CN1376147A - Pyrazole derivatives - Google Patents

Pyrazole derivatives Download PDF

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Publication number
CN1376147A
CN1376147A CN 00813257 CN00813257A CN1376147A CN 1376147 A CN1376147 A CN 1376147A CN 00813257 CN00813257 CN 00813257 CN 00813257 A CN00813257 A CN 00813257A CN 1376147 A CN1376147 A CN 1376147A
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alkyl
compound
hydrogen
amino
group
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戴维·米夏埃尔·戈尔德施泰因
莎拉达·申维·拉瓦迭
戴维·马克·罗特施泰因
埃里克·布里安·肖格伦
弗朗西斯科·哈维尔·塔拉马斯
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Abstract

The invention relates to pyrazole derivatives of formula I as p-38MPA kinase inhibitor, pharmaceutical compositions containing them, usage and a preparing method thereof.

Description

Pyrazole derivatives
Invention field
The present invention relates to the pyrazole derivatives that some suppresses the p38 map kinase, contain their pharmaceutical composition, its application method and prepare the method for these compounds.
Background information and associated viscera
TNF became the core participant already with IL-1 in many chronic inflammatory diseasess pathologic process relevant with autoimmune disorder.IL-1 relates to mediation or worsens disease, as rheumatoid arthritis ((referring to, Arend, W.P.Arthritis ﹠amp; Rheumatism 38 (2): 151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome, tuberculosis, atherosclerosis, diabetes, Hokdkin disease, (referring to, Benharroch .Euro.Cytokine Network7 (1) such as D.: 51-57) and alzheimer's disease.Have been found that excessively or the TNF of imbalance production participates in mediation or worsens disease, as rheumatoid arthritis ((referring to, Maini, APMIS.105 such as R.N. (4): 257-263, (1997); Feldmann, M., J.of the Royal College of Physicians of London30 (6): 560-570, (1996); Lorenz, H.M. wait J.of Immunology 156 (4): 1646-1653, (1996)), osteoarthritis, spondylitis, Sepsis, septic shock ((referring to, Abraham, E. wait JAMA.277 (19): 1531-1538, (1997), adult respiratory distress syndrome, asthma ((referring to, Shah .Clin.﹠amp such as A.; Exp.Allergy 1038-1044, (1995) and Lassalle, Clin.﹠amp such as P.; Exp.Immunol.94 (1): 105-110, (1993)), bone absorpting disease, pyreticosis ((referring to, Cooper, A.L. wait Am.J.of Physiology 267 (6 Pt.2): 1431-1436)), encephalomyelitis, demyelinization ((referring to, Klindert, W.E. wait J.ofNeuroimmunol.72 (2): 163-168, (1997)) and periodontal disease.
The clinical trial of IL-1 and TNF receptor antagonist shows, blocks these cytokines and can obviously improve inflammatory diseases by the ability that its acceptor sends signal in human body.So, the strategy that the regulation and control of these inflammatory cytokine are considered to the most effective a kind of blocking-up chronic inflammatory diseases and have the positive treatment effect.The p38 map kinase also shows in the translation of TNF and IL-1 control and plays an important role, and participates in the biochemical signals ((referring to, Lee .Nature.372 such as J.C. (6508): 739-46, (1994)) of these molecules.Can effectively suppress bone resorption, inflammation and other immunity and based on the pathology of inflammation in conjunction with the compound of p38 MAP.The feature of p38 map kinase and the central role in the biosynthesizing of TNF and IL-1 thereof make this kinases by these cytokines noticeable in the disease mediated treatment.
So people are desirable to provide the p38 map kinase inhibitor, and thereby obtain a kind of method of resisting the disease of pro-inflammatory cytokine such as TNF and IL-1 mediation.The present invention has satisfied this and relevant needs thereof.
Summary of the invention
In aspect first, the invention provides the compound of the compound group of the formula of being selected from (I) expression: Wherein:
R 1Be hydrogen or acyl group;
R 2It is hydrogen or alkyl;
A is aryl or heteroaryl ring;
B is aryl or heteroaryl ring;
R 3Be selected from:
(a) amino, alkylamino or dialkyl amido;
(b) acyl amino;
(c) the optional heterocyclic radical that replaces;
(d) optional aryl or the heteroaryl that replaces;
(e) heteroatom containing alkyl;
(f) contain the heteroatoms thiazolinyl;
(g) contain the heteroatoms alkynyl;
(h) contain the heteroatoms alkoxyl group;
(i) heteroatom containing alkyl amino;
(j) the optional heterocyclic radical alkyl that replaces;
(k) the optional heterocyclic radical thiazolinyl that replaces;
(l) the optional heterocyclic radical alkynyl that replaces;
(m) optional cycloalkyloxy, cycloalkyl alkoxy, heterocyclic radical alkoxyl group or the heterocyclic oxy group that replaces;
(n) the optional heterocyclic radical alkylamino that replaces;
(o) the optional heterocyclic radical alkyl-carbonyl that replaces;
(p) heteroatom containing alkyl carbonyl;
(q) the optional cycloalkyl amino that replaces;
(r)-NHSO 2R 6, R wherein 6Be alkyl, heteroatom containing alkyl or the optional heterocyclic radical that replaces
Alkyl;
(s)-NHSO 2NR 7R 8, R wherein 7And R 8Be hydrogen, alkyl independently of one another or contain heteroatoms
Alkyl;
(t)-Y-(thiazolinyl)-R 9, wherein:
Y be singly-bound ,-O-,-NH-or-S (O) n-(wherein n is the integer of 0-2); And R 9Be cyanogen
Basic, optional substituted heteroaryl ,-COOH ,-COR 10,-COOR 11,
-CONR 12R 13,-SO 2R 14,-SO 2NR 15R 16,-NHSO 2R 17Or
-NHSO 2NR 18R 19, R wherein 10Be alkyl or the optional heterocycle that replaces, R 11Be alkane
Base, and R 12, R 13, R 14, R 15, R 16, R 17, R 18And R 19Be independently of one another
Hydrogen, alkyl or heteroatom containing alkyl;
(u)-C (=NR 20) (NR 21R 22), R wherein 20, R 21And R 22Be hydrogen, alkyl or hydroxyl independently
Base; Or R 20And R 21Be together-(CH 2) n-, wherein n is 2 or 3, and R 22Be hydrogen or alkane
Base; (v)-NHC (X) NR 23R 24, wherein X be-O-or-S-, and R 23And R 24Be hydrogen, alkyl or heteroatom containing alkyl independently of one another; (w)-CONR 25R 26, R wherein 25And R 26Represent hydrogen, alkyl, heteroatom containing alkyl or optional substituted heterocyclic radical alkyl independently, or R 25And R 26The nitrogen that links to each other with them constitutes the optional heterocyclic ring that replaces; (x)-S (O) nR 27, wherein n is 0 to 2 integer, and R 27Be alkyl, heteroatom containing alkyl, optional substituted cycloalkyl, the optional heterocyclic radical alkyl that replaces; Or-NR 28R 29, R wherein 28And R 29Be hydrogen, alkyl or heteroatom containing alkyl independently of one another; (y) cycloalkylalkyl, cycloalkyl alkynyl and cycloalkyl alkynyl, they are all randomly by alkyl, halogen, hydroxyl or amino the replacement; (z) arylamino alkylidene group or heteroaryl amino alkylidene group; (aa) Z-alkylidene group-NR 30R 31Or Z-alkylidene group-OR 32, wherein Z be-NH-,-N (alkyl)-
Or-O-, and R 30, R 31And R 32Be hydrogen, alkyl independently of one another or contain heteroatoms
Alkyl; (bb)-OC (O)-alkylidene group-CO 2H or-OC (O)-NR ' R " (wherein R ' and R " is hydrogen independently
Or alkyl) (cc) heteroaryl alkenylene or heteroaryl alkynylene; (dd) X-(alkylidene group) CH[(CR ' R ") mOR 40] [(CR ' R ") nOR 40],
Wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) p-(wherein p is 0 to 2 integer);
R 40It is acyl group; C (O) OR 41(R wherein 41Be hydrogen, alkyl or cycloalkyl);
C (O) ONR 41R 42(R wherein 41Definition as above and R 42Be hydrogen or alkyl); Or
C (O) NR 41R 42(R wherein 41And R 42Definition as above);
R ' and R " are hydrogen or alkyls independently; And m and n be 0 to 3 integer independently, bar
Part is that m and n are not 0 simultaneously; (ee) X-(alkylidene group)-CH (OH) CH 2NHR 50, wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) n-(wherein n is 0 to 2
Integer); And R 50Be C (O) OR 51And C (O) NR 51R 52(R wherein 51Be hydrogen, alkyl
Or cycloalkyl and R 52Be hydrogen or alkyl); (ff) X-(alkylidene group)-CH (NR 50)-CH 2OH, wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) n-(wherein n is 0 to 2
Integer); And R 50Be C (O) OR 51And C (O) NR 50R 52(R wherein 51Be hydrogen, alkyl
Or cycloalkyl and R 52Be hydrogen or alkyl); R 4Be selected from: (a) hydrogen; (b) halogen; (c) alkyl; (d) alkoxyl group; (e) hydroxyl; R 5Be selected from: (a) hydrogen; (b) halogen; (c) alkyl; (d) haloalkyl; (e) alkylthio; (f) hydroxyl; (g) amino; (h) alkylamino; (i) dialkyl amido; (j) heteroatom containing alkyl; (k) optional substituted heterocycle; (l) optional substituted heterocyclic radical alkyl; (m) optional substituted heterocyclic radical alkoxyl group; (n) alkyl sulphonyl; (o) amino-sulfonyl, an alkyl amino sulfonyl or dialkyl amino sulfonyl; (p) contain the heteroatoms alkoxyl group; (q) carboxyl; R 6Be selected from: (a) hydrogen; (b) halo; (c) alkyl; (d) alkoxyl group; With
Its prodrug, various isomer, mixture of isomers and pharmacologically acceptable salts.
In second aspect, the invention provides and contain formula (I) compound for the treatment of significant quantity or the pharmaceutical composition of its pharmacologically acceptable salts and the acceptable vehicle of pharmacy.
In the third aspect, the invention provides a kind of the treatment in the Mammals by the method for the medicable disease of administration p38 map kinase inhibitor, this method comprises formula (I) compound or its pharmaceutically acceptable salt of administering therapeutic significant quantity.
In fourth aspect, the invention provides the method for the compound of preparation formula (I).The detailed Description Of The Invention definition
Unless otherwise noted, used following term has following implication in specification sheets and claims:
" alkyl " is meant the straight chain saturated mono valency alkyl of 1-6 carbon atom or the saturated univalence hydrocarbyl of side chain of 3-6 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, amyl group etc.
" alkylidene group " is meant the saturated bivalent hydrocarbon radical of side chain of saturated bivalent hydrocarbon radical of the straight chain of 1-6 carbon atom or 3-6 carbon atom, for example methylene radical, ethylidene, propylidene, 2-methyl propylidene, pentylidene etc.
" thiazolinyl " is meant the straight chain univalence hydrocarbyl of 2-6 carbon atom or the side chain univalence hydrocarbyl of 3-6 carbon atom, and they contain at least one two key, for example vinyl, propenyl etc.
" alkenylene " is meant the straight chain univalence hydrocarbyl of 2-6 carbon atom or the side chain bivalent hydrocarbon radical of 3-6 carbon atom, and they contain at least one two key, for example vinylidene, propenylidene etc.
" alkynyl " is meant the straight chain univalence hydrocarbyl of 2-6 carbon atom or the side chain bivalent hydrocarbon radical of 3-6 carbon atom, and they contain at least one three key, as ethynyl, proyl etc.
" alkynylene " is meant the straight chain bivalent hydrocarbon radical of 2-6 carbon atom or the side chain univalence hydrocarbyl of 3-6 carbon atom, and they contain at least one three key, for example ethynylene, inferior proyl etc.
" alkoxyl group " is meant group-OR, and wherein R is the alkyl that defines as above, for example methoxyl group, oxyethyl group, propoxy-, 2-propoxy-etc.
" acyl group " is meant group-C (O) R, and wherein R is hydrogen, alkyl, cycloalkyl or haloalkyl, for example ethanoyl, trifluoroacetyl group etc.
" acyl amino " is meant group-NRC (O) R ', and wherein R is a hydrogen or alkyl, and R ' is alkyl, heteroatom containing alkyl or optional substituted heterocyclic radical alkyl, for example acetylamino, 2-amino-2-methyl propionic acid amide etc.
" halo " is meant fluorine, chlorine, bromine or iodine, preferred fluorine and chlorine.
" haloalkyl " is meant the alkyl that is replaced by one or more identical or different halogen atoms, for example-and CH 2CI ,-CF 3,-CH 2CF 3,-CH 2CCl 3Deng.
" aryl " is meant the monocycle or the dicyclo alkyl of 6-10 annular atoms, for example phenyl, 1-naphthyl, 2-naphthyl etc.Aryl rings can randomly condense with 5-, 6-or 7-unit monocycle saturated rings, and described monocycle saturated rings randomly contains 1 or 2 heteroatoms that independently is selected from oxygen, nitrogen or sulphur, and remaining annular atoms is C, and wherein 1 or 2 carbon atom is randomly substituted by carbonyl.Typically have the fused rings aryl and include but not limited to 2, the 3-dihydrobenzo [1,4] diox, chroman, heterochromatic full, 2,3-Dihydrobenzofuranes, 1,3-dihydroisobenzofuran, benzo [1,3] dioxole, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-indoles, 2,3-dihydro-1H-isoindole, benzimidazolyl-2 radicals-ketone, 3H-benzoxazole-2-ketone etc.
" heteroaryl " is meant unit price monocycle or the bicyclic aromatic group with 5 to 10 annular atomses that contains 1,2 or 3 ring hetero atom, and described heteroatoms is selected from N, O or S, and remaining annular atoms is C.This term also comprises the group of the oxidized already or seasonization of heteroatoms in those rings, for example forms N-oxide compound or quaternary ammonium salt.Representative instance includes but not limited to: thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, quinolyl, quinoxalinyl, imidazolyl, furyl, benzofuryl, thiazolyl isoxazolyl, the benzoisoxazole base, benzimidazolyl-, triazolyl, pyrazolyl, pyrryl, indyl, the 2-pyriconyl, the 4-pyriconyl, N-alkyl-2-pyriconyl, the pyrazine ketone group, the pyridazine ketone group, pyrimidine ketone group; oxazole ketone group, with their corresponding N-oxide compound, (pyridyl N-oxide compound for example, quinolyl N-oxide compound), its quaternary ammonium salt etc.
" cycloalkyl " is meant the non-aromatic hydrocarbyl of the ring-type with 3-8 annular atoms, and one of them or two C atoms are randomly substituted by carbonyl.Representative instance includes but not limited to: cyclopropyl, cyclopentyl, cyclohexyl etc.
" heterocycle " or " heterocyclic radical " is meant the non-aromatic group of the ring-type with 3-8 annular atoms, and wherein 1,2 or 3 annular atoms is to be selected from N, O or S (O) nThe heteroatoms of (wherein n is 0 to 2 integer), remaining annular atoms is C, wherein 1 or 2 C atom is randomly substituted by carbonyl.This term also comprises the oxidized already or quaternised group of those theheterocyclic nitrogen atoms, for example forms N-oxide compound or quaternary ammonium salt.Representative instance includes but not limited to THP trtrahydropyranyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidino, 4-morpholinyl, 1-piperazinyl, 1-pyrrolidyl, epoxy ethyl, alkyl dioxin, 1,3-dioxolanyl, 2,2-dimethyl-1,3-dioxolanyl (dioxalanyl), tetramethylene sulfone base, 2-oxazolidine ketone group (oxazolidonyl), 2-tetrahydroglyoxaline ketone group, S, S-dioxo-thiomorpholine etc.
" heterocyclic radical amino " is meant the saturated unit price cyclic group of 4-8 annular atoms, and wherein at least one annular atoms is N and randomly contains an additional ring atom that is selected from N or O, and remaining annular atoms is C.This term includes but not limited to, for example 1-pyrrolidyl, piperidino, 4-morpholinyl, 1-piperazinyl etc.
" optional substituted aryl, heteroaryl, cycloalkyl or heterocyclic radical " is meant definition aryl, heteroaryl, cycloalkyl or heterocyclic ring as above, and they are selected from by 1 or 2 independently, and following substituting group is optional to be replaced: alkyl, phenyl, benzyl, haloalkyl, heteroatom containing alkyl, halogen, cyano group, cycloalkyl, acyl group ,-OR (wherein R is a hydrogen or alkyl) ,-NRR ' (wherein R and R ' are independently selected from hydrogen, alkyl or acyl group) ,-NHCOR (wherein R is an alkyl) ,-NRS (O) nR ' (wherein R is a hydrogen or alkyl, and n is that 0 to 2 integer and R ' are hydrogen, alkyl or heteroatom containing alkyl) ,-NRS (O) nNR ' R " (wherein R is a hydrogen or alkyl, and n is 0 to 2 integer and R ' and R " be hydrogen, alkyl or heteroatom containing alkyl independently) ,-S (O) nR (wherein n is that 0 to 2 integer and R are hydrogen, alkyl or heteroatom containing alkyl) ,-S (O) " NRR ' (wherein n is that 0 to 2 integer and R and R ' are hydrogen, alkyl or heteroatom containing alkyl independently) ,-COOR ,-(alkylidene group) COOR (wherein R is a hydrogen or alkyl) ,-CONR ' R " or-(alkylidene group) CONR ' R " (wherein R ' and R " be hydrogen or alkyl independently).
" heteroatom containing alkyl " is meant that having 1,2 or 3 is selected from-NR aR b,-R cSubstituent definition alkyl as above, R wherein a, R bAnd R cBe hydrogen, alkyl, cycloalkyl or acyl group independently of one another, or R aAnd R bOne constitutes heterocyclic amino group.Representative instance includes but not limited to methylol, acetoxy-methyl, 3-hydroxypropyl, 1,2-dihydroxyl-ethyl, 2-methoxy ethyl, 2-amino-ethyl, 2-dimethyl aminoethyl, 2-acetylamino ethyl, 3 (tetramethyleneimine-1-yl) ethyl etc.
" contain the heteroatoms thiazolinyl " and be meant that having 1,2 or 3 is selected from-NR aR b,-R cOr-S (O) nR dSubstituent definition thiazolinyl as above, R wherein a, R bAnd R cBe hydrogen or alkyl independently of one another, and R dBe alkyl or-NRR ' (wherein R and R ' they are hydrogen or alkyl independently of one another).Representative instance includes but not limited to: 3-hydroxyl-1-propenyl, 3-amino third-1-thiazolinyl, 2-amino-sulfonyl vinyl, 2-methyl sulphonyl vinyl etc.
" contain the heteroatoms alkynyl " and be meant that having 1 or 2 is selected from-NR aR b,-OR c,-S (O) nR dOr-S (O) nThe substituent alkynyl of NRR ' (wherein R and R ' are hydrogen or alkyl independently of one another), wherein R a, R bAnd R cBe hydrogen or alkyl independently of one another, and R dBe that alkyl and n are 0-2 integers.Representative instance includes but not limited to: 3-hydroxyl-1-proyl, 3-dimethylamino third-1-alkynyl etc.
" contain the heteroatoms alkoxyl group " and be meant group-OR, wherein R is the heteroatom containing alkyl that defines as above, for example 2-hydroxyl-oxethyl, 3-hydroxyl propoxy-, 2,3-dihydroxyl propoxy-, 2,3-dihydroxyl-1-methyl propoxy-, 2-amino ethoxy etc.
" heteroatom containing alkyl amino " is meant group-NR aR b, R wherein aBe hydrogen or alkyl, and R bBe the heteroatom containing alkyl that defines as above, for example 2-hydroxyethyl amino, 3-dimethylaminopropyl amino etc.
