyl; X is F, Cl or CH
3Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl, and Z is H or F.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is Ar
2, Ar wherein
2Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all randomly replaced by methoxycarbonyl, methyl carbamyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen; R
0Be H; X is F, Cl or CH
3Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl, and Z is H or F.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is Ar
2, Ar wherein
2Be thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl, all randomly replaced by methoxycarbonyl, methyl carbamyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen; R
0Be H or methoxyl group; X is F, Cl or CH
3Y is I, Br, Cl, CF
3Or C
1-C
3Alkyl, and Z is H or F.
In some embodiments, the compound or pharmaceutically acceptable salt thereof of described formula (I) is selected from
In some embodiments, the invention provides the compound or pharmaceutically acceptable salt thereof of formula I, it is selected from:
Wherein 2-OH carbon is in the R configuration.
In some embodiments, the invention provides the compound or pharmaceutically acceptable salt thereof of formula I, it is selected from:
Wherein 2-OH carbon is in the S configuration.
Further or in other the embodiment, the compound or pharmaceutically acceptable salt thereof of described formula (I) is
Further or in other the embodiment, the compound or pharmaceutically acceptable salt thereof of described formula (I) is
In some embodiments, the invention provides and comprise the formula I compound compositions that is selected from compound shown below, wherein 2-OH carbon is in the R configuration, the essentially no S-isomer of described composition.
In some embodiments, the invention provides and comprise the formula I compound compositions that is selected from compound shown below, wherein 2-OH carbon is in the S configuration, the essentially no R-isomer of described composition.
In some embodiments, the invention provides the compound of formula I, wherein Y is phenyl, pyridine radicals or pyrazolyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein Y is substituted phenyl, pyridine radicals or pyrazolyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein Y is Br or I.In the embodiment of a subgenus, the invention provides the compound of formula I, wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is 1-piperazinyl or 2-piperazinyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is morpholinyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is N-methyl-2-amino-ethyl.In the embodiment of a subgenus, the invention provides the compound of formula I, wherein G is N-methyl-3-amino-n-pro-pyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is (CH
3)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n is 1,2 or 3.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is (CH
3CH
2)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n is 1 or 2.The invention provides the compound of formula I at one more specifically in the embodiment of subgenus, wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl; R
0Be H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is 1-piperazinyl or 2-piperazinyl; R
0Be H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is morpholinyl; R
0Be H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is N-methyl-2-amino-ethyl; R
0Be H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is N-methyl-3-amino-n-pro-pyl; R
0Be H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is (CH
3)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n is 1,2 or 3; R
0Be H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is (CH
3CH
2)
2N-CH
2CH
2-NH-(CH
2)
n-, wherein n is 1 or 2; R
0Be H, halogen or methoxyl group; X is F; And Y is I.
In some embodiments, the invention provides pharmaceutical composition, it comprises compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or the prodrug of formula I.In some embodiments, described pharmaceutical composition also comprises at least a pharmaceutically acceptable carrier.
In some embodiments, the invention provides pharmaceutical composition, it comprises and is selected from:
Compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition also comprises at least a pharmaceutically acceptable carrier.In some embodiments, described compound is in the R configuration.In some embodiments, described compound is in the R configuration, its essentially no S-isomer.In some embodiments, described compound is in the S configuration.
In some embodiments, described compound is in the S configuration, essentially no R-isomer.In some embodiments, described compound is:
In some embodiments, described compound is:
In some embodiments, described compound is:
In some embodiments, described compound is:
The tabulation of the limiting examples of formula I compound
Following table is depicted as each examples for compounds that the invention provides or relate to.Never these examples should be interpreted as limitative examples.
Table 1 is depicted as the embodiment of formula I compound of the present invention, wherein R
0As defined herein, G is R
1a, R wherein
1aAs definition in this table, and in this table, define X, Y and Z.
Table 1
Table 2 is depicted as the embodiment of formula I compound of the present invention, wherein R
0As defined herein, G is R
1b, R wherein
1bAs definition in this table, and in this table, define X, Y and Z.
Table 2
Table 3 is depicted as the embodiment of formula I compound of the present invention, wherein R
0As defined herein, G is R
1c, R wherein
1cAs definition in this table, and in this table, define X, Y and Z.
Table 3
R
1c |
X |
Y |
Z |
|
|
3-(CH
3-SO
2-NH)-phenyl
|
|
CH
2CH
2OH
|
F |
3-(CH
3-SO
2-NH)-phenyl
|
F |
CH
2CH
2OH
|
Cl |
3-(CH
3-SO
2-NH)-phenyl
|
F |
CH
2CH
2OH
|
F |
Phenyl |
F |
CH
2CH
2OH
|
Cl |
Phenyl |
F |
CH
2CH
2OH
|
F |
Phenyl |
F |
CH
2CH
2OH
|
Cl |
The 3-pyridine radicals |
F |
CH
2CH
2OH
|
F |
The 3-pyridine radicals |
F |
CH
2CH
2OH
|
Cl |
The 4-pyridine radicals |
F |
|
|
Pyrazolyl |
|
CH
2CH
2CH
2O H
|
F |
Pyrazolyl |
F |
CH
2CH
2CH
2O H
|
Cl |
The 4-pyridine radicals |
F |
CH
2CH
2CH
2O H
|
F |
The 4-pyridine radicals |
F |
CH
2CH
2CH
2O H
|
Cl |
2-(CH
3-SO
2-NH)-phenyl
|
F |
CH
2CH
2CH
2O H
|
F |
3-(CH
3-SO
2-NH)-phenyl
|
F |
CH
2CH
2CH
2O H
|
Cl |
3-(CH
3-SO
2-NH)-phenyl
|
F |
CH
2CH
2CH
2O H
|
F |
3-(CH
3-SO
2-NH)-phenyl
|
F |
CH
2CH
2CH
2O H
|
Cl |
Phenyl |
F |
|
|
Phenyl |
|
(CH
2)
4OH
|
F |
Phenyl |
F |
(CH
2)
4OH
|
Cl |
The 3-pyridine radicals |
F |
(CH
2)
4OH
|
F |
The 3-pyridine radicals |
F |
(CH
2)
4OH
|
Cl |
The 4-pyridine radicals |
F |
(CH
2)
4OH
|
F |
Pyrazolyl |
F |
(CH
2)
4OH
|
Cl |
Pyrazolyl |
F |
(CH
2)
4OH
|
F |
The 4-pyridine radicals |
F |
(CH
2)
4OH
|
Cl |
The 4-pyridine radicals |
F |
|
|
2-(CH
3-SO
2-NH)-phenyl
|
|
CH
2CH
2OCH
3 |
F |
3-(CH
3-SO
2-NH)-phenyl
|
F |
R
1c |
X |
Y |
Z |
CH
2CH
2OCH
3 |
Cl |
3-(CH
3-SO
2-NH)-phenyl
|
F |
CH
2CH
2OCH
3 |
F |
3-(CH
3-SO
2-NH)-phenyl
|
F |
CH
2CH
2OCH
3 |
Cl |
Phenyl |
F |
CH
2CH
2OCH
3 |
F |
Phenyl |
F |
CH
2CH
2OCH
3 |
Cl |
Phenyl |
F |
CH
2CH
2OCH
3 |
F |
The 3-pyridine radicals |
F |
CH
2CH
2OCH
3 |
Cl |
The 3-pyridine radicals |
F |
|
|
The 4-pyridine radicals |
|
(CH
2)
3OCH
3 |
F |
Pyrazolyl |
F |
(CH
2)
3OCH
3 |
Cl |
Pyrazolyl |
F |
(CH
2)
3OCH
3 |
F |
The 4-pyridine radicals |
F |
(CH
2)
3OCH
3 |
Cl |
The 4-pyridine radicals |
F |
(CH
2)
3OCH
3 |
F |
2-(CH
3-SO
2-NH)-phenyl
|
F |
(CH
2)
3OCH
3 |
Cl |
3-(CH
3-SO
2-NH)-phenyl
|
F |
(CH
2)
3OCH
3 |
F |
3-(CH
3-SO
2-NH)-phenyl
|
F |
(CH
2)
3OCH
3 |
Cl |
3-(CH
3-SO
2-NH)-phenyl
|
F |
|
|
Phenyl |
|
CH
2CH
2OEt
|
F |
Phenyl |
F |
CH
2CH
2OEt
|
Cl |
Phenyl |
F |
CH
2CH
2OEt
|
F |
The 3-pyridine radicals |
F |
CH
2CH
2OEt
|
Cl |
The 3-pyridine radicals |
F |
CH
2CH
2OEt
|
F |
The 4-pyridine radicals |
F |
CH
2CH
2OEt
|
Cl |
Pyrazolyl |
F |
CH
2CH
2OEt
|
F |
Pyrazolyl |
F |
CH
2CH
2OEt
|
Cl |
The 4-pyridine radicals |
F |
[0494]Table 4a and 4b are depicted as the embodiment of formula I compound of the present invention, wherein G=R
1d, Z is F, X is F, and defines R in this table
1dAnd R
0Every row is corresponding to different five kinds of materials in the Y position only in this table.
Table 4a
Y
a=CH
3;Y
b=Br;Y
c=I;Y
d=Cl;
CMPD # |
A,A′ |
B |
R
0 |
1(a-d) |
H,H |
H |
OCH
3 |
2(a-d) |
H,H |
H |
NHCH
3 |
3(a-d) |
H,H |
H |
CH
2CH
3 |
4(a-d) |
H,H |
H |
CH
2CH=CH
2 |
5(a-d) |
H,H |
H |
CN |
6(a-d) |
H,H |
H |
CF
3 |
7(a-d) |
H,H |
H |
F |
8(a-d) |
H,H |
H |
C
6H
6 |
9(a-d) |
H,H |
-CH
2CH(OH)CH
2OH
|
OCH
3 |
10(a-d) |
H,H |
-CH
2CH(OH)CH
2OH
|
NHCH
3 |
11(a-d) |
H,H |
-CH
2CH(OH)CH
2OH
|
CH
2CH
3 |
12(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
OCH
3 |
13(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
NHCH
3 |
14(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
CH
2CH
3 |
15(a-d) |
-(CH
2)
2-
|
CH
3 |
F |
16(a-d) |
-(CH
2)
2-
|
-CH
2CH
2OH
|
F |
17(a-d) |
-(CH
2)
2-
|
-(CH
2)
2CH(OH)CH
2OH
|
F |
18(a-d) |
CH
3,H
|
-(CH
2)
2CH(OH)CH
2OH
|
F |
19(a-d) |
-(CH
2)
2-
|
CH
3 |
OCH
3 |
20(a-d) |
-(C H
2)
2-
|
-CH
2CH
2OH
|
OCH
3 |
21(a-d) |
-(CH
2)
2-
|
-(CH
2)
2CH(OH)CH
2OH
|
OCH
3 |
22(a-d) |
CH
3,H
|
-(CH
2)
2CH(OH)CH
2OH
|
OCH
3 |
23(a-d) |
-(CH
2)
2-
|
CH
3 |
H |
24(a-d) |
-(CH
2)
2-
|
-CH
2CH
2OH
|
H |
25(a-d) |
-(CH
2)
2-
|
-(CH
2)
2CH(OH)CH
2OH
|
H |
26(a-d) |
CH
3,H
|
-(CH
2)
2CH(OH)CH
2OH
|
H |
27(a-d) |
H,H |
H |
OCH
3 |
28(a-d) |
H,H |
H |
NHCH
3 |
29(a-d) |
H,H |
H |
CH
2CH
3 |
30(a-d) |
H,H |
H |
CH
2CH=CH
2 |
31(a-d) |
H,H |
H |
CN |
32(a-d) |
H,H |
H |
CF
3 |
33(a-d) |
H,H |
H |
F |
[0499]
CMPD # |
A,A′ |
B |
R
0 |
34(a-d) |
H,H |
H |
C
6H
6 |
35(a-d) |
H,H |
-CH
2CH(OH)CH
2OH
|
OCH
3 |
36(a-d) |
H,H |
-CH
2CH(OH)CH
2OH
|
NHCH
3 |
37(a-d) |
H,H |
-CH
2CH(OH)CH
2OH
|
CH
2CH
3 |
38(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
OCH
3 |
39(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
NHCH
3 |
40(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
CH
2CH
3 |
41(a-d) |
-(CH
2)
2-
|
CH
3 |
F |
42(a-d) |
-(CH
2)
2-
|
-CH
2CH
2OH
|
F |
43(a-d) |
-(CH
2)
2-
|
-(CH
2)
2CH(OH)CH
2OH
|
F |
44(a-d) |
CH
3,H
|
-(CH
2)
2CH(OH)CH
2OH
|
F |
45(a-d) |
-(CH
2)
2-
|
CH
3 |
OCH
3 |
46(a-d) |
-(CH
2)
2-
|
-CH
2CH
2OH
|
OCH
3 |
47(a-d) |
-(CH
2)
2-
|
-(CH
2)
2CH(OH)CH
2OH
|
OCH
3 |
48(a-d) |
CH
3,H
|
-(CH
2)
2CH(OH)CH
2OH
|
OCH
3 |
49(a-d) |
-(CH
2)
2-
|
CH
3 |
H |
50(a-d) |
-(CH
2)
2-
|
-CH
2CH
2OH
|
H |
51(a-d) |
-(CH
2)
2-
|
-(CH
2)
2CH(OH)CH
2OH
|
H |
52(a-d) |
CH
3,H
|
-(CH
2)
2CH(OH)CH
2OH
|
H |
Table 4b
CMPD # |
A,A′ |
B |
R
0 |
1(a-d) |
H,H |
H |
The 2-furyl |
2(a-d) |
H,H |
H |
1,2,3-triazoles-4-base |
3(a-d) |
H,H |
H |
The 4-imidazole radicals |
4(a-d) |
H,H |
H |
The 2-furyl |
5(a-d) |
H,H |
H |
1,2,3-triazoles-4-base |
6(a-d) |
H,H |
H |
The 4-imidazole radicals |
7(a-d) |
H,H |
-(CH
2)
2CH(OH)CH
2OH
|
The 2-furyl |
8(a-d) |
H,H |
-(CH
2)
2CH(OH)CH
2OH
|
1,2,3-triazoles-4-base |
9(a-d) |
H,H |
-(CH
2)
2CH(OH)CH
2OH
|
The 4-imidazole radicals |
10(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
The 2-furyl |
11(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
1,2,3-triazoles-4-base |
12(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
The 4-imidazole radicals |
13(a-d) |
-(CH
2)
2-
|
CH
3 |
The 4-thiazolyl |
14(a-d) |
-(CH
2)
2-
|
-CH
2CH
2OH
|
The 4-thiazolyl |
15(a-d) |
-(CH
2)
2-
|
-(CH
2)
2CH(OH)CH
2OH
|
The 4-thiazolyl |
16(a-d) |
CH
3,H
|
-(CH
2)
2CH(OH)CH
2OH
|
The 4-thiazolyl |
17(a-d) |
-(CH
2)
2-
|
CH
3 |
The 2-oxazolyl |
18(a-d) |
-(CH
2)
2-
|
-CH
2CH
2OH
|
The 2-oxazolyl |
19(a-d) |
-(CH
2)
2-
|
-(CH
2)
2CH(OH)CH
2OH
|
The 2-oxazolyl |
[0502]
CMPD # |
A,A′ |
B |
R
0 |
20(a-d) |
CH
3,H
|
-(CH
2)
2CH(OH)CH
2OH
|
The 2-oxazolyl |
21(a-d) |
H,H |
H |
The 2-furyl |
22(a-d) |
H,H |
H |
1,2,3-triazoles-4-base |
23(a-d) |
H,H |
H |
The 4-imidazole radicals |
24(a-d) |
H,H |
H |
The 2-furyl |
25(a-d) |
H,H |
H |
1,2,3-triazoles-4-base |
26(a-d) |
H,H |
H |
The 4-imidazole radicals |
27(a-d) |
H,H |
-CH
2CH(OH)CH
2OH
|
The 2-furyl |
28(a-d) |
H,H |
-CH
2CH(OH)CH
2OH
|
1,2,3-triazoles-4-base |
29(a-d) |
H,H |
-CH
2CH(OH)CH
2OH
|
The 4-imidazole radicals |
30(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
The 2-furyl |
31(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
1,2,3-triazoles-4-base |
32(a-d) |
-(CH
2)
2-
|
-CH
2(C
3H
5)
|
The 4-imidazole radicals |
33(a-d) |
-(CH
2)
2-
|
CH
3 |
The 4-thiazolyl |
34(a-d) |
-(CH
2)
2-
|
-CH
2CH
2OH
|
The 4-thiazolyl |
35(a-d) |
-(CH
2)
2-
|
-(CH
2)
2CH(OH)CH
2OH
|
The 4-thiazolyl |
36(a-d) |
CH
3,H
|
-(CH
2)
2CH(OH)CH
2OH
|
The 4-thiazolyl |
37(a-d) |
-(CH
2)
2-
|
CH
3 |
The 2-oxazolyl |
38(a-d) |
-(CH
2)
2-
|
-CH
2CH
2OH
|
The 2-oxazolyl |
39(a-d) |
-(CH
2)
2-
|
-(CH
2)
2CH(OH)CH
2OH
|
The 2-oxazolyl |
40(a-d) |
CH
3,H
|
-(CH
2)
2CH(OH)CH
2OH
|
The 2-oxazolyl |
Table 5a is depicted as the embodiment of formula I compound of the present invention, and wherein G is Ar
1, Ar
2Or R
1d, and R
0Be H, Z is F, and defines G and X in this table.Every row is corresponding to different five kinds of material (Y in the Y position only in this table
a, Y
b, Y
c, Y
dAnd Y
e), Y wherein
a=SCH
3Y
b=Br; Y
c=I; Y
d=Cl; Y
e=CH
3
Table 5a
Y
a=SCH
3;Y
b=Br;Y
c=I;Y
d=Cl;Y
e=CH
3
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
1(a-e) |
Phenyl |
Cl |
2(a-e) |
Phenyl |
F |
3(a-e) |
The 2-F-phenyl |
Cl |
4(a-e) |
The 2-F-phenyl |
F |
5(a-e) |
The 3-F-phenyl |
Cl |
6(a-e) |
The 3-F-phenyl |
F |
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
7(a-e) |
The 4-F-phenyl |
Cl |
8(a-e) |
The 4-F-phenyl |
F |
9(a-e) |
2,4-, two-F-phenyl |
Cl |
10(a-e) |
2,4-, two-F-phenyl |
F |
11(a-e) |
2,5-, two-F-phenyl |
Cl |
12(a-e) |
2,5-, two-F-phenyl |
F |
[0509]
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
13(a-e) |
2,6-, two-F-phenyl |
Cl |
14(a-e) |
2,6-, two-F-phenyl |
F |
15(a-e) |
3,4-, two-F-phenyl |
Cl |
16(a-e) |
3,4-, two-F-phenyl |
F |
17(a-e) |
3,5-, two-F-phenyl |
Cl |
18(a-e) |
3,5-, two-F-phenyl |
F |
19(a-e) |
2,6-, two-F-phenyl |
Cl |
20(a-e) |
2,6-, two-F-phenyl |
F |
21(a-e) |
2,3,4-, three-F-phenyl |
Cl |
22(a-e) |
2,3,4-, three-F-phenyl |
F |
23(a-e) |
3,4,5-, three-F-phenyl |
Cl |
24(a-e) |
3,4,5-, three-F-phenyl |
F |
25(a-e) |
Five-F-phenyl |
Cl |
26(a-e) |
Five-F-phenyl |
F |
27(a-e) |
