• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    Phenylquinolinecarboxylic acids and derivatives thereof, such as 2-(2'-fluoro-1,1'-biphenyl-4-yi)-6-fluoro-3-methyl-4-quinolinecarboxylic acid, or a sodium or potassium salt thereof, are useful as tumor inhibiting agents. Related Application This application is a continuation-in-part of my copending application U.S. Serial No. 516,319, filed July 22, 1983.
    公开号:SU1452480A3
    申请号:SU864000869
    申请日:1986-01-06
    公开日:1989-01-15
    发明作者:Поул Хессон Дейвид
    申请人:Е.И.Дюпон Де Немур Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    treated with thionyl or oxalyl chloride in benzene at 25-80 ° C and then with alcohol, where R has the indicated value in tetrahydrofuran in the presence of pyridine, triethylamine or 4-dimethylaminopyridine at 10-66 ° C. New compounds show activity against lymphoid albumen and colon cancer. 5 tab.
    one
    The invention relates to a method for producing new biologically active chemical compounds, namely, a method for producing phenylquinoline carboxylic acids or their esters or their pharmaceutically compatible salt exhibiting antitumor activity.
    The purpose of the invention is to obtain new derivatives of phenylquinoline carboxylic acids that exhibit a new, antitumor effect for compounds of this series.
    Example 1. 2- (4-Biphenyl) -5- -chloro-6-fluoro-3-methyl-4-quinolinecarboxylic acid.
    4.0 g (0.02 mol) of 4-chloro-5-fluorosatin, 1.46 g (0.02 mol) of diethyls and 4.4 g (0.02 mol) of 4-phenylpropano pyrophenone are weighed in 100 ml of ethanol, stirring for 12 hours. The precipitate is filtered, matched with ethanol and dried, yielding 2.1 g of crude adduct with m.p., 202-206 C.
    The latter is dissolved in 75 ml of tetrahydrofuran and 30 ml of concentrated HCl (50% by volume). The resulting solution was heated under reflux for 24 hours, cooled and diluted with water. The tetrahydrofuran is evaporated under reduced pressure. The precipitate is filtered, washed with ether and boiled together with methanol to obtain 0.90 g of the abovementioned acid as a crystalline solid with m.p.
    305-308 ° C.
    EXAMPLE 2. 6-Fluoro-3-methyl-2- (4-nitrophenoxyphenyl) -4-quinolinecarboxylic acid.
    2.0 g (0.0104 mol) 5-fluorizatin 0.77 g (0.0105 mol) diethylamine and 2.82 g (0.0104 mol) 4- (4-nitrophenoxy) propiophenol are weighed in 100 m of ethanol and 12 h stirred at 25 The precipitate is filtered, washed with toluene
    and air dried to obtain 3.0 g of a crude product.
    The crude product obtained from the two runs described above (5.0 g, 0.0108 mol) was combined in 180 ml of tetrahydrofuran and 40 ml of concentrated HCl. The resulting solution is treated for 12 hours under reflux, cooled, the solvent is evaporated under reduced pressure. The solid residue is washed with ethyl ether and dried, yielding 4.37 g of the above-mentioned acid as a white solid with m.p. 335-3 37 S.
     Using the methods described above, the compounds listed in Tables 1 and 2 are prepared (Examples 1-8 and 9-69),
    EXAMPLE 70 Sodium-2- (4-biphenylyl) -5-chloro-6-fluoro-3-methylquinoline-4-carboxylate.
    2- (4-Biphenyl) -5-chloro-6-fluoro-3-methyl-4-quinoline-carboxylic acid (7.85 g, 0.02 mol) is weighed into 150 ml of water and treated with 1N. NaOH (19.9 ml, 0.0199 mol) with the addition of 150 ml of ethanol. The mixture is stirred until clear and filtered to remove insoluble products. Ethanol and water are evaporated under reduced pressure to give 8.1 g of a white solid sodium salt with mp 7360 C,
    The compound of Example 70, prepared using the method described above, as well as other compounds that can be obtained according to this method (Examples 71-147), are listed in Table 3.