" the optional heterocyclic radical alkyl that replaces " is meant group-R aR b, R wherein aBe alkylidene group, and R is the optional substituted heterocyclic radical that defines as above, for example 2-(morpholine-4-yl) ethyl, 3-(piperidines-1-yl)-2-methyl-propyl etc.
" optional substituted heterocyclic radical thiazolinyl " is meant group-R aR b, R wherein aBe alkenylene and R bBe the optional substituted heterocyclic radical that defines as above, for example 3-(morpholine-4-yl) the third-1 thiazolinyl, 3-(piperidines-1-yl) third-1-thiazolinyl, 3-(4-methylpiperazine-1-yl) third-1-thiazolinyl etc.
" optional substituted heterocyclic radical alkynyl " is meant group-R aR b, R wherein aBe alkynyl and R bBe the optional substituted heterocyclic radical that defines as above, for example 3-(morpholine-4-yl) third-1-alkynyl, 3-(piperidines-1-yl)-1-alkynyl etc.
" optional substituted cyclo alkoxy " is meant group-OR, and wherein R is the optional substituted cycloalkyl that defines as above, for example cyclopentyloxy, cyclohexyloxy etc.
" optional substituted heterocyclyloxy " is meant group-OR, and wherein R is the optional substituted heterocyclic radical that defines as above, for example piperidines-2-base oxygen base, tetramethyleneimine-3-base oxygen base, piperazine-2-base oxygen base etc.
" optional substituted heterocyclic radical alkoxyl group " is meant group-OR, and wherein R is the optional substituted heterocyclic radical alkyl that defines as above, for example 2-(morpholine-4-yl)-oxyethyl group, 3-(piperazine-1-yl) propoxy-, 2-(2-oxo-pyrrolidine-1-yl) oxyethyl group etc.
" optional substituted cycloalkyl amino " is meant group-NR aR b, R wherein aBe hydrogen or alkyl and R bBe the optional substituted cycloalkyl that defines as above, for example cyclopropyl amino, cyclohexyl amino, 3,4-dihydroxyl cyclopentyl amino etc.
" the optional heterocyclic radical alkylamino that replaces " is meant group-NR aR bR wherein aBe hydrogen or alkyl, and R bBe the optional substituted heterocyclic radical alkyl that defines as above, for example 2-(tetramethyleneimine-2-yl) ethylamino, 3-(piperidines-1-yl) propyl group amino etc.
" the optional aralkoxy of mixing that replaces " is meant group-O-R a, R wherein aBe heteroaralkyl, for example 2-(pyridin-3-yl) oxyethyl group, 2-[3 (2H)-pyridazone-1-yl] oxyethyl group etc.
" choose wantonly " or " randomly " be meant that the incident described subsequently or environment can exist but not necessarily exist, and this description comprises situation that this incident or environment exist and wherein this incident or the non-existent situation of environment.For example, " optional replaced or dibasic aryl by alkyl one " be meant that this alkyl may exist but not necessarily exist, and this description comprises that aryl is replaced by alkyl one or dibasic situation and the situation that do not replaced by alkyl of this aryl wherein.
" amino protecting group " is meant that the organic group that reacts, for example benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl group etc. do not need not to take place those protection nitrogen-atoms in building-up process.
Compound of the present invention can have one or more asymmetric centers; This compounds can be prepared into (R)-or (S) steric isomer or its mixture.Unless otherwise noted, the description of particular compound or name comprise two kinds of enantiomers and composition thereof, racemoid or the like in specification sheets and claims.Affiliated technical field is known stereochemistry and the isolating method (referring to " Advanced Organic Chemistry " chapter 4, the 4th edition J.March, JohnWiley and Sons, New York, 1992) of measuring steric isomer.
" pharmaceutical acceptable excipient " be meant can effectively prepare the normally safe, nontoxic of pharmaceutical compositions and both the abiology activity do not have the vehicle of undesirable action yet, and comprise animal doctor and the acceptable vehicle of human pharmaceutical use." pharmaceutical acceptable excipient " that uses in specification sheets and claims comprises one or more vehicle.
" pharmaceutically acceptable salt " of compound is meant that pharmacy can accept and have the compound of the expection pharmacological activity of parent compound.This type of salt comprises:
(1) acid salt, with the acid salt that mineral acid forms, described mineral acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. for example; Or the acid salt that forms with organic acid, organic acid for example is an acetate, propionic acid, caproic acid, the pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, 3-(4-hydroxy benzoyl) phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, 1,2-ethane-disulfonic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, the 4-chlorobenzenesulfonic acid, the 2-naphthene sulfonic acid, the 4-toluenesulphonic acids, camphorsulfonic acid, 4-methyl bicycle [2.2.2]-oct-2-ene-1-formic acid, glucoheptonic acid, 4,4 '-methylene-bis-(3-hydroxyl-2-alkene-1-formic acid), the 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, dodecyl sulphate, glyconic acid, L-glutamic acid, hydroxynaphthoic acid, Whitfield's ointment, stearic acid, muconic acid etc.; Or
(2) salt that when the acid proton that exists in the parent compound is replaced by metal ion, generates, described metal ion for example is alkalimetal ion, alkaline-earth metal ions or aluminum ion; Or the salt that generates during with the organic bases coordination, described organic bases for example is thanomin, diethanolamine, trolamine, Trometamol, N-methylglucosamine etc.
" prodrug " is meant any compound that can discharge the active parent drug of formula (I) when this type of prodrug is administered to mammalian object.The prodrug of the compound of formula (I) is that the functional group that exists in the compound by modification formula (I) makes, and the mode that preparation is adopted should make this modification can the body implosion separate and discharge parent compound.Prodrug comprises the compound of formula (I), and hydroxyl, amino or sulfydryl combine with the group that any pyrolysis recycle is in vivo gone on a tour from hydroxyl, amino or sulfydryl respectively in the compound of its Chinese style (I).The example of prodrug includes but not limited to the ester (for example, acetic ester, manthanoate or benzoate derivatives), carbamate (for example N, N-dimethylamino carbonyl) of the hydroxyl in the compound of formula (I), or the like.
Disease " treatment " or " therapy " comprising:
(1) preventing disease just makes the clinical symptom of disease can not develop in Mammals, and described Mammals may contact with this disease or easily suffer from this disease but never experience or show this symptom of disease,
(2) suppress disease, the development that just stops or alleviate this disease or its clinical symptom, or
(3) alleviate disease, just cause the degeneration of disease or its clinical symptom.
" treatment significant quantity " be meant when being administered to Mammals and treating disease, is enough to treat the amount of the compound of this disease." treatment significant quantity " should be according to compound, disease and seriousness thereof, treated mammiferous body weight waits and changes.Nomenclature
The naming ﹠ numbering mode of compound of the present invention is described as follows.
Figure A0081325700241
Used nomenclature generally is to recommend based on IUPAC among the application, the compound of formula (I) for example, wherein:
R wherein 1, R 2, R 4, R 6Be hydrogen,
Figure A0081325700242
Be 4-(3-hydroxypropyl) phenyl and
Figure A0081325700243
Be the 4-fluorophenyl, it is named as 5-amino-1-(4-fluorophenyl)-4-[4-(3-hydroxypropyl)-benzoyl] pyrazoles.
R wherein 1, R 2, R 4, R 6Be hydrogen,
Figure A0081325700244
Be 3-[3-(morpholine-4-yl) third-1-alkynyl]-phenyl and
Figure A0081325700245
Be the 4-fluorophenyl, it is named as 5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholine-4-base-third-1-alkynyl) benzoyl] pyrazoles.
Representation compound of the present invention is following compound: the compound of I. formula (I), wherein R 1, R 2And R 4Be hydrogen, B is that phenyl and other group definition are as follows:
Figure A0081325700252
Figure A0081325700261
Figure A0081325700271
Figure A0081325700301
Figure A0081325700331
Listed compound 121-145 is as described in embodiment 14,15,19 and 23 in the table.
Preferred embodiment
Although in summary of the invention, stipulated generalized definition of the present invention, and the compound of some formula (I) is preferred.
For example, one group of preferred compound is R wherein 3Be selected from following those:
(a) optional substituted heterocyclic radical;
(b) aryl or heteroaryl, the both is optional be selected from halogen, alkyl, amino, alkoxyl group,
Carboxyl, elementary alkoxy carbonyl, SO 2R ' (wherein R ' is an alkyl) or SO 2NHR ' R " (wherein
R ' and R " be hydrogen or alkyl independently) substituting group replace;
(c) heteroatom containing alkyl;
(d) contain heteroatomic thiazolinyl;
(e) heteroatom containing alkyl amino;
(f) contain the heteroatoms alkoxyl group;
(g) the optional heterocyclic radical alkyl that replaces; Heterocyclic oxy group; Cycloalkyloxy or cycloalkyl alkoxy;
(h) the optional heterocyclic radical thiazolinyl that replaces;
(i) the optional heterocyclic radical alkynyl that replaces;
(j) the optional heterocyclic radical alkoxyl group that replaces
(k) optional heterocyclic radical alkylamino or the cycloalkyl amino that replaces;
(l) the optional heterocyclic radical alkyl-carbonyl that replaces;
(k)-Y-(alkylidene group)-R 9, wherein Y be singly-bound ,-O-or-NH-, and R 9It is optional the replacement
Heteroaryl, CONR 12R 13, SO 2R 14,-SO 2NR 15R 16-NHSO 2R 17Or
-NHSO 2NR 18R 19, R wherein 12, R 13, R 14, R 15, R 16, R 17, R 18And R 19Each other
Be hydrogen, alkyl or heteroatom containing alkyl independently;
(l) cycloalkylalkyl, cycloalkyl alkynyl and cycloalkyl alkynyl, they all by alkyl, halogen,
Hydroxyl or amino optional the replacement;
(m) arylamino alkylidene group or heteroaryl amino alkylidene group; Or
(n) Z-alkylidene group-NR 30R 31, wherein Z be-NH-,-N (alkyl)-or-O-, and R 30And R 31
Be hydrogen, alkyl or heteroatom containing alkyl independently of one another.
In above-mentioned preferred group, more preferably those wherein A and B are aryl, the compound of phenyl preferably.
Above-mentioned preferred and more preferably in the group, even preferred compound group is wherein:
R 1Be hydrogen;
R 2Be hydrogen or alkyl, preferred hydrogen or methyl, more preferably hydrogen;
R 4Be hydrogen, halogen or alkyl, preferred hydrogen, chlorine, fluorine or methyl, more preferably hydrogen;
R 5Be halogen or alkyl; With
R 6Be hydrogen, halogen, alkyl or alkoxyl group.
Above-mentioned preferred and more preferably in the group, particularly preferred compound group is R wherein 3Be positioned at 3, and it is the optional heteroaryl that replaces, preferred pyridyl, N-oxidation piperidyl or pyriconyl.
Another organizes particularly preferred compound is R wherein 3Be positioned at 3, and it is the optional phenyl that replaces, preferred sulfamyl phenyl, alkylsulfamoyl group phenyl, carboxyl phenyl, carboxamido phenyl, alkoxycarbonylphenyl, alkyl amino-carbonyl phenyl or dialkyl amino carbonyl phenyl.
The 3rd group of particularly preferred compound is wherein:
R 3Be positioned at 3 and be selected from:
(a) heteroatom containing alkyl;
(b) contain the heteroatoms alkoxyl group;
(c) heteroatom containing alkyl amino;
(d) the optional heterocyclic radical alkyl that replaces;
(e) optional heterocyclic radical alkoxyl group, the cycloalkyloxy that replaces; Or cycloalkyl alkoxy;
(f) the optional heterocyclic radical alkylamino that replaces;
(g)-Y-(alkylidene group)-R 9, wherein Y be singly-bound ,-O-or-NH-, and R 9Be optional
Substituted heteroaryl ,-CONR 12R 13, SO 2R 14,-SO 2NR 15R 16-NHSO 2R 17
Or-NHSO 2NR 18R 19, R wherein 12, R 13, R 14, R 15, R 16, R 17, R 18
And R 19Be hydrogen, alkyl or heteroatom containing alkyl independently of one another; Or
(h) Z-alkylidene group-NR 30R 31, wherein Z be-NH-,-N (alkyl)-or-O-, and R 30
And R 31Be hydrogen, alkyl or heteroatom containing alkyl independently of one another.
In above-mentioned preferred group, one group of preferred compound is R wherein 3Be positioned at 3 and be the compound of heteroatom containing alkyl.
Preferred group R 3Be 2-dimethyl aminoethyl, 3-dimethylaminopropyl, 4-dimethylamino butyl, hydroxymethyl, 1,2-dihydroxy ethyl, 3-hydroxy-3-methyl butyl or 3-hydroxybutyl.
Another organizes preferred compound is R wherein 3Be selected from following compound: amino, 3-dimethylamino propoxy, 2-dimethylamino ethoxy, 2-hydroxyl-oxethyl, 2-dimethyl aminoethyl amino, 3-dimethylaminopropyl amino, 3-dimethylamino third-1-thiazolinyl, 3-dimethylamino third-1-alkynyl and 2-dimethyl aminoethyl carbonyl.
Another is organized preferred R3 and is selected from 3-(morpholine-4-yl) propoxy-; 2-(morpholine-4-yl) oxyethyl group; 3-(morpholine-4-yl) propyl group; 2-(morpholine-4-yl) ethyl; 4-(morpholine-4-yl) butyl; 3-(morpholine-4-yl) propyl group amino; 2-(morpholine-4-yl)-ethylamino; 3-(morpholine-4-yl)-third-1-thiazolinyl; 3-(morpholine-4-yl) third-1-alkynyl; 4-methylpiperazine-1-base; piperazine-1-base; pyridin-3-yl; morpholine-4-ylmethyl carbonyl; 3-dimethylamino third-1-thiazolinyl; 3-dimethylamino third-1-alkynyl; 2-amino-sulfonyl ethyl; 2-amino-sulfonyl vinyl; acetylamino and trifluoroacetyl group amino, preferred 2-(morpholine-4-yl) oxyethyl group and 3-(morpholine-4-yl)-propyl group.
The 4th group of particularly preferred compound is R wherein 5Be halogen or alkyl, and R 6Be hydrogen, halogen or alkyl, preferred R 5Be 4-F or 2-Me and R 6Be hydrogen, perhaps R 5Be 2-F and R 6Be 4-F.
Another organizes preferred compound is that wherein A and B are aryl, preferred phenyl, and R 3Be positioned at 3, and it is selected from: contain heteroatoms alkoxyl group, optional substituted heterocyclic radical alkoxyl group, optional substituted cyclo alkoxy and optional substituted heterocyclic radical alkylamino.
Preferred R3 comprises 2,2-(dihydroxyl methyl) oxyethyl group, 2,3-dihydroxyl-propoxy-, (2,2-dimethyl-1,3-dioxolane-4 (S)-yl) methoxyl group, (2,2-diethyl-1,3-dioxolane-4 (S)-yl) methylamino, (1,3-dioxolane-2-ketone-4 (R)-yl) methoxyl group, (2-sulfenyl-1,3-dioxolane-4-yl) methoxyl group, (2,2-diethyl-1,3-dioxolane-4 (S)-yl) methoxyl group, 2-methyl-2-ethyl-1,3-dioxolane-4 (S)-yl) methoxyl group and 3,4-(dihydroxyl) cyclopentyloxy.
In above-mentioned preferred group, the compound of another preferred group be those wherein:
R 1Be hydrogen,
R 2Be hydrogen or alkyl, preferred hydrogen or methyl;
R 4It is hydrogen or alkyl;
R 5It is halogen; With
R 6It is hydrogen or alkyl.
The compound of another preferred group is R wherein 3Being positioned at 3 and its is selected from:
(a)-S (O) nR 27, wherein n is 0 to 2 integer, and R 27Be alkyl, heteroatom containing alkyl, appoint
Choose the cycloalkyl in generation, the optional heterocyclic radical alkyl that replaces or-NR 28R 29, R wherein 28With
R 29Be hydrogen, alkyl or heteroatom containing alkyl independently of one another;
(b) X-(alkylidene group) CH[(CR ' R ") mOR 40] [(CR ' R ") nOR 40], wherein X be-O-,
-NH-,-NR-(wherein R is an alkyl) or-S (O) p-(wherein p is 0 to 2 integer);
R 40It is acyl group; C (O) OR 41(R wherein 41Be hydrogen, alkyl or cycloalkyl);
C (O) ONR 41R 42(R wherein 41Definition as above and R 42Be hydrogen or alkyl); Or
C (O) NR 41R 42(R wherein 41And R 42Definition as above);
R ' and R " are hydrogen or alkyls independently; With
M and n are the integer of 0-3 independently, and condition is that m and n are not 0 simultaneously;
(c) X-(alkylidene group)-CH (OH) CH 2NHR 50, wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) n-(wherein n is the whole of 0-2
Number); R 50" and C (O) NR that is C (O) OR 51R 52(wherein R " be hydrogen, alkyl or cycloalkyl and
R 52Be hydrogen or alkyl); With
(d) X-(alkylidene group)-CH (NR 50)-CH 2OH, wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) n-(wherein n is the whole of 0-2
Number); R 50" and C (O) NR that is C (O) OR 51R 52(R wherein 51Be hydrogen, alkyl or cycloalkyl and
R 52Be hydrogen or alkyl).
Preferred R in this group 3Comprise 2 (S), 3-(diacetoxy) propoxy-, 2 (S), 3-(two isobutyl acyloxy) propoxy-, 2 (S), 3-(two new pentane acyloxies) propoxy-and 2 (S), 3-(dimethoxy ketonic oxygen base).
Particularly preferred examples of compounds is:
5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholine-4-base oxethyl) benzoyl] pyrazoles;
5-amino-1-(2,4 difluorobenzene base)-4-[3-(3-morpholine-4-base propyl group) benzoyl]-pyrazoles;
5-amino-4-(3-amino benzoyl)-1-(4-fluorophenyl) pyrazoles;
5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholine-4-base propyl group) benzoyl] pyrazoles.;
5-amino-4-[3-(2-amino-sulfonyl vinyl) benzoyl]-1-(4-fluorophenyl)-pyrazoles.;
5-amino-4-(3-acetylamino benzoyl)-1-phenylpyrazole;
5-amino-4-[3-(2-amino-ethyl) benzoyl]-1-(4-fluorophenyl) pyrazoles;
5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholine-4-base propyl group amino) benzoyl]-pyrazoles;
5-amino-4-[3-(2-amino-sulfonyl ethyl) benzoyl]-1-(4-fluorophenyl) pyrazoles;
5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl) benzoyl] pyrazoles;
5-amino-1-(2-aminomethyl phenyl)-4-[3-(pyridin-3-yl) benzoyl] pyrazoles;
5-amino-1-(2-aminomethyl phenyl)-4-[3-(N-oxo pyridine-3-yl) benzoyl] pyrazoles;
5-amino-4-[3-(2,3-dihydroxyl propoxy-) benzoyl]-1-(4-fluorophenyl) pyrazoles.;
5-amino-4-[3-(1, the 2-dihydroxy ethyl) benzoyl]-1-(4-fluorophenyl) pyrazoles;
5-amino-1-(4-fluorophenyl)-4-[3-sulfamyl benzoyl] pyrazoles;
5-amino-1-(4-fluorophenyl)-4-{3-[(2,2-dimethyl-1,3-dioxolane-4 (S)-yl) methoxyl group] benzoyl } pyrazoles;
5-amino-1-(4-fluorophenyl)-4-{3-[2 (S), 3-(diacetoxy) propoxy-] benzoyl } pyrazoles;
5-amino-1-(4-fluorophenyl)-4-{3-[2 (S), 3-(dimethoxy ketonic oxygen base) propoxy-] benzoyl } pyrazoles;
5-amino-1-(4-fluorophenyl)-4-{3-[(1,3-dioxolane-2-ketone-4 (R)-yl) methoxyl group] benzoyl } pyrazoles;
5-amino-1-(4-fluorophenyl)-4-{3-[(2-sulfenyl-1,3-dioxolane-4-yl) methoxyl group] benzoyl } pyrazoles; General synthetic route
Compound of the present invention can be by the preparation of the method shown in the reaction scheme.