The 3-Cl-4-F-phenyl |
Cl |
28(a-e) |
The 3-Cl-4-F-phenyl |
F |
29(a-e) |
The 2-Cl-4-F-phenyl |
Cl |
30(a-e) |
The 2-Cl-4-F-phenyl |
F |
31(a-e) |
The 2-F-3-Cl-phenyl |
Cl |
32(a-e) |
The 2-F-3-Cl-phenyl |
F |
33(a-e) |
The 2-F-4-Cl-phenyl |
Cl |
34(a-e) |
The 2-F-4-Cl-phenyl |
F |
35(a-e) |
The 2-F-5-Cl-phenyl |
Cl |
36(a-e) |
The 2-F-5-Cl-phenyl |
F |
37(a-e) |
3-cyano group-4-F-phenyl |
Cl |
38(a-e) |
3-cyano group-4-F-phenyl |
F |
39(a-e) |
The 2-Cl-phenyl |
Cl |
40(a-e) |
The 2-Cl-phenyl |
F |
41(a-e) |
The 3-Cl-phenyl |
Cl |
42(a-e) |
The 3-Cl-phenyl |
F |
43(a-e) |
The 4-Cl-phenyl |
Cl |
44(a-e) |
The 4-Cl-phenyl |
F |
45(a-e) |
2,3-, two-Cl-phenyl |
Cl |
46(a-e) |
2,3-, two-Cl-phenyl |
F |
47(a-e) |
2,5-, two-Cl-phenyl |
Cl |
48(a-e) |
2,5-, two-Cl-phenyl |
F |
49(a-e) |
2,6-, two-Cl-phenyl |
Cl |
50(a-e) |
2,6-, two-Cl-phenyl |
F |
51(a-e) |
3,5-, two-Cl-phenyl |
Cl |
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
52(a-e) |
3,5-, two-Cl-phenyl |
F |
53(a-e) |
2,4-, two-Cl-phenyl |
Cl |
54(a-e) |
2,4-, two-Cl-phenyl |
F |
55(a-e) |
3,4-, two-Cl-phenyl |
Cl |
56(a-e) |
3,4-, two-Cl-phenyl |
F |
57(a-e) |
2,4,6-, three-Cl-phenyl |
Cl |
58(a-e) |
2,4,6-, three-Cl-phenyl |
F |
59(a-e) |
2-Cl-4-CF
3-phenyl
|
Cl |
60(a-e) |
2-Cl-4-CF
3-phenyl
|
F |
61(a-e) |
2-CF
3-phenyl
|
Cl |
62(a-e) |
2-CF
3-phenyl
|
F |
63(a-e) |
3-CF
3-phenyl
|
Cl |
64(a-e) |
3-CF
3-phenyl
|
F |
65(a-e) |
4-CF
3-phenyl
|
Cl |
66(a-e) |
4-CF
3-phenyl
|
F |
67(a-e) |
2-CF
3The O-phenyl
|
Cl |
68(a-e) |
2-CF
3The O-phenyl
|
F |
69(a-e) |
3-CF
3The O-phenyl
|
Cl |
70(a-e) |
3-CF
3The O-phenyl
|
F |
71(a-e) |
4-CF
3The O-phenyl
|
Cl |
72(a-e) |
4-CF
3The O-phenyl
|
F |
73(a-e) |
2-CHF
2The O-phenyl
|
Cl |
74(a-e) |
2-CHF
2The O-phenyl
|
F |
75(a-e) |
2-methyl-5-nitro-phenyl |
Cl |
76(a-e) |
2-methyl-5-nitro-phenyl |
F |
77(a-e) |
2-cyano group-phenyl |
Cl |
78(a-e) |
2-cyano group-phenyl |
F |
79(a-e) |
3-cyano group-phenyl |
Cl |
80(a-e) |
3-cyano group-phenyl |
F |
81(a-e) |
4-cyano group-phenyl |
Cl |
82(a-e) |
4-cyano group-phenyl |
F |
83(a-e) |
4-methoxyl group-phenyl |
Cl |
84(a-e) |
4-methoxyl group-phenyl |
F |
85(a-e) |
3,4-dimethoxy-phenyl |
Cl |
86(a-e) |
3,4-dimethoxy-phenyl |
F |
87(a-e) |
3-carbamyl-phenyl |
Cl |
88(a-e) |
3-carbamyl-phenyl |
F |
89(a-e) |
3-carboxyl-phenyl |
Cl |
90(a-e) |
3-carboxyl-phenyl |
F |
[0511]
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
91(a-e) |
3-(N, N-dimethylamino formoxyl) phenyl |
Cl |
92(a-e) |
3-(N, N-dimethylamino formoxyl) phenyl |
F |
93(a-e) |
4-mesyl-phenyl |
Cl |
94(a-e) |
4-mesyl-phenyl |
F |
95(a-e) |
3-(1,3,4-oxadiazole-2-yl) phenyl |
Cl |
96(a-e) |
3-(1,3,4-oxadiazole-2-yl) phenyl |
F |
97(a-e) |
3-(1,3,4-thiadiazoles-2-yl) phenyl |
Cl |
98(a-e) |
3-(1,3,4-thiadiazoles-2-yl) phenyl |
F |
99(a-e) |
3-(5-methyl isophthalic acid-1,3,4-oxadiazole) phenyl |
Cl |
100(a-e) |
3-(5-methyl isophthalic acid-1,3,4-oxadiazole) phenyl |
F |
101(a-e) |
3-(5-methyl isophthalic acid-1,3,4-thiadiazoles) phenyl |
Cl |
102(a-e) |
3-(5-methyl isophthalic acid-1,3,4-thiadiazoles) phenyl |
F |
103(a-e) |
3-amidino groups-phenyl |
Cl |
104(a-e) |
3-amidino groups-phenyl |
F |
105(a-e) |
3-(1H-tetrazole radical) phenyl |
Cl |
106(a-e) |
3-(1H-tetrazole radical) phenyl |
F |
107(a-e) |
4-acetylaminohydroxyphenylarsonic acid phenyl |
Cl |
108(a-e) |
4-acetylaminohydroxyphenylarsonic acid phenyl |
F |
109(a-e) |
The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl |
Cl |
110(a-e) |
The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl |
F |
111(a-e) |
3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl |
Cl |
112(a-e) |
3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl |
F |
113(a-e) |
3,5-dimethyl isoxazole base |
Cl |
114(a-e) |
3,5-dimethyl isoxazole base |
F |
115(a-e) |
4-(N-morpholinyl sulfonyl) phenyl |
Cl |
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
116(a-e) |
4-(N-morpholinyl sulfonyl) phenyl |
F |
117(a-e) |
The 3-F-benzyl |
Cl |
118(a-e) |
The 3-F-benzyl |
F |
119(a-e) |
The 4-F-benzyl |
Cl |
120(a-e) |
The 4-F-benzyl |
F |
121(a-e) |
3-F-phenyl-ethyl |
Cl |
122(a-e) |
3-F-phenyl-ethyl |
F |
123(a-e) |
4-F-phenyl-ethyl |
Cl |
124(a-e) |
4-F-phenyl-ethyl |
F |
125(a-e) |
The 8-quinolyl |
Cl |
126(a-e) |
The 8-quinolyl |
F |
127(a-e) |
The 2-thienyl |
Cl |
128(a-e) |
The 2-thienyl |
F |
129(a-e) |
2,3-, two-Cl-thiophene-5-base |
Cl |
130(a-e) |
2,3-, two-Cl-thiophene-5-base |
F |
131(a-e) |
1,3,5-trimethyl-1H-pyrazolyl |
Cl |
132(a-e) |
1,3,5-trimethyl-1H-pyrazolyl |
F |
133(a-e) |
1,3-dimethyl-5-Cl-1H-pyrazolyl |
Cl |
134(a-e) |
1,3-dimethyl-5-Cl-1H-pyrazolyl |
F |
135(a-e) |
1-methyl-3-CF
3-1H-pyrazoles-4-base
|
Cl |
136(a-e) |
1-methyl-3-CF
3-1H-pyrazoles-4-base
|
F |
137(a-e) |
2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-Ji |
Cl |
138(a-e) |
2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-Ji |
F |
139(a-e) |
2,4-dimethyl-thiazole-5-base |
Cl |
140(a-e) |
2,4-dimethyl-thiazole-5-base |
F |
141(a-e) |
1,2-dimethyl-1H-imidazoles-4-base |
Cl |
142(a-e) |
1,2-dimethyl-1H-imidazoles-4-base |
F |
[0513]Table 5b is depicted as the embodiment of formula I compound of the present invention, and wherein G is Ar
1, Ar
2Or R
1d, and R
0Be H, Z is F, and defines G and X in this table.Every row is corresponding to different five kinds of material (Y in the Y position only in this table
a, Y
b, Y
c, Y
dAnd Y
e), Y wherein
a=phenyl; Y
b=3-substituted-phenyl; Y
c=3-pyridine radicals; Y
d=4-pyridine radicals; Y
e=3-pyrazolyl.
Table 5b
Y
a=phenyl; Y
b=3-substituted-phenyl; Y
c=3-pyridine radicals; Y
d=4-pyridine radicals; Y
e=3-pyrazolyl
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
1(a-e) |
Phenyl |
Cl |
2(a-e) |
Phenyl |
F |
3(a-e) |
The 2-F-phenyl |
Cl |
4(a-e) |
The 2-F-phenyl |
F |
5(a-e) |
The 3-F-phenyl |
Cl |
6(a-e) |
The 3-F-phenyl |
F |
7(a-e) |
The 4-F-phenyl |
Cl |
8(a-e) |
The 4-F-phenyl |
F |
9(a-e) |
2,4-, two-F-phenyl |
Cl |
10(a-e) |
2,4-, two-F-phenyl |
F |
11(a-e) |
2,5-, two-F-phenyl |
Cl |
12(a-e) |
2,5-, two-F-phenyl |
F |
13(a-e) |
2,6-, two-F-phenyl |
Cl |
14(a-e) |
2,6-, two-F-phenyl |
F |
15(a-e) |
3,4-, two-F-phenyl |
Cl |
16(a-e) |
3,4-, two-F-phenyl |
F |
17(a-e) |
3,5-, two-F-phenyl |
Cl |
18(a-e) |
3,5-, two-F-phenyl |
F |
19(a-e) |
2,6-, two-F-phenyl |
Cl |
20(a-e) |
2,6-, two-F-phenyl |
F |
21(a-e) |
2,3,4-, three-F-phenyl |
Cl |
22(a-e) |
2,3,4-, three-F-phenyl |
F |
23(a-e) |
3,4,5-, three-F-phenyl |
Cl |
24(a-e) |
3,4,5-, three-F-phenyl |
F |
25(a-e) |
Five-F-phenyl |
Cl |
26(a-e) |
Five-F-phenyl |
F |
27(a-e) |
The 3-Cl-4-F-phenyl |
Cl |
28(a-e) |
The 3-Cl-4-F-phenyl |
F |
29(a-e) |
The 2-Cl-4-F-phenyl |
Cl |
30(a-e) |
The 2-Cl-4-F-phenyl |
F |
31(a-e) |
The 2-F-3-Cl-phenyl |
Cl |
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
32(a-e) |
The 2-F-3-Cl-phenyl |
F |
33(a-e) |
The 2-F-4-Cl-phenyl |
Cl |
34(a-e) |
The 2-F-4-Cl-phenyl |
F |
35(a-e) |
The 2-F-5-Cl-phenyl |
Cl |
36(a-e) |
The 2-F-5-Cl-phenyl |
F |
37(a-e) |
3-cyano group-4-F-phenyl |
Cl |
38(a-e) |
3-cyano group-4-F-phenyl |
F |
39(a-e) |
The 2-Cl-phenyl |
Cl |
40(a-e) |
The 2-Cl-phenyl |
F |
41(a-e) |
The 3-Cl-phenyl |
Cl |
42(a-e) |
The 3-Cl-phenyl |
F |
43(a-e) |
The 4-Cl-phenyl |
Cl |
44(a-e) |
The 4-Cl-phenyl |
F |
45(a-e) |
2,3-, two-Cl-phenyl |
Cl |
46(a-e) |
2,3-, two-Cl-phenyl |
F |
47(a-e) |
2,5-, two-Cl-phenyl |
Cl |
48(a-e) |
2,5-, two-Cl-phenyl |
F |
49(a-e) |
2,6-, two-Cl-phenyl |
Cl |
50(a-e) |
2,6-, two-Cl-phenyl |
F |
51(a-e) |
3,5-, two-Cl-phenyl |
Cl |
52(a-e) |
3,5-, two-Cl-phenyl |
F |
53(a-e) |
2,4-, two-Cl-phenyl |
Cl |
54(a-e) |
2,4-, two-Cl-phenyl |
F |
55(a-e) |
3,4-, two-Cl-phenyl |
Cl |
56(a-e) |
3,4-, two-Cl-phenyl |
F |
57(a-e) |
2,4,6-, three-Cl-phenyl |
Cl |
58(a-e) |
2,4,6-, three-Cl-phenyl |
F |
59(a-e) |
2-Cl-4-CF
3-phenyl
|
Cl |
60(a-e) |
2-Cl-4-CF
3-phenyl
|
F |
61(a-e) |
2-CF
3-phenyl
|
Cl |
62(a-e) |
2-CF
3-phenyl
|
F |
[0519]
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
63(a-e) |
3-CF
3-phenyl
|
Cl |
64(a-e) |
3-CF
3-phenyl
|
F |
65(a-e) |
4-CF
3-phenyl
|
Cl |
66(a-e) |
4-CF
3-phenyl
|
F |
67(a-e) |
2-CF
3The O-phenyl
|
Cl |
68(a-e) |
2-CF
3The O-phenyl
|
F |
69(a-e) |
3-CF
3The O-phenyl
|
Cl |
70(a-e) |
3-CF
3The O-phenyl
|
F |
71(a-e) |
4-CF
3The O-phenyl
|
Cl |
72(a-e) |
4-CF
3The O-phenyl
|
F |
73(a-e) |
4-CHF
2The O-phenyl
|
Cl |
74(a-e) |
4-CHF
2The O-phenyl
|
F |
75(a-e) |
2-methyl-5-nitro-phenyl |
Cl |
76(a-e) |
2-methyl-5-nitro-phenyl |
F |
77(a-e) |
2-cyano group-phenyl |
Cl |
78(a-e) |
2-cyano group-phenyl |
F |
79(a-e) |
3-cyano group-phenyl |
Cl |
80(a-e) |
3-cyano group-phenyl |
F |
81(a-e) |
4-cyano group-phenyl |
Cl |
82(a-e) |
4-cyano group-phenyl |
F |
83(a-e) |
4-methoxyl group-phenyl |
Cl |
84(a-e) |
4-methoxyl group-phenyl |
F |
85(a-e) |
3,4-dimethoxy-phenyl |
Cl |
86(a-e) |
3,4-dimethoxy-phenyl |
F |
87(a-e) |
3-carbamyl-phenyl |
Cl |
88(a-e) |
3-carbamyl-phenyl |
F |
89(a-e) |
3-carboxyl-phenyl |
Cl |
90(a-e) |
3-carboxyl-phenyl |
F |
91(a-e) |
3-(N, N-dimethylamino formoxyl) phenyl |
Cl |
92(a-e) |
3-(N, N-dimethylamino formoxyl) phenyl |
F |
93(a-e) |
4-mesyl-phenyl |
Cl |
94(a-e) |
4-mesyl-phenyl |
F |
95(a-e) |
3-(1,3,4-oxadiazole-2-yl) phenyl |
Cl |
96(a-e) |
3-(1,3,4-oxadiazole-2-yl) phenyl |
F |
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
97(a-e) |
3-(1,3,4-thiadiazoles-2-yl) phenyl |
Cl |
98(a-e) |
3-(1,3,4-thiadiazoles-2-yl) phenyl |
F |
99(a-e) |
3-(5-methyl isophthalic acid, 3,4-Evil diazole) phenyl |
Cl |
100(a-e) |
3-(5-methyl isophthalic acid, 3,4-Evil diazole) phenyl |
F |
101(a-e) |
3-(5-methyl isophthalic acid, 3,4-thiadiazoles) phenyl |
Cl |
102(a-e) |
3-(5-methyl isophthalic acid, 3,4-thiadiazoles) phenyl |
F |
103(a-e) |
3-amidino groups-phenyl |
Cl |
104(a-e) |
3-amidino groups-phenyl |
F |
105(a-e) |
3-(1H-tetrazole radical) phenyl |
Cl |
106(a-e) |
3-(1H-tetrazole radical) phenyl |
F |
107(a-e) |
4-acetylaminohydroxyphenylarsonic acid phenyl |
Cl |
108(a-e) |
4-acetylaminohydroxyphenylarsonic acid phenyl |
F |
109(a-e) |
The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl |
Cl |
110(a-e) |
The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl |
F |
111(a-e) |
3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl |
Cl |
112(a-e) |
3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl |
F |
113(a-e) |
3,5-dimethyl isoxazole base |
Cl |
114(a-e) |
3,5-dimethyl isoxazole base |
F |
115(a-e) |
4-(N-morpholinyl sulfonyl) phenyl |
Cl |
116(a-e) |
4-(N-morpholinyl sulfonyl) phenyl |
F |
117(a-e) |
The 3-F-benzyl |
Cl |
118(a-e) |
The 3-F-benzyl |
F |
119(a-e) |
The 4-F-benzyl |
Cl |
120(a-e) |
The 4-F-benzyl |
F |
121(a-e) |
3-F-phenyl-ethyl |
Cl |
122(a-e) |
3-F-phenyl-ethyl |
F |
[0521]
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
123(a-e) |
4-F-phenyl-ethyl |
Cl |
124(a-e) |
4-F-phenyl-ethyl |
F |
125(a-e) |
The 8-quinolyl |
Cl |
126(a-e) |
The 8-quinolyl |
F |
127(a-e) |
The 2-thienyl |
Cl |
128(a-e) |
The 2-thienyl |
F |
129(a-e) |
2,3-, two-Cl-thiophene-5-base |
Cl |
130(a-e) |
2,3-, two-Cl-thiophene-5-base |
F |
131(a-e) |
1,3,5-trimethyl-1H-pyrazolyl |
Cl |
132(a-e) |
1,3,5-trimethyl-1H-pyrazolyl |
F |
133(a-e) |
1,3-dimethyl-5-Cl-1H-pyrazolyl |
Cl |
134(a-e) |
1,3-dimethyl-5-Cl-1H-pyrazolyl |
F |
135(a-e) |
1-methyl-3-CF
3-1H-pyrazoles-4-base
|
Cl |
136(a-e) |
1-methyl-3-CF
3-1H-pyrazoles-4-base
|
F |
137(a-e) |
2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-Ji |
Cl |
Compound # |
G=R
1d、Ar
1Or Ar
2 |
X |
138(a-e) |
2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-Ji |
F |
139(a-e) |
2,4-dimethyl-thiazole-5-base |
Cl |
140(a-e) |
2,4-dimethyl-thiazole-5-base |
F |
141(a-e) |
1,2-dimethyl-1H-imidazol-4 yl |
Cl |
142(a-e) |
1,2-dimethyl-1H-imidazol-4 yl |
F |
143(a-e) |
1-(2-hydroxyethyl) cyclopropyl |
F |
144(a-e) |
1-(3-hydroxypropyl) cyclopropyl |
F |
145(a-e) |
1-(2,3-dihydroxypropyl) cyclopropyl |
F |
146(a-e) |
1-(3,4-dihydroxy butyl) cyclopropyl |
F |
147(a-e) |
1-(2,3-dihydroxypropyl) cyclobutyl |
F |
[0523]Synthesis step
The method of synthetic compound as herein described is provided on the other hand.In some embodiments, compound as herein described can be by following method preparation.Following steps and embodiment are intended to illustrate those methods.Described step and embodiment should not be interpreted as restriction the present invention by any way.Use standard synthetic method well known by persons skilled in the art, perhaps use methods known in the art in conjunction with method as herein described, also can synthesize compound as herein described.In addition, solvent as herein described, temperature and other reaction conditions can change according to those skilled in the art's practice and knowledge.
Raw material for the synthesis of compound described herein can obtain from commercial source, for example Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St.Louis, Mo.), perhaps can synthesis material.Use method known to those skilled in the art and material, for example at March, A
DVANCEDO
RGANICC
HEMISTRYThe 4th edition, (Wiley 1992); Carey and Sundberg, A
DVANCEDO
RGANICC
HEMISTRYThe 4th edition, volume A and B (Plenum2000,2001) and Green and Wuts, P
ROTECTIVEG
ROUPS INO
RGANICS
YNTHESISThe 3rd edition, (Wiley1999) described in (it all intactly quotes adding), other relevant compounds that can synthesize compound as herein described and have different substituents.Universal method for the preparation of compound disclosed herein may come from reaction known in the art, and, in order to introduce the various groups as finding in the formula provided herein, known to the technical staff, can change described reaction by using suitable reagent and condition.Can use following synthetic method as guidance.
Form covalent bond by the electric body of parent and nucleophile reaction
Use the electric body of various parents or nucleophile, can modify compound as herein described to form new functional group or substituting group.Title is listed the covalent bond that generates and the selected example of precursor functional group for the following table of " example of covalent bond and precursor thereof ", and can be as the guidance of the various close electric bodies that get and nucleophile combination.Precursor functional group is expressed as electrophilic group and nucleophilic group.