    Example 148. 6-Fluoro-2- (2- -fluoro-1,1-biphenyl-4-yl) -3-methyl- (2-dimethylamino) ethyl ester-4-quinoline carboxylic acid.
    The compound from example 95 (20.00 g, 0.0504 mol) was weighed into a solution of 1000 ml of anhydrous benzene, 1000 ml of anhydrous THF and 20.0 ml (excess)
     i1 D S
    oxalyl chlord. The suspension is heated under reflux for 9 hours in a nitrogen atmosphere. The reaction mixture is cooled, the precipitate is filtered and the resulting solution is evaporated to dryness under reduced pressure. The resulting solid was dissolved in 1000 ml of anhydrous THF and 20.0 ml (excess) of N, H-dimethylethanolamine containing 0.01 g of dimethylaminopyridine. The resulting solution was heated under reflux for 12 hours in nitrogenous medium. The reaction mixture is cooled, the precipitate is dried to dryness under reduced pressure. The solid obtained is chromatographed (silica gel: CH-C1-MeOH gradient 0-5%); yield 17.88 g of the title compound with a mp. 146-149 ° C.
    PRI me R 149. Hydrochloride (salt) 6-fluoro-2- (2-fluoro-1,1-biphenyl-4-yl) -3-methyl- (2-dimethylamino) ethyl-ester-4-quinolinecarboxylic acid.
    The compound from Example 148 (18.66 g, 0.0417 mol) was dissolved in 50 ml of anhydrous THF and 500 ml of anhydrous diethyl ether. The solution is gradually added to 1000 ml of anhydrous diethyl ether saturated with hydrogen chloride. The resulting suspension is stirred for 30 minutes at 25 ° C. The reaction mixture is then filtered, washed with ether and dried in vacuo overnight, and a yellow solid is obtained, 20.62 g of the title compound with mp. 238 With decomposition.
    The compounds of examples 148 and 149 and other compounds obtained by the above mentioned methods are listed in Table 4 o.
    The results obtained during various biological tests and described below show that the proposed compounds have the property of inhibiting not only the development of transplanted tumors in mice, but also the development of tumors transplanted to human beings.
    The efficacy of the proposed compounds on transplanted tumors in mice was evaluated in a test system that is being conducted and is now at the National Cancer Research Institute for the purpose of studying and evaluating the antitumor effect. Most drugs
    .I () 4
    The Klienchesk and the effect of the actions are effective in the ode of these studies, with a great twist to the predictability of the clinical action.
    Lymphoid leukemia. In this experiment, we worked with us (,). All animals weighed at least 18 g, and by the beginning of the experiment within 4 g. The test group consisted of 6 mice. The tumor was transplanted with each mouse by intraperitoneal injection of 0.1 ml of diluted Ascites fluid containing 10 cells transferred with leukemia L 1210. Test compounds were weighed in hydroxypropyl cellulose or saline with Tween 80 surfactant or diluted in physiological saline and administered by intraperitoneal injection in different doses once a day, for nine days at a time, starting on day No. 1 relative to
     for tumor inoculation (day number 0). Control mice were injected with saline or hydroxypropylcellulose vehicle. Children are weighed, survivors are calculated regularly for 30 days. Average
    the survival rate and the ratio of the average survival time of the treated (0) and control (K) animals are calculated. The average age of 35 untreated tumor-infected animals ranges from 8 to 9 days. The efficacy of the drug is determined on the basis of the survival time. The results are expressed in 40 percent of the survival time of the control animals (average survival time: O / K 100%). The criterion of effectiveness is determined by: O / K MOO 7-125%.
    45
    The results of the testing of the proposed compounds are given in table.5.
    The data show that the proposed compounds have an effect against protein L 1210 y.
    Test for colon tumors in humans in vitro.
    The proposed compounds are also tested for their ability to inhibit the development of cancer cells in the human colon in vitro. Compounds inhibiting the development of these cells also inhibit L 1210 leukemia in mice.