Prepare employed starting raw material of these compounds and reagent or derive from commercial supplier, Aldrich Chemical Co. (Milwaukee for example, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie or Sigma (St.Louis, Missouri, USA), perhaps prepare according to the process of stipulating in the reference by the known method of one of ordinary skill in the art, " Reagents for Organic Synthesis " 1-17 volume (JohnWiley and Sons, 1991) that for example Fieser and Fieser showed; " Chemistry of Carbon Compounds " 1-5 of Rodd rolls up and augments (Elsevier Science Publishers, 1989); " Organic Reactions " 1-40 rolls up (John Wiley and Sons, 1991), " Advanced Organic Chemistry " (JohnWiley and Sons of March, the 4th edition), " Comprehensive OrganicTransformations " (VCH Publishers Inc., 1989) with Larock.These reaction schemes only illustrate some methods that can synthesize The compounds of this invention, and one of ordinary skill in the art can finish and propose multiple improvement to these reaction schemes with reference to this paper content.
The starting raw material and the intermediate of reaction can be separated, and can utilize the routine techniques purifying if desired, include but not limited to filtration, distillation, crystallization, chromatogram etc.The feature of these materials be can measure with usual manner, physical constant and spectroscopic data comprised.The preparation of the compound of formula (I)
Synthetic route A, B and C have described the method for the compound of preparation formula (I).
Reaction scheme A
R wherein 2The compound that is the formula (I) that defines in hydrogen and other groups such as the summary of the invention is as follows:
Method (a)
Method (b)
Figure A0081325700401
Usually, the compound of formula (I) can be according to following method (a) or (b) preparation.Method (a)
2-ketone group acetonitrile of formula 1 [wherein Z is halogen (as bromine or iodine), alkoxyl group, nitro or acetylamino] and N, the 2-ketone group-3-phenyl amino-vinyl cyanide of the reaction production 2 of N-amitraz diphenylurea.This reaction is to take place under the heating in height ebullient aromatic hydrocarbon such as toluene, dimethylbenzene etc.
Usually, the compound of formula 1 or be purchased, perhaps their the method preparations that can know by affiliated technical field.For example, the 2-aroyl cyanide compound of formula 1 such as 4-anisoyl acetonitrile, 3-nitro benzoyl acetonitrile can be purchased.Other compound can be by handling acetonitrile with alkali such as n-Butyl Lithium, acetonitrile negatively charged ion and Sjogren that order subsequently generates, E.B. etc.; J.Med.Chem; 34,3295, (1991) described aroyl/4-hetaroylpyrazol halogenide or aryl/hetaryl ester prepared in reaction.
The reaction of the 2-ketone group-3-phenyl amino vinyl cyanide of formula 2 and the hydrazine of formula 3 obtains the 5-amino-4-ketone group pyrazoles of formula 4.This reaction is generally carried out in polar solvent such as ethanol, Virahol etc.The aryl/hetaryl hydrazine class compound of formula 2 such as 2-or 3-chloro-phenyl-hydrazine, 2-, 3-or 4-fluorophenyl hydrazine, phenyl hydrazine, 2-hydrazino pyridine, 2-diazanyl benzothiazole, 2-diazanyl quinoline etc. can be purchased.
The method that compound 4 is known by affiliated field subsequently is converted into the compound of formula (I), and wherein R ' is hydrogen and R 3As defining in the summary of the invention.Some these class methods is as mentioned below.(i) R wherein 3The compound that is the formula (I) of heterocyclic radical alkoxyl group can prepare by following method:
(a) R wherein 3Formula (I) compound that is the heterocyclic radical alkoxyl group can be that the compound of the formula 4 of alkoxyl group makes by Z wherein, and is as follows:
Figure A0081325700411
R wherein 3Be the heterocyclic radical alkoxyl group formula (I) compound can by Z wherein be alkoxyl group formula 4 compound, at first making the alkoxyl group dealkylation generate corresponding wherein Z is the compound of the formula 5 of hydroxyl, reacts with heterocyclic radical alkyl halide [for example 4-(2-chloroethyl) morpholine, 1-(2-chloroethyl) tetramethyleneimine etc.] subsequently.This dealkylation reacts or carries out in halogenated organic solvent (as methylene dichloride) with boron tribromide, perhaps by heat 4 in the pure hydrochloric acid pyridinium salt.Alkylated reaction is to carry out in polar organic solvent (as acetonitrile, dimethyl formamide, acetone etc.) in the presence of the alkali (as salt of wormwood, cesium carbonate etc.).
(b) additionally, under above-mentioned reaction conditions, can be connected the heterocyclic radical alkyl by 5 with the alkyl halide reaction, the halogenated alkoxy intermediate of gained and heterocyclic radical (as piperazine, morpholine, tetramethyleneimine etc.) reaction subsequently.Alkyl dihalide such as 1-bromo-2-monochloroethane, 1-chloro-3-iodopropane etc. can be purchased.
(c) compound by wushu 5 is converted into two hydroxy alkoxy radical derivatives (as the glycol of embodiment 24), handles under acidic conditions with ketone or aldehyde subsequently, can make wherein R 3It is the compound of other formulas (I) of heterocyclic radical alkoxyl group (for example in embodiment 25, wherein this heterocycle is optional substituted cyclic ketal).
(d) compound by wushu 5 is converted into two hydroxy alkoxy radical derivatives (as the glycol of embodiment 24), handles with carbonylation agent such as phosgene, trichloromethylchloroformate and triphosgene subsequently, can make wherein R 3It is the compound of other formulas (I) of heterocyclic radical alkoxyl group (for example in embodiment 28, wherein this heterocycle is optional substituted cyclic carbonic ether).(ii) R wherein 3Be-O-(alkylidene group)-R 9(R wherein 9Be-COOH ,-COR 10,-COOR 11Or-CONR 12R 13) the compound of formula (I) can be by the preparation as described below of the compound of formula 5:
R wherein 3Be-O-(alkylidene group)-COOR " the compound of formula (I) be the compound and formula X-(alkylidene group) CO of through type 5 2R 11Alkylating reagent (wherein X is a halogen group) prepared in reaction.The hydrolysis of ester group produces free acid (R 9Be-COOH), if desired, use formula NR down by existence at suitable coupling agent (as carbonyl dimidazoles, N, N-dicyclohexylcarbodiimide etc.) 12R 13Amine (R wherein 12And R 13As defining in the summary of the invention) handle this acid, it can be converted into wherein R 9=-CONR 12R 13The compound of formula (I).
R wherein 9Be-COR 10The compound of formula (I) can be by R wherein 9Be-compound of the formula (I) of COOH, at first this acid be converted into the Weinreb acid amides, subsequently respectively with Grignard reagent or formula R 10MgBr or R 10The organolithium reagent of Li is handled.(iii) be converted into two hydroxy alkoxy radical derivatives (as the glycol of embodiment 24), use acid anhydrides R subsequently by compound with formula 5 40C (O) OC (O) R 40, acyl chlorides R 40C (O) Cl or chloro-formic ester ClC (O) OR 41Handle, can prepare other wherein R 3Be X (alkylidene group) CH[(CR ' R ") OR 40] [(CR ' R ") nOR 40] { as in embodiment 26 and 27, wherein X is-O-; R 40Be acyl group or C (O) OR 41(R wherein 41Be hydrogen, alkyl or cycloalkyl); R ' and R " are hydrogen; M is 0; With n be formula (I) compound of 1}.
Compound by wushu 5 is converted into two hydroxy alkoxy radical derivatives (for example glycol of embodiment 24), uses alkyl carbamoyl chlorine R subsequently 41R 42NC (O) Cl handles the wherein R that can prepare other 3Be X (alkylidene group) CH[(CR ' R ") mOR 40] [(CR ' R ") nOR 40] { wherein X is-O-; R 40Be C (O) NR 41R 42(R wherein 41Be hydrogen, alkyl or cycloalkyl and R 42Be hydrogen or alkyl); R ' and R " are hydrogen; M is 0; With n be 1) the compound of formula (I).(iv) by Z wherein be the compound of formula 4 of nitro by being this nitroreduction amino, and carry out according to the method described above subsequently preparing wherein R 3Be-NH-(alkylidene group)-R 9The compound of formula (I), R wherein 9Be-COOH ,-COR 10,-COOR 11,-CONR 12R 13Or heterocyclic radical alkylamino.(v) R wherein 3Be contain the heteroatoms thiazolinyl, contain the heteroatoms alkynyl, the compound of the formula (I) of heterocyclic radical-thiazolinyl, heterocyclic radical alkynyl, heteroatom containing alkyl or heterocyclic radical alkyl can be according to following described method preparation.
Figure A0081325700431
By Z wherein be formula 4 compounds of halogen in the presence of palladium (II) catalyzer (two (triphenylphosphine)-palladiums (II)), in organic bases (as Diisopropylamine) as dichloro respectively with contain heteroatoms alkene, contain heteroatoms alkynes, heterocyclic radical alkene or the reaction of heterocyclic radical alkynes can make wherein R 3Be contain the heteroatoms thiazolinyl, contain the heteroatoms alkynyl, the compound of the formula (I) of heterocyclic radical thiazolinyl or heterocyclic radical alkynyl.Contain the heteroatoms olefin(e) compound, contain heteroatoms acetylene hydrocarbon compound such as allyl alcohol, propargyl ethanol, 3-butine-1-alcohol, propargyl amine can be purchased.Heterocyclic radical alkene can react by alkynyl halogenide and heterogeneous ring compound to be made.For example, can make 2-morpholine-1-base third-1-alkynes by propargyl bromide and morpholine reaction.Two keys or the reduction reaction of three key under the catalytic hydrogenation condition produce wherein R 3It is the compound of the corresponding formula (I) of heterocyclic radical alkyl or heteroatom containing alkyl.(vi) by R wherein 3The compound that is the formula (I) of amino can prepare wherein R by PCT application WO 97/46524 described synthetic method 3Be-NHSO 2R 6,-NHSO 2NR 7R 8Or NHC (X) R 23R 24(wherein X be-O-or-compound of S-) formula (I).
R wherein 1The compound that is the formula (I) of acyl group can be by R wherein under the acylation reaction condition 1Be the compound and the formula R of the corresponding formula (I) of hydrogen 1The acylating reagent of COL reacts and prepares, wherein the L leavings group that is, for example halogen.This reaction is to carry out in the presence of alkali such as sodium hydroxide, cesium carbonate etc.Method (b)
Additionally, the compound of formula (I) can be by the ester preparation of the definition of Z wherein formula 6 as above, and at first utilizing the reaction conditions of aforesaid method (a) described in (i-v) to make the Z groups converted in Z formula 6 compounds is required R 3Group.7 with the 2-ketone group acetonitrile of the anionic condensation production 8 of acetonitrile, utilize the described reaction conditions of aforesaid method (a) to be translated into the compound of formula (I) subsequently.
R wherein 2The compound that is the formula (I) of alkylthio or alkyl can be according to United States Patent (USP) 5,712, the method preparation described in 303.Reaction scheme B
R wherein 2The another kind of preparation method of compound who is the formula (I) that defines in hydrogen and other groups such as the summary of the invention is as described below.
The 5-amino of the 2-cyano group-3-ethoxy propylene acid esters of formula 9 and the hydrazine condensation production 10 of formula 3-4-ethoxy carbonyl pyrazoles.This condensation reaction is suitably being carried out in polar organic solvent such as ethanol, the Virahol etc.10 with aqueous base (for example sodium hydroxide, lithium hydroxide etc.) hydrolysis reaction in pure organic solvent (as methyl alcohol, ethanol etc.), generate the 5-amino-4-carboxyl pyrazoles of corresponding formula 11.11 usefulness pyridyl disulfides are handled, and the sulfo-pyridyl ester derivative 12 of gained and organometallic reagent such as Grignard reagent or above-mentioned organolithium reagent react subsequently, obtain the compound of formula (I).Reaction scheme C
R wherein 2The another kind of preparation method of compound who is the formula (I) that defines in hydrogen and other groups such as the summary of the invention is as described below.
The thermal decarboxylation effect of the 5-amino of formula 11-4-carboxyl pyrazoles generates the 5-amino-pyrazol of corresponding formula 13.Compound 13 is converted into the compound of formula (I) according to above-mentioned (a) or method (b) subsequently.
In method (a), 13 compound is converted into the compound of formula (I), at first uses the amino of suitable amino protecting group (as tert-butoxycarbonyl etc.) protection compound 13, generates the amido protecting compound of corresponding formula 14.Under the organo-metallic conditions of replacement reaction, use formula R 3The acid derivative of COL handles 14, and wherein L is leavings group [for example alkoxyl group (preferred methoxy or ethoxy), dialkyl amido, preferred N, O-dimethyl hydroxyl amino], and the deaminize protecting group obtains the compound of formula (I) subsequently.Nucleophilic substitution is in the presence of 2 normal lithium alkylides (for example tert-butyl lithium etc.) and carries out in aprotic organic solvent such as tetrahydrofuran (THF).The reaction conditions that is used to remove amino protecting group depends on the essence of protecting group.For example, if tert-butoxycarbonyl is a protecting group, then just can remove as processing such as trifluoroacetic acid hydrochloric acid with acid.
Formula R 3The acid derivative of COL can utilize the method preparation of knowing in the organic chemistry filed.For example, wherein L is N, and the acid derivative of O-dimethyl hydroxyl amino can at first use suitable chlorination reagent (as oxalyl chloride) that acid is converted into acyl chlorides by its corresponding acid preparation, use N subsequently, O-dimethyl hydroxyl amine hydrochlorate is handled in the presence of organic bases such as triethylamine.
In method (b), the compound bromination of formula 10 becomes the 5-amino-4-bromo-pyrazoles of formula 15.This bromination reaction adopts suitable bromide reagent such as N-bromosuccinamide, is suitably carrying out in polar organic solvent such as the dimethyl formamide.Utilize the described reaction conditions of said synthesis route C method (a) compound 15 to be converted into the compound of formula (I) subsequently.Practicality, experiment and administration practicality
The compound of formula (I) is the p38 map kinase inhibitor, the compound of formula (I) can effectively be treated disease with the composition that contains them thus, as rheumatoid arthritis, osteoarthritis, spondylitis, bone absorpting disease, sepsis, septic shock, toxic shock syndrome, endotoxin shock, tuberculosis, atherosclerosis, diabetes, adult respiratory distress syndrome, chronic pulmonary inflammation disease, pyreticosis, periodontal disease, ulcerative colitis, pyresis, alzheimer's disease and Parkinson's disease.Experiment
Come the compound of confirmation formula (I) to suppress the ability of p38 map kinase by embodiment 15 described in vitro testss.Embodiment 16 and 17 in vivo test of describing in detail have verified that respectively the compound of formula (I) suppresses the ability of the release of TNF-α.
Utilize adjuvant brings out in the rat described in the embodiment 18 sacroiliitis to measure the anti-inflammatory activity of compound of the present invention.Administration and pharmaceutical composition
Usually, but compound of the present invention can with the treatment significant quantity use by the accepting method of the drug administration of any suitable similar applications.The actual amount of compound of the present invention, promptly absorption of active ingredient will depend on the multiple factor, for example by approach and form and other factors of the tiring of the age of treatment severity of disease, object and relative healthy state, compound used therefor, administration.
The treatment significant quantity of the compound of formula (I) can be about 0.1-50mg/kg recipient body weight/day, preferably about 1-30mg/kg/ days.Therefore, for people's administration to 70kg, the first-selected about 70mg to 2.1g/ of dosage range sky.
Usually, compound of the present invention as pharmaceutical composition by any following administration: oral, systematicness (as in skin, nose or utilize suppository) or non-enteron aisle (for example intramuscular, intravenously or subcutaneous) administration.Preferred administering mode is to utilize routine dosage oral administration every day, and it can be adjusted according to the degree of slight illness.Composition can be taked the form of tablet, pill, capsule, semisolid, powder, sustained release preparation, solution, suspension, elixir, aerosol or any suitable composition.
Different factors is depended in the selection of formulation, for example mode of administration (for example, for oral administration, preferred formulation is tablet, pill or capsular form) and bioavailability of medicament.At present, based on by increasing the principle that surface-area (promptly reducing granularity) can improve bioavailability, developed pharmaceutical preparation, especially drugs with low bioavailability.For example, U.S. patent 4,107,288 has been described granular size at 10-1, the pharmaceutical preparation in the 000nm scope, and wherein active substance loads on the macromolecular crosslinked matrix.U.S. the patent No. 5,145,684 have described the preparation of pharmaceutical preparation, and medicine wherein is ground into nano particle (mean particle size 400nm) and is dispersed in the liquid medium in the presence of surface-modifying agent, obtain having the pharmaceutical preparation of very high bioavailability.
Described composition generally contains the compound of the formula (I) of uniting with at least a pharmaceutical acceptable excipient.Acceptable vehicle is nontoxic, assists administration and the treatment benefit of the compound of formula (I) is not had detrimentally affect.This type of vehicle can be solid, liquid, the semisolid that any one of ordinary skill in the art use always, or this is the gas vehicle in the situation of aerosol composition.
The solid pharmaceutical vehicle comprises starch, Mierocrystalline cellulose, talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica gel, Magnesium Stearate, sodium stearate, Zerol, sodium-chlor, drying defatted breast etc.Liquid and semisolid excipient can be selected from glycerine, propylene glycol, water, ethanol and multiple oil, comprise the oil in those oil, animal, plant or synthetic source, for example peanut oil, soybean oil, mineral oil, sesame wet goods.Preferred liquid vehicle particularly for Injectable solution, comprises water, salt solution, dextrose hydrate and glycols compound.
Pressurized gas can be used for disperseing compound of the present invention to become aerosol form.The rare gas element that is fit to this purpose is nitrogen, carbonic acid gas etc.
Other drug excipient and preparations thereof that are suitable for are disclosed in Remington ' s PharmaceuticalSciences, and E.W.Martin edits in (Mack Publishing Company, 18 editions, 1990).
The content of compound in preparation can change in the available four corner in affiliated field.Usually, with weight percent (wt%) base, preparation should be based on about 0.01-99.99 (wt%) of said preparation gross weight, and surplus is one or more suitable pharmaceutical excipients.More preferably, described compound is the level existence with about 1-80 (wt%).Be disclosed in the representative drugs preparation of the compound that contains formula (I) among the embodiment 14.Embodiment
Provide preparation method and embodiment below and can be expressly understood and implement the present invention more to guarantee one of ordinary skill in the art.They should not be regarded as limiting scope of the present invention, and only are to illustrate and their example.Numeral in the Table I bracket is meant CPD number.Embodiment 15-amino-1-(4-fluorophenyl)-4-[3-{3-(morpholine-4-yl) third-1-alkynyl } benzoyl] pyrazoles (3) Step 1
(23.8ml is 460mmol) in the solution in dry tetrahydrofuran (1000ml) under-78 ℃ n-Butyl Lithium (214ml, 340mmol, the hexane solution of 1.6M) to be added drop-wise to acetonitrile.Behind the stirred reaction mixture 20 minutes, the solution of oligomeric 4-bromo-benzoyl chloride in dry tetrahydrofuran (50ml) in 20 minutes.After 1 hour, add saturated ammonium chloride (200ml) and make this reaction mixture rise to room temperature.Product washs with ether extraction and with 1N hydrochloric acid (400ml).Vacuum is removed organism, and resistates is dissolved in ethyl acetate.Add ammonium hydroxide and obtain solid, filter this solid, be dissolved in ethyl acetate again and use 2N salt acid elution.Organic layer salt water washing obtains 2-(3-benzoyl bromide)-acetonitrile (16.6g) with dried over sodium sulfate and vacuum concentration, and it is a solid.Step 2
With 2-(3-benzoyl bromide) acetonitrile (16.5g, 73.6mmol) and N, N amitraz diphenylurea (14.5g, 73.6mmol) reflux under nitrogen atmosphere of the mixture in dimethylbenzene (100ml).After 3 hours, reaction mixture is cooled to room temperature, with the ether dilution, obtains 2-(3-benzoyl bromide)-3-phenyl amino-vinyl cyanide (17.9g), it is a solid.Step 3
4-fluorophenyl hydrazine (4.25g, 33.7mmol) and 2-(3-benzoyl bromide)-3-phenyl amino vinyl cyanide (10.0g, 30.7mmol) reflux under nitrogen atmosphere of the mixture in ethanol (100ml).After 4 hours, make reaction mixture be cooled to room temperature, obtain 5-amino-4-(3-benzoyl bromide)-1-(4-fluorophenyl) pyrazoles (9.7g) with the hexane dilution, it is a solid.