The example of covalent bond and precursor thereof
The covalent bond product |
The electric body of parent |
Nucleophile |
Amide-type |
Active ester |
Amine/phenyl amines |
Amide-type |
Acyl azide |
Amine/phenyl amines |
Amide-type |
Carboxylic acid halides |
Amine/phenyl amines |
The ester class |
Carboxylic acid halides |
Alcohols/phenol |
The ester class |
The acyl group nitrile |
Alcohols/phenol |
Amide-type |
The acyl group nitrile |
Amine/phenyl amines |
The imines class |
Aldehydes |
Amine/phenyl amines |
The hydrazone class |
Aldehydes or ketone |
The hydrazine class |
Oximes |
Aldehydes or ketone |
The azanol class |
Alkyl amine |
Alkyl halide |
Amine/phenyl amines |
The ester class |
Alkyl halide |
Carboxylic acids |
The thioether class |
Alkyl halide |
Thio-alcohol |
Ethers |
Alkyl halide |
Alcohols/phenol |
The thioether class |
Alkyl sulfonates |
Thio-alcohol |
The ester class |
Alkyl sulfonates |
Carboxylic acids |
Ethers |
Alkyl sulfonates |
Alcohols/phenol |
The ester class |
Anhydrides |
Alcohols/phenol |
Amide-type |
Anhydrides |
Amine/phenyl amines |
The thio phenyl phenols |
The aryl halides |
Thio-alcohol |
The aryl amine |
The aryl halides |
Amine |
The thioether class |
The ethylene imine class |
Thio-alcohol |
[0530]
Borate ester |
Borate |
Glycols |
Amide-type |
Carboxylic acid |
Amine/phenyl amines |
The ester class |
Carboxylic acid |
Alcohols |
The hydrazine class |
Hydrazides |
Carboxylic acid |
N-acylureas or acid anhydrides |
Carbodiimide |
Carboxylic acid |
The ester class |
Diazoparaffins |
Carboxylic acid |
The thioether class |
Epoxides |
Thio-alcohol |
The thioether class |
Halogen acid amide |
Thio-alcohol |
Amino triazine class (ammotriazine) |
The halo triazine |
Amine/phenyl amines |
Triazinyl ether |
The halo triazine |
Alcohols/phenol |
The amidine class |
Imino-ester |
Amine/phenyl amines |
Urea |
Isocyanates |
Amine/phenyl amines |
Carbamate |
Isocyanates |
Alcohols/phenol |
Thiocarbamide |
Isothiocyanates |
Amine/phenyl amines |
The thioether class |
Maleimide |
Thio-alcohol |
Phosphorous acid esters |
Phosphoramidite |
Alcohols |
Silyl ether |
Silicyl halo thing |
Alcohols |
Alkyl amine |
Sulfonic acid esters |
Amine/phenyl amines |
The thioether class |
Sulfonic acid esters |
Thio-alcohol |
The ester class |
Sulfonic acid esters |
Carboxylic acid |
Ethers |
Sulfonic acid esters |
Alcohols |
Sulfonamides |
Sulfonic acid halide |
Amine/phenyl amines |
Sulfonic acid esters |
Sulfonic acid halide |
Phenol/alcohols |
The use of protecting group
In described reaction, the reactive functional groups that may need protection (in end product, needing under the situation of these groups), for example hydroxyl, amino, imino group, thio group (thio) or carboxylic group unnecessarily participate in reaction to avoid them.Protecting group is used for the some or all of reactive groups of blocking-up and stops such group to participate in chemical reaction being removed until described protecting group.In some embodiments, each protecting group can be removed by diverse ways.The protecting group of cutting off under diverse reaction condition satisfies the needs that otherness is removed.Can remove protecting group by acid, alkali and hydrogenolysis.Group for example trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl is unsettled to acid; and; with Cbz group (it can be removed through hydrogenolysis) with in the presence of to the amino group of alkali labile Fmoc radical protection, they can be used to protect carboxyl and hydroxyl reactive group.Use to acid unsettled group for example t-butyl carbamate or use bronsted lowry acids and bases bronsted lowry all stablized but in the presence of the amine of the removable carbamate blocking-up of hydrolysis, uses and can block carboxylic acid and hydroxyl reactive group to alkali labile group such as but not limited to methyl, ethyl and acetyl group.
Carboxylic acid and hydroxyl reactive group can also be used through for example benzyl group blocking-up of the removable protecting group of hydrolysis, and can use for example Fmoc blocking-up of alkali labile group with the amine groups that acid forms hydrogen bond.As this paper example; by changing into simple ester compounds; can protect the carboxylic acid reaction group; perhaps they can be used through the removable protecting group of oxidation for example 2; the blocking-up of 4-dimethoxy-benzyl, and the amino group of coexistence can be used the unsettled silicyl carbamate blocking-up of fluoride.
Allyl-based protection is used to because it is stable, and can remove with metal or π acid catalyst subsequently under the situation of acid and alkaline protecting group existence.For example, to acid unsettled t-butyl carbamate or to alkali labile acetic acid esters amine protecting group in the presence of, the carboxylic acid of pi-allyl blocking-up can be with the reaction deprotection of Pd catalysis.The another form of protecting group is the resin that compound or intermediate can be attached thereto.As long as residue is connected with resin, this functional group just is blocked and can not reacts.In case discharge from resin, described functional group can be in order to reaction.
Protecting group or blocking group can be selected from:
Other protecting groups, and be applicable to that producing protecting group is described in detail in Greene and Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley ﹠amp with the technology of removing them; Sons, New York, NY, 1999, and Kocienski, Protecting Groups, Thieme Verlag, New York, NY is described in 1994, and it intactly quotes adding herein.
The compound of preparation formula I
Can prepare compound of the present invention by the whole bag of tricks.Following steps are intended to illustrate those methods, and the embodiment that provides is intended to illustrate scope of the present invention.These methods and embodiment all should not be interpreted as restriction the present invention by any way.
I. the preparation of formula VI compound is summarized as follows
Above route I has illustrated the method for the sulfamide derivative of preparation formula VI.Can easily prepare 1,2-diamine derivative (formula IV) from the nitro-derivative (formula I) of expectation through two steps.The compound of formula IV can form the sulfonamide of expectation with sulfonyl chloride derivatives (formula V is referring to next route) reaction.Perhaps, before reacting with corresponding sulfonic acid chloride, 1,2-diamine derivative IV protection can be imidazolidinone (formula VII).Deprotection 1 under alkali condition, the raw material (formula VI) that 2-diamines VIII obtains expecting.
II. the general routes outlined of synthetic general formula V compound is summarized as follows
Above route II represents to prepare an example of complicated sulfonic acid chloride.Can synthetic compound XX from IX, it can and be converted to sylvite XII by alkylation.Use SOCl
2Or POCl
3Handle this salt and obtain desired compounds.Other that reported sulfonyl chloride derivatives that preparation is unique at experimental section are method more specifically.
III. route 3 has been summarized the general routes outlined of synthetic general formula X III compound.
Above route III has illustrated the preparation of the sulfamide derivative of general formula X III.For example, under the Suzuki condition, use palladium catalyst, can easily obtain these compounds by making compound VI and acid reaction.
IV. route 4 has been summarized the general routes outlined of synthetic general formula X III compound.
Above route IV has illustrated the preparation of the sulfamide derivative of general formula X V.Vinyl sulfonamide (XIV) reacts the derivative that forms general formula X V with amine.
Other forms of formula I compound
The isomer of formula I compound
Compound as herein described can exist with geometric isomer.Compound as herein described may have one or more pairs of keys.The given compound of this paper comprises all cis, trans, anti-(E) and suitable (Z) isomer and their corresponding mixtures.In some cases, compound can exist with dynamic isomer.Compound as herein described comprises all possible dynamic isomer in the molecular formula described herein.Compound as herein described can have one or more chiral centres, and each center can exist with R or S configuration.Compound as herein described comprises all diastereomer forms, enantiomeric form and epimer form, and their corresponding mixtures.In other embodiments of Compounds and methods for provided herein, by single preparation process, merging or transform the enantiomer of gained mutually and/or the mixture of diastereoisomer, also can be used for application as herein described.Racemic mixture by making described compound and the reaction of the resolving agent of optical activity form a pair of diastereomeric compound, separating obtained diastereomer also reclaims optically pure enantiomer, and compound as herein described can be prepared into their stereoisomer separately.Use the non-enantiomer derivative of the covalency of compound as herein described, perhaps can use dissociable complex compound (as the diastereoisomeric salt of crystallization), can carry out enantiomer and split.Diastereomer has different physical property (as fusing point, boiling point, solvability, reactivity etc.), can be easily separated by utilizing these differences.By chiral chromatography or based on the separation/disassemble technique of dissolubility difference, can separate diastereomer.Then, reclaim optically pure enantiomer and resolving agent by any feasible method that can not cause racemization.At Jean Jacques, Andre Collet, Samuel H.Wilen, " Enantiomers, Racemates and Resolutions, " John Wiley and Sons, Inc., in 1981, can find to be applicable to the more detailed description that from the compound racemic mixture, splits their alloisomerism body method, intactly quote adding herein.
The formula I compound of mark
Isotope-labeled formula I compound and sanatory method are also described herein.For example, the invention provides method by the isotope-labeled formula I compounds for treating of administration disease.Can be with the described isotope-labeled formula I compound of the mode administration of pharmaceutical composition.Therefore, the compound of formula I also comprises isotope-labeled compound, it is identical with those compounds that this paper enumerates, but in fact one or more atoms are had the different atomic mass of the atomic mass usually found with occurring in nature or mass number or the atom of mass number substitutes.Can be contained in isotopic example in the compound of the present invention and comprise the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, respectively for example
2H,
3H,
13C,
14C,
15N,
18O,
17O,
31P,
32P,
35S,
18F and
36Cl.Comprise other isotopic compounds as herein described of above-mentioned isotope and/or other atoms or the acceptable salt of its pharmacy within the scope of the invention.Some isotope-labeled formula I compound, for example radioisotope for example
3H and
14C is contained in those compounds wherein, is useful in medicine and/or substrate tissue distribution mensuration.Tritium namely
3H and carbon-14 are namely
14The C isotope is easy to preparation usually and detects.In addition, for example deuterium is namely with heavier isotope
2H replaces some the treatment advantage can generate because of due to the better metabolic stability, for example, increases in the body half life period or reduces the dosage demand, and so may need in some cases.By using method as herein described, replace the heterotope labelled reagent with the isotope labeling reagent that is easy to get, generally can prepare the acceptable salt of isotope-labeled compound and pharmacy thereof.
Compound as herein described can pass through the additive method mark, and described additive method includes but not limited to use chromophore or fluorophor, bioluminescence marker or chemiluminescent labeling.
The acceptable salt of the pharmacy of formula I compound
The acceptable salt of pharmacy and the sanatory method of formula I compound have also been described herein.For example, the invention provides method by the acceptable salts for treating disease of pharmacy of Medicine-feeding type I compound.Can be with the acceptable salt of pharmacy of the mode Medicine-feeding type I compound of pharmaceutical composition.
Therefore, compound as herein described can be prepared into the acceptable salt of pharmacy, and for example alkali metal ion, alkaline-earth metal ions or aluminium ion substitute the acid proton that exists in parent compound by metal ion; During perhaps with the organic base coordination, form the acceptable salt of described pharmacy.By free acid form and the acceptable inorganic base of pharmacy or the organic base reaction that makes compound as herein described, also can prepare base addition salts, described inorganic base or organic base include but not limited to for example for example aluminium hydroxide, slaked lime, potassium hydroxide, sodium carbonate, sodium hydroxide etc. of monoethanolamine, diethanol amine, triethanolamine, tromethamine, N-methylglucosamine etc. and inorganic base of organic base.In addition, use the salt of raw material or intermediate, can prepare the salt form of compound disclosed herein.
In addition, compound as herein described can be prepared into the acceptable salt of pharmacy, the acceptable inorganic or organic acid reaction of its free alkali form by described compound and pharmacy forms, and described inorganic or organic acid includes but not limited to: inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc. for example; With organic acid acetic acid for example; propionic acid; caproic acid; the pentamethylene propionic acid; glycolic acid; pyruvic acid; lactic acid; malonic acid; succinic acid; malic acid; maleic acid; fumaric acid; the Q-toluenesulfonic acid; tartaric acid; trifluoroacetic acid; citric acid; benzoic acid; 3-(4-hydroxy benzoyl) benzoic acid; cinnamic acid; mandelic acid; aryl sulfonic acid; methanesulfonic acid; ethyl sulfonic acid; 1; the 2-ethane disulfonic acid; the 2-ethylenehydrinsulfonic acid; benzene sulfonic acid; the 2-naphthalene sulfonic acids; 4-methyl bicycle-[2.2.2] oct-2-ene-1-carboxylic acid; glucoheptonic acid; 4,4 '-di-2-ethylhexylphosphine oxide-(3-hydroxyl-2-alkene-1-carboxylic acid); the 3-phenylpropionic acid; trimethylace tonitric; butylacetic acid; dodecyl sulphate; gluconic acid; glutamic acid; hydroxynaphthoic acid; salicylic acid; stearic acid and muconic acid.
The solvate of the compound of formula I
This paper has also described the solvate and the method for the treatment of disease of the compound of formula I.For example, the invention provides the method for the treatment of disease by the solvate of Medicine-feeding type I compound.Can be with the solvate of the mode Medicine-feeding type I compound of pharmaceutical composition.
Solvate comprises stoichiometric or non-stoichiometric quantity of solvent, and can for example form in the process of crystallization such as water, ethanol with the pharmacy acceptable solvent.When described solvent is water, form hydrate, perhaps when described solvent is alcohol, form alcohol adduct.In method as described herein, can prepare or form the solvate of compound as herein described easily.Only as example, by the mixture recrystallization from water/organic solvent, can prepare the hydrate of compound as herein described easily, the organic solvent of use includes but not limited to diox, oxolane or methyl alcohol.In addition, the compound that provides of this paper can exist with form solvation and solvation.Generally speaking, the purpose of the Compounds and methods for that provides for this paper thinks that described solvation form is equivalent to the not form of solvation.
The polymorph of the compound of formula I
Polymorph and the sanatory method of the compound of formula I are also described herein.For example, the polymorph that the invention provides the compound by Medicine-feeding type I is treated the method for disease.Can be with the polymorph of the mode Medicine-feeding type I compound of pharmaceutical composition.
Therefore, compound as herein described comprises all their crystal types, is called polymorph.Polymorph comprises the different crystal accumulation arrangement that the identical element of compound is formed.Polymorph may have different X-ray diffractograms, infrared spectrum, fusing point, density, hardness, crystalline form, optics and electrical properties, stability and dissolubility.Various factors for example recrystallization solvent, crystallization rate and reserve temperature may to cause that single crystal form accounts for leading.
The crystalline polymorph of N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide
The invention still further relates to N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide that demonstrates the particular powder X-ray diffractogram:
Crystalline polymorph A.In some embodiments, described x-ray diffractogram of powder comprises at least about the peak shown in Fig. 5 of 50%.In some embodiments, described x-ray diffractogram of powder comprises at least about the peak shown in Fig. 5 of 70%.In some embodiments, described x-ray diffractogram of powder comprises at least about the peak shown in Fig. 5 of 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.
The invention still further relates to the crystalline polymorph A of N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, it demonstrates specific differential scanning calorimetric figure.In some embodiments, the differential scanning calorimetric figure shown in described specific differential scanning calorimetric figure and Fig. 6 is basic identical.In some embodiments, described crystalline polymorph A has and is about 143 ℃ fusing point starting point through determine with dsc method.
The invention still further relates to N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) polymorph of cyclopropane-1-sulfonamide, it makes unbodied N-(S)-(3 by comprising from solvent, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the method preparation of the step of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization.The invention still further relates to N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) polymorph of cyclopropane-1-sulfonamide, it makes unbodied N-(S)-(3 by comprising from the mixture of hexane and ethyl acetate, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the method preparation of the step of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization.
The invention still further relates to pharmaceutical composition, it comprises the N-(S)-(3 of effective dose, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-crystalline polymorph A and pharmaceutically acceptable carrier or the carrier of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.Other aspects of the present invention relate to pharmaceutical composition, and it comprises described crystalline polymorph A and at least a excipient or carrier.
The crystalline polymorph A of N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is used to treatment or pre-anti-cancer or inflammatory disease.The invention further relates to the method for the treatment of or pre-anti-cancer or inflammatory disease, it comprises the N-(S)-(3 to experimenter's effective dosage that these needs are arranged, the crystalline polymorph A of 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.Other other aspects of the present invention relate to the method for the treatment of or preventing inflammatory disease, and it comprises to the crystalline polymorph of experimenter's effective dosage that these needs are arranged.Further aspect of the present invention relates to the method for the treatment of or preventing proliferative diseases, and it comprises to the crystalline polymorph of experimenter's effective dosage that these needs are arranged.
The prodrug of formula I compound
This paper has also described prodrug and the sanatory method of formula I compound.For example, the invention provides the method for the treatment of disease by the prodrug of Medicine-feeding type I compound.Can be with the prodrug of the mode Medicine-feeding type I compound of pharmaceutical composition.
Prodrug generally is the precursor of medicine, and to patient's administration and after absorbing subsequently, it is converted into active or active stronger material through some process, for example the conversion by metabolic pathway.Some prodrugs have chemical group at prodrug, and described chemical group makes the prodrug activity lower and/or give described medicine dissolubility or some other character.When described chemical group when described prodrug is cut off and/or modifies, produce active medicine.Because prodrug may be easier to administration than parent drug in some cases, all they normally useful.For example, prodrug may be biological available by oral administration, and its parent is not biological available.Than parent drug, prodrug also may have better dissolubility in pharmaceutical composition.The limiting examples of prodrug can be compound as described herein, administration promotes to pass through the transportation of cell membrane as ester (" prodrug ") with it, water-soluble unfavorable to mobility at the cell membrane place, but, in case it enters cell (water-soluble therein is favourable), just be hydrolyzed into the active entity of carboxylic acid through metabolism.Other examples of prodrug may be and the small peptide (polyaminoacid) of acid groups Cheng Jian, state peptide in this key place and discharge active part through metabolism.
In order to be used as dressing agent to promote drug transport to site-specific sex organization, prodrug can be designed to reversible medicaments derivative.So far, thus the design of prodrug be for effective water solubility of improving the treatment compound be that targeting is carried out in the zone of primary solvent to water.Referring to for example Fedorak etc., Am.J.Physiol., 269:G210-218 (1995); McLoed etc., Gastroenterol, 106:405-413 (1994); Hochhaus etc., Biomed.Chrom., 6:283-286 (1992); J.Larsen and H.Bundgaard, Int.J.Pharmaceutics, 37,87 (1987); J.Larsen etc., Int.J.Pharmaceutics, 47,103 (1988); Sinkula etc., J.Pharm.Sci., 64:181-210 (1975); T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, A.C.S. meeting series the 14th volume; With Edward B.Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, intactly add herein.
In addition, (for example, more details are referring to Saulnier etc. can to prepare the prodrug derivant of compound as described herein by method known to those skilled in the art, (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p.1985).Only as example; formula I compound by making non-derivative and suitable carbamoyl reagent are such as but not limited to 1; 1-acyloxy alkyl chloride formic acid esters (1,1-acyloxyalkylcarbanochloridate), reaction such as p-nitrophenyl carbonic ester, can prepare suitable prodrug.Produce derivative as described herein through metabolism in the prodrug forms of compound described herein, wherein said prodrug body, be included within the scope of the claims.In fact, some compound described herein may be the prodrug of another derivative or reactive compound.
In some embodiments, prodrug comprises compound, and wherein the polypeptide chain of amino acid residue or two or more (as 2,3 or 4) amino acid residue is by amido link or covalently bound free amino, hydroxyl or the hydroxy-acid group to compound of the present invention of ester bond.Described amino acid residue includes but not limited to use usually 20 kinds of naturally occurring amino acid of trigram symbolic representation, also comprises 4-hydroxy-proline, oxylysine, desmosine, isodensmosine, 3-Methyl histidine, norvaline, Beta-alanine, γ-An Jidingsuan, citrulling, homocysteine, homoserine, ornithine and methionine sulfone.The prodrug that also comprises other types.
Formula I compound with free amino, hydroxyl or carboxylic group can change into prodrug.For example, the free carboxy group can be derived and changed into acid amides or Arrcostab.As at Advanced Drug Delivery Reviews 1996,19, summarize in 115, the free hydroxyl group group can be changed into the group that includes but not limited to hemisuccinic acid ester, phosphate, dimethylamino acetic acid esters and phosphinylidyne oxygen ylmethyl oxygen base carbonyl by deriving.The carbamate prodrugs of hydroxyl and amino group, and in carbonic ester prodrug, sulphonic acid ester and the sulfuric ester of oh group be also included within.
Comprising also that oh group is derived changes into (acyloxy) methyl ether and (acyloxy) ethyl ether; wherein said acyl group can be Arrcostab; it randomly is included but the group that is not limited to ether, amine and carboxylic acid functional replaces, and perhaps wherein said carboxyl groups is aforesaid amino-acid ester.This type of prodrug is described in J.Med.Chem.1996, in 39,10.Unhindered amina can also be derived turns to acid amides, sulfonamide or phosphamide.All these prodrug moieties can be introduced the group that includes but not limited to ether, amine or carboxylic acid functional.
Site on the aromatic ring part of formula I compound may be easy to take place various metabolic responses, therefore introduces suitable substituting group at described aromatic ring structure and can reduce, minimizes or eliminate this metabolic pathway.
Pharmaceutical composition
This paper describes pharmaceutical composition.In some embodiments, described pharmaceutical composition comprises formula I compound or the acceptable salt of its pharmacy of effective dose.In some embodiments, described pharmaceutical composition comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative and at least a pharmaceutically acceptable carrier of effective dose.In some embodiments, described pharmaceutical composition is used for the treatment of illness.In some embodiments, described pharmaceutical composition is used for the treatment of the illness in the mammal.In some embodiments, described pharmaceutical composition is used for the treatment of the illness among the mankind.