    514
    Human colon cancer cells, designated HCT-15, are derived from a sample of human colon adenocarcinoma removed during surgery. The cells are grown in the medium of 1640 of the Roswell Park Medical Institute (RPMl), to which 10% of thermally deactivated calf fetal serum, penicillin (100 units / ml), streptomycin (100 µg / ml), gentamycin (20 µg / ml), fungison (25 µg / ml), 0.075% sodium bicarbonate, Yumkmol 4- (2-oxistil) -1-piperazine ethanesulfonic acid and 10 µm N-tris (oxy methyl) methylglycine. In order to determine the strength of the tested compounds while inhibiting the development of these cells, the following experiment was carried out. On day No. 0, reproducible 35 millimeter tissue culture samples are inoculated with 1.5x10 HCT-15 cells in 2 ml of RPMI 1640 medium described above. On day 1, cells are harvested from the plates using trypsin treatment (0.25%) to count the amount of hemoschitometro in order to determine the number of cells on the plate at the time of addition of the compounds. The proposed compounds are added in different concentrations to other cultures. On the 4th day, treated and control cultures were harvested by trypsin treatment and the number of cells was determined. The number of duplicate control cells is determined by the number of cells on the 1st and 4th days. The LDjp value of the compound required to inhibit 50% of the number of duplicates is calculated from the dose-response curve, with which the cell number is applied to logarithmic paper of type 1 ° -1 relative to the compound concentrations in µg / ml and reference drugs used in clinical practice are summarized in Table 5.
    The data indicate that the compounds have an effect in the sense of inhibiting the growth of cancer cells in the human colon.
    Formulas
    the invention
    The method of obtaining phenylquinoline carboxylic acids of general formula I
    where R means a group
    at: - OOR
    9
    15

    -5 (0) shYa8 ILM
    n,
     H.
    where R, - СНзСН2 (СНз) СН, kil, cyclohexyl, group
    .W or -SI
    provided.
    what if
    Rr 5 (0) „H8
    then ya can additionally mean
    p C j-C-alkyl;
    R is H, Ct-Cz-alkoxy or C, alkyl;
    E3 -,, „, where R,„ - (CH2) i.3-N (R „) 2, where K 1, - C, -Cj-alkyl;
     and R-, independently of one another, means H, F, C1, Br, J, CH, CFj, SCHj or, moreover, at least two of the radicals Ra, Rj, R (,
    And R 7 means H,
    Rg means a group
    .W z
    OR
    -snVj I 1g
    W
    W, Y and Z - independently of one another denote H, fluorine, chlorine, bromine, Ci-Cj-alkyl, NO, C, -C-alkoxy, or OH;
    m O or 1,
    provided that if R j- is phenyl or hydroxyphenyl, aR4, Rg and R, is H, then R cannot mean bromine,
    R, RC and R cannot all mean H if Rg is cyclohexyl, and R means H, Kg must mean chlorine or fluorine, but R and R7 cannot both mean chlorine if Rj is -CO CH2CH5H (CH3) 2. K5-CH: HC or Rfc is C1, then Rjj cannot mean cyclohexyl.
    or their esters, or their pharmaceutically compatible salt, characterized in that an appropriately substituted isatin of general formula II
    where X and Xj are as defined above for Ryj Rf or R, are reacted with a substituted ketone of general formula III O
    R. - C
    R,