In step 3, replace 4-fluorophenyl hydrazine to obtain 5-amino-4-(3-benzoyl bromide)-1-(2,4 difluorobenzene base) pyrazoles with above-mentioned 2,4 difluorobenzene base hydrazine.Step 4
With 5-amino-4-(3-benzoyl bromide)-1-(4-fluorophenyl) pyrazoles (1.3g; 4.16mmol), 4-(Propargyl) morpholine (2.1g; 16.6mmol) [its preparation is by morpholine (14.7ml; 168mmol) solution in ether (50ml) in 30 minutes, be added drop-wise to the hydroxypropyl bromine that is present in the ether (50ml) (7.5ml, 84mmol) in and heat this reaction mixture to refluxing.After 16 hours, reaction mixture is cooled to room temperature, and filters through B (Buchner funnel).Concentrated filtrate also passes through purification by flash chromatography (gradient elution, the 20-100%EtOAc/ hexane) obtain 4-(Propargyl) morpholine (5.0g)], two (triphenylphosphine)-Palladous chloride (0.29g, 0.42mmol) and cupric iodide (0.079g, 0.42mmol) mixture in Diisopropylamine (60ml) is heated to 70 ℃ under argon gas.After 10 hours, make this reaction mixture be cooled to room temperature, with ethyl acetate dilution, with the salt water washing and use dried over sodium sulfate.Vacuum is removed organism.(gradient, EtOAc-5%MeOH/EtOAc contain 0.2%NH to crude product by purification by flash chromatography 4OH), obtain 5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholine-4-base third-1-alkynyl) benzoyl]-pyrazoles, it is converted into hydrochloride, and in the mixture of methanol/ethyl acetate/hexane recrystallization, obtain the clean product of (1.4g).
Carry out but 4-(Propargyl)-morpholine in the step 4 is replaced by following material: 1-(Propargyl)-4-methylpiperazine according to the foregoing description 1 described method, 1-(Propargyl) piperidines, 2-propine-1-alcohol, 1-dimethylamino-2-propine and 2-methyl-3-butyne-2-alcohol; Obtain 5-amino-1-(4-fluorophenyl)-4-{3-[3-(4-methylpiperazine-1-yl) third-1-alkynyl respectively]-benzoyl } pyrazoles dihydrochloride (8); 5-amino-1-(4-fluorophenyl)-4-[3-{3-(piperidines-1-yl) third-1-alkynyl } benzoyl] pyrazole hydrochloride (9); 5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxyl third-1-alkynyl) benzoyl] pyrazoles (7); 5-amino-4-[3-(3-dimethylamino third-1-alkynyl) benzoyl]-1-(4-fluorophenyl) pyrazole hydrochloride (12) and 5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxy-3-methyl-Ding-1-alkynyl) benzoyl] pyrazoles (87).
According to top embodiment 1 described method but the 4-fluorophenyl hydrazine in the step 3 by 2; 4-difluorophenyl hydrazine replaces; 4-(Propargyl) morpholine in the step 4 is replaced by 3-ethynyl piperidines simultaneously; obtain 5-amino-1-(2; the 4-difluorophenyl)-and 4-[3-(3-pyridyl ethynyl) benzoyl] pyrazoles (88); with 3-(S; S-dioxo-thiomorpholine-4-yl)-the 1-propine replaces obtaining 5-amino-1-(2; the 4-difluorophenyl)-4-[3-{3-(S; S-dioxo-thiomorpholine-4-yl)-and the 1-proyl } benzoyl] pyrazoles (89); with replace obtaining 5-amino-1-(2,4 difluorobenzene base)-4-[3-{2-(1-hydroxycyclopent base) ethynyl with 1-ethynyl cyclopentanol-benzoyl] pyrazoles (94).Embodiment 25-amino-1-(4-fluorophenyl)-4-[3-(3-morpholine-4-base propyl group) benzoyl]-pyrazoles hydrochloric acid (6)
Figure A0081325700521
5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholine-4-base third-1-alkynyl)-benzoyl] (0.45g, 1.0mmol) [according to embodiment 1 preparation] and the mixture of 5%Pd/C (0.07g) in ethanol (20ml) stir under nitrogen atmosphere pyrazoles.After 16 hours, reaction mixture is through diatomite (Celite ) filter and vacuum concentrated filtrate.(gradient, EtOAc-15%MeOH/EtOAc wherein contain 0.2%NH to crude product by purification by flash chromatography 4OH).Product is converted into hydrochloride, and the mixture recrystallization of methanol/ethyl acetate, obtaining 5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholine-4-base propyl group) benzoyl] (0.3g, mpt.211.9-212.6C), it is a solid to pyrazoles .HCl.
Carry out according to top embodiment 2 described methods, but 5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholine-4-base third-1-alkynyl) benzoyl] pyrazoles replaces with following compound: 5-amino-1-(4-fluorophenyl)-4-{3-[3-(4-methylpiperazine-1-yl) third-1-alkynyl]-benzoyl } pyrazoles, 5-amino-1-(4-fluorophenyl)-4-[3-{3-(piperidines-1-yl) third-1-alkynyl } benzoyl] pyrazoles, 5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxyl third-1-alkynyl) benzoyl] pyrazoles, 5-amino-4-[3-(3-dimethylamino third-1-alkynyl) benzoyl]-1-(4-fluorophenyl) pyrazoles, 5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxy-3-methyl-ethyl acetylene base) benzoyl] pyrazoles, 5-amino-1-(2, the 4-difluorophenyl)-and 4-[3-(3-pyridyl ethynyl) benzoyl] pyrazoles, 5-amino-1-(2, the 4-difluorophenyl)-4-[3-{3-(S, S-dioxo-thiomorpholine-4-yl)-and the 1-proyl } benzoyl] pyrazoles, 5-amino-1-(4-fluorophenyl)-4-[3-{2-(1-hydroxycyclopent base) ethynyl } benzoyl]-pyrazoles, with 5-amino-1-(2, the 4-difluorophenyl)-and 4-[3-{2-(1-hydroxycyclopent base) ethynyl } benzoyl]-pyrazoles, obtain 5-amino-1-(4-fluorophenyl)-4-{3-[3-(4-methylpiperazine-1-yl) propyl group respectively] benzoyl } pyrazoles (30); 5-amino-1-(4-fluorophenyl)-4-[3-(3-piperidines-1-base propyl group) benzoyl] pyrazoles (32); 5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxypropyl) benzoyl] pyrazoles; 5-amino-4-[3-(3-dimethylaminopropyl) benzoyl]-1-(4-fluorophenyl) pyrazoles; 5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxy-3-methyl butyl) benzoyl] pyrazoles (90); 5-amino-1-(2; the 4-difluorophenyl)-and 4-[3-(3-pyridyl ethyl) benzoyl] pyrazoles (91); 5-amino-1-(2; the 4-difluorophenyl)-4-[3-{3-(S; S-dioxo-thiomorpholine-4-yl) propyl group } benzoyl] pyrazoles (92); 5-amino-1-(4-fluorophenyl)-4-[3-{2-(1-hydroxycyclopent base) ethyl } benzoyl] pyrazoles (93); with 5-amino-1-(2,4 difluorobenzene base)-4-[3-{2-(1-hydroxycyclopent base) ethyl } benzoyl] pyrazoles (94).Embodiment 35-amino-1-(4-fluorophenyl)-4-[3-{2-(morpholine-4-yl) oxyethyl group } benzoyl] pyrazole hydrochloride (14)
Figure A0081325700531
Step 1
The 3-methyl hydroxybenzoate (8.0g, 56mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (15.7g, 84mmol) and salt of wormwood (11.5g, 83mmol) mixture heating up in toluene (50ml) refluxes.After 4 days, make reaction mixture be cooled to room temperature and dilute with ethyl acetate.Organic layer washes with water, uses dilute hydrochloric acid extraction subsequently.Separate acidic layer, with the alkalization of 5N sodium hydroxide, product extracts in the ethyl acetate.Vacuum removes organism and resistates passes through purification by flash chromatography (gradient 3% acetone/methylene dichloride), obtains 3-(2-morpholine-4-base oxethyl) methyl benzoate (9.0g), and it is a solid.Step 2
Under-78 ℃, di-isopropyl lithamide (2.0M solution is in heptane/tetrahydrofuran/ethyl benzoate for 18.8ml, 37mmol) is added drop-wise in the acetonitrile in dry tetrahydrofuran (50ml) (1.58g, 37mmol).Stir after this reaction mixture 30 minutes, in 10 minutes, drip the solution of 3-(2-morpholine-4-base oxethyl) methyl benzoate in dry tetrahydrofuran (50ml).After 15 minutes, add entry and make reaction mixture rise to room temperature.Separate water layer and be acidified to pH7 with dilute hydrochloric acid.Product extracts in the ethyl acetate, and dried over mgso is used in water and salt water washing.Vacuum is removed organism and is obtained 2-[3-(2 morpholines-4-base oxethyl) phenyl] acetonitrile (5.0g), it is an oil, this product amylene is further purified and just can be used for the step down.Step 3
Under the nitrogen atmosphere with 2-[3-(2-morpholine-4-base oxethyl) phenyl] acetonitrile (5.0g) and N, (5.0g, 25.5mmol) mixture in dimethylbenzene (150ml) is 100 ℃ of heating for the N-amitraz diphenylurea.After 3 hours, make reaction mixture be cooled to room temperature, obtain 2-[3-(2-morpholine-4-base oxethyl) benzoyl with the hexane dilution]-3-phenyl amino-vinyl cyanide (5.0g), it is a solid.Step 4
Under the nitrogen atmosphere with 4-fluorophenyl hydrazine (1.0g, 6.8mmol) and 2-[3-(2-morpholine-4-base oxethyl)-benzoyl]-(2.0g, 5.3mmol) mixture heating up in ethanol (30ml) refluxes 3-phenyl amino vinyl cyanide.After 6 hours, make reaction mixture be cooled to room temperature, dilute with water.Product extracts in the ethyl acetate, and organic layer salt water washing is with dried over sodium sulfate and vacuum concentration.Utilize purification by flash chromatography (gradient: CH 2Cl 2-3%MeOH/CH 2Cl 2), obtain 5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholine-4-base oxethyl) benzoyl] pyrazoles, be translated into hydrochloride (0.7g, mpt.191.6-192.5 ℃).
4-fluorophenyl hydrazine in the step 4 is replaced by following compounds: 2-fluorophenyl hydrazine and 2; 6-dichlorophenyl hydrazine; obtain respectively: 5-amino-1-(2-fluorophenyl)-4-[3-(2-morpholine-4-base oxethyl) benzoyl] pyrazoles (97); with 5-amino-1-(2, the 6-dichlorophenyl)-4-[3-(2-morpholine-4-base oxethyl) benzoyl] pyrazoles (98).Embodiment 45-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl) benzoyl] pyrazoles (20)
Figure A0081325700551
Step 1
Under the argon atmospher with 5-amino-4-(3-benzoyl bromide)-1-(4-fluorophenyl) pyrazoles (0.9g; 2.5mmol) [according to top embodiment 1 described preparation], pyridine-3-boric acid, 1; ammediol cyclic ester (0.5g; 3mmol), potassiumphosphate (0.8g; 3.73mmol) and four (triphosphine) palladium (0.3g, the 0.25mmol) heating under 85 ℃ of the mixture in the Zai diox (20ml).After 16 hours, this reaction mixture is cooled to room temperature and impouring salt solution.Product extracts in the ethyl acetate, with dried over sodium sulfate and filtration.Vacuum is removed organic layer; resistates is by purification by flash chromatography (gradient: the 40-80% ethyl acetate/hexane); obtain 5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl) benzoyl]-pyrazoles (0.50g), it is by re-crystallizing in ethyl acetate (mpt.222.2-223.0).
5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl) benzoyl] methyl iodide that is used in the ethyl acetate of pyrazoles handles, and obtains 5-amino-1-(4-fluorophenyl)-4-[3-(N-methyl piperidine-3-yl) benzoyl] pyrazoles iodide (59).
5-amino-4-in the step 1 (3-benzoyl bromide)-1-(4-fluorophenyl) pyrazoles 5-amino-4-(3-benzoyl bromide)-1-(2; the 4-difluorophenyl) pyrazoles replaces; subsequent transformation is a hydrochloride; obtain 5-amino-1-(2,4 difluorobenzene base)-4-[3-(pyridin-3-yl) benzoyl] pyrazoles .HCl (99).Embodiment 55-amino-4-[3-(2-amino-sulfonyl ethyl) benzoyl]-1-(4-fluorophenyl) pyrazoles (50) Step 1
5-amino-4-under the argon gas (3-benzoyl bromide)-1-(4-fluorophenyl) pyrazoles (1.5g; 4.14mmol) [according to above embodiment 1 described preparation], vinyl sulphonamide (1.33g; 12.4mmol), two (triphenylphosphine) Palladous chloride (0.3g; 0.42mmol) and triethylamine (6ml, the 43mmol) heating under 100 ℃ of the mixture in dimethyl formamide (18ml).After 16 hours, make reaction mixture be cooled to room temperature and impouring 1N hydrochloric acid.Product extracts ethyl acetate, uses the salt water washing, with dried over sodium sulfate and filtration.Vacuum is removed organic layer; resistates is by purification by flash chromatography (gradient: the 40-80% ethyl acetate/hexane); obtain 5-amino-4-[3-(2-amino-sulfonyl-vinyl) benzoyl]-1-(4-fluorophenyl) pyrazoles; it obtains the expection product of 0.78g by the mixture recrystallization of methanol/ethyl acetate/hexane.Step 2
In the Parr device with 5-amino-4-[3-(2-amino-sulfonyl vinyl) benzoyl]-1-(4-fluorophenyl)-pyrazoles (2.1g, 5.43mmol) and mixture under 50psi nitrogen atmosphere the jolting of palladium hydroxide (0.6g) in methyl alcohol (150ml).After 4 days, this reaction mixture is through Celite Filter and with filter liquor concentration.Resistates is by purification by flash chromatography (gradient: the 40-100% ethyl acetate/hexane); obtain crude product; it is by methanol/ethyl acetate/hexane recrystallization; obtain 5-amino-4-[3-(2-amino-alkylsulfonyl ethyl) benzoyl]-1-(4-fluorophenyl) pyrazoles (0.95g; mpt.170-170.4 ℃), it is a solid.