Further, the present invention relates to pharmaceutical composition, it comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition also comprises pharmaceutically acceptable carrier.Reagent, filler, adhesive, adsorbent, buffer, disintegrant, solubilizer, other carriers that such composition can comprise assistant agent, excipient and preservative, be used for postponing absorption, and other inert fractions.The compound method of such composition is well known in the art.
In some embodiments, described pharmaceutical composition is the form that is suitable for oral administration.Further or in other the embodiment, described pharmaceutical composition is the form of tablet, capsule, pill, powder, sustained release preparation, solution, supensoid agent, be aseptic solution, supensoid agent or emulsion for parenteral injection, being ointment or cream for topical, is suppository for rectally perhaps.
Further or in other the embodiment, described pharmaceutical composition adopts the unit dosage forms that is suitable for the accurate dosage of single-dose.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, described pharmaceutical composition is used for to the mammal administration.Further or in other the embodiment, described mammal is human.
Further or in other the embodiment, described pharmaceutical composition also comprises pharmaceutical carriers, excipient and/or assistant agent.Further or in other the embodiment, described pharmaceutical composition also comprises at least a therapeutic agent.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from by alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is taxol, bortezomib or the two.Further or in other the embodiment, the described pharmaceutical composition of administration is with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, described pharmaceutical composition comprises the pharmaceutically acceptable salt of formula I compound.
The invention still further relates to and comprise
Composition.In some embodiments, the 2-OH carbon on the described compound is in the R configuration.In some embodiments, the S-isomer of the essentially no described compound of composition.In some embodiments, described compound comprises the S-isomer that is less than 10% described compound.In some embodiments, described compound comprises the S-isomer that is less than 5% described compound.In some embodiments, described compound comprises the S-isomer that is less than 1% described compound.In some embodiments, described compound is in the R configuration.
In some embodiments, the 2-OH carbon on the described compound is in the S configuration.In some embodiments, the R-isomer of the essentially no described compound of composition.In some embodiments, described compound comprises the R-isomer that is less than 10% described compound.In some embodiments, described compound comprises the R-isomer that is less than 5% described compound.In some embodiments, described compound comprises the R-isomer that is less than 1% described compound.In some embodiments, described compound is the S configuration.
In some embodiments, described composition comprises the compound at least about 50%, and described compound exhibits goes out to comprise the x-ray diffractogram of powder at the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 50%.In some embodiments, described x-ray diffractogram of powder comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.
In some embodiments, described composition comprises the compound at least about 75%, and described compound exhibits goes out to comprise the powder x-ray diffraction figure at the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 50%.In some embodiments, described x-ray diffractogram of powder comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.
In some embodiments, described composition comprises the compound at least about 90%, and described compound exhibits goes out to comprise the powder x-ray diffraction figure at the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 50%.In some embodiments, described x-ray diffractogram of powder comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.
In some embodiments, in the described composition basically whole described compounds all demonstrate the powder x-ray diffraction figure that comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 50%.In some embodiments, described x-ray diffractogram of powder comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak of identifying in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.
In some embodiments, be present in described crystalline polymorph in the described composition and have 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.
In some embodiments, described composition comprises the compound at least about 50%, and described compound exhibits goes out and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.
In some embodiments, described composition comprises the compound at least about 75%, and described compound exhibits goes out and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.
In some embodiments, described composition comprises the compound at least about 90%, and described compound exhibits goes out and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.
In some embodiments, in the described composition basically whole described compounds all demonstrate and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.
In some embodiments, N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2, the 3-dihydroxypropyl) polymorph of cyclopropane-1-sulfonamide makes unbodied N-(3 by comprising, the method of the step of 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization prepares.In some embodiments, described crystallisation step comprises crystallization from the mixture of ethyl acetate and heptane, and for example, the ratio of the mixture of ethyl acetate and heptane is that about 1-4 part ethyl acetate is than about 2-10 part heptane, or more specifically, ratio is that about 2 parts of ethyl acetate are than about 5 parts of heptane.
In some embodiments, described compound is prepared into the preparation of the described compound of direct release.In some embodiments, described compound is prepared into the preparation that continues to discharge described compound.In other embodiments, described compound is prepared into the preparation that postpones to discharge described compound.
In some embodiments, described composition is Tabules.In other embodiments, described composition is capsule formulation.Described composition can be prepared into capsule or Tabules, and can use optional composition and the preparation method of broad range, list of references: (1) Remington, The Science and Practice of Pharmacy, the 20th edition, 2000, (2) Pharmaceutical Dosage Forms Tablets 1-3 volume, 1989 and (3) ModernPharmaceuticals the 4th edition, 2002.Can use a series of preparation methods, it comprises dry mixed method, wet granulation process, rolled-on method, extrusion, spheronization, coating method and spray drying process.Soft gelatin formulation and preparation method also are fit to.
In some embodiments, described composition comprises filler or thinner.In various embodiments, described filler or thinner are selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, sompressible sugar, calcium phosphate, calcium sulphate, calcium carbonate, calcium silicates and starch.In other embodiments, described filler or thinner are microcrystalline celluloses.
In some embodiments, described composition comprises disintegrant.In various embodiments, described disintegrant is selected from cross-linked carboxymethyl cellulose sodium, primojel, Crospovidone, methylcellulose, alginic acid, mosanom, starch derivatives, bentonite and aluminium-magnesium silicate.In certain embodiment, described disintegrant is cross-linked carboxymethyl cellulose sodium.
In some embodiments, described composition comprises lubricant.In various embodiments, described lubricant is selected from dolomol, metallic stearate, talcum, sodium stearyl fumarate and stearic acid.In some embodiments, described lubricant is dolomol.
In some embodiments, described composition comprises wetting agent or surfactant.In various embodiments, described wetting agent or surfactant are selected from lauryl sodium sulfate, glycerine, sorbitan monooleate, Span60, polyoxyethylene anhydrous sorbitol laurate, palmitate, stearate, oleate or six oleates, the pure and mild sorbitan mono-laurate of polyoxyethylene stearyl.In some embodiments, described wetting agent or surfactant are lauryl sodium sulfate.
Can also add other excipient for example glidant, flavor enhancement and colouring agent.At The Handbook ofPharmaceutical Excipients, the 5th edition, 2005 and FDA non-active ingredient database in can find other optional excipient.
The invention still further relates to composition, it comprises:
About 1mg structure is
Compound (such as in any above-mentioned embodiment definition);
About 222.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises:
About 10mg structure is
Compound (such as in any above-mentioned embodiment definition);
About 213.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises:
About 20mg structure is
Compound (such as in any above-mentioned embodiment definition);
About 203.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises:
About 40mg structure is
Compound (such as in any above-mentioned embodiment definition);
About 183.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises: the structure of about 0.4 weight % is
Compound (such as in any above-mentioned embodiment definition); Pharmaceutically acceptable carrier or carrier with about 99.6 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 92.6 weight % of described composition.Further or in other the embodiment, described composition also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.
The invention still further relates to composition, it comprises: the structure of about 4.2 weight % is
Compound (such as in any above-mentioned embodiment definition); Pharmaceutically acceptable carrier or carrier with about 95.8 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 88.8 weight % of described composition.Further or in other the embodiment, described composition also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.
The invention still further relates to composition, it comprises: the about 2 weight % extremely structure of about 10 weight % are
![Figure GPA00001070418800833](https://patentimages.storage.googleapis.com/ad/45/3c/1caf4717280b7d/GPA00001070418800833.png)
Compound (such as in any above-mentioned embodiment definition); With pharmaceutically acceptable carrier or the carrier of about 98 weight % to about 90 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.Further or in other the embodiment, described composition also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; About 0.1 weight % is to the lauryl sodium sulfate of about 2 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.Further or in other the embodiment, described composition also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.
The invention still further relates to composition, it comprises:
About 1mg structure is
Compound;
About 222.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises:
About 10mg structure is
Compound;
About 213.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises:
About 20mg structure is
Compound;
About 203.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises:
About 40mg structure is
Compound;
About 183.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises: the structure of about 0.4 weight % is
Compound; Pharmaceutically acceptable carrier or carrier with about 99.6 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 92.6 weight % of described composition.Further or in other the embodiment, described composition also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.
The invention still further relates to composition, it comprises: the structure of about 4.2 weight % is
Compound; Pharmaceutically acceptable carrier or carrier with about 95.8 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 88.8 weight % of described composition.Further or in other the embodiment, described composition also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.
The invention still further relates to composition, it comprises: the about 2 weight % extremely structure of about 10 weight % are
![Figure GPA00001070418800852](https://patentimages.storage.googleapis.com/d3/bb/2d/b4859177c7c17c/GPA00001070418800852.png)
Compound; With pharmaceutically acceptable carrier or the carrier of about 98 weight % to about 90 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.Further or in other the embodiment, described composition also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; About 0.1 weight % is to the lauryl sodium sulfate of about 2 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.Further or in other the embodiment, described composition also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.
The invention still further relates to composition, it comprises:
About 1mg structure is
Compound;
About 222.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises:
About 10mg structure is
Compound;
About 213.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises:
About 20mg structure is
Compound;
About 203.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises:
About 40mg structure is
Compound;
About 183.2mg microcrystalline cellulose;
About 12.0mg cross-linked carboxymethyl cellulose sodium;
About 2.4mg lauryl sodium sulfate; With
About 2.4mg dolomol.
The invention still further relates to composition, it comprises: about 0.4 weight % structure is
Compound; Pharmaceutically acceptable carrier or carrier with about 99.6 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 92.6 weight % of described composition.Further or in other the embodiment, described composition also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.
The invention still further relates to composition, it comprises: the structure of about 4.2 weight % is
Compound; Pharmaceutically acceptable carrier or carrier with about 95.8 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 88.8 weight % of described composition.Further or in other the embodiment, described composition also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.
The invention still further relates to composition, it comprises: the about 2 weight % extremely structure of about 10 weight % are
Compound; With pharmaceutically acceptable carrier or the carrier of about 98 weight % to about 90 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.Further or in other the embodiment, described composition also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; About 0.1 weight % is to the lauryl sodium sulfate of about 2 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.Further or in other the embodiment, described composition also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.
Also describe pharmaceutical composition herein, it comprises the crystalline polymorph A of N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide of effective dose.In some embodiments, described pharmaceutical composition comprises the N-(S)-(3 of effective dose, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-crystalline polymorph A and at least a pharmaceutically acceptable carrier of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.In some embodiments, described pharmaceutical composition is used for the treatment of illness.In some embodiments, described pharmaceutical composition is used for the treatment of the illness in the mammal.In some embodiments, described pharmaceutical composition is used for the treatment of the illness among the mankind.In some embodiments, described pharmaceutical composition is used for the treatment of or prevents inflammatory disease.In some embodiments, described pharmaceutical composition is used for the treatment of or prevents proliferative diseases.
Comprise the described compound of polymorph and the using method of described composition
In other respects, the present invention relates to obtain among the patient method of effect, it comprises that wherein said effect is selected from the inhibition to various cancers, immunological disease and inflammatory disease to the formula I compound of patient's effective dosage or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, with the composition administration as the composition that also comprises pharmaceutically acceptable carrier or carrier of described compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described effect is to suppress various cancers.Further or in other the embodiment, described effect is to suppress immunological disease.Further or in other the embodiment, described effect is to suppress inflammatory disease.
Any composition described herein and prescription can be used for the method that this part provides.
In some embodiments, administration comprises formula I compound compositions, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy or operation or their any combination.Further or in other the embodiment, comprise formula I compound compositions and at least a therapeutic agent administering drug combinations.
In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), the described composition of topical or rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
In some embodiments of composition provided herein and method, the MEK kinases inhibitor that also comprises formula I compound is provided, the compound of wherein said formula I exists to the amount of about 200mg with about 0.1m.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 100mg with about 0.2mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 90mg with about 0.3mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 80mg with about 0.4mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 70mg with about 0.5mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 80mg with about 0.4mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 70mg with about 0.5mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 60mg with about 1mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 50mg with about 1.5mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 45mg with about 2mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 40mg with about 2.5mg.In further embodiment, the MEK kinases inhibitor of the formula I compound that the dosage that also comprises to provide herein exists is selected from
![Figure GPA00001070418800881](https://patentimages.storage.googleapis.com/d8/d4/54/d3fdb7498d3df8/GPA00001070418800881.png)
In some embodiments of composition provided herein and method, the MEK kinases inhibitor that also comprises formula I compound is provided, the compound of wherein said formula I is with about 0.1mg, about 0.2mg, about 0.25mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4.0mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 11.5mg, about 12mg, about 12.5mg, and/or about 13mg, the amount of about 14mg or about 15mg exists.In further embodiment, the formula I compound that exists with dosage provided herein is selected from
In some embodiments of composition provided herein and method, the MEK kinases inhibitor that also comprises formula I compound is provided, and the compound of wherein said formula I is with about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 125mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 175mg, about 180mg, the amount of about 190mg or about 200mg exists.In further embodiment, the formula I that exists with dosage provided herein
Compound is selected from
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality of suffering from cancer is mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
In some respects, the present invention relates to treat the method for disease in the individuality of suffering from described disease, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.
In other respects, the present invention relates to treat the method for illness in the mammal, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.
In other respects, the present invention relates to treat the method for illness among the mankind, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.
Disease and illness that MEK regulates
Also described herein by making MEK contact the method for regulating the MEK activity with a certain amount of formula I compound that is enough to regulate the MEK activity.Adjusting can be to suppress or activation MEK activity.In some embodiments, the invention provides by making the method for MEK and a certain amount of formula I compound contact inhibition MEK activity that is enough to suppress the MEK activity.In some embodiments, the invention provides by making the method for MEK activity in solution and the described solution of a certain amount of formula I compound contact inhibition that is enough to suppress MEK activity in the described solution.In some embodiments, the invention provides by making the method for MEK activity in cell and the described cell of compound contact inhibition a certain amount of as herein described that is enough to suppress MEK activity in the described cell.In some embodiments, the invention provides by making the method for MEK activity in tissue and the described tissue of compound contact inhibition a certain amount of as herein described that is enough to suppress MEK activity in the described tissue.In some embodiments, the invention provides by making the method for MEK activity in biological and the described biology of compound contact inhibition a certain amount of described herein that is enough to suppress MEK activity in the described biology.In some embodiments, the invention provides by making the method for MEK activity in animal and the described animal of compound contact inhibition a certain amount of as herein described that is enough to suppress MEK activity in the described animal.In some embodiments, the invention provides by making the method for MEK activity in mammal and the described mammal of compound contact inhibition a certain amount of as herein described that is enough to suppress MEK activity in the described mammal.In some embodiments, the invention provides by making the method for MEK activity among human and the described mankind of compound contact inhibition a certain amount of as herein described that are enough to suppress MEK activity among the described mankind.
The compound of formula I and comprise formula I compound with and the composition of the acceptable salt of pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug, the activity that can regulate the MEK enzyme; And similarly be used to treat unusual MEK enzymic activity and cause the symptom of disease or the patient's condition and/or disease or the patient's condition of symptom.
In some respects, the present invention relates to treat and comprise the illness of being regulated by the MEK cascade in the human mammal or the method for the patient's condition, it comprises a certain amount of formula I compound or the acceptable salt of its pharmacy, ester, prodrug, solvate, hydrate or the derivative of regulating described cascade to described mammal administration effectively.Those skilled in the art can determine suitable dosage for particular patient according to known method.
In other respects, the present invention relates to suppress the method for MEK enzyme.In some embodiments, described method comprises makes described MEK enzyme contact with a certain amount of composition that is enough to suppress described enzyme, described composition comprises compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or the prodrug of formula I, and wherein said enzyme is suppressed.Further or in other the embodiment, described enzyme is suppressed at least about 1%.Further or in other the embodiment, described enzyme is suppressed at least about 2%.Further or in other the embodiment, described enzyme is suppressed at least about 3%.Further or in other the embodiment, described enzyme is suppressed at least about 4%.Further or in other the embodiment, described enzyme is suppressed at least about 5%.Further or in other the embodiment, described enzyme is suppressed at least about 10%.Further or in other the embodiment, described enzyme is suppressed at least about 20%.Further or in other the embodiment, described enzyme is suppressed at least about 25%.Further or in other the embodiment, described enzyme is suppressed at least about 30%.Further or in other the embodiment, described enzyme is suppressed at least about 40%.Further or in other the embodiment, described enzyme is suppressed at least about 50%.Further or in other the embodiment, described enzyme is suppressed at least about 60%.Further or in other the embodiment, described enzyme is suppressed at least about 70%.Further or in other the embodiment, described enzyme is suppressed at least about 75%.Further or in other the embodiment, described enzyme is suppressed at least about 80%.Further or in other the embodiment, described enzyme is suppressed at least about 90%.Further or in other the embodiment, described enzyme is suppressed basically fully.Further or in other the embodiment, described MEK enzyme is the MEK kinases.Further or in other the embodiment, described MEK enzyme is MEK1.Further or in other the embodiment, described MEK enzyme is MEK2.Further or in other the embodiment, described contact occurs in the cell.Further or in other the embodiment, described cell is mammiferous cell.Further or in other the embodiment, described mammiferous cell is the human cell.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt of the involved formula I compound of described MEK enzyme suppresses.
Further or other aspect, the present invention relates to treat the method for illness described in the individuality of the illness of suffering from MEK mediation, it comprises the composition to described individual effective dosage, and described composition comprises compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or the prodrug of formula I.In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or rectally comprise formula I compound compositions.In some embodiments, described pharmaceutical composition is the form that is suitable for oral administration.Further or in other the embodiment, described pharmaceutical composition is the form of tablet, capsule, pill, powder, sustained release preparation, solution, supensoid agent, be aseptic solution, supensoid agent or emulsion for parenteral injection, being ointment or emulsifiable paste for topical, is suppository for rectally perhaps.Further or in other the embodiment, described pharmaceutical composition is the unit dosage forms that is suitable for accurate dosage single-dose.Further or in other the embodiment, described pharmaceutical composition also comprises pharmaceutical carriers, excipient and/or assistant agent.
Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality of suffering from the illness of MEK mediation is mammal.Further or in other the embodiment, described individuality is human.
In some embodiments, administration comprises formula I compound compositions, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.
In some embodiments, the illness of described MEK mediation is selected from inflammatory disease, infection, autoimmune disease, apoplexy, ischemic, cardiac conditions, neurological disorders, fibrillatable illness, proliferative disorders, excess proliferative illness, non-cancer excess proliferative illness, tumour, leukemia, knurl, cancer, cancer, metabolic disease, malignant diseases, reangiostenosis, psoriasis, atherosclerotic, rheumatoid arthritis, osteoarthritis, heart failure, chronic ache, neuropathic pain, dry eyes, angle-closure glaucoma and open-angle glaucoma.Further or in other the embodiment, the illness of described MEK mediation is inflammatory disease.Further or in other the embodiment, the illness of described MEK mediation is excess proliferative disease.Further or in other the embodiment, the illness of described MEK mediation is selected from tumour, leukemia, knurl, cancer, cancer and malignant diseases.Further or in other the embodiment, described illness is cancer of the stomach, the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
The invention still further relates to by making MEK and being enough to regulate a certain amount of N-(S)-(3 of MEK activity, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the crystalline polymorph A contact of 1-(2,3-dihydroxypropyl) ring third-1-sulfonamide regulates the method for MEK activity.Adjusting can be to suppress or activation MEK activity.In some embodiments, the invention provides by making MEK and a certain amount of N-(S)-(3 that is enough to suppress the MEK activity, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-method of the crystalline polymorph A contact inhibition MEK activity of 1-(2,3-dihydroxypropyl) ring third-1-sulfonamide.In some embodiments, the invention provides by making solution and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described solution, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described solution of crystalline polymorph A contact inhibition of 1-(2,3-dihydroxypropyl) ring third-1-sulfonamide in the method for MEK activity.In some embodiments, the invention provides by making cell and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described cell, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described cell of 1-(2,3-dihydroxypropyl) ring third-1-sulfonamide crystalline polymorph A contact inhibition in the method for MEK activity.In some embodiments, the invention provides by making tissue and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described tissue, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described tissue of crystalline polymorph A contact inhibition of 1-(2,3-dihydroxypropyl) ring third-1-sulfonamide in the method for MEK activity.In some embodiments, the invention provides by making biology and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described biology, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described biology of crystalline polymorph A contact inhibition of 1-(2,3-dihydroxypropyl) ring third-1-sulfonamide in the method for MEK activity.In some embodiments, the invention provides by making animal and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described animal, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-method of MEK activity in the described animal of crystalline polymorph A contact inhibition of 1-(2,3-dihydroxypropyl) ring third-1-sulfonamide.In some embodiments, the invention provides by making mammal and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described mammal, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described mammal of crystalline polymorph A contact inhibition of 1-(2,3-dihydroxypropyl) ring third-1-sulfonamide in the method for MEK activity.In some embodiments, the invention provides by making the mankind and a certain amount of N-(S)-(3 that is enough to suppress MEK activity among the described mankind, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described mankind of crystalline polymorph A contact inhibition of 1-(2,3-dihydroxypropyl) ring third-1-sulfonamide in the method for MEK activity.