    1 de R, and R have the indicated values 20 in a solvent, such as ethanol, with a base, such as distilamine or triethylamine, at a temperature of 25 for 2-48 hours, followed by dissolving the obtained intermediate compound of formula IV in an appropriate solvent , such as tetrahydrofuran, containing 25–50% by volume of mineral acid, such as HC1, and heating — from 50 CfW to refluxing the solvent mixture for 2–48 h, and isolating the desired product in free form or in the salt of the carboxylic acid, while the quinoline Arbonic acid 35 of formula I is dissolved in a proton solvent, such as ethanol, then treated with metal oxide or metal hydroxide, such as potassium or sodium oxide or with an amine, 40 as 1-aminobutanol, or lysine at a temperature from 0 ° C to boiling point of the solvent and, if appropriate, obtaining the salt of the amine group by dissolving the amine in a solvent such as diethyl. ester by adding a mineral acid, such as HC1, or isolating the desired product as an ester, and the quinoline-jarboxylic acid salt of formula (I) is reacted with thionyl chloride or oxalyl chloride in an inert solvent, such as benzod, with temperature from 25 ° C to the boiling point of the solvent, the resulting 55 acid halide is reacted with an alcohol R, gOH in a solvent such as tetrahydro
    a furan, at a temperature of from about 1 ° C to about 1 ° C of a solvent in the presence of a base such as pyridine, triethylamine or 4-dimethylaminopyridine,
    Priority featured:
    07.22.83 with RI - group

     OR JTll
    S RS
    where Rg - C (-C d-alkyl, cyclohexyl,
    .W
    Group
    provided that if (0) {j, R8
    then RO may additionally mean Cj-C-alkyl;
    R is H or C, -Se-alkyl;
    R 3 - CO, jH;
    R, R 5, R and R 7 independently of one another denote H, F,, Br, J, CHj, CF-J, SCH 3, with at least two of the radicals R, R5, R and R denote H;
    Ro - group
    / - A7
    W.Y and Z - independently of one another denote H, F, C1, Br, OH, C, -Cj-alkyl;
    m O or 1, provided that if R3 -,
    RJ is phenyl or phenoxy, phenyl; R, R and R7 are H, then R5 cannot mean bromine,, Rfc cannot all mean H, if Rj, cyclohexyl, R — H, R 5 must mean chlorine or fluorine, but RJ- and R 7 chlorine.
    30-04.84 with Ry - group
    SCO) mR8 OR Jjl
    W
    RS
    where, R j - CH jCH (CH j) CH or group
    -sn
    -.w
    2L-)
    W
    -CH // 3
    provided that R ;, - -S (0) Rg,
    then Rj may additionally mean
    Gj-C4-alkyl;
    RIJ C-C3-alkoxy; IQ where W,.; And Z are independently of each other RJ - (,, where RI - (CH) .2, .s - ga means NO,
    - N (R,), - C j-alkoxy or OH;
    where R, C1-Cr-alkyl; ha O or 1.
    Table 1
    Phenylquinoline carboxylic acids obtained according to
    examples 1-8
    A - C, H, C, H,
    4- (4-N05C H O) CtIU
    -CfcHjC H,
    H
    4- () 4- (.,) 4-С, Н5С, Н „
    CHZ CHZ CHj CHZ CHj CHj
    sn,
    SNS
     independently of flpyrti means H or, and at least two of the radicals Rj ,, RJ, R and R mean H, R is a group
    W
    -CH // 3
    RZ, SOGN
    FK H305-308 (decomp.)
    FНН335-337
    HHH295-296 (decomp.)
    HC1H301-305 (decomp.)
    CHNNN295-298 (decomp.)
    FНН300-305
    FНН293-296
    HFN307-31 (decomp.)
    I
    I 2
    1A52480
    Table 2
    Phenylquinoline carboxylic acids, obtained according to
    examples 9-69
    I 2
    Continuation of table 2
    Note i is cyclohexyl.
    Phenylquinolinecarboxylic acid derivatives prepared according to Examples 71-H7
    4-c-C H,
    -CfcHjC H
    4-c-C
    4-с-С (, Н ,,
    CH, CHj СНэ Н
    Continued ia6ji, 2
    Table 3
    R C02Y
    HFHNNa 350 (decomp.)
    HFHNNa7360
    N. S1HNNa 350
    HC1NNNa7350
    Compounds prepared in Examples 148-15 4
    "C-OR, o
    R,
    VCH3
    VS
    4 - () C, H4
    four-()
    4- () CfcH4
    four-()
    four-()
    four-(),
    CH jCH NCCHp, H
    CH2CH, jN (CH3) -HClH
    (CH2) eK (CH3) .H
    (СН5,) ЗН (СНз) .. НС1H
    CH CH NCCHjCHj) ,, H
    (j) HClH
    ,) HClH
    Tables-a5
    Antitumor effect of phenylquinocarbonic acids
    VCH3
    146-149
    238 (decomp.)
    88-92
    118-123 (decomp.)
    63-68
    90-95 (decomp.)