Vinyl sulphonamide in the step 1 replaces obtaining with vinyl methyl sulfone: 5-amino-4-[3-(2-methyl sulphonyl ethyl) benzoyl]-1-(4-fluorophenyl) pyrazoles (100).Embodiment 65-amino-1-(4-fluorophenyl)-4-[3-(morpholine-4-ylmethyl carbonyl)-benzoyl] pyrazoles (18)
Figure A0081325700571
Step 1
Under the argon gas with 5-amino-4-(3-benzoyl bromide)-1-(4-fluorophenyl) pyrazoles (3.5g; 9.7mmol) [according to above embodiment 1 described preparation], tributyl-(1-vinyl ethyl ether base) tin (4.3ml; 12.36mmol) and tetrakis triphenylphosphine palladium (1.0g, the 0.87mmol) heating under 95 ℃ of the mixture in dimethyl formamide (25ml).After 16 hours, make reaction mixture be cooled to room temperature, and slowly add 10% aqueous hydrochloric acid (25ml).After 30 minutes, reaction mixture dilutes with ethyl acetate, through Celite Filter.Separate organic layer and use the salt water washing, with dried over sodium sulfate and vacuum concentration.Resistates by purification by flash chromatography (gradient: the 10-60% ethyl acetate/hexane), obtain 5-amino-4-[3-(1-vinyl ethyl ether base) benzoyl]-1-(4-fluorophenyl) pyrazoles, it is dissolved in tetrahydrofuran (THF) (50ml).Add 1N hydrochloric acid (20ml), this reaction mixture at room temperature stirred 16 hours.Separate organic layer, use the salt water washing, with dried over sodium sulfate and vacuum concentration.Crude product by purification by flash chromatography (gradient: the 20-50% ethyl acetate/hexane),, obtain 5-amino-4-[3-acetylbenzene formyl radical subsequently by the mixture recrystallization of ethyl acetate/hexane]-1-(4-fluoro-phenyl) pyrazoles (2.0g).Step 2
Under the nitrogen; to the cupric bromide (2.2g that refluxes; 9.85mmol) in the suspension of ethyl acetate/dichloromethane (1: 1) in (100ml), add the amino 4-[3-acetylbenzene of the 5-formyl radical that is present in the methylene dichloride (25ml)]-1-(4-fluorophenyl) pyrazoles (1.6g, solution 4.95mmol).After 16 hours, concentrate this reaction mixture, make resistates in sodium bisulfite and ethyl acetate, distribute.Separate organic layer, use the salt water washing, with dried over sodium sulfate and vacuum concentration.Resistates by purification by flash chromatography (gradient: the 10-40% ethyl acetate/hexane), obtain 5-amino-4-[3-(2-acetyl bromide)-benzoyl]-1-(4-fluorophenyl) pyrazoles (0.47g), it is a solid.Step 3
To morpholine (0.25ml; 2.79mmol) add 5-amino-4-[3-(2-acetyl bromide) benzoyl that is present in the dimethyl formamide (5ml) in the solution in dimethyl formamide (5ml)]-1-(4-fluorophenyl) pyrazoles (0.22g, solution 0.56mmol).After 16 hours, reaction mixture impouring salt solution, product extracts in the ethyl acetate.Separate organic layer, use the salt water washing, with dried over sodium sulfate and vacuum concentration.Resistates by purification by flash chromatography (gradient: ethyl acetate-10% methanol/ethyl acetate), obtain 5-amino-1-(4-fluorophenyl)-4-[3-(morpholine-4-ylmethyl carbonyl) benzoyl] pyrazoles (0.05g), it is a solid.Embodiment 75-amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl) benzoyl] pyrazoles (118)
Figure A0081325700581
Step 1
(10g 46.5mmol) adds diborane (70ml, 1.0M solution is contained in the tetrahydrofuran (THF)) in the solution in tetrahydrofuran (THF) (100ml) to 3-bromophenyl acetate under 0 ℃.Make this reaction mixture rise to room temperature.After 16 hours, make this reaction mixture be cooled to 0 ℃, drip entry (50ml).Separate organic layer, use the salt water washing, with dried over sodium sulfate and vacuum concentration.Resistates is by purification by flash chromatography (gradient: the 40-60% ethyl acetate/hexane), obtain 3-(2-hydroxyethyl) bromobenzene (9.0g).Step 2
Under 0 ℃, to 3-(2-hydroxyethyl) bromobenzene (4.0g, 20mmol) add in the solution in methylene dichloride (100ml) tert-butyldimethylsilyl chloride (3.6g, 24mmol), dimethyl aminopyridine (0.61g, 5mmol) and triethylamine (3.6ml, 25.9mmol).After 1 hour, this reaction mixture is with salt solution, saturated ammonium chloride washing, with dried over sodium sulfate and vacuum concentration.Resistates is by purification by flash chromatography (gradient: the 0-10% hexane/ethyl acetate), obtain 3-(the 2-tertiary butyl-dimethylsilane oxygen base ethyl) bromobenzene (6.0g).Step 3
(26ml, 154mmol) (19.4g, 154mmol) mixture heating up in ethanol (125ml) refluxes with 4-fluorophenyl hydrazine (oxyethyl group methylene radical) ethyl cyanacetate.After 16 hours, make this reaction mixture be cooled to room temperature.Filter out and filter and drying, obtain 5-amino-4-ethyl carboxyl-1-(4-fluorophenyl) pyrazoles (28g), it is suspended in the mixture of 1N lithium hydroxide (100ml) and methyl alcohol (250ml).With this reaction mixture reflux.After 16 hours, this reaction mixture filters through sinter funnel (sinterfunnel), and filtrate is filtered with 2N hydrochloric acid (65ml).Filter out solid and dry, obtain 5-amino-4-carboxyl-1-(4-fluorophenyl) pyrazoles (21g).Step 4
Stir under the room temperature 5-amino-4-carboxyl-1-(4-fluorophenyl) pyrazoles (15g, 68mmol), aldrathiol-2 (14.9g, 68mmol) and triphenylphosphine (17.8g, 68mmol) mixture in acetonitrile (21).After 16 hours, filter out product and dry, obtain 5-amino-1-(4-fluorophenyl)-4-(2-pyridylthio carboxyl)-pyrazoles (14g).Step 5
To contain magnesium chips (0.386g, 15.9mmol) and add in the oven dry flask of tetrahydrofuran (THF) (10ml) 3-(2-t-butyldimethylsilyloxy base ethyl) bromobenzene (5.0g, 15.9mmol), with this reaction mixture reflux.After 3 hours, make reaction mixture be cooled to room temperature, and adding 5-amino-1-(4-fluorophenyl)-4-(2-pyridylthio carboxyl) pyrazoles (2.37g, 7.6mmol), continuously stirring 16 hours.With the reaction mixture vacuum concentration.Resistates is dissolved in ethyl acetate,, and uses dried over sodium sulfate with aqueous ammonium chloride solution and salt water washing.Vacuum is removed organism, resistates by purification by flash chromatography (gradient: the 10-30% ethyl acetate/hexane), obtain 5-amino-1-(4-fluorophenyl)-4-[3-(2-tertiary butyl dimethyl-siloxy-ethyl) benzoyl] pyrazoles (1.20g).Step 6
To 5-amino-1-(4-fluorophenyl)-4-[3-(2-tertiary butyl dimethyl-siloxy-ethyl)-benzoyl] pyrazoles (1.2g; 3.0mmol) add tertiary butyl Neutral ammonium fluoride (3.6ml in the solution in tetrahydrofuran (THF) (25ml); 3.6mmol, the tetrahydrofuran solution of 1M).After 1 hour, with this reaction mixture impouring salt solution, product extracts ethyl acetate.The organic layer dried over sodium sulfate is filtered and vacuum concentration.Resistates by purification by flash chromatography (gradient: the 40-100% ethyl acetate/hexane), obtain the amino 1-(4-fluorophenyl) of 5--4-[3-(2-hydroxyethyl) benzoyl] pyrazoles (0.8g).Embodiment 85-amino-1-(4-fluorophenyl)-4-{3-[4-methylpiperazine-1-yl) ethyl)-and benzoyl] pyrazoles dihydrochloride (31) synthetic
Figure A0081325700601
Step 1
To 5-amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl)-benzoyl] pyrazoles (0.8g, 2.5mmol) add in the solution in pyridine (10ml) methylsulfonyl chloride (0.29ml, 3.7mmol).After 2 hours, with reaction mixture impouring 2N hydrochloric acid (40ml), product extracts ethyl acetate.Dried over sodium sulfate is used in organic layer salt water washing, filters and vacuum concentration.Resistates by purification by flash chromatography (gradient: the 40-100% ethyl acetate/hexane), obtain 5-amino-1-(4-fluorophenyl)-4-[3-(2-mesyloxy ethyl) benzoyl] pyrazoles (0.87g).Step 2
5-amino-1-(4-fluorophenyl)-4-[3-(2-mesyloxy ethyl) benzoyl] pyrazoles (0.22g; 0.55mmol), N methyl piperazine (0.18ml; 1.64mmol) and salt of wormwood (0.22g, the 1.64mmol) heating under 70 ℃ of the mixture in dimethyl formamide (10ml).After 4 hours, make reaction mixture be cooled to room temperature, in the impouring water, product extracts in the ethyl acetate.Dried over sodium sulfate is used in organic layer salt water washing, filters and vacuum concentration.Resistates is by purification by flash chromatography (gradient: ethyl acetate-20% methanol/ethyl acetate); obtain 5-amino-1-(4-fluorophenyl)-4-{3-[4-methylpiperazine-1-yl) ethyl) benzoyl] pyrazoles, it is converted into hydrochloride (mpt.272.9-273.9).Embodiment 95-amino-4-[3-(2-amino-ethyl) benzoyl]-1-(4-fluorophenyl)-pyrazole hydrochloride (47) Step 1
At room temperature stir 5-amino-1-(4-fluorophenyl)-4-[3-(2-mesyloxy-ethyl)-benzoyl] pyrazoles (0.40g; 0.99mmol), sodiumazide (0.19ml; 2.97mmol) and salt of wormwood (0.41g, 2.97mmol) mixture in dimethyl formamide (15ml).After 16 hours, with reaction mixture impouring salt solution, product extracts in the ethyl acetate.The organic layer dried over sodium sulfate is filtered and vacuum concentration.Resistates by purification by flash chromatography (gradient: the 20-50% ethyl acetate/hexane), obtain 5-amino-1-(4-fluorophenyl)-4-[3-(2-azido-ethyl) benzoyl] pyrazoles (0.32g).Step 2
To 5-amino-1-(4-fluorophenyl)-4-[3-(2-azido-ethyl) benzoyl]-pyrazoles (0.31g, 0.9mmol) add in the solution in tetrahydrofuran (THF) (15ml) triphenylphosphine (3.55g, 1.36mmol).After 48 hours, with the reaction mixture vacuum concentration.Resistates is dissolved in 2N sodium hydroxide, and product extracts in the ethyl acetate.The organic layer dried over sodium sulfate is filtered and vacuum concentration.This product is converted into its hydrochloride, and by the mixture recrystallization of methyl alcohol-ethyl acetate, obtains 5-amino-4-[3-(2-amino-ethyl) benzoyl]-1-(4-fluorophenyl) pyrazole hydrochloride (0.22g).Embodiment 105-amino-4-[3-(tert-butoxycarbonyl methoxyl group) benzoyl]-1-(4-fluorophenyl) pyrazoles
Figure A0081325700621
Step 1
Contain magnesium chips (0.408g, add 179mmol) and in the oven dry flask of tetrahydrofuran (THF) (10ml) the 3-bromoanisole (3.1g, 17mmol), with this reaction mixture reflux.After 2 hours, make reaction mixture be cooled to room temperature, add 5-amino-1-(4-fluorophenyl)-4-(2-pyridylthio carboxyl) pyrazoles (1.5g, 4.8mmol) and continuously stirring 1 hour.Water is ended this reaction mixture, and product extracts in the ethyl acetate.Organic layer aqueous ammonium chloride solution and salt water washing, and use dried over sodium sulfate.Vacuum is removed organism, and filtration residue is used hexane wash, obtains 5-amino-1-(4-fluoro-phenyl)-4-(3 anisoyl) pyrazoles (1.20g).Step 2
(3.0g 10.0mmol) adds boron tribromide (1M solution is contained in the methylene dichloride for 51ml, 5lmmol) in the ice-cold solution in methylene dichloride (25ml) to 5-amino-1-(4-fluorophenyl)-4-(3-anisoyl)-pyrazoles.After 1 hour, with reaction mixture impouring salt solution, product extracts in the ethyl acetate.The organic layer dried over sodium sulfate is filtered and vacuum concentration, obtains 5-amino-1-(4-fluorophenyl)-4-[3-hydroxy benzoyl]-pyrazoles (2.4g).Step 3
With 5-amino-1-(4-fluorophenyl)-4-[3-hydroxy benzoyl] pyrazoles (1.0g, 3.3mmol), bromo-acetic acid tert-butyl (1.4g, 7.2mmol) and salt of wormwood (1g, 7.2mmol) mixture in acetonitrile is 70 ℃ of following heated overnight.Cool off this reaction mixture, with ethyl acetate dilution and filtration.Vacuum concentrated filtrate, resistates by purification by flash chromatography (gradient: 10% acetone/hexane) obtain 5-amino-4-[3-(tert-butoxycarbonyl methyl oxygen base) benzoyl]-1-(4-fluorophenyl) pyrazoles (1.2g), it is a solid.Embodiment 115-amino-4-[3-carboxyl methoxyl group) benzoyl]-1-(4-fluorophenyl) pyrazoles (119)
Figure A0081325700631
Step 1
Stir 5-amino-4-[3-(tert-butoxycarbonyl methoxyl group) benzoyl under the room temperature]-1-(4-fluorophenyl) pyrazoles (1.0g, 3.3mmol) and trifluoroacetic acid (15ml, 194mmol) mixture overnight in methylene dichloride (15ml).Vacuum is removed organism, and resistates is dissolved in the toluene.Concentrate this solution, resistates is developed between ethyl acetate and hexane, obtains 5-amino-4-[3-(carboxyl methoxyl group) benzoyl]-1-(4-fluorophenyl) pyrazoles (0.8g), it is a solid.Embodiment 125-amino-1-(4-fluorophenyl)-4-[3-(methylamino carbonyl methoxyl group)-benzoyl] pyrazoles (34)
Figure A0081325700632
Step 1
To 5-amino-4-[3-(carboxyl methoxyl group) benzoyl]-(0.5g, (0.3g 1.85mmol), heats this reaction mixture down at 60 ℃ to 1-(4-fluorophenyl)-pyrazoles 1.43mmol) to add carbonyl dimidazoles in the solution in tetrahydrofuran (THF) (10ml).After 1 hour, add methylamine (0.5 M solution is contained in tetrahydrofuran (THF) for 10ml, 5mmol), this is reflected under 60 ℃ and continues to spend the night.Make the reaction mixture cooling, dilute with ethyl acetate.Separate organic layer, with the salt water washing and use dried over sodium sulfate.Vacuum is removed organism; resistates is by purification by flash chromatography (gradient: the 20-30% acetone/hexane); obtain 5-amino-1-(4-fluorophenyl)-4-[3-(methylamino carbonyl methoxyl group) benzoyl] pyrazoles (0.25g, mpt.195.6-196.3 C), it is a solid.
Carry out according to embodiment 12 above, but methylamine with morpholino for obtaining 5-amino-1-(4-fluorophenyl)-4-[3-(morpholine-4-base carbonyl methoxyl group)-benzoyl] pyrazoles (35).Embodiment 135-amino-1-(4-fluorophenyl)-4-[3-{3-(morpholine-4-yl) propyl group amino } benzoyl]-pyrazoles (48)
Figure A0081325700641
Step 1
(14.5g 10mmol) joins the refrigerative nitrosonitric acid with the benzoyl acetonitrile off and in 10 minutes.Stirred this reaction mixture 15 minutes, the ice of impouring subsequently.Filter out solid, by ethyl alcohol recrystallization, obtain 2-(3-nitro benzoyl)-acetonitrile (5.4 g), it is a brown solid.Step 2
(13.75g, 72.3mmol) and N, (14.2g, 72.3mmol) mixture heating up in dimethylbenzene (200ml) refluxes the N-amitraz diphenylurea with 2-(3-nitro benzoyl) acetonitrile under nitrogen atmosphere.After 3 hours, make this reaction mixture be cooled to room temperature, with the dimethylbenzene dilution, obtain 2-(3-nitro benzoyl)-3-phenyl amino-vinyl cyanide (15.7g), it is a yellow solid.Step 3
Under nitrogen atmosphere with 4-fluorophenyl hydrazine (2.24g, 15.57mmol) and 2-(3-nitro benzoyl)-3-phenyl amino vinyl cyanide (4.15g, 14.16mmol) mixture heating up in ethanol (50ml) refluxes.After 1 dilution, make reaction mixture be cooled to room temperature, continue to stir 3 hours.Filter out solid and dry, obtain 5-amino-1-(4-fluorophenyl)-4-(3-nitro benzoyl) pyrazoles (4.5g), it is a solid.Step 4
Under nitrogen atmosphere with 5-amino-1-(4-fluorophenyl)-4-(3-nitro benzoyl) pyrazoles (4.0g; 24.52), Fe powder (3.84g; 68mmol) and ammonium chloride (3.84,71.78mmol) mixture heating up in ethanol (135ml) and water (64ml) refluxes.After 1 hour, make reaction mixture be cooled to room temperature and stir and spend the night.Through Celite Filter this reaction mixture and vacuum concentrated filtrate.Resistates distributes between water and ethyl acetate.Separate organic layer, use the salt water washing, with dried over sodium sulfate and vacuum concentration, obtain 5-amino-4-(3-amino-benzoyl)-1-(4-fluoro-phenyl) pyrazoles (3.5g), it is a solid.Step 5
The amino 4-(3-amino benzoyl) of 5--1-(4-fluorophenyl) pyrazoles (0.5g, 1.6mmol), 1-bromo-3-chloropropane (0.26g, 1.6mmol) and cesium carbonate (0.52g 1.6mmol) heats down in 80 ℃ in dimethyl formamide (25ml).After 2 days, make reaction mixture be cooled to room temperature, dilute with ethyl acetate.Organic layer salt water washing is with dried over sodium sulfate and vacuum concentration.Resistates by purification by flash chromatography (gradient: 20% acetone/hexane), obtain 5-amino-4-[3-(3-chloropropyl amino) benzoyl]-1-(4-fluorophenyl) pyrazoles (0.2g), it is a solid.Step 6
With 5-amino-4-[3-(3-chloropropyl amino) benzoyl]-1-(4-fluorophenyl)-pyrazoles (0.05g, 0.13mmol), morpholine (0.1ml, 1.1mmol), salt of wormwood (0.1g) and potassiumiodide (0.1g) mixture heating up in acetonitrile (3ml) refluxes.After 2 days, this reaction mixture impouring salt solution, product extracts in the ethyl acetate.Separate organic layer, use the salt water washing, with dried over sodium sulfate and vacuum concentration.Resistates is by purification by flash chromatography (gradient: 3%MeOH/CH 2Cl 2), obtain 5-amino-1-(4-fluorophenyl)-4-[3-{-(morpholine-4-yl) propyl group amino }-benzoyl] pyrazoles, it is a solid.Embodiment 145-amino-1-(4-fluorophenyl)-4-[3-{2-(piperidines-1-yl) oxyethyl group } benzoyl] pyrazole hydrochloride (81)
Figure A0081325700661
Step 1
5-amino-1-(4-fluorophenyl)-4-[3-hydroxy benzoyl] and pyrazoles (derive from embodiment 10, step 2,1.5g 5.05mmol) mixes with toluene (50mL).(1.79mL 25.23mmol), makes this reaction mixture be cooled to 0 ℃ subsequently to add ethylene bromohyrin.Add triphenylphosphine (5.425g, 20.69mmol) and diethyl azodiformate (3.26mL, 20.69mmol).The order reaction rises to room temperature.After stirring 16 hours, the saturated NH of this reaction 4The Cl aqueous solution is ended, and uses ethyl acetate extraction, dry (MgSO 4), concentrate under filtration and the vacuum.Product (5-amino-1-(4-fluorophenyl)-4-[3-(2-bromine oxethyl) benzoyl] pyrazoles) by column chromatography on silica gel with 40: 1 CH 2Cl 2/ MeOH purifying subsequently with stirring 20 minutes, filters and drying, obtains the product of 0.785g.Step 2
5-amino-1-(4-fluorophenyl)-4-[3-(2-bromine oxethyl) benzoyl] pyrazoles (0.6g, 1.48mmol) with piperidines (1.47mL, 14.8mmol) and ethanol (1OmL) mixed also reflux 16 hours.Concentrate this reaction mixture under the vacuum.The resistates of gained is at NaHCO 3Saturated aqueous solution and ethyl acetate between distribute, and with ethyl acetate extraction 3 times.Dry organic extraction (MgSO 4), filter, concentrate under the vacuum, by column chromatography on silica gel with 16: 1 CH 2Cl 2/ MeOH purifying.Product is dissolved in ethyl acetate; add hydrochloric acid (1.0M subsequently; 1.0 equivalent) form hydrochloride, it is filtered and drying, obtain 5-amino-1-(4-fluorophenyl)-4-[3-{2-(piperidines-1-yl) oxyethyl group of 0.413g } benzoyl]-pyrazoles .HCl (1.2 ℃ of mpt 210.2-21).
Carry out according to step 2, but piperidines by diethanolamine, dimethylamine, N methyl piperazine, 2-monoethanolamine, two (2-methoxy ethyl) amine, diethylamine, methylamine, ammonia and 3-oxo pyridazine replace, and obtains following compounds: Embodiment 155-amino-1-(4-fluorophenyl)-4-[3-(pyridine-2-ylmethoxy) benzoyl] pyrazoles (82)
5-amino-1-(4-fluorophenyl)-4-[3-hydroxy benzoyl] pyrazoles (derives from embodiment 10; step 2) (0.5g; 1.68mmol), 2-pyridyl methyl alcohol (0.81mL; 8.41mmol), triphenylphosphine (1.81g; 6.9mmol) and azido-dicarboxylate (1.09mL, 6.9mmol)) be blended in the toluene (50mL).Reaction mixture was stirred 16 hours, use NH subsequently 4The saturated aqueous solution of Cl is ended, and uses ethyl acetate extraction 3 times.Product is by being extracted in the ethyl acetate in 10% the HCl aqueous solution.Water layer neutralizes with NaOH, uses ethyl acetate extraction.Dry organic extraction (MgSO 4), concentrate under filtration and the vacuum.Resistates by column chromatography on silica gel with 1: 1 hexane/ethyl acetate purifying, obtain 5-amino-1-(4-fluorophenyl)-4-[3-(pyridine-2-ylmethoxy) benzoyl of 0.165g] pyrazoles (mpt.176.1-177.3 ℃).
2-pyridyl methyl alcohol replaces with oxyacetic acid (glycolic acid), 1-(2-hydroxyethyl)-2-Pyrrolidone and 4-hydroxy piperidine, obtains following compounds.
Figure A0081325700681
Embodiment 165-amino-1-(4-fluorophenyl)-4-[3-sec.-propyl aminocarboxyl oxygen base benzoyl] pyrazoles (83)
Figure A0081325700691
With 5-amino-1-(4-fluorophenyl)-4-[3-hydroxy benzoyl] and pyrazoles (deriving from embodiment 10, step 2) (0.30g, 1.01mmol) and K 2CO 3(0.418g, 3.03mmol) and THF (6mL) mix.This mixture cools off in ice bath, add subsequently n-Isopropyl isocyanate (0.12mL, 1.21mmol).The order reaction rises to room temperature, stirs 16 hours.This reaction mixture water is ended, and extracts in the ethyl acetate, dry (MgSO 4), filter and be concentrated into dried.Resistates was stirred 1 hour in methyl alcohol and methylene dichloride, filters, obtain 5-amino-1-(4-fluorophenyl)-4-[3-sec.-propyl amino-carbonyl oxygen base benzoyl of 0.118g] pyrazoles (mpt.225.2-230.1 ℃).