Cancer
In other respects, the present invention relates to method for cancer in treatment or prevention (prevention or prophylaxis) individuality, it comprises to the formula I compound of described individual effective dosage or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, with the composition administration as the composition that also comprises pharmaceutically acceptable carrier or carrier of described compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer, cancer of the stomach or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer, leukemia, melanoma, thyroid cancer, or basal-cell carcinoma.Further or in other the embodiment, described cancer is the cancer of the brain or adrenocortical carcinoma.Further or in other the embodiment, described cancer is breast cancer.Further or in other the embodiment, described cancer is oophoroma.Further or in other the embodiment, described cancer is cancer of pancreas.Further or in other the embodiment, described cancer is prostate cancer.Further or in other the embodiment, described cancer is kidney.Further or in other the embodiment, described cancer is colorectal cancer.Further or in other the embodiment, described cancer is myeloid leukemia.Further or in other the embodiment, described cancer is glioblastoma.Further or in other the embodiment, described cancer is folliculus type lymphoma.Further or in other the embodiment, described cancer is preceding B acute leukemia.Further or in other the embodiment, described cancer is chronic lymphocytic B leukemia.Further or in other the embodiment, described cancer is celiothelioma.Further or in other the embodiment, described cancer is small-cell carcinoma of the lung.In some embodiments, described cancer is cancer of the stomach.
In some embodiments, administration comprises formula I compound compositions, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.
Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality of suffering from cancer is mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
Unusual cell growth
The compound, pharmaceutical composition and the method that are used for the unusual cell growth of inhibition have also been described herein.In some embodiments, described unusual cell growth occurs in the mammal.The method that suppresses the growth of unusual cell comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or the derivative of effective dosage, and wherein unusual cell growth is suppressed.The method of unusual cell growth comprises to a certain amount of formula I compound of described mammal administration or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative in the inhibition mammal, and the compound of wherein said amount or salt suppress cell growth unusual in the mammal effectively.
In some embodiments, described method comprises the formula I compound of effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative, with a certain amount of chemotherapeutant administering drug combinations, the amount of wherein said compound or its salt, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative and described chemotherapeutant suppresses unusual cell growth jointly effectively.Many chemotherapeutants are known in the art at present, and can with compound coupling of the present invention.In some embodiments, described chemotherapeutant is selected from mitotic inhibitor, alkylating agent, antimetabolite, embedding antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme, topoisomerase enzyme inhibitor, biological response modifier, antihormones, angiogenesis inhibitor and antiandrogen.
The method of the cell growth that suppresses unusual in the mammal has also been described, it comprises to a certain amount of formula I compound of described mammal administration or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative, with the radiotherapy coupling, wherein said compound or its salt, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, the amount of hydrate or derivative and radiotherapy coupling suppress cell growth unusual in the mammal effectively or treat excess proliferative disease in the mammal.It is known in the art using radiotherapeutic technology, and these technology can with therapy coupling as herein described.The administration that can determine at this conjoint therapy Chinese style I compound as described herein.
The invention still further relates to method and the pharmaceutical composition of the cell growth that suppresses unusual in the mammal, described pharmaceutical composition comprises a certain amount of formula I compound, or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative, or its isotope-labeled derivative and a certain amount of one or more materials that are selected from antiangiogenic agent, signal transduction inhibitor and antiproliferative.
Antiangiogenic agent, for example MMP-2 (matrix metalloproteinase 2) inhibitor, MMP-9 (matrix metalloproteinase 9) inhibitor and COX-11 (cyclo-oxygenase 11) inhibitor, can with compound of the present invention and pharmaceutical composition coupling as herein described.The example of useful COX-II inhibitor comprises: CELEBREX
TM(Sai-Mi-Xi-Bu (alecoxib)), valdecoxib and rofecoxib.The case description of useful NMPI is in WO 96/33172 (being published on October 24th, 1996), WO 96/27583 (being published on March 7th, 1996), No. 97304971.1, european patent application (being filed on July 8th, 1997), No. 99308617.2, european patent application (being filed on October 29th, 1999), WO 98/07697 (being published on February 26th, 1998), WO 98/03516 (being published on January 29th, 1998), WO 98/34918 (being published on August 13rd, 1998), WO 98/34915 (being published on August 13rd, 1998), WO 98/33768 (being published on August 6th, 1998), WO 98/30566 (being published on July 16th, 1998), European patent publication 606,046 (being published on July 13rd, 1994), European patent publication 931,788 (being published on July 28th, 1999), WO 90/05719 (being published in May 31 nineteen ninety), WO 99/52910 (being published on October 21st, 1999), WO 99/52889 (being published on October 21st, 1999), WO 99/29667 (being published on June 17th, 1999), PCT International Application Serial No. PCT/IB98/01113 number (being filed on July 21st, 1998), No. 99302232.1, european patent application (being filed on March 25th, 1999), No. 9912961.1, British Patent Application (being filed on June 3rd, 1999), U.S. Provisional Application 60/148, No. 464 (being filed on August 12nd, 1999), United States Patent (USP) 5,863,949 (being issued on January 26th, 1999), United States Patent (USP) 5,861, No. 510 (being issued on January 19th, 1999), and European patent publication 780, in 386 (being published on June 25th, 1997), it is all intactly quoted and adds as herein.Some MMP-2 and MMP-9 inhibitor almost do not have MMP-1 and suppress active or do not have the MMP-1 inhibition active, and with respect to other matrix metalloproteinases (being MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13), some MMP-2 and MMP-9 inhibitor optionally suppress MMP-2 and/or AMP-9.Some instantiations that are used for the present invention's MMP inhibitor are AG-3340, RO32-3555 and RS 13-0830.
In other respects, the present invention relates to make cancer cell to degenerate, suppress the method for growth of cancer cells or kill cancer cell, it comprises that the composition that makes described cell and make described cell degradation effectively, suppress described cell growth or kill the amount of described cell contacts, and described composition comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described cancer cell comprises brain cancer cell, breast cancer cell, lung carcinoma cell, ovarian cancer cell, pancreatic cancer cell, prostate gland cancer cell, kidney cancer cell or colorectal cancer cell.
Further or in other the embodiment, described composition and at least a therapeutic agent administering drug combinations.Further or in other the embodiment, described therapeutic agent is taxol, bortezomib or the two.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.
In some embodiments, described cancer cell is degenerated.Further or in other the embodiment, 1% described cancer cell is degenerated.Further or in other the embodiment, 2% described cancer cell is degenerated.Further or in other the embodiment, 3% described cancer cell is degenerated.Further or in other the embodiment, 4% described cancer cell is degenerated.Further or in other the embodiment, 5% described cancer cell is degenerated.Further or in other the embodiment, 10% described cancer cell is degenerated.Further or in other the embodiment, 20% described cancer cell is degenerated.Further or in other the embodiment, 25% described cancer cell is degenerated.Further or in other the embodiment, 30% described cancer cell is degenerated.Further or in other the embodiment, 40% described cancer cell is degenerated.Further or in other the embodiment, 50% described cancer cell is degenerated.Further or in other the embodiment, 60% described cancer cell is degenerated.Further or in other the embodiment, 70% described cancer cell is degenerated.Further or in other the embodiment, 75% described cancer cell is degenerated.Further or in other the embodiment, 80% described cancer cell is degenerated.Further or in other the embodiment, 90% described cancer cell is degenerated.Further or in other the embodiment, 100% described cancer cell is degenerated.Further or in other the embodiment, whole described cancer cells are degenerated.
In some embodiments, described cancer cell is killed.Further or in other the embodiment, 1% described cancer cell is killed.Further or in other the embodiment, 2% described cancer cell is killed.Further or in other the embodiment, 3% described cancer cell is killed.Further or in other the embodiment, 4% described cancer cell is killed.Further or in other the embodiment, 5% described cancer cell is killed.Further or in other the embodiment, 10% described cancer cell is killed.Further or in other the embodiment, 20% described cancer cell is killed.Further or in other the embodiment, 25% described cancer cell is killed.Further or in other the embodiment, 30% described cancer cell is killed.Further or in other the embodiment, 40% described cancer cell is killed.Further or in other the embodiment, 50% described cancer cell is killed.Further or in other the embodiment, 60% described cancer cell is killed.Further or in other the embodiment, 70% described cancer cell is killed.Further or in other the embodiment, 75% described cancer cell is killed.Further or in other the embodiment, 80% described cancer cell is killed.Further or in other the embodiment, 90% described cancer cell is killed.Further or in other the embodiment, 100% described cancer cell is killed.Further or in other the embodiment, whole described cancer cells all are killed basically.
Further or in other the embodiment, the growth of described cancer cell is suppressed.Further or in other the embodiment, the growth of described cancer cell is suppressed about 1%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 2%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 3%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 4%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 5%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 10%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 20%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 25%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 30%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 40%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 50%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 60%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 70%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 75%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 80%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 90%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 100%.Further or in other the embodiment, use the composition of the pharmaceutically acceptable salt that comprises formula I compound.
The method that suppresses abnormal cell growth is also described herein.In some embodiments, described abnormal cell growth occurs in the mammal.The method that suppresses abnormal cell growth comprises the N-(S)-(3 of effective dosage, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide, wherein abnormal cell growth is suppressed.The method that suppresses abnormal cell growth in the mammal comprises to a certain amount of N-of described mammal administration (S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide, N-(S)-(3 wherein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-amount of the crystalline polymorph A of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide suppresses the abnormal cell growth in the mammal effectively.
In some embodiments, described method comprises the N-(S)-(3 of administering drug combinations effective dose, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide and a certain amount of chemotherapeutant, N-(S)-(3 wherein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-crystalline polymorph A of 1-sulfonamide and the amount of described chemotherapeutant suppress abnormal cell growth jointly effectively.
At present, many chemotherapeutants are known in the art, and can with compound of the present invention and composition coupling.In some embodiments, described chemotherapeutant is selected from mitotic inhibitor, alkylating agent, antimetabolite, embedding antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme, topoisomerase enzyme inhibitor, biological response modifier, antihormones, angiogenesis inhibitor and antiandrogen.
In some embodiments, the method that suppresses abnormal cell growth in the mammal comprises to a certain amount of N-of described mammal administration (S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide, with the radiotherapy coupling, N-(S)-(3 wherein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-amount and the described radiotherapy coupling of the crystalline polymorph A of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide suppress abnormal cell growth effectively.It is known in the art using radiotherapeutic technology, and these technology can be used for conjoint therapy as herein described.
Treatment excess proliferative illness
In other respects, the present invention relates to treat the method that mammal comprises excess proliferative illness among the mankind, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.
In other respects, the present invention relates to treat or prevent the method for proliferative diseases in the individuality, it comprises to the formula I compound of described individual effective dosage or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug are as the composition administration of composition, and described composition also comprises pharmaceutically acceptable carrier or carrier.In some embodiments, described proliferative diseases is cancer, psoriasis, ISR, autoimmune disease or atherosclerotic.Further or in other the embodiment, described proliferative diseases is excess proliferative disease.Further or in other the embodiment, described proliferative diseases is selected from tumour, leukemia, knurl, cancer, cancer and malignant diseases.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, cancer of the stomach, colorectal cancer or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of the stomach, cancer of pancreas, prostate cancer, kidney, colorectal cancer or leukemia.Further or in other the embodiment, described cancer is the cancer of the brain or adrenocortical carcinoma.Further or in other the embodiment, described cancer is breast cancer.Further or in other the embodiment, described cancer is oophoroma.Further or in other the embodiment, described cancer is cancer of pancreas.Further or in other the embodiment, described cancer is prostate cancer.Further or in other the embodiment, described cancer is kidney.Further or in other the embodiment, described cancer is colorectal cancer.Further or in other the embodiment, described cancer is myeloid leukemia.Further or in other the embodiment, described cancer is glioblastoma.Further or in other the embodiment, described cancer is folliculus type lymphoma.Further or in other the embodiment, described cancer is preceding B acute leukemia.Further or in other the embodiment, described cancer is chronic lymphocytic B leukemia.Further or in other the embodiment, described cancer is celiothelioma.Further or in other the embodiment, described cancer is small-cell carcinoma of the lung.In some embodiments, described cancer is cancer of the stomach.
In some embodiments, administration comprises formula I compound compositions, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their combination.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.
In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from proliferative diseases is mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
The tumour size
In other respects, the present invention relates to reduce the tumour size in individuality, suppress the method that the tumour size increases, reduces tumor proliferation or prevention tumor proliferation, it comprises to the formula I compound of described individual effective dosage or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug are as the composition administration of composition, and described composition also comprises pharmaceutically acceptable carrier or carrier.In some embodiments, the size of tumour is reduced.Further or in other the embodiment, the size of tumour is reduced at least 1%.Further or in other the embodiment, the size of tumour is reduced at least 2%.Further or in other the embodiment, the size of tumour is reduced at least 3%.Further or in other the embodiment, the size of tumour is reduced at least 4%.Further or in other the embodiment, the size of tumour is reduced at least 5%.Further or in other the embodiment, the size of tumour is reduced at least 10%.Further or in other the embodiment, the size of tumour is reduced at least 20%.Further or in other the embodiment, the size of tumour is reduced at least 25%.Further or in other the embodiment, the size of tumour is reduced at least 30%.Further or in other the embodiment, the size of tumour is reduced at least 40%.Further or in other the embodiment, the size of tumour is reduced at least 50%.Further or in other the embodiment, the size of tumour is reduced at least 60%.Further or in other the embodiment, the size of tumour is reduced at least 70%.Further or in other the embodiment, the size of tumour is reduced at least 75%.Further or in other the embodiment, the size of tumour is reduced at least 80%.Further or in other the embodiment, the size of tumour is reduced at least 85%.Further or in other the embodiment, the size of tumour is reduced at least 90%.Further or in other the embodiment, the size of tumour is reduced at least 95%.Further or in other the embodiment, described tumour is uprooted.In some embodiments, the size of tumour does not increase.
In some embodiments, tumor proliferation is slowed down few.In some embodiments, tumor proliferation is reduced at least 1%.In some embodiments, tumor proliferation is reduced at least 2%.In some embodiments, tumor proliferation is reduced at least 3%.In some embodiments, tumor proliferation is reduced at least 4%.In some embodiments, tumor proliferation is reduced at least 5%.In some embodiments, tumor proliferation is reduced at least 10%.In some embodiments, tumor proliferation is reduced at least 20%.In some embodiments, tumor proliferation is reduced at least 25%.In some embodiments, tumor proliferation is reduced at least 30%.In some embodiments, tumor proliferation is reduced at least 40%.In some embodiments, tumor proliferation is reduced at least 50%.In some embodiments, tumor proliferation is reduced at least 60%.In some embodiments, tumor proliferation is reduced at least 70%.In some embodiments, tumor proliferation is reduced at least 75%.In some embodiments, tumor proliferation is reduced at least 75%.In some embodiments, tumor proliferation is reduced at least 80%.In some embodiments, tumor proliferation is reduced at least 90%.In some embodiments, tumor proliferation is reduced at least 95%.In some embodiments, tumor proliferation is prevented from.
In some embodiments, administration comprises formula I compound compositions, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.
In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from cancer is mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
Inflammatory disease
In other respects, the present invention relates to treat or prevent the method for inflammatory disease in the individuality, it comprises to the formula I compound of described individual effective dosage or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug are as the composition administration of composition, and described composition also comprises pharmaceutically acceptable carrier or carrier.Further or in other the embodiment, described inflammatory disease is to be selected from chronic inflammatory disease, rheumatoid arthritis, rheumatoid arthritis, spondyloarthropathy, ankylosing spondylitis, gout, myotenositis, bursal synovitis, sciatica, urarthritis, osteoarthritis, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, pyogenic arthritis, atherosclerotic, systemic loupus erythematosus, inflammatory bowel disease, IBS, ulcerative colitis, reflux esophagitis, Crohn's disease, gastritis, asthma, anaphylaxis, Respiratory Distress Syndrome(RDS), pancreatitis, COPD, pulmonary fibrosis, psoriasis, eczema or chorionitis.
In some embodiments, administration comprises the compound compositions of formula, with other therapy couplings.Further or in other the embodiment, comprise described composition and at least a therapeutic agent administering drug combinations of formula I compound.In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.
Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with the multiple dose every day of the compound more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from inflammatory disease is mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.
Mode of administration
This paper describes formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative.The pharmaceutical composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative has also been described.Compound as herein described and composition can be individually dosed, perhaps according to standard pharmaceutical practice, in pharmaceutical composition with pharmaceutically acceptable carrier, excipient or thinner combination medicine-feeding.
This paper also describes pharmaceutical composition, and it comprises the crystalline polymorph (A type) of N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.Compound as herein described and composition can be individually dosed, perhaps according to standard pharmaceutical practice, in pharmaceutical composition with pharmaceutically acceptable carrier, excipient or thinner combination medicine-feeding.Can realize administration by any method that described compound can be delivered to action site.These methods comprise, but be not limited to, (comprise oral by approach in the intestines, stomach or duodenum feeding tube, rectal suppository and rectal enema), parenteral route (injection or infusion, comprise in the artery, intracardiac, in the corium, in the duodenum, in the marrow, intramuscular, in the bone, in the peritonaeum, in the sheath, in the blood vessel, intravenous, in the vitreum, dura mater is outer and subcutaneous), suck, transdermal, saturating mucous membrane, the hypogloeeis, contain clothes and the part (comprise epicuticle (epicutaneous), corium, enema, eye drops, auristilla, in the nose, vagina) administration is sent, but the optimum approach may depend on for example recipient's the patient's condition and illness.Those skilled in the art can know the medicine-feeding technology that can be used for The compounds of this invention and method.Only as example, can be by local infusion, local application such as cream or ointment, injection, conduit or implant during the operation for example, to the regional administration compound as herein described of needs treatment, described implant is made by material (comprising film or fiber such as the sialastic film) for example porous, non-porous or glue partly.Also can carry out administration by directly injecting at the position of illing tissue or organ.
Can realize the administration of compound described herein and composition by any method that described compound can be released into action site.These methods comprise oral route, intraduodenal route, parenteral injection (comprise in intravenous, subcutaneous, the peritonaeum, in the intramuscular, blood vessel or infusion), topical and rectally.For example, can be to the regional topical compound as herein described of needs treatment.This can be by for example cream, ointment, injection, conduit or implant realize that described implant is made by material (comprising film or fiber such as the sialastic film) for example porous, non-porous or glue such as but not limited to local infusion, local application during the operation.Also can directly inject by the position (or former position) of before tumour or tumor tissue or knurl, organizing and carry out administration.Those skilled in the art know preparation and the medicine-feeding technology that can be used for The compounds of this invention and method, for example at Goodman and Gilman, and The PharmacologicalBasis of Therapeutics, current edition; Pergamon; And Remington ' s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton discusses among the Pa.
Described preparation comprises and is applicable to administration in oral administration, parenteral (comprising administration in administration in subcutaneous administration, the corium, intramuscular administration, intravenous administration, intra-articular administration and the marrow), the peritonaeum, transmucosal administration, cutaneous penetration, rectally and topical (comprise the corium administration, contain clothes administration, sublingual administration and eye drops), but the optimum approach may depend on for example recipient's the patient's condition and illness.Described preparation can be unit dosage forms easily, and can be by known any method preparation in the pharmaceutical field.All methods comprise makes compound of the present invention or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative (" active component ") and the carrier-bound step that constitutes one or more auxiliary agents.Generally speaking, evenly and closely be combined by making active component and liquid-carrier or the solid carrier that grinds or the two, then, if necessary, make product be configured as required preparation and prepare described preparation.
The preparation that is applicable to oral administration can be the unit that separates for example capsule, cachet or tablet, and it respectively comprises the active component of scheduled volume; Powder or granule; Solution in waterborne liquid or the non-aqueous liquid or supensoid agent; Perhaps oil-in-water liquid emulsion or Water-In-Oil liquid emulsion.Described active component can also be for injecting agent, electuary or paste.