    80-84

    70.1 0.50
    17
    (100) 178 410-3
    Not tested 0.01
    Not tested 0.66
    27
    3
    权利要求:
    Claims (1)
    [1]
    Claim
    A method for producing phenylquinoline carboxylic acids of the general formula I then R may additionally mean
    C jC 4 -alkyl;
    30 R 2 - H, C ^ -C j-alkoxy or C, -C 3 ~ alkyl;
    R 3 - CO 2 H, CO 2 R ί 0 , where R I0 ~ ~ (CH 2 ) 2 . 3- N (R n ) 2 , where R b is C, -C 2 alkyl;
    35 R 4 , R 5 , R i and R 7 independently from each other mean H, F, Cl, Br, J, CH E , CF 3 , SCH 3 or CH 2 CH E , and at least two of the radicals Rd, R R fc and R; mean H
    Rg means a group
    W, Y and Z - independently from each other, mean H, fluorine, chlorine, bromine, St-Sdalkyl, N0, C, -C e ~ alkoxy, or OH;
    w = 0 or 1, provided that if R 3 is CO., H; phenyl or hydroxyphenyl, a R 4 , R g and R 7 H, then R 5 cannot mean bromine,
    R ( , RjH R έ cannot all mean H if Rg is cyclohexyl, and Rg is H, R 5 should mean chlorine or fluorine, but R s and R 7 cannot both mean chlorine if Rj is -CO 2 CH 2 CH 2 N (CH 3 ) 2 ,, R 3 - CH, CH 3 or R fc - Cl, then Rg cannot mean cyclohexyl, or their esters, as a compatible salt with the image of mule II or their pharmaceuticals, characterized in that correspondingly substituted isatin of general form Xi χ 2 where X ( and X £ have
    R 4 , R 5 , R t or R 7 are reacted with a substituted ketone as defined above for the meaning
    R, General formula III O
    II
    C x / R j, 7 have the indicated values of 20 furan, at a temperature from 10 ^ C to the boiling point of the solvent in the presence of a base, ridine, triethylamine pyridine.
    or such as pi4-dimethylaminor and o r and a m:
    07/22/83 at R η
    - ^^ - SCO ^ Rg where π ρ and s
    0R 9 1 where R ( and R in a solvent such as ethanol, with a base such as diethylamine or triethylamine, at a temperature of 25-50 C for 2-48 hours, followed by dissolution of the resulting intermediate compound of formula IV in an appropriate solvent, such as tetrahydrofuran, with a content of 25 to 50% by volume of a mineral acid such as HC1 and heating from 50 ° C30 to the reflux temperature of the solvent mixture for 2 to 48 hours, and the desired product is isolated in free form or in the form of a carboxylic acid salt while quinolinecarboxylic acid of the formula I dissolved in a protic solvent, such as ethanol, then treated with metal oxide or metal hydroxide, such as oxide or hydroxide of potassium or sodium, or an amine, like 1-aminobutanol, or lysine at a temperature of from 0 ° C to the boiling point of the solvent, and in the corresponding case, obtaining a salt of an amine group by dissolving the amine in a solvent such as diethyl ether, adding a mineral acid such as HCl, or isolating the desired product in the form of an ether, the quinoline carboxylic acid salt of formula (I) is reacted with thionyl chloride or oxalyl chloride in an inert solvent, such as benzene, at a temperature of 25 ° C to the boiling point of the solvent, the resulting acid halide is reacted with R to OH alcohol in a solvent such as tetrahydropri or
    S rg
    Rg “C fe —C (0- alkyl, cyclohexyl, group, provided that if Rj may additionally mean C 3 -C 4 -alkyl;
    R 7 is H or C ^ C ^ alkyl;
    R s - SOUN;
    R 4 , R 5 , R 6 and R 7 independently from each other mean H, F
    CF 3 of
    SCH h, with radicals R 4 , R 5 , H;
    R 5 - group
    Cl, W, less
    R (, and r 7
    J, CH 3 , at least two mean-
    WY and Z — independently each other, mean H, F, C1, Br, OH, from others — crc 3 ha alkyl;
    m = 0 or 1, provided that if Rj - СО ^ Н,
    Rj is phenyl or phenoxy, phenyl;
    R 4 , R 6 and R 7 are H, then R 5 cannot mean bromine, R 4 , R i, R t cannot all mean H, if Rg is cyclohexyl, R 2 is H, R j- must mean chlorine or fluorine, but Rj and R 7 cannot mean chlorine.