N-Isopropyl isocyanate replaces making 5-amino-1 (4-fluorophenyl)-4-[3-ethylamino carbonyl oxygen base benzoyl with ethyl isocyanate] pyrazoles (84).Mpt.201.2-202.8℃。Embodiment 175-amino-1-(4-fluorophenyl)-4-[3-iodobenzene formyl radical] pyrazoles
Figure A0081325700692
Step 1
N-Butyl Lithium (30.5ml, 76mmol, the solution of 2.5 M in hexane) is added drop-wise to Diisopropylamine, and (10.6ml is in the 76mmol) cooling in the 10ml dry tetrahydrofuran (0 ℃) solution.In case reinforced finishing, this solution kept 10 minutes down at 0 ℃, was cooled to-50 ℃ subsequently.(2.37ml, 45.3mmol) (10.0g is 36.2mmol) in the solution in dry tetrahydrofuran (18ml) with the 4-iodo ethyl benzoate subsequently this cooling LDA solution to be joined-50 ℃ acetonitrile.In case reinforced finishing stirs this reaction down at-50 ℃, rises to 0 ℃ subsequently.Add saturated ammonium chloride (20ml), make this reaction mixture rise to room temperature.Product extracts in the ether, with 1N hydrochloric acid (50ml) washing.Organism is used MgSO with salt solution (50ml) washing 4Drying, vacuum concentration is a reddish oil subsequently.This oil through little silica gel plug with 3: 1-2: 1 hexane/ethyl acetate is as the eluent purifying.Vacuum concentration post cut obtains 2-(3-iodobenzene formyl radical)-acetonitrile (8.3g), and it is a yellow oil.Step 2
Reflux 2-under the nitrogen atmosphere (3-iodobenzene formyl radical) acetonitrile (36.2g, 133.5mmol) and N, N-amitraz diphenylurea (26.2g, 133.5mmol) mixture in toluene (200ml).After 8 hours, make reaction mixture be cooled to room temperature, with ether dilution (200ml), obtain 2-(3-iodobenzene formyl radical)-3-phenyl amino vinyl cyanide (31.2g), it is a solid.Step 3
Reflux 4-fluorophenyl hydrazine under the nitrogen atmosphere (26.6g, 211mmol) and 2-(3-iodobenzene formyl radical)-3-phenyl amino vinyl cyanide (79g, 211mmol) mixture in ethanol (400ml).After 30 minutes, make this reaction mixture be cooled to room temperature, with the hexane dilution, obtain 5-amino-4-(3-iodobenzene formyl radical)-1-(4-fluorophenyl) pyrazoles (75.1g), it is a solid.
4-fluorophenyl hydrazine 4-methylphenylhydrazine in the step 3; 3-p-methoxy-phenyl hydrazine; 4-sulfamyl phenyl hydrazine; 2; 4-3,5-dimethylphenyl hydrazine; the 2-methylphenylhydrazine; 4-chloro-2-methylphenylhydrazine; 4-methyl sulphonyl phenyl hydrazine; 2-ethylphenyl hydrazine and 2; 4-difluorophenyl hydrazine replaces obtaining respectively: 5-amino-4-(3-phenyl-iodide formyl radical)-1-(4-aminomethyl phenyl) pyrazoles; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(3-p-methoxy-phenyl) pyrazoles; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(4-sulfamyl phenyl) pyrazoles; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(2; the 4-3,5-dimethylphenyl) pyrazoles; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(2-aminomethyl phenyl) pyrazoles; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(4-chloro-2-aminomethyl phenyl) pyrazoles; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(4-methyl sulphonyl phenyl) pyrazoles; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(2-ethylphenyl) pyrazoles; with 5-amino-4-(3-phenyl-iodide formyl radical)-1-(2,4 difluorobenzene base) pyrazoles.Embodiment 185-amino-1-(4-fluorophenyl)-4-[3-(1, the 2-dihydroxy ethyl) benzoyl] pyrazoles (85)
Figure A0081325700711
Step 1
To 5-amino-1-(4-fluorophenyl)-4-[3-phenyl-iodide formyl radical] pyrazoles (10g; 24.6mmol) add vinyl tributyl tin (8.57g in the solution in the 100ml dimethyl formamide; 27.0mmol) and tetrakis triphenylphosphine palladium (O) (1.42g, 1.23mmol).The solution argon-degassed of gained rises to 100 ℃ subsequently and reaches 12 hours.
Make this reaction be cooled to room temperature, impouring 500ml distilled water is with 1: 1 ether/ethyl acetate extraction of 3x100ml.Organism is used MgSO with salt solution (150ml) washing 4Dry and vacuum concentration is a brown oil.This oil by flash chromatography with 5: 1-4: 1 hexane/ethyl acetate purifying is removed impurity and with 3: 1-2: 1 hexane/ethyl acetate wash-out goes out to expect product.Vacuum concentration post cut obtains 5-amino-1-(4-fluorophenyl)-4-[3-vinyl benzene formyl radical] pyrazoles (4.48g), it is a white solid.Step 2
To 5-amino-1-(4-fluorophenyl)-4-[3-vinyl benzene formyl radical] pyrazoles (4.48g, 13.95mmol) add in the suspension in the 50ml trimethyl carbinol N-methylmorpholine N-oxide compound be present in the 50ml distilled water (1.79g, 15.35mmol).In this mixture, add under the room temperature 2.5% be present in perosmic anhydride in the trimethyl carbinol (5.25ml, 0.42mmol).After 5 hours, this homogeneous reaction is diluted with ethyl acetate (25ml), and separation of organic substances with salt solution (25ml) washing, is used MgSO 4Drying, vacuum concentration is a brown oil subsequently.This oil is removed impurity by flash column chromatography with 1: 1 hexane/ethyl acetate purifying, and goes out to expect product with eluent ethyl acetate.Vacuum concentration post cut obtains 5-amino-1-(4-fluorophenyl)-4-[3-(1, the 2-dihydroxy ethyl) benzoyl] pyrazoles (4.48g), it is a white foam.Is solid (2.36g) by hexane with this foam development.
5-amino-1-in the above-mentioned steps 1 (4-fluorophenyl)-4-[3-phenyl-iodide formyl radical] pyrazoles replaces with following compounds: 5-amino-1-(2; the 4-difluorophenyl)-and 4-[3-phenyl-iodide formyl radical] pyrazoles; with 5-amino-1-(2-aminomethyl phenyl)-4-[3-phenyl-iodide formyl radical] pyrazoles; obtain 5-amino-1-(2 respectively; the 4-difluorophenyl)-4-[3-(1; the 2-dihydroxy ethyl) benzoyl] pyrazoles (103); with 5-amino-1-(2-aminomethyl phenyl)-4-[3-(1, the 2-dihydroxy ethyl) benzoyl] pyrazoles (109).Embodiment 195-amino-1-(2,4 difluorobenzene base)-4-[3-(piperidino methyl) benzoyl] pyrazoles (86)
Figure A0081325700721
Step 1
To 5-amino-1-(2,4 difluorobenzene base)-4-[3-(1,2 dihydroxyl ethane) benzoyl] pyrazoles (10.1g, 28mmol) add in the suspension in the 100ml trimethyl carbinol 100ml distilled water and sodium periodate (18.06g, 84mmol).After 2 hours, collect solid precipitation by vacuum filtration, use the 300ml distilled water wash, vacuum-drying obtains 5-amino-1-(2,4 difluorobenzene base)-4-[3-formyl radical benzoyl of 8.28g] pyrazoles, it is a white solid.Step 2:
To 5-amino-1-(2; the 4-difluorophenyl)-4-[3-formyl radical benzoyl] pyrazoles (0.3g, 0.92mmol), piperidines (0.1ml, 1.0mmol), acetate (0.05ml) is 1; adding sodium triacetoxy borohydride in the solution in the 2-ethylene dichloride (5ml) (0.29g, 1.37mmol).Stirred 12 hours under the room temperature, this reaction is diluted with 10% hydrochloric acid and ethyl acetate (10ml).Separate water layer, be neutralized to pH9, dilute with ethyl acetate subsequently with sodium hydroxide.Isolate the organism of merging,, use MgSO with salt solution (25ml) washing 4Drying, vacuum concentration obtains brown oil subsequently.This oil is removed impurity by flash column chromatography with 1: 1 hexane/ethyl acetate purifying, and goes out to expect product with eluent ethyl acetate.Vacuum concentration post cut obtains 5-amino-1-(4-fluorophenyl)-4-[3-(piperidino-methyl)-benzoyl] pyrazoles, it is an oil (0.211g).Is solid by hexane/ethyl acetate with this compound development.
Piperidines in the above-mentioned steps 1 replaces with following compounds: morpholine, and N methyl piperazine, the 4-hydroxy piperidine, the 2-aminopyridine, the 3-aminopyridine, 4-methylimidazole, 3-amino-pyrazol, and glyoxal ethyline obtain following compounds:
Figure A0081325700731
Embodiment 205-amino-1-(3-aminomethyl phenyl)-4-[3-{N-oxo pyridine-3-yl) 1 benzoyl] pyrazoles (70)
Figure A0081325700741
Under argon atmospher; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(2-aminomethyl phenyl) pyrazoles (deriving from embodiment 17) (0.98g; 2.4mmol), tetramethyl ethylene ketone two boron (0.68g; 2.7mmol), [1; 1 '-two (diphenylphosphino) ferrocene] dichloro palladium (0.2g; .24mmol) and potassium acetate (0.72g, 7.3mmol) mixture in DMF (10ml) is 80 ℃ of down heating.After 2 hours, make reaction mixture be cooled to room temperature, add 3-bromopyridine N-oxide compound (0.47g, 2.7mmol), [1,1 '-two (diphenylphosphino) ferrocene] (0.2g is .24mmol) with 2M yellow soda ash (6.1ml for the dichloro palladium, 12.2mmol), 80 ℃ of heating down.After 16 hours, make reaction mixture be cooled to room temperature, impouring salt solution, product extracts in the ethyl acetate.The organic layer dried over sodium sulfate is filtered, and subsequently this solution evaporation is extremely done.Resistates is by purification by flash chromatography (gradient elution: ethyl acetate-20% methanol/ethyl acetate); behind methanol/ethyl acetate/hexane recrystallization; obtain 5-amino-1-(3-aminomethyl phenyl)-4-[3-(N-pyridine oxide-3-yl) benzoyl] pyrazoles (0.57g, mpt.190.5-191.2 ℃).
5-amino-4-(3-phenyl-iodide formyl radical)-1-(2-aminomethyl phenyl) pyrazoles/3-bromopyridine N-oxide compound replaces with following compounds: 5-amino-4-(3-phenyl-iodide formyl radical)-1-(4-aminomethyl phenyl) pyrazoles/3-bromopyridine; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(3-p-methoxy-phenyl) pyrazoles/3-bromopyridine; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(4-sulfamyl phenyl) pyrazoles/3-bromopyridine; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(2; the 4-3,5-dimethylphenyl) pyrazoles/3-bromopyridine; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(2-aminomethyl phenyl) pyrazoles/3-bromopyridine-N-oxide compound; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(4-chloro-2-aminomethyl phenyl) pyrazoles/3-bromopyridine; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(4-methyl sulphonyl phenyl) pyrazoles/3-bromopyridine; 5-amino-4-(3-phenyl-iodide formyl radical)-1-(2-ethylphenyl) pyrazoles/3-bromopyridine; with 5-amino-4-(3-phenyl-iodide formyl radical)-1-(2; the 4-difluorophenyl) pyrazoles/2-bromine imidazoles; obtain following compounds (if suitably it is hydrochloride) respectively: 5-amino-1-(4-aminomethyl phenyl)-4-[3-(pyridin-3-yl) benzoyl] pyrazoles (65); 5-amino-1-(3-p-methoxy-phenyl)-4-[3-(pyridin-3-yl) benzoyl] pyrazoles (66); 5-amino-1-(4-sulfamyl phenyl)-4-[3-(pyridin-3-yl) benzoyl] pyrazoles (68); 5-amino-1-(2; the 4-3,5-dimethylphenyl)-and 4-[3-(pyridin-3-yl) benzoyl] pyrazoles (69); 5-amino-1-(2-aminomethyl phenyl)-4-[3-(N-oxo pyridine-3-yl) benzoyl] pyrazoles (70); 5-amino-1-(4-chloro-2-aminomethyl phenyl)-4-[3-(pyridin-3-yl) benzoyl] pyrazoles (73); 5-amino-1-(4-methyl sulphonyl phenyl)-4-[3-(pyridin-3-yl) benzoyl] pyrazoles (75); 5-amino-1-(2-ethylphenyl)-4-[3-(pyridin-3-yl) benzoyl] pyrazoles (76) and 5-amino-1-(2,4 difluorobenzene base)-4-[3-(imidazoles-2-yl) benzoyl] pyrazoles (77).Embodiment 215-amino-1-(2,4 difluorobenzene base)-4-[N-oxo pyridine-3-yl) benzoyl] pyrazoles (60)
Figure A0081325700751
To 5-amino-1-(2,4 difluorobenzene base)-4-[3-(pyridin-3-yl) benzoyl] (4.6g, (5.6g 18.3mmol), stirs this mixture to pyrazoles under the room temperature 12.2mmol) to add 3-chlorine peroxybenzoic acid in the solution in methylene dichloride (100ml).After 4 hours, add 10% sodium sulfite aqueous solution (50ml).0.5 after hour, separate organic layer, use the salt water washing, with dried over sodium sulfate and filtration.Filtrate is concentrated into dried; resistates is by purification by flash chromatography (gradient elution: ethyl acetate-30% methanol/ethyl acetate); after recrystallizing methanol; obtain 5-amino-1-(2; the 4-difluorophenyl)-and 4-[3-(N-oxo pyridine-3-yl) benzoyl] pyrazoles (1.3g, Mpt.251.1-251.7 ℃).Embodiment 225-amino-1-(2,4 difluorobenzene base)-4-[pyridin-4-yl) benzoyl] pyrazoles (61)
Figure A0081325700761
Under the argon gas with 5-amino-4-(3-benzoyl bromide)-1-(2; the 4-difluorophenyl) pyrazoles (.93g; 2.5mmol), 4-tributyl Shen stannane yl pyridines (1.0g, 2.7mmol) and two (triphenylphosphine) Palladous chlorides (.17g, 2.5mmol) mixture in DMF (15ml) is 100 ℃ of heating down.After 16 hours, make reaction mixture be cooled to room temperature, add 10% potassium fluoride aqueous solution (30ml).After 1 hour,, use ethyl acetate extraction, use dried over sodium sulfate, filter and be concentrated into dried reaction mixture impouring salt solution.Resistates is by purification by flash chromatography (gradient elution: 50-100% ethyl acetate/hexane to 5% methanol/ethyl acetate); behind the methanol/ethyl acetate recrystallization; obtain 5-amino-1-(2; the 4-difluorophenyl)-and 4-[3-(pyridin-4-yl) benzoyl] pyrazoles (0.42g, Mpt.218-226 ℃).Embodiment 235-amino-1-(2, the 4-3,5-dimethylphenyl)-4-[3-(pyridin-3-yl) Benzoylpyrazols hydrochloride (69)
Figure A0081325700762
Step 1
Under nitrogen and-78 ℃ to n-Butyl Lithium (165ml, 264mmol) the adding 3-bromopyridine solution in butyl ether (250ml) in (25.4ml, 264mmol).After 1 hour, and adding diethyl methoxyl group borine (52ml, 396mmol).Make this mixture rise to room temperature.After 16 hours, add entry and salt solution, separate organic layer, use dried over sodium sulfate, concentrate subsequently.The gained slurries are dissolved in Virahol (500ml), and cooling by filtering to isolate product, obtains diethyl (3-pyridyl) borine (29.8g).Step 2
Under the argon gas with diethyl (3-pyridyl) borine (176.4g, 1.2mole), 3-iodobenzoic acid methyl esters (262g, 1mole), potassiumphosphate (318.4g, 1.5mole) and tetrakis triphenylphosphine palladium (O) (57.8g .05mole) mixture in DMF (1000ml) is 80 ℃ of down heating.After 10 hours, this mixture dilute with water is also used ethyl acetate extraction.Filter organic layer and wash with water.In organic fraction, add dense HCl (65ml).Separate organic layer, use the HCl extraction with aqueous solution.The acid extraction liquid that merges is handled with ethyl acetate, uses 50% aqueous sodium hydroxide solution (55ml) to handle subsequently.Separate organic layer, after this water and saturated sodium bicarbonate solution washing use dried over sodium sulfate.Filter this solution, concentrate and obtain 3-(pyridin-3-yl) methyl benzoate (145.3g).Step 3
(126.2g, (37ml 0.71mole), cools off this solution to 40 ℃ 0.59mole) to add acetonitrile in the solution in THF (600ml) to 3-(pyridin-3-yl) methyl benzoate.Dropping LDA thing solution (590ml, 1.18mole).After 30 minutes, add methyl alcohol (25ml), through after 30 minutes, add entry (110ml) again.Make this reaction mixture rise to 10 ℃, add ethyl acetate.Separate each layer, and water layer 1M HCl acidifying.The water layer ethyl acetate extraction is with hexane dilution and use the salt water washing.Concentrate organic phase, (120g 0.61mole) is mixed in the ethyl acetate of 800ml with itself and N subsequently.Stir this mixture under the room temperature.After 3 days, collect product by filtering, by Virahol, the hexane recrystallization obtains 2-(3-pyridin-3-yl) phenyl-3-phenyl vinyl cyanide (100g).Step 4
Under the nitrogen, with 2-(3-pyridin-3-yl phenyl)-3-phenyl vinyl cyanide (1.0g, 3mmol) and 2,4-3,5-dimethylphenyl hydrazine (0.4g, 3mmol) vlil in ethanol (30ml).After 6 hours, make this reaction be cooled to room temperature, be concentrated into driedly, resistates is by flash column chromatography purifying (gradient: 40-100% ethyl acetate/hexane-10% methanol/ethyl acetate).The resistates of purifying is dissolved in ethyl acetate, adds the HCl/ ether and make salt.By isolate behind the methanol/ethyl acetate purifying 5-amino-1-(2,4 3,5-dimethylphenyl)-4-[3-(pyridin-3-yl) Benzoylpyrazols hydrochloride (0.74g, m.pt.250.7-251.8).