The pharmaceutical preparation that is used for oral administration comprises tablet, agrees with capsule by pushing of making of gelatin, and the sealing soft capsule of being made by gelatin and plasticizer such as glycerine or sorbierite.Can be by randomly compressing with one or more auxiliary agents or molding prepares tablet.Can prepare compressed tablets by the active component that is in free-flowing form (as powder or particle) that compression in suitable machine randomly mixes with adhesive, inert diluent or lubricant, surfactant or surface dispersant.Can be by in suitable machine, preparing molded tablet through the mixture molding of the moistening powdered compounds of inert liquid diluent.Can be randomly with described tablet coating or indentation, and can prepare described tablet with provide active component therefrom slowly or control discharge.All preparations that are used for oral administration should be the dosage that is suitable for administration like this.Described pushing agreed with capsule or tablet can comprise active component; Be mixed with filler for example microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, lactose, calcium monohydrogen phosphate or sompressible sugar; Adhesive such as Hydroxypropyl methylcellulose, polyvidone or gelatinized corn starch; Disintegrant such as cross-linked carboxymethyl cellulose sodium, Crospovidone or primojel; Surfactant such as lauryl sodium sulfate and/or lubricant and processing aid such as talcum, dolomol, stearic acid or cataloid, and optional stabilizing agent.In soft capsule, described reactive compound can be dissolved in or be suspended in suitable liquid for example in fat oil, atoleine or the liquid macrogol.In addition, can add stabilizing agent.The dressing dragee sheet heart suitably.For this reason, use concentrated sugar solution, it can randomly comprise gum Arabic, talcum, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to distinguish or the various combination of characterization active compound doses, dyestuff or pigment can be added described tablet or dragee dressing.
Pharmaceutical preparation can be prepared into for the preparation that carries out parenteral by injection as bolus infusion or continuous infusion.The preparation that is used for injection can be unit dosage forms, as in ampoule or in multi-dose container, and is added with preservative.Described composition can adopt supensoid agent, solution or the emulsion form in oiliness for example or the aqueous carrier, and can comprise formula agent (formulatory agents) for example suspending agent, stabilizing agent and/or dispersant.Described preparation can be unit-dose container or multi-dose container, for example Mi Feng ampoule and bottle, and can preserve with powder type or freeze-drying (freeze drying) state, before use, only need to add at once aseptic liquid-carrier, for example salt solution or aseptic apyrogenic water.From aseptic powder, granule and the tablet of the above-mentioned type, can prepare instant injection solution and supensoid agent.
The preparation that is used for parenteral comprises water-based and non-aqueous (oiliness) aseptic parenteral solution of reactive compound, and it can comprise antioxidant, buffer, bacteriostatic agent, and makes described preparation and have a mind to the solute that recipient's blood etc. oozes; And water-based can comprise suspending agent and thickener with nonaqueous aseptic supensoid agent.The lipophilic solvent or the carrier that are fit to comprise fat oil for example sesame oil or Acrawax such as ethyl oleate or glyceryl ester, or liposome.The water-based injection suspension can comprise the material that improves described supensoid agent viscosity, for example sodium carboxymethylcellulose, sorbierite or glucan.Randomly, for solution that can compounding high concentration, described supensoid agent can also comprise suitable stabilizing agent or improve the reagent of described compound solvability.
Pharmaceutical preparation can also be prepared into depot formulation.By implantation (for example subcutaneous implantation or intramuscular are implanted) or by intramuscular injection, can the such long-acting type preparation of administration.Therefore, for example, described compound can be prepared with suitable polymer or hydrophobic material (for example as the emulsion in acceptable oil) or ion exchange resin, or as sl. sol. derivative, for example sl. sol. salt is prepared.
For containing clothes administration or sublingual administration, described composition can adopt tablet, lozenge, pastille or the gel of preparation in a usual manner.Such composition can be contained in active component flavoured base for example in sucrose and gum Arabic or the bassora gum.
Pharmaceutical preparation can also be prepared into rectal compositions for example suppository or enema,retention, for example comprises conventional suppository base for example cocoa butter, polyethylene glycol or other glyceride.
Can the topical pharmaceutical preparation, namely by non-general administration.This comprises compound of the present invention externally is applied to epidermis or oral cavity, and with such compound instil pleasant, eye and nose, so that described compound does not enter in the blood flow in large quantities.By contrast, the general administration means administration and intramuscular administration in oral administration, intravenous administration, the peritonaeum.
The pharmaceutical preparation that is suitable for topical comprises and is suitable for liquid or the semi-liquid preparations that transdermal enters inflammation part, for example gel, liniment, lotion, cream, ointment or paste, and be suitable for to the drops of eye, ear or nasal administration.For topical, active component can account for described preparation 0.001% to 10%w/w, 1 weight % to 2 weight % for example.But active component can account for the nearly 10%w/w of described preparation, perhaps can account for the 5%w/w that is lower than of described preparation, or 0.1% to 1%w/w.
Pharmaceutical preparation by inhalation can be easily from other facilitated method dispensers of insufflator, sprayer pressurized package or administration aerosol spray.Pressurized package can comprise suitable propellant for example dicholorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbonic acid gas or other suitable gas.Under the situation of the aerosol that pressurizes, described dosage unit can be by providing valve quantitative administration.Perhaps, for by sucking or being blown into administration, pharmaceutical preparation can adopt the form of dry powder composite, for example described compound and suitable powder matrix such as the mixture of powders of lactose or starch.Described powder composition can be unit dosage form, for example is capsule, cartridge case (cartridge), gelatin or blisterpack, relies on inhalator or the insufflator can be from the described powder of administration wherein.
Should be understood that except the composition of above specially mentioning compound as herein described and composition can comprise about other conventional in the field of the preparation type of discussing reagent, the composition that for example is suitable for oral administration can comprise flavor enhancement.
Preparation
It should be noted that any composition as herein described and compound can be used with any preparation that discuss this part, its intention is not restriction and should be understood that restrictive.
Compound as herein described or composition can with for example liposome administration of vesicle (referring to for example, Langer, Science1990,249,1527-1533; Treat etc., Liposomes in the Therapy of Infectious Disease andCancer, Lopez-Bemstein and Fidler, Ed., Liss, N.Y., pp.353-365,1989).Compound as herein described and pharmaceutical composition can also be with the controlled release system administrations.In one embodiment, can use pump (referring to, Sefton, 1987, CRC Crit.Ref.Biomed.Eng.14:201; Buchwald etc., Surgery, 1,980 88,507; Saudek etc., N.Engl.J.Med.1989,321, (574).In addition, controlled release system can be placed near the treatment target spot (referring to, Goodson, Medical Applications of Controlled Release, 1984, Vol.2, pp.115-138).Pharmaceutical composition as herein described can also be included in active component in the form that is suitable for orally using, for example, adopt tablet, dragee, lozenge, water-based or oiliness supensoid agent, dispersible powder or granule, emulsion, hard shell capsules or soft capsule, or syrup or elixir.Any method according to pharmaceutical compositions known in the art, can prepare intention and be used for oral composition, and for pharmaceutically attractive in appearance and good to eat preparation is provided, such composition can comprise one or more reagent that is selected from sweetener, flavor enhancement, colouring agent and preservative.Tablet comprises described active component and mixes the acceptable excipient of avirulent pharmacy that is applicable to the preparation tablet.These excipient for example can be, inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulation agent and disintegrant; Filler is microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, lactose, calcium monohydrogen phosphate or sompressible sugar for example; Adhesive is Hydroxypropyl methylcellulose, polyvidone or gelatinized corn starch for example; Disintegrant is cross-linked carboxymethyl cellulose sodium, Crospovidone or primojel for example; Surfactant is lauryl sodium sulfate for example, and/or lubricant, and processing aid for example talcum, cross-linked carboxymethyl cellulose sodium, corn starch or alginic acid; Bond (binding agents) is starch, gelatin, polyvinylpyrrolidone or gum Arabic for example, and lubricant for example dolomol, stearic acid or cataloid, and optional talcum.For the taste of masking agents or postpone in intestines and stomach disintegration and absorb and more long-term continuous action is provided thus, by known method, can carry out not dressing or dressing to described tablet.For example, can suitably use water-soluble taste masked material for example HYDROXY PROPYL METHYLCELLULOSE or hydroxy propyl cellulose, or delay time material for example ethyl cellulose or acetylbutyrylcellulose.The preparation that orally uses can also be hard gelatin capsule, for example calcium carbonate, calcium phosphate or kaolin mix wherein said active component with inert solid diluent, perhaps be Perle, wherein said active component and water-solubility carrier be polyethylene glycol or oil medium such as peanut oil, atoleine or mixed with olive oil for example.Comprise dry mixed and wet granulation technique by various process technologies, can prepare described capsule and Tabules.In the dry mixed preparation method, by with the excipient dry mixed, be encapsulated in the capsule shells then or be pressed into tablet form, described medicine can be contained in the formulation.The operation of described dry mixed can be carried out step by step, and is included in the step of sieving between the blend step so that form uniform mixture.In the wet granulation method, described medicine can be added in the dry excipient, mix, add binder solution then, perhaps described medicine can be dissolved, and add as the solution of the part of granulating.In wet granulation technique, if use surfactant, then it can be added in the dry excipient, perhaps it is added in the binder solution, and be contained in wherein with the solution form.By described medicine is dissolved in can be packed into the hard gelatin capsule shell and with subsequently can colligation and the compatible material of the hard gelatin capsule shell of sealing in, also can prepare capsule formulation.In the material that described medicine is dissolved in the fusion form of the polyethylene glycol of HMW for example, be cooled to solid forms, grind, and this material is comprised to the process of conventional capsule and tablet, also can prepare capsule and Tabules.
Aqueous suspension comprises described active component, and mixed the excipient that is applicable to the preparation aqueous suspension is arranged.Such excipient is suspending agent, for example sodium carboxymethylcellulose, methylcellulose, HYDROXY PROPYL METHYLCELLULOSE, mosanom, polyvinylpyrrolidone, gum tragacanth and gum Arabic; Dispersant or wetting agent can be naturally occurring phosphatide, lecithin for example, the perhaps condensation product of alkylene oxide and fatty acid, Myrj 45 for example, the perhaps condensation product of oxirane and long-chain fatty alcohol, for example 17 vinyl-oxygen hexadecanol (heptadecaethylene-oxycetanol), or oxirane and derived from the condensation product of the partial ester (as octadecanoic acid ester of polyethylene glycol) of fatty acid and hexitol, perhaps oxirane and condensation product derived from the partial ester (for example polyethylene sorbitan monooleate) of fatty acid and hexitol dehydrate.Described aqueous suspension can also comprise one or more preservatives (for example ethyl-para-hydroxybenzoate or P-hydroxybenzoic acid n-propyl), one or more colouring agents, one or more flavor enhancements and one or more sweeteners (for example sucrose, asccharin or aspartame).
By active component being suspended in vegetable oil (for example peanut oil, olive oil, sesame oil or cocoa butter), perhaps in the mineral oil (as atoleine), can prepare the oiliness supensoid agent.Described oiliness supensoid agent can comprise thickener, for example beeswax, hard paraffin or hexadecanol.Can add all sweeteners as indicated above and flavor enhancement good to eat oral formulations is provided.By adding antioxidant, for example Butylated Hydroxyanisole or alpha-tocopherol can be preserved these compositions.
Generate the mixed active component that dispersant or wetting agent, suspending agent and one or more preservatives are arranged by water being added in the dispersible powder that is suitable for preparing aqueous suspension and the particle.Suitable dispersant or wetting agent and suspending agent are by illustrating of above having mentioned.Other excipient, for example sweetener, flavor enhancement and colouring agent also can exist.By adding antioxidant such as ascorbic acid, can preserve these compositions.
Pharmaceutical composition can also be the form of oil in water emulsion.Oil phase can be vegetable oil (for example olive oil or peanut oil), perhaps mineral oil (for example atoleine), perhaps these mixture.Suitable emulsifier can be naturally occurring phosphatide (for example soybean lecithin), with derived from the ester of fatty acid and hexitol dehydrate or the condensation product (for example polyoxyethylene 20 sorbitan monooleate) of partial ester (for example sorbitan monooleate) and described partial ester and oxireme.Described emulsion can also comprise sweetener, flavor enhancement, preservative and antioxidant.
For example glycerine, propane diols, sorbierite or sucrose can prepare syrup and elixir with sweetener.Such preparation can also comprise moderator, preservative, flavor enhancement and colouring agent and antioxidant.
Pharmaceutical composition can be the form of the aqueous solution agent of sterile injectable.Water, ringer's solution and isotonic sodium chlorrde solution are arranged in operable acceptable carrier and solvent.Described sterile injectable preparation can also be aseptic injectable oil-in-water microemulsion, wherein described active component is dissolved in the oil phase.For example, at first described active component can be dissolved in the mixture of soybean oil or soybean lecithin.Then this oily solution is imported in the mixture of water and glycerine, through being processed to form microemulsion.By local bolus infusion, described injectable solutions or microemulsion can be imported in patient's the blood flow.Perhaps, administration solution or microemulsion may be favourable with the constant circulation concentration that keeps instant compound by this way.In order to keep such constant density, can use continuation intravenous administration device.The example of such device is Deltec CADD-PLUS
TMType 5400 intravenous pumps.Described pharmaceutical composition can be for being used for intramuscular and the sterile injectable water-based of subcutaneous administration or the form of oiliness supensoid agent.According to known technique, use those the suitable dispersants above mentioned or wetting agent and suspending agent can prepare this supensoid agent.Described sterile injectable preparation can also be sterile injectable solution agent or the supensoid agent in avirulence parenteral acceptable diluent or solvent, for example solution in 1,3-butanediol.In addition, aseptic fixed oil is routinely as solvent or suspension medium.For this reason, can use any non-irritating fixed oil that comprises synthetic monoglyceride or double glyceride.In addition, fatty acid for example oleic acid for the preparation of the injectable agent.
Pharmaceutical composition can also be to be used for the suppository form administration of the described medicine of rectally.Can prepare these compositions by described inhibitor is mixed with suitable non-irritating excipient, described excipient is solid at normal temperatures but is liquid under rectal temperature, and therefore can melt in rectum with the release medicine.Such material comprises the mixture of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, various molecular weight polyethylene glycol and the fatty acid ester of polyethylene glycol.
Use for the part, cream, ointment, jelly, solution or the supensoid agent etc. that comprise compound of the present invention or composition are used for topical.Local application used herein can comprise collutory and gargle.
Use carrier and doser in the suitable nose by the part, perhaps by through the skin approach, use well known to those skilled in the art those through skin patch form, can be with form administration pharmaceutical composition in the nose.
Described preparation can be unit dosage form easily, and can prepare by the method that pharmaceutical field is known.All methods comprise compound or the acceptable salt of its pharmacy, ester, prodrug or the solvate (" active component ") and the carrier-bound step that constitutes one or more auxiliary agents that makes the invention of this main body.Generally speaking, the two evenly and closely is combined by making active component and liquid-carrier or the solid carrier that grinds or this, then, if desired, product is shaped as required preparation prepares described preparation.To those skilled in the art, the method for preparing various pharmaceutical compositions with the reactive compound of specified quantitative is known, and is perhaps apparent.For with the percutaneous dosing form administration, formulation can be continuity but not intermittent certainly in whole dosage regimen.
Dosage
The dosage of pharmaceutical composition at first depends on the mammal of receiving treatment.In the situation of human experimenter's administration medicine composition, daily dose is determined by the evolution doctor usually, dosage is generally along with seriousness, administration time, method of administration, the disposal of described composition, drainage rate, the drug combination of the seriousness of each patient's age, sex, diet, body weight, general health and reaction, patient's symptom, the idicatio accurately of receiving treatment or the patient's condition, the idicatio of receiving treatment or the patient's condition, and evolution doctor's judgment.And method of administration can depend on the patient's condition and seriousness thereof and change.Described pharmaceutical composition can be unit dosage form.With such form, preparation is subdivided into the unit dose that comprises an amount of active component, the effective dose that for example accomplishes the end in view.Determine that in light of the circumstances suitable dosage is in the technology category of this area.Generally speaking, use the smaller dose begin treatment of the dose,optimum that is lower than described compound.After this, with a small amount of increase dosage until the suitableeest effect that reaches in said case.For convenience, if desired, by day can be with total daily dose portioning and by a part administration.Consider factor mentioned above, adjust dosage and the administration frequency of compound as herein described according to the judgement that cures mainly clinician (doctor), and if suitable, adjust amount of application and the frequency of other treatment agent and/or therapy.Therefore, the dosage of pharmaceutical composition may differ greatly.Dosage can for about 0.001mg/kg body weight to about 100mg/kg body weight every day (with single dose or broken dose administration), perhaps at least about 0.1mg/kg body weight every day.Concrete therapeutic dose can comprise, for example, about 0.01mg is to the compound of about 7000mg, perhaps about 0.05mg about 2500mg extremely for example.According to concrete purposes, can be at about 0.1mg to 1000mg, about 1mg to 300mg, perhaps in the 10mg to 200mg, change or unit of adjustment's dosage formulation in the content of reactive compound.In some cases, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus, and in other cases, can use even bigger dosage and do not cause any harmful side effect, for example by so heavy dose is divided into the administration in all day of some low doses.Dosage can depend on the specific IC of the compound of use
50Value changes.Be not in the associating dispenser of unique therapy at described compound, the compound of the low amount of possible administration also still has treatment or prevention effect.
Other dosage is provided in whole specification and claim.
Formulation
Described pharmaceutical composition can be the form of the tablet that for example is suitable for oral administration, capsule, pill, powder, sustained release preparation, solution, supensoid agent, the form that is suitable for sterile solution agent, supensoid agent or the emulsion of parenteral injection, the form that is suitable for ointment or the cream of topical perhaps is suitable for the form of the suppository of rectally.Described pharmaceutical composition can be for being suitable for the unit dosage form of the accurate dosage of single-dose.Described pharmaceutical composition can comprise conventional pharmaceutical carriers or excipient and as the compound of the present invention of active component.In addition, it can comprise other medicinal or pharmaceutical agents, carrier, assistant agent etc.
Exemplary parenteral form comprises solution or the supensoid agent of reactive compound in aseptic aqueous solution (for example, moisture propane diols or glucose solution).If desired, can suitably carry out buffered to such formulation.
The pharmaceutical carriers that is fit to comprises inert diluent or filler, water and various organic solvent.If desired, described pharmaceutical composition can comprise other compositions, for example flavor enhancement, adhesive, excipient etc.Therefore, for oral administration, tablet comprises various excipient, and for example citric acid can use with various disintegrants (for example starch, alginic acid and silicate that some is complicated) and adhesive (for example sucrose, gelatin and gum Arabic).In addition, lubricant such as dolomol, lauryl sodium sulfate and talcum are through being usually used in the film-making purpose.The solid composite of similar type also can be used for soft-filled gelatin capsule and hard-filled gelatin capsule, and it comprises the polyethylene glycol of lactose and HMW.When needs aqueous suspension or elixir are used for oral administration, reactive compound wherein can with various sweeteners or flavor enhancement, colouring agent or dyestuff, and, if need, emulsifier or suspending agent, thinner (as water, ethanol, propane diols, glycerine or their combination) mixing in addition.
To those skilled in the art, the compound method of various pharmaceutical compositions that contains the reactive compound of specified quantitative is known, perhaps can be apparent.For example referring to Remington ' s Pharmaceutical Sciences, MackPublishing Company, ester, Pa., the 18th edition (1990).
Conjoint therapy
Compound as herein described or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative can be used as monotherapy and use.All right administration compound as herein described or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative are with other one or more therapy couplings.
This paper also describes N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type), and it can be used as monotherapy and uses.The crystalline polymorph type A of all right administration N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is with other one or more therapy couplings.
Only as example, if when accepting one of compound as herein described, one of side reaction that the patient stands is hypertension, then suitably administering drug combinations antihypertensive and described compound.Perhaps, only as example, can improve the treatment benefit (be that adjuvant itself may only have minimum treatment benefit, but the another kind of therapeutic agent of coupling, total treatment benefit of patient is increased) of one of compound as herein described by the administration adjuvant.Perhaps, only as example, the therapeutic agent (it also comprises therapeutic scheme) by one of administering drug combinations compound as herein described and another kind also have the treatment benefit can improve the benefit that the patient is subjected to.Only as example, in the treating diabetes that relates to one of administration compound as herein described, can also improve the treatment benefit in fact by another kind of Remedies for diabetes is provided to the patient.Under any circumstance, do not consider disease, illness or the patient's condition of receiving treatment, total benefit that the patient stands may be the simple adduction of two kinds of therapeutic agents, perhaps patient's benefit that may stand to work in coordination with.