    30 ° 04.84 at Ry - group
    -0 ^ 8 'O- ° R s'
    - <2> - s (0) m R 8 where R - - CH 3 CH 7 (CH 3 ) CH or a group
    10
    5 provided that R 1 = - ~ S (O) w Rg, then R e may additionally mean Gj-C 4 -anKHn;
    R, j is C f-C 3 ~ alkoxy;
    Rj - CO ^ R io , where R, - (СН ) 2 . E - N (R „) 2 , where R 4 = C 4 -C g -alkyl;
    R 4 ” R i” Ri 5 R independently from each other, mean H or CH 2 CH E , and at least two of the radicals R 4 , R ,, R t and R 7 mean H, R 9 - group
    -SI where W, Y.:HZ independently mean N0 2 ,
    C, -C j-alkoxy or OH;
    w = 0 or I.
    Table I
    Phenylquinoline carboxylic acids prepared according to
    examples 1-8 Il CO 2 N bi R1 r 7
    Example R- _. ................R R 5R 6R 7 Mp. ° C ....1 4-C 6 H iCi H 4CH 3Cl F H H 305-308 (decomp.) 2 4- (4-NO C t H 4 O) C fc H 4CH 3H F H H 335-337 3 4-C 6 H 5 C fe H 4CH Cl H H H 295-296 (decomp.) 4 4-C b N / N 4CH 3Cl H Cl H 301-305 (decomp.) 5 4-C 6 H 5 C 6 H 4CH 5Cl CH 3H H 295-298 (decomp.) 6 4- (2-FC t H 4 ) C fc H 4CH j Cl F H H 300-305 7 4- (4 - CH 3 C t H 4 ) C 6 H 4CH 4Cl F H H 293-296 8 4-C t H 5 C 6 H, (CH H H F H 307-311 (decomp.)
    Table
    Phenylquinoline carboxylic acids obtained according to examples 9-69
    Example Rf 4R 5 1 1 1 1 1 A 1 1 ** 1 i Pi I 1 r 1eleven! oT 'i oh ieleven1___________________________1 Mp. ° C 1 2 3 4 5 6 7 9 4-s-C 6 H “C ^ 111i δ11 F Ή H 316-323 10 4-C 6 H 5 C 6 H 4sun 3F H H 303-306 (decomp.) eleven 4-s-C ^ H „C 6 H 4CH 3Cl H H 320-322 (decomp.) 12 4-cC t H ,, C 6 H 4H Cl H H 264-265 thirteen 4-s-C ά H ,, C 6 H 4H F H H 280-284 14 4-s-C 6 N „C 6 N 4CH 3CH j H H 308-312 (decomp.) fifteen 4 — p — C, 0 N C 6 H 4sn eF H H 256-261 16 4-p ~ C 6 H ,, C ^ H 4CH 5 F H H 278-285 17 4-sn 3 sn 2 (sn 3 ) sns ^ n 4CH 3F H H 290-297 18 4-s-C ^ H ,, C 6 H 4CH 3 CH, F H H 295-297 19 4-C 6 H 5 OC t H 4CH, ' F H H 318-320 (decomp.) 20 4- (4-BrC t H 4 ) C fc H 4ch 3F H H 318-323 (decomp.) 21 4- (CH 3 ) 2 CHSC 6 H4 ch 3F. H H 280-283 22 4-C fe H 5 C 6 H 4CH ch 3H H 327-329 (decomp.) 23 4-cC t H ,, C 6 H 4CH ,, CH-2 CH J H H 290 (decomp.) 24 4-0 6 Η 5 0Η 4 00 6 Η 4CH 3F H H 297-302 25 4-CH 3 CH.2 (CH3) CHC € H 4CH, CH 2 FH H 286-291 26 4-C 4 H 5 C £ H 4sn, sn 2 FH H 274-279 (decomp.) 27 4-C 6 HjC 6 H 4ch Cl H H 302-305 28 4-C 6 N, OS, N 4sun 3Cl H H 296-301 29th 4-CHSC.H.6 5 CH Cl H H 313-316