Carry out according to the foregoing description 23, but 2 in the step 4,4-3,5-dimethylphenyl hydrazine replaces with following compounds respectively: phenyl hydrazine; 2-methyl-4-chloro-phenyl-hydrazine; 4-p-methoxy-phenyl hydrazine, 4-methyl sulphonyl phenyl hydrazine, 2-ethylphenyl hydrazine; 4-isopropyl phenyl hydrazine; 2-p-methoxy-phenyl hydrazine, 3-chloro-4-methylphenylhydrazine, 3-fluorophenyl hydrazine; with 3-fluoro-6-methylphenylhydrazine, obtain following compounds: Embodiment 245-amino-1-(4-fluorophenyl)-4-[3-{2 (R), 3-dihydroxyl propoxy-} benzoyl] pyrazoles (106)
Figure A0081325700801
Step 1
To 5-amino-4-(3-hydroxy benzoyl)-1-(4-fluorophenyl) pyrazoles (0.5g; 1.68mmol) add the D-mouth in the solution in the dry dimethyl formamide of 5ml; mouth-different third subunit glycerine-mouth-tosylate (0.72g; 2.52mmol); add subsequently Anhydrous potassium carbonate (0.695g, 5.04mmol).Argon gas this reaction of ordering is warming up to 80 ℃.After 24 hours, make this reaction be cooled to room temperature, add the D-mouth of other 500mg, this reaction of ordering of mouth-different third subunit glycerine-mouth-tosylate, argon gas is warming up to 80 ℃ again.Through after 8 hours, make this reaction be cooled to room temperature again, with distilled water (50ml) dilution, product extracts in the ether.The organism that merges is used MgSO with salt solution (50ml) washing 4Drying, vacuum concentration is a yellow oil subsequently.This oil by flash column chromatography on silica gel with 2: 1-1: 1 hexane/ethyl acetate is as the eluent purifying.Vacuum concentration post cut obtains the expection acetal of 556mg.Step 2
(0.556g 1.35mmol) adds distilled water (2ml) and tosic acid monohydrate (5mg) in the solution in methyl alcohol (10ml) upwards to go on foot the acetal that makes.Make this solution be warming up to 80 ℃ under the argon atmospher.After 2 hours, make reaction mixture be cooled to room temperature, vacuum concentration obtains yellow oil, and it is dissolved in ethyl acetate (50ml) and saturated sodium bicarbonate (50ml) once more.Separate organic layer, use MgSO 4Drying, vacuum concentration obtains white solid subsequently.By the hexane/ethyl acetate recrystallization, obtain the expection diol compound (Mpt.150.2-153.0 ℃) of 196mg.Embodiment 255-amino-1-(4-fluorophenyl)-4-{3-[(2,2-dimethyl-1,3-dioxolane-4 (S)-yl) methoxyl group] benzoyl } pyrazoles (170)
Figure A0081325700811
To 5-amino-1-(4-fluorophenyl)-4-[3-{2 (S), 3-dihydroxyl propoxy-} benzoyl] pyrazoles (and 0.6g, 1.6mmol) add in the solution in 30ml acetone zinc chloride (0.34g, 2.6mmol).Stir this reaction mixture and reflux.After 13 hours, this reaction mixture is concentrated into dried, product by flash column chromatography on silica gel with the 40%EtOAc/ hexane as the eluent purifying.Product and 1: 1 ether/hexane stir, and obtain 5-amino-1-(4-fluorophenyl)-4-{3-[(2,2-dimethyl-1,3-dioxolane-4 (S)-yl) methoxyl group] benzoyl } pyrazoles.
Carry out according to the method described above; but acetone replaces with following compounds: propione and methyl ethyl ketone; obtain following compounds respectively: 5-amino-1-(4-fluorophenyl)-4-{3-[(2; 2-diethyl-1; 3-dioxolane-4 (S)-yl) methoxyl group] benzoyl } pyrazoles (173) and 5-amino-1-(4-fluorophenyl)-4-{3-[(2-methyl-2-ethyl-1,3-dioxolane-4 (S)-yl) methoxyl group] benzoyl } pyrazoles (174).Embodiment 265-amino-1-(4-fluorophenyl)-4-[3-{2 (S), 3-(diacetoxy) propoxy-} benzoyl] pyrazoles (165)
To 5-amino-1-(4-fluorophenyl)-4-[3-{2 (S); 3-dihydroxyl-propoxy-} benzoyl] pyrazoles (and 1g, 2.7mmol) add in the solution in pyridine (5ml) diacetyl oxide (0.5ml, 5.4mmol) and DMAP (0.066g; 0.5mmol), stir this reaction under the room temperature.After 16 hours,, use EtOAc, use dried over sodium sulfate, be concentrated into dry doubling and pass through purification by flash chromatography (gradient elution, 20-60%EtOAc/ hexane) this reaction mixture impouring salt solution.Product obtains 5-amino-1-(4-fluorophenyl)-4-[3-{2 (S) of 0.75g, 3-(diacetoxy) propoxy-by EtOAc/ hexane recrystallization } benzoyl] pyrazoles,
Carry out according to the method described above; but diacetyl oxide replaces with following compounds: isobutyryl chloride; and pivalyl chloride; obtain following compounds respectively: 5-amino-1-(4-fluorophenyl)-4-[3-{2 (S); 3-(two isobutyl acyloxy) propoxy-} benzoyl]-pyrazoles (166) and 5-amino-1-(4-fluorophenyl)-4-[3-{2 (S), 3-(two new pentane acyloxies) propoxy-} benzoyl] pyrazoles (167).Embodiment 275-amino-1-(4-fluorophenyl)-4-[3-{2 (S), 3-(dimethoxy carbonyl oxygen base) propoxy-} benzoyl] pyrazoles (168)
Figure A0081325700831
To 5-amino-1-(4-fluorophenyl)-4-[3-{2 (S), 3-dihydroxyl-propoxy-} benzoyl] pyrazoles (and 1g, 2.7mmol) add in the solution in pyridine (5ml) methyl-chloroformate (2ml, 25.4mmol).After 4 days,, extract, use dried over sodium sulfate, be concentrated into dried with EtOAc this reaction mixture impouring salt solution.Resistates obtains 5-amino-1-(4-fluorophenyl)-4-[3-{2 (S) of 0.55g, 3-(dimethoxy carbonyl oxygen base) propoxy-by purification by flash chromatography (gradient elution, 40-80%EtOAc/ hexane) } benzoyl] pyrazoles.Embodiment 285-amino-1-(4-fluorophenyl)-4-{3-[(1,3-dioxolane-2-ketone-4 (R)-yl) methoxyl group] benzoyl } pyrazoles (171)
To 15.0g (40.4mmol) 5-amino-1-(4-fluorophenyl)-4-[3-{2 (S), 3-dihydroxyl propoxy-} benzoyl] add 17ml (168mmol) triethylamine in the suspension of pyrazoles in 150ml THF.Make this mixture be cooled to-5 ℃, the phosgene (20%in toluene) that added 18ml in 30 minutes makes temperature of reaction maintain below 0 ℃ simultaneously.In case reinforced finishing continues to stir this reaction 1 hour down at 0 ℃.The distilled water and the 5%HCl that add 20ml subsequently are 5-6 until the pH of this solution.After 30 minutes, add ethyl acetate, separate organic layer, use the salt water washing, use MgSO 4Dry.Filter and vacuum concentration, obtain yellow oil, its by flash column chromatography with 1: 1-1: 2 hexane/ethyl acetate are as the eluent purifying.When the evaporating column cut, be settled out the carbonic ether of expection, obtain the expection product of 7.38g.Embodiment 295-amino-1-(4-fluorophenyl)-4-thenoyl-pyrazoles (114)
Carry out according to embodiment 1 step 2, but 2-(3-bromo-benzoyl) acetonitrile replaced by 2-(2-Thenoyl) acetonitrile, and carry out step 3 subsequently, obtain 5-amino-1-(4-fluorophenyl)-4-(2-Thenoyl)-pyrazoles.
Carry out according to embodiment 1 step 2, but 2-(3-bromo-benzoyl) acetonitrile replaced by 2-(2-furans acyl group (furanoyl)) acetonitrile, and carry out step 3 subsequently, obtain 5-amino-1-(4-fluorophenyl)-4-(2-furans acyl group)-pyrazoles (115).
Carry out according to embodiment 1 step 2; but 2-(3-bromo-benzoyl) acetonitrile is replaced by 2-(2-methyl-3-furans acyl group) acetonitrile; and the 4-fluorophenyl hydrazine in the step 3 is with 2; 4-difluorophenyl hydrazine replaces; obtain 5-amino-1-(2,4 difluorobenzene base)-4-(2-methyl furan-3-acyl group)-pyrazoles (116).
According to EXAMPLE Example 1; step 2 is carried out; but 2-(3-bromo-benzoyl) acetonitrile 2-(6-quinoline formyl base (quinolinoyl)) acetonitrile; and the 4-fluorophenyl hydrazine in the step 3 is with 2; 4-difluorophenyl hydrazine replaces; (6-quinoline formyl base)-pyrazole hydrochloride (117) (mpt.220-259.2) to obtain 5-amino-1-(2,4 difluorobenzene base)-4-.Embodiment 30
Be the representative drugs preparation that contains formula (I) compound below.Tablet
With following ingredients uniform mixing and the single scored tablet of boil down to.Composition quality/sheet, mg compound 400 W-Gums of the present invention 50 croscarmellose sodiums 25 lactose 120 Magnesium Stearates 5 capsule preparations
With the following ingredients uniform mixing and be contained in the duricrust gelatine capsule.Composition quality/capsule, mg compound 200 lactose of the present invention, 148 Magnesium Stearates, 2 suspension formulations are done in spray
Following ingredients is mixed suspension component content compound 1.0g of the present invention fumaric acid 0.5g sodium chloride 2.0g methyl p-hydroxybenzoate 0.15g propylparaben 0.05g granular sucrose 25.5g D-sorbite (70% solution) 12.85gVeegum (colloidal magnesium manosil AS) K (Vanderbilt Co.) the 1.0g flavouring 0.035ml colouring agent 0.5mg distilled water of formation oral administration in right amount to the 100ml injectable formulation
Mix following ingredients and form injectable formulation.Component content compound 0.2g of the present invention sodium acetate buffer, 0.4M an amount of extremely suitably pH water of 2.0mlHCl (1N) or NaOH (1N) (distillation, sterilization) is in right amount to 20ml
Except water, above-mentioned whole compositions are mixed and heating stirring simultaneously under 60-70 ℃.At 60 ℃ of water that add q.s down, vigorous stirring makes composition emulsification simultaneously.Add suitable quantity of water subsequently and reach 100g.Suppository
The preparation gross weight is the suppository of 2.5g, and its preparation is passed through compound of the present invention and the Witepsol  H-15 (triglyceride level of saturated vegetable fatty acid; Riches-Nelson, Inc., NewYork), and have a following composition: the kinase whose inhibition of compound 500mgWitepsol  H-15 surplus embodiment 31p-38 of the present invention (MAP) ... in vitro tests
Utilize Ahn, J.Biol.Chem.Vol.266 such as N.G. (7), 4220-4227, the less improvement of (1991) described method, by measure under the p-38 zymogenesis from γ- 33P-ATP shifts the p-38 map kinase inhibition activity that γ-ATP can measure compound of the present invention.
The phosphorylated form of reorganization p38 map kinase is expressed with SEK-1 and MEKK in E.Coli, and utilizes the Nickel post by the affinity chromatography purifying subsequently.
Phosphorylated p38 map kinase is diluted in kinase buffer liquid (20mM 3-(N-morpholinyl) propane sulfonic acid pH 7.2,25mM β-glycerophosphate, 5mM ethylene glycol-two (beta-aminoethyl ether)-N; N, N ', N '-tetraacethyl; the 1mM vanadic acid sodium, 1mM dithiothreitol (DTT), 40mM magnesium chloride) in.Adding is dissolved in the test compound among the DMSO or only adds DMSO (contrast) and make sample cultivate 10 minutes down at 30 ℃.By adding contain MBP and γ- 33The substance mixture of ATP causes kinase reaction.After this continue down to cultivate 20 minutes at 30 ℃, add 0.75% phosphoric acid and end this reaction.Utilize the phosphorus cellulose membrane (Millipore, Bedford, MA) from remaining γ- 33ATP isolates phosphorylated MBP, and utilize the scintillometer quantitative assay (Packard, Meriden, CT).
Compound of the present invention has activity in this test.The p-38 of some The compounds of this invention suppresses active and (is expressed as IC 50, the concentration when suppressing 50% quilt test p-38 enzyme) be:
????CPD# ??IC 50，μM ????CPD# ?IC 50，μM
????1 ????1.81 ????19 ????1.45
????2 ????3.29 ????21 ????2.18
????3 ????1.78 ????27 ????2.72
????4 ????6.18 ????33 ????1.12
????6 ????1.74 ????38 ????6.31
????9 ????1.32 ????43 ????6.52
????14 ????1.27 ????50 ????1.25
The restraining effect that embodiment 32 produces LPS inductive TNF-α in the IHP1 cell ... in vitro tests
Utilize Blifeld, Transplantation such as C., Vol.51 (2), 498-503, the little improvement of (1991) described method is measured compound of the present invention and is suppressed the ability that TNF-α discharges.(a) TNF is biosynthetic induces
Make the THP-1 cell suspension at substratum [RPMI (Gibco-BR1, Gailthersburg MD) contains 15% foetal calf serum, the 0.02mM 2 mercapto ethanol], reach the concentration of 2.5x106 cell/ml, bed board (contains the 0.2ml sample aliquot) in each hole in 96 hole flat boards subsequently.Test compound is dissolved in DMSO, and after this with the substratum dilution, the final concentration that makes DMSO is 5%.In each hole, add the testing liquid of 20 μ l equal portions or only contain the substratum of DMSO.Cell was cultivated 30 minutes down at 37 ℃.Xiang Kongzhong adds LPS, and (MO) reaching final concentration is 0.5 μ g/ml for Sigma, St.Louis, and makes cell continue to cultivate 2 hours.After incubation period finishes, collect culture supernatant, the amount of utilizing ELISA test determination TNF-α described below to exist.(b) ELISA test:
Catch ELISA test human body, utilize Reimund by specificity, GUT.Vol.39 such as J.M. (5), the described anti-TNF-Alpha antibodies of 684-689 (1996) (2TNF-H22 and 2TNF-H34) is measured the amount that TNF-α exists.
Polystyrene 96 holes dull and stereotyped with 50 μ l/ holes be present among the PBS (10ug/ml) antibody 2TNFH22 coating and in 4 ℃ humidifying chamber overnight incubation.Dull and stereotyped with the PBS washing, and then with blockading 1 hour under the 5% degreaser drying breast room temperature that is present among the PBS and washing with the 0.1%BSA (bovine serum albumin) that is present among the PBS.
The TNF standard substance are by people TNF-α (the R ﹠amp that recombinates; D Systems, Minneapolis, stock solution preparation MN).The concentration of standard substance in this test is 10ng/ml when beginning, carries out 6 semilog serial dilutions subsequently.
After this above-mentioned culture supernatant of 25 μ l equal portions or TNF standard substance or only be substratum (contrast) and the biotinylation monoclonal antibody 2TNF-H34 (2 μ g/ml are present among the PBS that contains 0.1%BSA) of 25 μ l equal portions mixes join in each hole.Culture sample jolting gently simultaneously in 2 hours under the room temperature is subsequently with the PBS washing that contains 0.1%BSA 3 times.(CA) solution wherein contains peroxidase-streptavidin and the 0.1%BSA of 0.416 μ g/ml in PBS for Zymed, S.San Francisco to add peroxidase-streptavidin of 50 μ l in each hole.Sample continues to cultivate 1 hour under the room temperature, subsequently with the PBS washing that contains 0.1%BSA 4 times.Under the O-phenylenediamine solution of 50 μ l in each hole (1ug/mlO-phenylenediamine and 0.03% hydrogen peroxide are present among the 0.2M citrate buffer pH 4.5) and the room temperature sample was cultivated 30 minutes under the lucifuge condition.Read sample and the object of reference optical density(OD) under 450nm and 650nm respectively.Optical density(OD) and the relational graph of the used concentration level of measuring TNF-α of utilization under 450nm.
IC 50Value is defined as test compound corresponding concentration when the absorbancy maximum value of 450nm is reduced to half.Compound of the present invention has activity in this test.Selected compound active as follows:
????CPD# ??IC 50，μM ????CPD# ??IC 50，μM
????1 ????1.77 ????21 ????0.61
????2 ????6.30 ????27 ????0.83
????4 ????1.26 ????33 ????0.14
????6 ????1.04 ????38 ????0.69
????10 ????1.62 ????43 ????0.17
????13 ????0.77 ????50 ????0.51
????19 ????0.17
The restraining effect that LPS-inductive TNF-α produces in embodiment 33 rats ... in vivo test
Utilize Zanetti, G.; Heumann, " in the mouse medium sized vein or intraperitoneal Gram-negative bacteria stimulate back cytokine production (Cytokine production after intravenous or peritonealGram-negative bacterial challenge in mice) " J.Immunol. such as D., 148,1890, (1992) and Sekut, L., Menius, " assessment of high-caliber whole body or the local tumor necrosin importance in the different animals model of inflammation (Evaluation of the significance of elevatedlevels of systemic and localized tumor necrosis factor in different animalmodels of inflammation) " J.Lab.Clin.Med. such as J.A., 124,813, the slight improvements of (1994) described method is measured and is suppressed the ability that TNF-α discharges in the chemical combination object of the present invention.
(ChaRles River, Hollister's female Sprague-Dawley rat of body weight 110-140g CA) conformed for 1 week.Comprise the Orally administered test compound of group of 8 mouse or only use carrier (control group), test compound wherein is dissolved in the water carrier that contains 0.9% sodium-chlor, 0.5% Xylo-Mucine, 0.4% tween 80,0.9% benzylalcohol (CMC carrier).After 30 minutes, give injection 50g/kg in the mouse peritoneum LPS (Sigma, St.Louis, MO).1.5 after hour, put to death mouse and gather blood by cardiopuncture by sucking CO2.Under 15,600 Xg, made the blood sedimentation in centrifugal 5 minutes, serum transfers in clean test tube and-20 ℃ freezing down, until by the ELISA test according to the scheme of manufacturers measure TNF-α (Biosource International, Camarillo, CA).
It is active that the TNF-α of selected compound of the present invention suppresses, i.e. TNF-alpha content measuring for vehicle treated group (control group) in the test group under 30mg is:
????CPD# % suppresses ????CPD# % suppresses
????3 ????96 ????19 ????76
????8 ????86 ????34 ????75
????16 ????86
Adjuvant arthritis test in embodiment 34 rats ... experiment in the .. body
Utilize adjuvant brings out in the rat sacroiliitis to measure the anti-inflammatory activity of compound of the present invention.Briefly, the female Sprague Dawley rat of body weight 120-155g (ChaRles River, Hollister, CA) before using at indoor adaptation 1 all environment.At the 1st day, give the mineral oil (Sigma of animal intradermal injection 0.1ml at 1/4 near-end position of afterbody, St.Louis, MO) suspension, this suspension is through heat sterilization and contain the drying cheese mycobacterium (Difco that concentration is 1mg/0.1ml, Bacto., Des., Lot 115979JA/EXP9/99).
In the time of the 7th day, use the test compound that is present in the CMC carrier until the 18th day.In the time of the 18th day, after giving compound, the body weight of weighing animal.Obtain clinical score, the intensity of consumption assessment oedema in 4 claws and afterbody.The scoring of each claw is appointed as 0-4 and afterbody is appointed as 0-3, and making maximum scores is 19.When not having inflammation sign (swelling and redness) in little joint (in the phalanges, between metacarpal-phalangeal, between sole of the foot toe) or big joint (wrist/carpal bone, ankle/shank), this multi-joint animal can be 0 by scoring.This animal is cited as 1 when observing light inflammation, and medium oedema is 2, and serious oedema is 3, and when existing the very serious oedema news commentary to be divided into 4.The afterbody scoring is 0 when observing afterbody and do not have oedema or necrotic tissue sign, when showing the Mild edema news commentary with contiguous surrounding tissue, the vaccinal injection site is divided into 1, afterbody when about 1/4 or inflammation or show the necrotic tissue news commentary and be divided into 2 are when showing serious necrosis at 1/4 afterbody or the oedema news commentary is divided into 3.According to clinical score, distal tibia, with the crosscut of tarsometatarsal joint close vicinity under rear solid end.The weight and the record of a difference weighing left side and right back pawl.
When testing in this test, compound of the present invention has anti-inflammatory activity.
The present invention illustrate by way of example with the mode of embodiment in more detail in addition description, purpose is clarification and easy to understand.It should be apparent that for one of ordinary skill in the art, can change and revise in appended scope.So, should be understood that foregoing description illustrates and do not play the qualification effect.So the qualification of the scope of the invention can not be with reference to foregoing description, and should be with reference to following claims, and the generalized whole equivalency range of these claims.
Whole patents, patent application and the document quoted for various purposes among the application are incorporated herein by reference in full at this, reach the same degree of representing respectively with each patent, patent application or document.