Other therapies include but not limited to, use other treatment agent, radiotherapy or the two.Under the situation of compound as herein described and other treatment agent administering drug combinations, compound as herein described does not need with the other treatment agent in identical administered in pharmaceutical compositions, and since different physics and chemical feature, can pass through different administrations.For example, described compound can be taken orally to produce and keeps its good blood level, and another kind of therapeutic agent can intravenous administration.Under possible situation, determine mode of administration and administration adaptability in the identical pharmaceutical composition, be that specialized clinician is known.Can carry out the initial stage administration according to the scheme that this area is set up, then, effect according to the observation, specialized clinician can be adjusted dosage, mode of administration and administration time.The concrete selection of compound (and suitably time, other treatment agent and/or radiation) depends on that attending doctor's diagnosis and they are to the judgement of patient's patient's condition and suitable therapeutic scheme.The other treatment agent can comprise the chemotherapeutant such as antitumorigenic substance, for example is selected from mitotic inhibitor (for example vincaleukoblastinum); Alkylating agent (for example cis-platinum, carboplatin and cyclophosphamide); Antimetabolite (for example 5 FU 5 fluorouracil, cytarabine and hydroxycarbamide, perhaps for example be disclosed in antimetabolite N-(5-[N-(3,4-dihydro-2-methyl-4-oxo quinazoline-6-ylmethyl))-N-methylamino for example in No. 239362, the european patent application]-the 2-Thenoyl)-L-glutamic acid); Growth factor receptor inhibitors; Cell cycle inhibitor; Embed antibiotic (for example adriamycin and bleomycin); Enzyme (for example interferon); And antihormones (antiestrogenic Nolvadex for example for example
TM(Tamoxifen) or for example antiandrogen such as Casodex
TM(4 '-cyano group-3-(4-fluorophenyl sulfonyl)-2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide)).By side by side, in turn or respectively component is respectively treated in administration, can realize such therapeutic alliance.
Compound as herein described and composition (with suitable chemotherapeutant and/or radiotherapy) can be used (for example side by side, basically side by side or in same therapeutic scheme) jointly, perhaps in turn use, this depends on the character of described disease of patient or illness, and with chemotherapeutant and/or the radiotherapeutic actual selection of described compound coupling (namely in single therapeutic scheme).
In co-administered and use, described compound and chemotherapeutant and/or radiotherapy do not need side by side or basically side by side to use, and described compound and chemotherapeutant and/or the radiotherapeutic initial order of using may be inessential.Therefore, at first administration compound of the present invention is used chemotherapeutant and/or radiotherapy then; Perhaps can at first use chemotherapeutant and/or radiotherapy, then administration compound of the present invention.During single therapeutic scheme, can repeat this optional application process.After the disease of receiving treatment and the patient's condition of evaluate patient, determine order of administration during therapeutic scheme and the number of times of each therapy of repetitive administration, in the ken of specialist.For example, can at first use chemotherapeutant and/or radiotherapy, if particularly it is cytotoxic agent, continue treatment by the compound of the present invention of administration subsequently then, in determining favourable situation, then use chemotherapeutant and/or radiation etc., finish until therapeutic scheme.Therefore, rule of thumb and knowledge, along with treatment is carried out, each dosage regimen of the compound that the medical practitioner can be used for the treatment of according to the needs adjustment of individual patient.In the treatment under judging dosage whether effectively, cure mainly the general health that the clinician will consider the patient, and clearer and more definite sign, for example the actual contraction of the inhibition of the alleviation of disease related symptom, tumor growth, tumour or shift and suppress.By standard method such as for example CAT or MRI scanning of radiologic investigation, can measure the size of tumour, and follow-up measured value can be used for judging whether growth of tumor has been suppressed or even reverse.The disease related symptom for example improvement of the alleviation of pain and the overall patient's condition also can be used for helping to judge the validity for the treatment of.
The concrete limiting examples of possible conjoint therapy comprises the medicament in coupling compound of the present invention and the following pharmacotherapy classification as described below.These tabulations should not be construed as sealing, and should be used as the common illustrative example in present associated treatment field.And the coupling scheme can comprise various methods of administration, and should comprise oral, intravenous, intraocular, subcutaneous, local skin and local inhalation.
In order to treat tumor disease, proliferative disorders and cancer, compound of the present invention can be selected from down the group the medicament administering drug combinations, described medicament group comprises: aromatase inhibitor, antiestrogenic, antiandrogen, corticosteroid, the Gonadorelin activator, topoisomerase 1 and 2 inhibitor, the microtubule activator, alkylating agent, nitroso ureas, antitumor antimetabolite, contain platinum compounds, fat or the agent of protein kinase target, IMiDs, albumen or the agent of lipophosphatidic acid enzyme target, antiangiogenic agent, the Akt inhibitor, the IGF-I inhibitor, the FGF3 conditioning agent, the mTOR inhibitor, the Smac analogies, hdac inhibitor, the medicament of inducing cell differentiation, bradykinin 1 receptor antagonist, the Angiotensin II antagonist, cyclooxygenase-2 inhibitor, heparitinase (heparanse) inhibitor, the lymphokine inhibitor, cell factor inhibitors, the IKK inhibitor, the P38MAPK inhibitor, ARRY-797, the HSP90 inhibitor, many inhibitors of kinases, diphosphonate (bisphosphanate), rapamycin derivative, anti-apoptosis pathway inhibitor, the apoptosis pathway activator, the PPAR activator, the RAR activator, Ras isoform inhibitor, telomerase inhibitor, protease inhibitors, metal protease inhibitors, amastatin, SHIP activator-AQX-MN100, Humax-CD20 (ofatumumab), the CD20 antagonist, IL2-diphtheria toxin fusions.
In order to treat tumor disease, proliferative disorders and cancer, compound of the present invention can with the medicament administering drug combinations that is selected from down group, described group comprises: Dacarbazine (DTIC), act-C
2, act-C
3, actinomycin D and actinomycin F
1, cyclophosphamide, melphalan, Estramustine, maytansinol, rifamycin, dalacin, Doxorubicin, daunorubicin, epirubicin, idarubicin, Detorubicin, carminomycin, idarubicin, epirubicin, esorubicin, mitoxantrone, bleomycin A, bleomycin A
2With bleomycin B, camptothecine, Irinotecan .RTM., Hycamtin .RTM., 9-aminocamptothecin, 10,11-methylene-dioxy camptothecine, the 9-nitrocamptothecin, bortezomib, Temozolomide, TAS103, NPI0052, Combretastatin, Combretastatin A-4-2, Combretastatin A-4-4, calicheamycin, neoearcinostain, Epothilones A, epothilone B, Epothilone C and semisynthetic variant, Trastuzumab .RTM., Mabthera .RTM., CD40 antibody, L-Asparaginasum, interleukins, interferon, leuproside and Pegaspargase, 5 FU 5 fluorouracil, fluorodeoxyuridine, ptorafur, 5 '-doxifluridine, UFT, MITC, the S-1 capecitabine, diethylstilbestrol, Tamoxifen, Toremifene, Tomudex (tolmudex), thymitaq, Flutamide, Fluoxymesterone, Bicalutamide, Finasteride, estradiol, Trioxifene, dexamethasone, leuprorelin acetate, Estramustine, Droloxifene, Medroxyprogesterone, megestrol acetate, aminoglutethimide, the testis lactone, testosterone, diethylstilbestrol, hydroxyprogesterone, Mitomycin A, Mitomycin B and mitomycin C, porfiromycin, cis-platinum, carboplatin, oxaliplatin, four platinum, platinum-DACH, Ormaplatin, Thalidomide, lenalidomide, CI-973, the telomere chalone, CHIR258, Rad 001, SAHA, Tubacin, 17-AAG, Sorafenib, JM-216, podophyllotoxin, epipodophyllotoxin, Etoposide, Teniposide, it fills in watt .RTM., Iressa .RTM., Imatinib .RTM., Miltefosine .RTM., piperazine founds the new .RTM. of good fortune, aminopterin, methotrexate (MTX), methopterin, dichioromethotrexate, the 6-mercaptopurine, thioguanine, azattuoprine, allopurinol, the upright shore of carat, fludarabine, Pentostatin, 2-chlorine adenosine, deoxycytidine, cytarabine, cytarabine, azacitidine, 5-azepine cytimidine, gemcitabine, 5-azepine cytimidine-Arabinoside, vincristine, vincaleukoblastinum, vinorelbine, leurosine, leurosidine and eldisine, taxol, taxotere and docetaxel.
In order to treat inflammatory disease or pain, the acceptable salt of the pharmacy of compound of the present invention and described compound can with the medicament administering drug combinations that is selected from down group, described medicament group comprises: corticosteroid, on-steroidal AID, muscle relaxant and with the combination of other medicaments, anaesthetic and with the combination of other medicaments, expectorant and with combination, antidepressants, anticonvulsive drug and the combination thereof of other medicaments; Antihypertensive, opiates, local Cannabinoids, capsaicine, BDP (synergy with non-beneficiated), betamethasone valerate, clobetasol propionate, metacortandracin, methylprednisolone, the oxalic acid diflorasone, halobetasol propionate, Amcinonide, dexamethasone, Desoximetasone (dexosimethasone), fluocinolone acetonide, Fluocinonide, Halcinonide (halocinonide), the neopentanoic acid clocortolone, Desoximetasone (dexosimetasone), flurandrenolide, salicylate (salt), brufen, Ketoprofen, Etodolac, Diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, Baclofen, cyclobenzaprine/lidocaine, Baclofen/cyclobenzaprine, cyclobenzaprine/lidocaine/Ketoprofen, lidocaine, lidocaine/DDG, prilocaine, EMLA cream (the eutectic mixture of local anesthetic (lidocaine 2.5% and prilocaine 2.5%), gualfenesin, gualfenesin/Ketoprofen/cyclobenzaprine, amitriptyline (amitryptiline), doxepin, desipramine, imipramine, amoxapine, clomipramine, nortriptyline, protriptyline, Duloxetine, Mirtazapine (mirtazepine), Nisoxetine, maprotiline, Reboxetine, Prozac, Fluvoxamine, carbamazepine, Felbamate, Lamotrigine, Topiramate, Tiagabine, Oxcarbazepine, carbamazepine (carbamezipine), Zonisamide, mexiletine, Gabapentin/clonidine, Gabapentin/carbamazepine, carbamazepine/cyclobenzaprine, antihypertensive comprises: clonidine, codeine, Loperamide, bent horse is many, morphine, fentanyl, Oxycodone, hydrocodone, levorphanol, butorphanol, menthol, wintergreen, camphor, eucalyptus oil, turpentine oil; The CB1/CB2 part, paracetamol, English monoclonal antibody of sharp former times, nitric oxide synthase inhibitors, the inhibitor of derivable nitricoxide synthase particularly, PDE4 inhibitor-mechanism is similar in appearance to Ibudilast (AV-411), CDC-801, jnk inhibitor-CC-401, TNF/PDE4 composite restrainer-CDC-998, IL1 antagonist such as anakinra-Kineret, AMG 108, (mAb) of target IL-1, SHIP activator-AQX-MN100, the C5 antagonist, the C5a inhibitor, training gram pearl monoclonal antibody, pyrimidine synthesis inhibitors, the lymphokine inhibitor, cell factor inhibitors, the IKK inhibitor, the P38MAPK inhibitor, ARRY-797, the HSP90 inhibitor, many inhibitors of kinases, bisphosphonates (salt), the PPAR activator, Cox1 and cox2 inhibitor, anti--the CD4 therapy, the B-cytostatics, the COX/LOX double inhibitor, immunosuppressive drug, the iNOS inhibitor, NSAID, the sPLA2 inhibitor, colchicine, allopurinol, oxipurinol, gold, Ruide-Anranofin, Febustat, Puricase, PEG-uricase preparation, Benzbromarone, long-acting type β-2 activator (LABA), salmeterol (Serevent Diskus) and Formoterol (Foradil), the leukotriene conditioning agent comprises montelukast (Singulair) and zafirlukast (Accolate), induction type look sweet acid (Intal) or nedocromil (Tilade), theophylline.Fugitive type β-2 activator, ipratropium (Atrovent), immunotherapeutic agent-(allergia desensitization injection), anti--IgE monoclone antibody-Xolair, common DMARD comprises: hydroxychloroquine (Plaquenil), gold compound Anranofin (Ruide), Sulfasalazine (Azulfidine), minocycline (Dynacin, Minocin) and methotrexate (MTX) (Rheumatrex), leflunomide (Arava), imuran (according to lily magnolia), cyclosporin (Neoral, Sandimmune) and cyclophosphamide (Cytoxan), antibiotic, the CD80 antagonist, the costimulator antagonist, Humax-CD20 (ofatumumab); CD20 antagonist, mek inhibitor, NF κ-B inhibitor, anti-B-cell antibody, Shu Dankang, the mAb of the receptor activators of target nuclear factor κ B part (RANKL) specifically.IL17 deactivation antibody, IL-17 receptor antagonist/inhibitor, the CTLA inhibitor, the CD20 inhibitor, soluble VEGFR-1 acceptor, anti-VEGFR-1 receptor antibody, anti-VEGF antibodies, integrain receptor antagaonists, select protein inhibitor, P-selects protein inhibitor and E-to select protein inhibitor, PLA 2 inhibitors, lipoxidase inhibitor, RANKL and RANK antagonist/antibody, protect the ossein antagonist, the lymphotoxin inhibitor, B-lymphocyte stimulatory factors, the MCP-1 inhibitor, the MIF inhibitor, the CD2 inhibitor, the CD3 inhibitor, the CD4 inhibitor, the CD25 inhibitor, CD40 inhibitor and CD40 part CD152 (CTLA4) inhibitor, the macrolide immunosuppressive drug, the selective depressant of nucleotide metabolism, the inhibitor of chemotaxis, CXC acceptor and CXC ligand inhibitor, chemokine antagonists, the leukocyte chemotaxis inhibitor, the adhesion molecule retarding agent, select albumen lymphocyte function antigen-1 (LFA-1, CD11a) antagonist, Vla-4-4 (VLA-4) antagonist, NMPI, elastatinal, cathepsin inhibitors.
In order to treat eye disorders and eye illness, the acceptable salt of the pharmacy of compound of the present invention and described compound can be selected from down the group the medicament administration, described group comprises: beta-Blocking agent, carbonic anhydrase inhibitor, alpha-adrenergic antagonist and beta-adrenergic antagonist comprise alpha 1 adrenergic antagonist, α 2 activators, myotic, prostaglandin analogue, corticosteroid and immunosuppressive drug.
In order to treat eye disorders and eye illness, the acceptable salt of the pharmacy of compound of the present invention and described compound can be selected from down the group the medicament administering drug combinations, described group comprises: timolol, betaxolol, Levobetaxolol, carteolol, levobunolol, Propranolol, brinzolamide, Dorzolamide, nipradilol, p-aminoclonidine, Brimonidine, pilocarpine, adrenaline, Latanoprost, travoprost, bimatoprost, Unoprostone, dexamethasone, metacortandracin, methylprednisolone, imuran, cyclosporin and immunoglobulin.
In order to treat autoimmune disease, the acceptable salt of the pharmacy of compound of the present invention or described compound can with the medicament administering drug combinations that is selected from down group, described group comprises: corticosteroid, immunosuppressive drug, prostaglandin analogue and antimetabolite.
In order to treat autoimmune disease, compound of the present invention can be selected from down the group the medicament administering drug combinations, described group comprises: dexamethasone, metacortandracin, methylprednisolone, imuran, cyclosporin, immunoglobulin, Latanoprost, travoprost, bimatoprost, Unoprostone, English monoclonal antibody of sharp former times, Rituximab, methotrexate (MTX), the on-steroidal AID, muscle relaxant and with the combination of other medicaments, anaesthetic and with the combination of other medicaments, expectorant and with the combination of other medicaments, antidepressants, anticonvulsive drug and combination thereof; Antihypertensive, opiates, local Cannabinoids, and other medicaments, capsaicine for example, BDP (synergy with non-beneficiated), betamethasone valerate, clobetasol propionate, metacortandracin, methylprednisolone, the oxalic acid diflorasone, halobetasol propionate, Amcinonide, dexamethasone, Desoximetasone, fluocinolone acetonide, Fluocinonide, Halcinonide, the neopentanoic acid clocortolone, Desoximetasone, flurandrenolide, salicylate (salt), brufen, Ketoprofen, Etodolac, Diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, Baclofen, cyclobenzaprine/lidocaine, Baclofen/cyclobenzaprine, cyclobenzaprine/lidocaine/Ketoprofen, lidocaine, lidocaine/DDG, prilocaine, EMLA cream (the eutectic mixture of local anesthetic (lidocaine 2.5% and prilocaine 2.5%), gualfenesin, gualfenesin/Ketoprofen/cyclobenzaprine, amitriptyline, doxepin, desipramine, imipramine, amoxapine, clomipramine, nortriptyline, protriptyline, Duloxetine, Mirtazapine, Nisoxetine, maprotiline, Reboxetine, Prozac, Fluvoxamine, carbamazepine, Felbamate, Lamotrigine, Topiramate, Tiagabine, Oxcarbazepine, carbamazepine, Zonisamide, mexiletine, Gabapentin/clonidine, Gabapentin/carbamazepine, carbamazepine/cyclobenzaprine, antihypertensive comprises: clonidine, codeine, Loperamide, bent horse is many, morphine, fentanyl, Oxycodone, hydrocodone, levorphanol, butorphanol, menthol, wintergreen, camphor, eucalyptus oil, turpentine oil; CB1/CB2 part, paracetamol, English monoclonal antibody of sharp former times; The inhibitor of nitric oxide synthase inhibitors, particularly derivable nitricoxide synthase; And other medicaments, for example capsaicine.PDE4 inhibitor-mechanism is similar in appearance to Ibudilast (AV-411), CDC-801, jnk inhibitor-CC-401, TNF/PDE4 composite restrainer-CDC-998, IL1 antagonist such as anakinra-Kineret, AMG 108, (mAb) of target IL-1, SHIP activator-AQX-MN100, the C5 antagonist, the C5a inhibitor, training gram pearl monoclonal antibody, pyrimidine synthesis inhibitors, the lymphokine inhibitor, cell factor inhibitors, the IKK inhibitor, the P38MAPK inhibitor, ARRY-797, the HSP90 inhibitor, many inhibitors of kinases, bisphosphonates (salt), the PPAR activator, Cox1 and cox2 inhibitor, anti--the CD4 therapy, the B-cytostatics, the COX/LOX double inhibitor, immunosuppressive drug, the iNOS inhibitor, NSAID, the sPLA2 inhibitor, colchicine, allopurinol, oxipurinol, gold, Ruide-Anranofin, Febustat, Puricase, PEG-uricase preparation, Benzbromarone, long-acting type β-2 activator (LABA), salmeterol (Serevent Diskus) and Formoterol (Foradil), the leukotriene conditioning agent comprises montelukast (Singulair) and zafirlukast (Accolate).Induction type look sweet acid (Intal) or nedocromil (Tilade), theophylline.Fugitive type β-2 activator, ipratropium (Atrovent), immunotherapeutic agent-(allergia desensitization injection), anti--IgE monoclone antibody-Xolair, common DMARD comprises hydroxychloroquine (Plaquenil), gold compound Anranofin (Ruide), Sulfasalazine (Azulfidine), minocycline (Dynacin, Minocin) and methotrexate (MTX) (Rheumatrex), leflunomide (Arava), imuran (according to lily magnolia), cyclosporin (Neoral, Sandimmune) and cyclophosphamide (Cytoxan), antibiotic, the CD80 antagonist, the costimulator antagonist, Humax-CD20 (ofatumumab); CD20 antagonist, mek inhibitor, NF kB inhibitor, anti-B cell antibody, Shu Dankang, the mAb of the receptor activators of target nuclear factor κ B part (RANKL) specifically.IL17 deactivation antibody, IL-17 receptor antagonist/inhibitor, the CTLA inhibitor, the CD20 inhibitor, soluble VEGFR-1 acceptor, anti-VEGFR-1 receptor antibody, anti-VEGF antibodies, integrain receptor antagaonists, select protein inhibitor, P-selects protein inhibitor and E-to select protein inhibitor, PLA 2 inhibitors, lipoxidase inhibitor, RANKL and RANK antagonist/antibody, protect the ossein antagonist, the lymphotoxin inhibitor, B-lymphocyte stimulatory factors, the MCP-1 inhibitor, the MIF inhibitor, the CD2 inhibitor, the CD3 inhibitor, the CD4 inhibitor, the CD25 inhibitor, CD40 inhibitor and CD40 part CD152 (CTLA4) inhibitor, the macrolide immunosuppressive drug, the selective depressant of nucleotide metabolism, the inhibitor of chemotaxis, CXC acceptor and CXC ligand inhibitor, chemokine antagonists, the leukocyte chemotaxis inhibitor, the adhesion molecule retarding agent, select albumen lymphocyte function antigen-1 (LFA-1, CD11a) antagonist, Vla-4-4 (VLA-4) antagonist, NMPI, elastatinal, cathepsin inhibitors.