    thirteen
    Continuation of the table, 2
    1 '2 3 4 5 6 7 thirty 4-C 6 H 5 CH 2 C £ H 4CH 3Cl H H 265-275 31 4- (4-FC t H 4 ) C 6 H 4CH 3Cl H H 319-323 32 4- (4-CH 3 OC 6 H 4 ) C t H 4ch 3Cl H H 310-314 33 4-C 6 H. 5 CH 7 SC 6 H 4CH 3F H H 281-287 34 4- (4-BrC £ H 4 ) C fi H 4Ch j Cl H H 319-324 (decomp.) 35 4- (2-FC e H 4 ) C fe H 4CH 3F H H 315-317 36 4- (4-ClC 6 H40) C 6 H 4CH 3F H H 299-303 37 4- (4-CH 3 C 6 H 4 ) C 6 H 4CH 3F H H 317-319 38 4- (4-FC b H 4 ) C 6 H 4CH 3F H H 310-314 39 4-C 6 H 5 C £ H 4H F H H 272-278 40 4 - C t H 5 S (O) C 6 H4 Ch j F H H 239-247 41 4- (4-FC fe H 4 O) C £ H 4CH 3F H H ' 291-297 42 4- (3,4-C1 z C 6 H 5 ) C 6 H 4CH 3F H H 315-319 43 4-C £ H s C c H 4CH 3 0 F H H 219-223 44 4- (3-01,4-CH 3 s 6 n e ) s 6 n 4CH 3F H H 316-324 45 4- (3,4- (CH 3 ) 2 C 6 H 3 ) C 6 H 4 CH 3 F H H 321-324 46 4- (4- (CH 3 CH 2 ) C 6 H + ) C £ H 4 CH . 3F H H 309-315 47 4-C £ H { .-2-thienyl CH 3F H H 345-350 ' 48 4-cC t H 41 C 6 H 4CH Br H H 325-330 49 4-CC 6 H H C t H 4CH 3Br H Br 275-280 fifty 4-c ~ C 6 H n C 6 H 4CH 3CF 3 H H 32’0-325 51 4-C 6 H 5 C f H 4CH 3 H Cl H 315-320 52 4- (C £ H 5 0) C 6 H + . CH 3 H Cl H 315-318 53 4-C, H 5 C £ H 4CH 3CH3 CH ,, H H 295-300 54 4-C s H 5 C 4 H 4CH 3Br H H 313-314 55 4- (C 6 H 5 O) C & H 4CH 3Br H H 273-278 56 4-C t H 5 C t H 4Chj H CH H 324-328
    fifteen
    I 6
    Continuation of the table, 2
    Ί ΞΞΣΖΞΞ ’ 3 4 • ”.......5 -6 7 57 4 - </ Η 5 Ο έ Η 4sn CF N n 320-323 58 4 _ (C £ H 5 O) C £ H 4sun 3cf 4N n 294-298 59 4-C fc H 5 C fc H 4sun 3he, C1 n 333-336 60 4- (C t H ) C t H, sn esun iC1 n 314-318 61 4-C (.H 5 C 6 H 4CH 3Vg n Vg 270-273 62 4-C t H 5 C fe H 4sun 3F C1 n 327-332 63 (4-¾ Н 5 , 2-СН е ) С £ Н эCH e F n n 316-320 64 4-C £ H 5 C £ H 4sun aI n n 325-327 65 4- (3-FC t H 4 ) C £ H 4sn eF n n 305-310 66 4- (2,4-¾¾¾) ¾¾ sun 3F n n 325-328 67 4- (4-FC £ H 4 O) C £ H 4n F n n 310-315 68 4-C £ H s C t H 4sun 3ch 3 s n n 316-318 (decomp.) 69 4- (NOS 6 H 4 ) C 6 H 4sn eF n n > 360
    Note c-C 6 H p - cyclohexyl.