Claims (44)

1. compound that is selected from formula (I), and prodrug, each isomer, mixture of isomers and pharmaceutically acceptable salt: Wherein: R 1Be hydrogen or acyl group; R 2It is hydrogen or alkyl; A is aryl or heteroaryl ring; B is aryl or heteroaryl ring; R 3Be selected from: (a) amino, alkylamino or dialkyl amido; (b) acyl amino; (c) the optional heterocyclic radical that replaces; (d) optional aryl or the heteroaryl that replaces; (e) heteroatom containing alkyl; (f) contain the heteroatoms thiazolinyl; (g) contain the heteroatoms alkynyl; (h) contain the heteroatoms alkoxyl group; (i) heteroatom containing alkyl amino; (j) the optional heterocyclic radical alkyl that replaces; (k) the optional heterocyclic radical thiazolinyl that replaces; (l) the optional heterocyclic radical alkynyl that replaces; (m) optional cycloalkyloxy, cycloalkyl alkoxy, heterocyclic radical alkoxyl group or the heterocyclic oxy group that replaces; (n) the optional heterocyclic radical alkylamino that replaces; (o) optional substituted heterocyclic radical alkyl-carbonyl; (p) heteroatom containing alkyl carbonyl; (q) the optional cycloalkyl amino that replaces; (r)-NHSO 2R 6, R wherein 6Be alkyl, heteroatom containing alkyl or the optional heterocyclic radical alkyl that replaces; (s)-NHSO 2NR 7R 8, R wherein 7And R 8Be hydrogen, alkyl or heteroatom containing alkyl independently of one another; (t)-Y-(thiazolinyl)-R 9, wherein:
Y be singly-bound ,-O-,-NH-or-S (O) n-(wherein n is the integer of 0-2); And R 9Be cyano group, optional substituted heteroaryl ,-COOH ,-COR 10,-COOR 11,-CONR 12R 13,-SO 2R 14,-SO 2NR 15R 16,-NHSO 2R 17Or-NHSO 2NR 18R 19, R wherein 10Be alkyl or optional substituted heterocycle, R 11Be alkyl, and R 12, R 13, R 14, R 15, R 16, R 17, R 18And R 19Be hydrogen, alkyl or heteroatom containing alkyl independently of one another; (u)-C (=NR 20) (NR 21R 22), R wherein 20, R 21And R 22Be hydrogen, alkyl or hydroxyl independently; Or R 20And R 21Be together-(CH 2) n-, wherein n is 2 or 3, and R 22It is hydrogen or alkyl; (v)-NHC (X) NR 23R 24, wherein X be-O-or-S-, and R 23And R 24Be hydrogen, alkyl or heteroatom containing alkyl (w)-CONR independently of one another 25R 26, R wherein 25And R 26Represent hydrogen, alkyl, heteroatom containing alkyl or optional substituted heterocyclic radical alkyl independently, or R 25And R 26The nitrogen that links to each other with them constitutes the optional heterocyclic ring that replaces; (x)-S (O) nR 27, wherein n is 0 to 2 integer, and R 27Be alkyl, heteroatom containing alkyl, optional substituted cycloalkyl, the optional heterocyclic radical alkyl that replaces; Or-NR 28R 29, R wherein 28And R 29Be hydrogen, alkyl or heteroatom containing alkyl independently of one another; (y) cycloalkylalkyl, cycloalkyl alkynyl and cycloalkyl alkynyl, they all randomly by alkyl,
Halogen, hydroxyl or amino the replacement; (z) arylamino alkylidene group or heteroaryl amino alkylidene group; (aa) Z-alkylidene group-NR 30R 31Or Z-alkylidene group-OR 32, wherein Z be-NH-,-N (alkyl)-or
-O-, and R 30, R 31And R 32Be hydrogen, alkyl independently of one another or contain heteroatoms alkane
Base; (bb)-OC (O)-alkylidene group-CO 2H or-OC (O)-NR ' R " (wherein R ' and R " be independently hydrogen or
Alkyl) (cc) heteroaryl alkenylene or heteroaryl alkynylene; (dd) X-(alkylidene group) CH[(CR ' R ") mOR 40] [(CR ' R ") nOR 40],
Wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) p-(wherein p is 0
Integer to 2);
R 40It is acyl group; C (O) OR 41(R wherein 41Be hydrogen, alkyl or cycloalkyl);
C (O) ONR 41R 42(R wherein 41Definition as above and R 42Be hydrogen or alkyl); Or
C (O) NR 41R 42(R wherein 41And R 42Definition as above);
R ' and R " are hydrogen or alkyls independently; And m and n be independently 0 to 3 whole
Number, condition is that m and n are not 0 simultaneously; (ee) X-(alkylidene group)-CH (OH) CH 2NHR 50, wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) n-(wherein n is 0
Integer to 2); With
R 50Be C (O) OR 51And C (O) NR 51R 52(R wherein 51Be hydrogen, alkyl or cycloalkyl
And R 52Be hydrogen or alkyl); (ff) X-(alkylidene group)-CH (NR 50)-CH 2OH, wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) n-(wherein n is 0
Integer to 2); With
R 50Be C (O) OR 51And C (O) NR 51R 52(R wherein 51Be hydrogen, alkyl or cycloalkyl
And R 52Be hydrogen or alkyl) R 4Be selected from: (a) hydrogen; (b) halogen; (c) alkyl; (d) alkoxyl group; (e) hydroxyl; R 5Be selected from: (a) hydrogen; (b) halogen; (c) alkyl; (d) haloalkyl; (e) alkylthio; (f) hydroxyl; (g) amino; (h) alkylamino; (i) dialkyl amido; (j) heteroatom containing alkyl; (k) optional substituted heterocycle; (l) optional substituted heterocyclic radical alkyl; (m) optional substituted heterocyclic radical alkoxyl group; (n) alkyl sulphonyl; (o) amino-sulfonyl, an alkyl amino sulfonyl or dialkyl amino sulfonyl; (p) contain the heteroatoms alkoxyl group; (q) carboxyl; R 6Be selected from: (a) hydrogen; (b) halo; (c) alkyl; With
(d) alkoxyl group.
2. the compound of claim 1, wherein R 3Be:
(a) optional substituted heterocyclic radical;
(b) aryl or heteroaryl, optional halogen, alkyl, amino, alkoxyl group, carboxyl, elementary alkoxy carbonyl, the SO of being selected from of both 2R ' (wherein R ' is an alkyl) or SO 2NHR ' R " (wherein R ' and R " is hydrogen or alkyl independently) substituting group replace;
(c) heteroatom containing alkyl;
(d) contain heteroatomic thiazolinyl;
(e) heteroatom containing alkyl amino;
(f) contain the heteroatoms alkoxyl group;
(g) the optional heterocyclic radical alkyl that replaces, heterocyclyloxy base, cycloalkyloxy or cycloalkyl alkoxy;
(h) the optional heterocyclic radical thiazolinyl that replaces;
(i) the optional heterocyclic radical alkynyl that replaces;
(j) the optional heterocyclic radical alkoxyl group that replaces
(k) optional heterocyclic radical alkylamino or the cycloalkyl amino that replaces;
(l) the optional heterocyclic radical alkyl-carbonyl that replaces;
(k)-Y-(alkylidene group)-R 9, wherein Y be singly-bound ,-O-or-NH-, and R 9Be optional substituted heteroaryl, CONR 12R 13, SO 2R 14,-SO 2NR 15R 16,-NHSO 2R 17Or-NHSO 2NR 18R 19, R wherein 12, R 13, R 14, R 15, R 16, R 17, R 18And R 19Be hydrogen, alkyl or heteroatom containing alkyl independently of one another;
(l) cycloalkylalkyl, cycloalkyl alkynyl and cycloalkyl alkynyl, they are all optional by alkyl, halogen, hydroxyl or amino the replacement;
(m) arylamino alkylidene group or heteroaryl amino alkylidene group; Or
(n) Z-alkylidene group-NR 30R 31, wherein Z be-NH-,-N (alkyl)-or-O-, and R 30And R 31Be hydrogen, alkyl or heteroatom containing alkyl independently of one another.
3. the compound of claim 2, wherein R 1And R 2Be hydrogen; With B be phenyl.
4. the compound of claim 3, wherein A is a phenyl.
5. the compound of claim 4, wherein R 4Be hydrogen; And R 5Be halogen or alkyl.
6. the compound of claim 5, wherein R 5Be chlorine, fluorine or methyl; And R 6Be hydrogen, chlorine, fluorine, methyl or methoxy.
7. the compound of claim 5, wherein R 3It is the optional heteroaryl that replaces.
8. the compound of claim 7, wherein R 3Be pyridine-2-base, pyridin-3-yl, pyridin-4-yl, N-oxo pyridine-2-base, N-oxo pyridine-3-base, N-oxo pyridine-4-base or pyridone-2-base, they all can be optionally substituted.
9. the compound of claim 8, wherein R 3Be positioned at 3.
10. the compound of claim 9, wherein R 5Be 4-F and R 6Be hydrogen.
11. the compound of claim 9, wherein R 5Be 2-Me and R 6Be hydrogen.
12. the compound of claim 5, wherein R 3It is the optional phenyl that replaces.
13. the compound of claim 12, wherein R 3Be 3-sulfamyl phenyl, 3-methyl sulphonyl phenyl, 3-carboxyl phenyl or 3-ethoxy carbonyl phenyl.
14. the compound of claim 13, wherein R 3Be positioned at 3.
15. the compound of claim 14, wherein R 5Be 4-F and R 6Be hydrogen.
16. the compound of claim 5, wherein R 3Be:
(a) heteroatom containing alkyl;
(b) contain the heteroatoms alkoxyl group;
(c) heteroatom containing alkyl amino;
(d) the optional heterocyclic radical alkyl that replaces;
(e) optional heterocyclic radical alkoxyl group, the cycloalkyloxy that replaces; Or cycloalkyl alkoxy;
(f) the optional heterocyclic radical alkylamino that replaces;
(g)-Y-(alkylidene group)-R 9, wherein Y be singly-bound ,-O-or-NH-, and R 9Be optional substituted heteroaryl ,-CONR 12R 13, SO 2R 14,-SO 2NR 15R 16,-NHSO 2R 17Or-NHSO 2NR 18R 19, R wherein 12, R 13, R 14, R 15, R 16, R 17, R 18And R 19Be hydrogen, alkyl or heteroatom containing alkyl independently of one another; Or
(h) Z-alkylidene group-NR 30R 31, wherein Z be-NH-,-N (alkyl)-or-O-, and R 30And R 31Be hydrogen, alkyl or heteroatom containing alkyl independently of one another.
17. the compound of claim 16, wherein R 3It is heteroatom containing alkyl.
18. the compound of claim 17, wherein R 3Be positioned at 3, and it is selected from 2-dimethyl aminoethyl, 3-dimethylaminopropyl, 4-dimethylamino butyl, methylol, 1,2-dihydroxy ethyl, 3-hydroxy-3-methyl-1-butyl or 3-hydroxybutyl.
19. the compound of claim 18, wherein R 5Be 2-F, and R 6Be 4-F.
20. the compound of claim 18, wherein R 5Be 4-F, and R 6Be hydrogen.
21. the compound of claim 18, wherein R 5Be 2-Me and R 6Be hydrogen.
22. the compound of claim 16, wherein R 3Be to contain heteroatoms alkoxyl group or heteroatom containing alkyl amino.
23. the compound of claim 22, wherein R 3Be positioned at 3, and it is selected from 3-dimethylamino propoxy, 2-dimethylamino ethoxy, 2-hydroxyl-oxethyl, 2,3-dihydroxyl propoxy-, 2,2-(dihydroxyl methyl) oxyethyl group, 2-dimethyl aminoethyl amino and 3-dimethylaminopropyl amino.
24. the compound of claim 23, wherein R 5Be 4-F or 2-Me, and R 6Be hydrogen.
25. the compound of claim 16, wherein R 3Be the optional heterocyclic radical alkyl that replaces, the optional heterocyclic radical alkoxyl group that replaces or the optional heterocyclic radical alkylamino that replaces.
26. the compound of claim 25, wherein R 3Be positioned at 3, and it is selected from 3-(morpholine-4-yl) propoxy-, 2-(morpholine-4-yl) oxyethyl group, 2-(2-oxo-tetramethyleneimine-1-yl) oxyethyl group, 3-(morpholine-4-yl) propyl group, 2-(morpholine-4-yl) ethyl, 4-(morpholine-4-) butyl, 3-(morpholine-4-yl) propyl group amino, 2-(morpholine-4-yl) ethylamino, 4-hydroxy piperidine ylmethyl, 2-(S, S-dioxo-thiomorpholine-4-yl) ethyl, 3-(S, S-dioxo-thiomorpholine-4-yl) propyl group and N methyl piperazine ylmethyl.
27. the compound of claim 26, wherein R 5Be 4-F or 2-Me, and R 6Be hydrogen.
28. the compound of claim 25, wherein R 3Be positioned at 3, and it is selected from (2,2-dimethyl-1,3-dioxolane-4 (S)-yl) methoxyl group, (1,3-dioxolane-2-ketone-4 (R)-yl) methoxyl group, (2-sulfo--1,3-dioxolane-4-yl) methoxyl group, (2,2-diethyl-1,3-dioxolane-4 (S)-yl) methoxyl group, (2,2-diethyl-1,3-dioxolane-4 (S)-yl) methylamino and (2-methyl-2-ethyl-1,3-dioxolane-4 (S)-yl) methoxyl group.
29. the compound of claim 28, wherein R 5Be 4-F or 2-Me, and R 6Be hydrogen.
30. the compound of claim 16, wherein R 3Be-Y-(alkylidene group)-R 9, wherein Y be singly-bound ,-O-or-NH-, and R 9Be the optional heteroaryl that replaces ,-CONR 12R 13, SO 2R 14,-SO 2NR 15R 16,-NHSO 2R 17Or-NHSO 2NR 18R 19, R wherein 12, R 13, R 14, R 15, R 16, R 17, R 18And R 19Be hydrogen, alkyl or heteroatom containing alkyl independently of one another.
31. the compound of claim 30, wherein Y is a singly-bound, and R 9Be SO 2R 14Or-SO 2NR 15R 16
32. the compound of claim 31, wherein R 3Be methyl sulphonyl ethyl or sulfamyl ethyl.
33. the compound of claim 32, wherein R 5Be 4-F or 2-Me, and R 6Be hydrogen.
34. the compound of claim 1, wherein R 3Be selected from:
(a)-S (O) nR 27, wherein n is 0 to 2 integer, and R 27Be alkyl, heteroatom containing alkyl,
Optional substituted cycloalkyl, the optional heterocyclic radical alkyl that replaces; Or-NR 28R 29, R wherein 28
And R 29Be hydrogen, alkyl or heteroatom containing alkyl independently of one another;
(c) X-(alkylidene group) CH[(CR ' R ") mOR 40] [(CR ' R ") nOR 40],
Wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) p-(wherein p is 0
Integer to 2);
R 40It is acyl group; C (O) OR 41(R wherein 41Be hydrogen, alkyl or cycloalkyl);
C (O) ONR 41R 42(R wherein 41Definition as above and R 42Be hydrogen or alkyl); Or
C (O) NR 41R 42(R wherein 41And R 42Definition as above);
R ' and R " are hydrogen or alkyls independently; And m and n be independently 0 to 3 whole
Number, condition is that m and n are not 0 simultaneously;
(c) X-(alkylidene group)-CH (OH) CH 2NHR 50, wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) n-(wherein n is 0
Integer to 2); With
R 50Be C (O) OR 51And C (O) NR 51R 52(R wherein 51Be hydrogen, alkyl or cycloalkanes
Base, and R 52Be hydrogen or alkyl); With
(d) X-(alkylidene group)-CH (NR 50)-CH 2OH, wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) n-(wherein n is 0
Integer to 2); With
R 50Be C (O) OR 51And C (O) NR 51R 52(R wherein 51Be hydrogen, alkyl or cycloalkyl
And R 52Be hydrogen or alkyl)
35. the compound of claim 34, wherein R 3Be positioned at 3 and be:
X-(alkylidene group) CH[(CR ' R ") mOR 40] [(CR ' R ") nOR 40], wherein:
X is-O-,-NH-,-NR-(wherein R is an alkyl), or-S (O) p-(wherein p is 0
Integer to 2);
R 40It is acyl group; C (O) OR 41(R wherein 41Be hydrogen, alkyl or cycloalkyl);
C (O) ONR 41R 42(R wherein 41Definition as above and R 42Be hydrogen or alkyl); Or
C (O) NR 41R 42(R wherein 41And R 42Definition as above);
R ' and R " are hydrogen or alkyls independently; And
M and n are 0 to 3 integer independently, and condition is that m and n are not 0 simultaneously.
36. the compound of claim 35, wherein R 3Be positioned at 3, and it is selected from (diacetoxy) propoxy-, (two isobutyl acyloxy) propoxy-, (two new pentane acyloxies) propoxy-and (dimethoxy ketonic oxygen base) propoxy-.
37. the compound of claim 36, wherein R 4Be hydrogen, R 5Be 4-F or 2-Me, and R 6Be hydrogen.
38. the compound of claim 37, wherein R 1And R 2Be hydrogen, and A and B are phenyl.
39. a pharmaceutical composition wherein contains the compound and the acceptable vehicle of pharmacy of the claim 1 for the treatment of significant quantity.
40. treat in the Mammals by the method for the medicable disease of administration p38 map kinase inhibitor for one kind, this method comprises the compound of the claim 1 of administering therapeutic significant quantity.
41. the method for claim 40, wherein said disease is an inflammatory diseases.
42. the method for claim 41, wherein said disease are sacroiliitis.
43. a method for preparing formula (I) compound of the compound that is selected from claim 1, wherein this method comprises:
(i) with the 2-ketone group-3-phenyl amino vinyl cyanide of formula 1:
Figure A0081325700111
Hydrazine reaction with formula 2:
Figure A0081325700112
R wherein 3, R 4, R 5And R 6As defined in claim 1, obtain wherein R 1It is the compound of the formula (I) of hydrogen; Or
(ii) with the 2-ketone group-3-phenyl amino vinyl cyanide of formula 3:
Wherein Z is hydroxyl, nitro or halogen and R 4As definition in the claim 1, obtain the compound of formula 4 with the hydrazine reaction of formula 2:
Figure A0081325700114
Subsequently with the R of Z groups converted for expection 3Group obtains wherein R 1It is the compound of the formula (I) of hydrogen;
(iii) randomly modify any one R 1, R 3, R 4, R 5Or R 6Group;
(iv) randomly by acid treatment make top step (i), (ii) or (iii) the compound of the formula (I) of preparation is converted into corresponding acid salt;
(v) randomly by alkaline purification make top step (i), (ii) or (iii) the compound of the formula (I) of preparation is converted into corresponding free alkali;
(step (i)-(mixture of the steric isomer of formula (I) compound of preparation obtains single steric isomer v) above vi) randomly separating.
44. a method for preparing formula (I) compound of the compound that is selected from claim 1, this method comprises the compound with formula 5: Wherein L is the leavings group under the organo-metallic conditions of replacement reaction, with formula
Figure A0081325700122
Organometallic reagent reaction, wherein M is the metal part,
Obtain wherein R 1It is formula (I) compound of hydrogen;
(ii) randomly modify any one R 1, R 3, R 4, R 5Or R 6Group;
(iii) randomly by acid treatment make top step (i) or (ii) in the compound of formula (I) of preparation be converted into corresponding acid salt;
(iv) randomly by alkaline purification make top step (i) or (ii) in the compound of formula (I) of preparation be converted into corresponding free alkali;
(mixture of the steric isomer of formula (I) compound for preparing in the step (i)-(iv) above v) randomly separating obtains single steric isomer.
CN 00813257 1999-09-22 2000-09-14 Pyrazole derivatives Pending CN1376147A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018059533A1 (en) * 2016-09-29 2018-04-05 南京明德新药研发股份有限公司 P38α mapk kinase inhibitor, preparation method thereof and use thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018059533A1 (en) * 2016-09-29 2018-04-05 南京明德新药研发股份有限公司 P38α mapk kinase inhibitor, preparation method thereof and use thereof

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