In order to treat metabolic disorder; the acceptable salt of the pharmacy of compound of the present invention and described compound can be selected from down the group the medicament administering drug combinations; described group comprises: insulin; insulin derivates and analogies; the insulin secretagogue element; the insulin sensitiser thing; biguanides reagent; alpha-glucosidase restrainer; pancreotropic hormone sulfonylureas receptors ligand; Protein-tyrosine-phosphatase-1B (PTP-1B) inhibitor; GSK3 (glycogen synthase kinase-3) inhibitor; GLP-1 (glucagon-like-peptide-1); the GLP-1 analog; DPPIV (DPP IV) inhibitor; RXR part sodium dependent glucose cotransporter inhibitor; glycogen phosphorylase A inhibitor; the AGE disrupting agent; the PPAR conditioning agent; LXR and FXR conditioning agent; Fei Gelie ketone type PPARS activator; selectivity glucocorticoid antagonist; melbine; Glipizide; glibenclamide; Ya Moli; meglitinide; nateglinide; Repaglinide; PT-112; SB-517955; SB4195052; SB-216763; NN-57-05441; NN-57-05445; GW-0791; AGN-.sup.194.sup.204; T-1095; BAY R3401; acarbose Exendin-4; DPP728; LAF237; vildagliptin; MK-0431; Sha Gelieting; GSK23A; Pioglitazone; Rosiglitazone; (R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-ylmethoxy of in patent application WO 03/043985, describing]-benzenesulfonyl } 2; 3-dihydro-1H-indole-2-carboxylic acid; as the compound 19 of embodiment 4, and GI-262570.
Disease
This paper describes the method that treatment suffers from disease described in the individuality of disease, and it comprises to the formula I compound of described individual effective dosage or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative.
This paper also describes the method that treatment suffers from disease described in the individuality of disease or illness or illness, it comprises the N-(S)-(3 to described individual effective dosage, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type).The present invention relates to N-(S)-(3,4-, two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type) for the preparation of the purposes in the medicine for the treatment of disease or illness.
In some embodiments, the present invention relates to prevent or treat any disease or the illness that the MEK kinases plays a role, it comprises without limitation: tumor disease, hematologic disease, inflammatory disease, eye disease, neuropathy, immunological disease, cardiovascular disease, and skin disease, and because exceedingly or not producing the caused disease of proinflammatory cytokine to regulation and control, comprise and for example in human or other mammals, exceedingly or not regulate and control ground generation TNF, IL-1, IL-6 and IL-8.The present invention relates to such purposes of described compound, and the purposes of described compound in the medicine of the cytokine mediated disease such for the preparation for the treatment of or illness.In addition, the present invention relates to treat any such disease or illness to the mek inhibitor of human effective dosage.
The MEK kinases directly or through proinflammatory cytokine (comprises cytokine TNF, IL-1, IL-6 and IL-8) disease or the illness that play a role comprise without limitation: dry eyes, glaucoma, autoimmune disease, inflammatory disease, destructive osteopathy, proliferative diseases, neurodegenerative disorders, viral disease, anaphylaxis, infectious disease, heart attack, blood vessel generation illness, perfusion/ischemic again during apoplexy, blood vessel hyperplasia, the organ anoxic, cardiomegaly, the platelet aggregation that fibrin ferment causes, and the patient's condition relevant with prostaglandin endoperoxidase synthase-2 (COX-2).
Of the present invention aspect some, described disease is the excess proliferative patient's condition of the mankind or animal body, and it includes but not limited to the propagation that causes behind cancer, hyperplasia, ISR, inflammation, immunological diseases, cardiomegaly, atherosclerotic, pain, antimigraine, the blood vessel generation correlation patient's condition or illness, the medical conditions (including but not limited to operation, angioplasty or other situations).
In further embodiment, the described excess proliferative patient's condition is selected from hematologic disease cancer and non-hematologic disease cancer.In other other embodiments, described hematologic disease cancer is selected from Huppert's disease, leukemia and lymphoma.In embodiment further, described leukemia is to be selected from acute leukemia and chronic leukemia.In embodiment further, described acute leukemia is selected from acute lymphoblastic leukemia (ALL) and acute non lymphocytic leukemia (ANLL).In embodiment further, described chronic leukemia is selected from chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML).In further embodiment, described lymphoma is selected from Hodgkin lymphoma and non-Hodgkin lymphoma.In further embodiment, described hematologic disease cancer is Huppert's disease.In other embodiments, described hematologic disease cancer is low cancer, moderate cancer or height cancer.In other embodiments, described non-hematologic disease cancer is selected from the cancer of cancer, cancer of pancreas and urinary system of cancer, the digestive system of the cancer of the brain, head and neck cancer, lung cancer, breast cancer, genital system.In further embodiment, the cancer of described digestive system is upper gastrointestinal cancer or colorectal cancer.In further embodiment, the cancer of described urinary system is carcinoma of urinary bladder or clear-cell carcinoma.In further embodiment, the cancer of described genital system is prostate cancer.
Use the cancer of the treatable other types of Compounds and methods for as herein described to comprise: the cancer of cancer, neural cancer, lymphoid cancer and the endocrine system of cancer, eye and the eye socket of the cancer in the cancer of oral cavity and pharynx, the cancer of respiratory system, bone and joint, the cancer of soft tissue, cutaneum carcinoma, genital system.In certain embodiments, these cancers can be selected from the cancer by tongue, mouth, pharynx or other oral cavities; The cancer of the esophagus, cancer of the stomach, or carcinoma of small intestine; Colon cancer or the carcinoma of the rectum, cancer of anus or anal orifice and rectal intestine cancer; Liver cancer, stones in intrahepatic bile duct cancer, carcinoma of gallbladder, cancer of pancreas, or other gall-bladders or Alimentary cancer; The cancer of laryngocarcinoma, bronchiolar carcinoma and other respiratory apparatus; Heart cancer, melanoma, basal-cell carcinoma, squamous cell carcinoma, other non-epithelium cancers; The cancer of the uterus or cervical carcinoma; Carcinoma of uterine body; Oophoroma, carcinoma of vulva, carcinoma of vagina, or the cancer of other female genital organs; The cancer of prostate cancer, carcinoma of testis, penis or other male genitals; The uropoiesis carcinoma of urinary bladder; The cancer of kidney; Kidney, pelvic cancer or urethra cancer, or other cancers of Genito-urinary organ; The cancer of thyroid cancer or other endocrine gland; Chronic lymphocytic leukemia; And granulocyte and single celled CTCL.
Use the cancer of the treatable other other types of Compounds and methods for as herein described to comprise: gland cancer, angiosarcoma, astrocytoma, acoustic neurinoma, glioblastoma multiforme, basal-cell carcinoma, glioblastoma (blastoglioma), chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma, ewing's tumor, epithelioma, fibrosarcoma, cancer of the stomach, the genitourinary tract cancer, glioblastoma multiforme, angioblastoma, hepatocellular carcinoma, liver cancer, Kaposi sarcoma, large cell carcinoma, leiomyosarcoma, embryonal-cell lipoma, lymphangioendothelial sarcoma, lymphangioendothelial sarcoma, medullary carcinoma of thyroid gland, medulloblastoma, meningioma, celiothelioma, myeloma, myxosarcoma, neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, the epithelium oophoroma, papillary carcinoma, papillary adenocarcinoma, parathyroid adenoma, pheochromocytoma, pinealoma, plasmacytoma, retinoblastoma, rhabdomyosarcoma, carcinoma of sebaceous glands, seminoma, cutaneum carcinoma, melanoma, small-cell carcinoma of the lung, squamous cell carcinoma, syringocarcinoma, synovialoma, thyroid cancer, uvea melanoma and wilms' tumor.
The method of excess proliferative disease in the treatment mammal is also described, it comprises to formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or the derivative of described mammal administering drug combinations treatment effective dose, and antineoplastic.In some embodiments, described antineoplastic is selected from mitotic inhibitor, alkylating agent, antimetabolite, embedding antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme inhibitor, topoisomerase enzyme inhibitor, biological response modifier, antihormone, angiogenesis inhibitor, antiandrogen, SHIP activator-AQX-MN100, Humax-CD20 (ofatumumab), CD20 antagonist, IL2-diphtheria toxin fusions.
Using the disease of compound as herein described, composition and method treatment can be blood disorder.In certain embodiments, described blood disorder is selected from sickle cell anemia, myeloproliferative disorder disease (MDS) and bone marrow proliferative diseases.In further embodiment, described bone marrow proliferative diseases is selected from polycythemia vera, myelofibrosis and primary thrombocytosis.
Compound as herein described, composition and method can and have significantly lower additional benefits of harmful side effect as antiinflammatory agent.Compound as herein described, composition and method are used for the treatment of arthritis, include but not limited to rheumatoid arthritis, spondyloarthropathy, ankylosing spondylitis, gout, urarthritis, osteoarthritis, systemic loupus erythematosus, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis.Compound as herein described, composition and method also are used for the treatment of osteoporosis and other relevant bone disorders.These compounds as herein described, composition and method also are used for the treatment of the stomach and intestine patient's condition, for example reflux esophagitis, diarrhoea, inflammatory bowel disease, Crohn's disease, gastritis, IBS and ulcerative colitis.Compound as herein described, composition and method can also be used for the treatment of such as the lung inflammation relevant with virus infections and cystic fibrosis.In addition, compound as herein described, composition and method are also united for the organ transplant patient individually or with the immunomodulator of routine.Further, compound as herein described, composition and method are used for the treatment of itch and leucoderma.Particularly, compound as herein described, composition and method are used for the treatment of specific inflammatory disease rheumatoid arthritis.
Other inflammatory diseases that can prevent or treat comprise without limitation: asthma, anaphylaxis, Respiratory Distress Syndrome(RDS), perhaps acute or chronic pancreatitis.In addition, the respiratory disease that can prevent or treat includes but not limited to chronic obstructive pulmonary disease and pulmonary fibrosis.In addition, MEK inhibitors of kinases as herein described is also relevant with the generation of prostaglandin endoperoxidase synthase-2 (COX-2).Derived from the pro-inflammatory mediator of arachidonic cyclo-oxygenase approach, for example prostaglandin is produced by derivable COX-2 enzyme.The adjusting of COX-2 can be regulated and control these pro-inflammatory mediators, and it has influence on various kinds of cell, and is the important and crucial inflammatory mediator of various disease states and the patient's condition.Particularly, these inflammatory mediators have related to pain (for example sensitization of pain receptor) and oedema.Therefore, the kinase mediated illness of other MEK that can prevent or treat comprises oedema, analgia, fever and pain (for example neuromuscular pain, headache, toothache, arthritis ache and by the pain due to the cancer).
In addition, the disease through compound as herein described, composition and method treatment can be eye disease.Ophthalmology disease and blood vessel occur in the other diseases that plays a role in the pathogenesis, can be treated or be prevented, and include but not limited to: dry eyes (comprising Sjogren syndrome), macular degeneration, angle-closure glaucoma and open-angle glaucoma, ganglia retinae sex change, eye ischemic, the retinitis, PVR, uveitis, eye photophobia, and inflammation and the pain relevant with the ocular tissue acute injury.Compound as herein described, composition and method are used for the treatment of glaucoma PVR and/or BDR. and compound as herein described, composition and method also are used for the treatment of inflammation or the pain of postoperative, as the ophthalmic surgery inflammation or the pain that cause of cataract operation and refractive surgery for example.In further embodiment, described eye disease is to be selected from dry eyes, angle-closure glaucoma and open-angle glaucoma.
In addition, the disease through compound as herein described, composition and method treatment can be autoimmune disease.The autoimmune disease that can be prevented or treat includes but not limited to: rheumatoid arthritis, inflammatory bowel disease, inflammatory pain, ulcerative colitis, Crohn's disease, periodontosis, temporomandibular arthrosis, multiple sclerosis, diabetes, glomerulonephritis, systemic loupus erythematosus, chorionitis, chronic thyroiditis, Graves disease, hemolytic anemia, autoimmunity gastritis, autoimmune neutropenia, thrombopenia, CAH, myasthenia gravis, atopic dermatitis, graft versus host disease and psoriasis.The inflammatory disease that can prevent or treat includes but not limited to: asthma, anaphylaxis, Respiratory Distress Syndrome(RDS) or acute pancreatitis or chronic pancreatitis.Particularly, compound as herein described, composition and method are used for the treatment of specific autoimmune disease rheumatoid arthritis and multiple sclerosis.
In addition, the disease through compound as herein described, composition and method treatment can be skin disorder.In certain embodiments, described skin disorder is selected from down group, described group comprises melanoma, basal-cell carcinoma, squamous cell carcinoma without limitation, with other non-epithelium cutaneum carcinomas, and psoriasis and continuation itch, also have the other diseases relevant with skin and skin texture, can treat or prevent described skin disorder with MEK inhibitors of kinases of the present invention.
The metabolic disease that can treat or prevent comprises metabolic syndrome, insulin resistance without limitation, and I type and type ii diabetes.In addition, composition described herein can be used for the treatment of insulin resistance and typically with excessive inflammatory signal correction such as atherosclerotic other metabolic disorder.
Compound as herein described, composition and method also are used for the treatment of such as angiosis, antimigraine, kussmaul's disease, thyroiditis, alpastic anemia, Hodgkin's disease, chorionitis (sclerodoma), rheumatic fever, type i diabetes, neuromuscular junction disease (comprising myasthenia gravis), white matter disease (comprising multiple sclerosis), sarcoidosis, ephritis, nephrotic syndrome, behcet's syndrome, polymyositis, oulitis, periodontitis (periodontis), hypersensitivity, damage back swelling, ischemic (comprises myocardial ischemia, cardiovascular ischemic and heart stopping collecting Secondary cases ischemic) etc. disease in tissue damage in.Compound as herein described, composition and method can also be used for the treatment of allergic rhinitis, Respiratory Distress Syndrome(RDS), endotoxin shock syndrome and atherosclerotic.
In addition, the disease through compound as herein described, composition and method treatment can be the cardiovascular patient's condition.In certain embodiments, the described cardiovascular patient's condition is selected from atherosclerotic, cardiomegaly, idiopathic cardiomyopathy, heart failure, the relevant patient's condition or the illness of blood vessel generation, and the propagation that causes behind the medical conditions, described medical conditions includes but not limited to because of the ISR due to operation and the angioplasty.
In addition, the disease through compound as herein described, composition and method treatment can be neurological disorders.In certain embodiments, described neurological disorders is selected from Parkinson's, Alzheimer disease, Alzheimer and because of the central lesion due to apoplexy, ischemic and the wound.In other embodiments, described neurological disorders is selected from epilepsy, neuropathic pain, depression and bipolar disorder.
In addition, through compound as herein described, the disease of composition and method treatment can be cancer, for example acute myeloid leukemia, thymic carcinoma, the cancer of the brain, lung cancer, squamous cell carcinoma, cutaneum carcinoma, cancer eye, retinoblastoma, the intraocular melanoma, oral cavity and oropharynx cancer, carcinoma of urinary bladder, stomach (gastric) cancer, stomach (stomach) cancer, pancreas, carcinoma of urinary bladder, breast cancer, cervical carcinoma, the head cancer, neck cancer, kidney, kidney, liver cancer, oophoroma, prostate cancer, colorectal cancer, the cancer of the esophagus, carcinoma of testis, gynecological cancer, thyroid cancer, the CNS cancer, the PNS cancer, the cancer that the cancer (as lymphoma and Kaposi sarcoma) that AIDS is relevant or virus cause.In some embodiments, described compound and composition are used for the treatment of non-cancer excess proliferative illness, as the hyperplasia of prostate of skin (as psoriasis), ISR or prostate (as benign prostatauxe (BPH)).
In addition, through compound as herein described, the disease of composition and method treatment can be the pancreatitis in the mammal, kidney trouble (comprising the ephrosis that proliferative glomerulonephritis and diabetes cause), pain, with the disease that blood vessel generates or the blood vessel generation is relevant, tumor vessel takes place, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerotic, skin disease is (as psoriasis, eczema and chorionitis), diabetes, BDR, retinopathy of prematurity, the macular degeneration that age is relevant, angioma, myotenositis, bursal synovitis, sciatica, glioma, melanoma, Kaposi sarcoma and oophoroma, breast cancer, lung cancer, cancer of pancreas, prostate cancer, colon cancer and epidermoid carcinoma.
In addition, the disease through compound as herein described, composition and method treatment can be to stop the blastocyte in the mammal to be implanted.
According to method of the present invention, can comprise with the patient of compound as herein described or the acceptable salt of their pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivatives for treatment, for example, diagnosed the patient who suffers from following disease, described disease comprises: psoriasis; ISR; Atherosclerotic; BPH; Breast cancer, for example duct carcinoma in the tracheal tissue in the mammary gland, cephaloma, mucinous carcinoma, tubule cancer and IBC; Oophoroma (comprise the gland cancer in epithelium ovarian neoplasm such as the ovary and be transferred to gland cancer the abdominal cavity from ovary); The cancer of the uterus; Cervix cancer is as the gland cancer in the epithelium of cervix uteri (comprising squamous cell carcinoma and gland cancer); Prostate cancer, as be selected from following prostate cancer: the gland cancer that has been transferred to bone; Cancer of pancreas is as the last dermoid cancer in the pancreatic duct tissue and the gland cancer in the pancreatic duct; Carcinoma of urinary bladder is as tumour, squamous cell carcinoma, gland cancer and the cellule cancer in the urothelium cell in the transitional cell carcinoma in the uropoiesis bladder, urothelium cancer (transitional cell carcinoma), the bladder lining; Leukemia is acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell, myelodysplasia and bone marrow proliferative illness for example; Osteocarcinoma; Lung cancer is non-small cell lung cancer (NSCLC) for example, is divided into squamous cell carcinoma, gland cancer and maxicell undifferentiated carcinoma, and small-cell carcinoma of the lung; Cutaneum carcinoma is basal-cell carcinoma, melanoma, squamous cell carcinoma and actinic keratoma (it is the skin disease that develops into squamous cell carcinoma sometimes) for example; The eyes retina blastoma; Cutaneous melanoma or intraocular (eye) melanoma; Primary carcinoma of liver (originating in the cancer of liver); Kidney; Thyroid cancer such as papillary thyroid carcinoma, folliculus thyroid cancer, medullary thyroid carcinoma and polymorphy thyroid cancer; AIDS correlation lymphoma such as diffuse large B cell lymphoma, B immunoblast's cell lymphoma and small non-cleaved cell lymphoma; Kaposi sarcoma; The cancer that virus causes (comprising hepatitis b virus (HBV), hepatitis C virus (HCV) and hepatocellular carcinoma); People's lymphotropic virus 1 type (HTLV-1) and Adult T-cell leukemia/lymphoma; And human papilloma virus (HPV) and cervical carcinoma; Central nervous system cancer (CNS) is as primary brain tumor, and it comprises glioma (astrocytoma, glioblastoma multiforme or glioblastoma multiforme), oligodendroglioma, ependymoma, meningioma, lymphoma, neurinoma and medulloblastoma; Peripheral neverous system (PNS) cancer such as acoustic neurinoma and pernicious peripheral nerve sheath knurl (MPNST) comprise neurofibroma and neurinoma, malignant fibrous sexual cell knurl, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma and pernicious Combination muller's steatoma; Carcinoma of mouth and oropharynx cancer are for example swallowed cancer, laryngocarcinoma, nasopharyngeal carcinoma and oropharynx cancer; Cancer of the stomach such as lymphoma, stomach stromal tumor and carcinoid tumor; Carcinoma of testis such as gonioma (GCTs), it comprises seminoma and nonseminoma and sexual gland stromal tumor, it comprises leydig cell tumor and Sai Ertuoli cytoma; Thymic carcinoma such as thymoma, thymic carcinoma, Hodgkin's disease, non-Hodgkin lymphoma carcinoid or carcinoid tumor; The carcinoma of the rectum; And colon cancer.
Medicine box
Compound as herein described, composition and method are provided for treating the medicine box such as those illnesss as herein described.These medicine boxs comprise one or more compounds as herein described or composition in container, and randomly comprise the specification that uses described medicine box according to the whole bag of tricks as herein described and step instruction.Such medicine box can also comprise such information, for example science list of references, package insert material, clinical test results and/or these summary etc., its explanation or prove activity and/or the advantage of described composition, and/or it describes dosage, medication, side effect, drug interaction, or other information useful to the health care supplier.Such information can be based on the result of various researchs, and for example, the research of service test animal comprises the body inner model and based on human clinical trial's research.Can comprise that doctor, nurse, pharmacists, prescription official etc. provide, sell and/or promote medicine box as herein described to medical supplier.In some embodiments, can also directly sell medicine box to the consumer.
Compound as herein described can be used for diagnostics and be used as research reagent.For example, compound as herein described makes up individually or with other compounds, can be as the instrument in difference and/or the combinatory analysis to illustrate the expression of gene pattern of expression in cell and the tissue.As a limiting examples, contrast is with the interior expression pattern of the cell or tissue of one or more compound treatment with without control cells or the in-house expression pattern of compound treatment, the pattern of analyzing gained is measured the level of difference of gene expression, because they relate to, for example, disease association, signal path, celluar localization, detection expression of gene level, size, structure or function.Through stimulate or without stimulated cells on, and in other compounds existence that influences expression pattern or not, can carry out these analyses.
Except being used for the human treatment, compound of the present invention and preparation also are used for the veterinary treatment of pet (as dog, cat), rare animal and domestic animal (as horse), and it comprises mammal, rodent etc.
The embodiment that below provides and preparation method further illustrate and illustrate compound of the present invention and prepare the method for such compound.Should understand the scope that scope of the present invention never is subject to following examples and preparation method.