    Table 3
    Derivatives of phenylquinoline carboxylic acids obtained according to examples 71-147
    r 4 coy about 5 W ° 1 Vg br / fli -Dh
    Example *1 "G R +111- 1eleveni. 1r 7Y T *. Pl., ° C 1 2 3 4 5 6 7 8 9 71 4-c _ C f H CH H F H H Na 350 (decomp.) 72 4-C t H 5 C 6 H 4Ch j H F H H Na 7 360 73 4-s-C.H „C £ H 4sn eH> Cl H H Na 7350 74 4-s-C £ H „C t H 4'H H Cl H H Na 7350
    17 1 452480 ’18
    Continuation of table.Z
    1 · 2π 4 tpe: HER i: z: 75 4-s-C.H „C 4 H 4Η n F n n Na > 350 76 4-s-C 6 N o S b N 4sun 3n sn en n Na 342-351 77 4-nC fe Η g , C 4 H 4Chj n 'F n n Na 332-335 78 4-CH 3 CH 2 (CH 3 ) CHS 4 H 4sn en F n n Na 340-345 79 4- s C (N p s 6 n 4sn 3 sn n F n n Na > 350 80 4-C, N, OS 4 N 4sn en F n n Na > 350 81 4- (4-HCV 4 N.,) C 4 H 4sn en F n n Na > 350 82 4- (CH 3 ) ^ CH SC 6 H 4 with " en F n n Na 339-343 83 4-C 4 H, C y N 4sun 4 - n sn n n Na > 350 84 4-s-C 4 H + , <C 4 H 4CH 3 CH 2n CH 3n n Na > 350 85 4-C 4 H 5 CH 2 OS 4 H 4sun 3n F n n Na > 350 86 4-sn C sn 2 (sn r SNS 4 N 4CH 3 CH 2n F n n Na 302-306 87 4-C t H : j C 4 H 4sun 3 sun 2n • F n n Na > 350 88 4'C 6 H f C t H 4CH 3n C1 n n Na > 350 89 4-C 6 H 5 OS 6 H 4sun 4n C1 n n Na 170-175 90 4-C 4 NZhS 4 N 4CH n C1 n n Na 319-324 91 4-C t H s CHjC fc H 4sun 3n C1 n n Na 305-315 92 4- (4-FC 4 H 4 ) C <H 4sun 3n C1 n n Na > 350 93 4- (4 ~ CH, OS 4 H 4 ) C 4 H 4sun 3n C1 n n Na > 3'60 94 4- (4-HCS 6 H 4 ) C 6 H 4sun 3n C1 n n Na > 360 95 4- (2-FC e Hpcpi 4CH n F n n Na > 360 96 4- (4-ClC t H 4 0) C t H 4CH n F n n Na > 350 97 4- (4-CH 5 C 4 H 4 ) C 4 H 4sn n F n n Na > 350 98 4- (4-FC 4 H 4 ) C 4 H 4sn n F n n Na > 360 99 4-C t HsC 6 H 4n n F n n Na > 360 100 4-C t H 5 S (O) C 6 H 4sun 3n F n n Na 251-260 101 4- (3.4-01 ^ 4 N,) C 4 H 4Chj n F n n Na 338-351
    I
    I 4 5 2480
    II birth table 3
    1 2 3 4 5 6 7 8 9 102 4-0 ^., 0 ^ 4sn er about n F N n Na 345-349 103 4- (3-01,4-CH £ e C H 3) W 4 H sun 3n F N n Na 360 104 4- (3,4- (СН 3 ) 2 С 6 Н ^) О 6 Н4 sn en F n n Na 7350 105 4- (4- (СН 3 СН ) С 4 Н 4 ) 0 έ Η 4SNE n F n n Na 360 106 4-C ^ H 3 -2-thienylCH 3n F n n Na > -360 107 4-s-C 6 N „C N 4 CH en Vg n n Na 360 108 4-s-C ( H 7 , C, H 4 sun 3n Vg n Vg Na 298-300(decomp.) 109 4-C 6 HjC 6 H4sun 3n n C1 n Na > 360 110 4- th th. 5 C 6 H 4 sn en sun 3 sun 7n and Na > 360 111 4-0 ^ 0 ^ 4CH 3n Tue n n Na > 360 .112 4- (0 ^ / 3) 0 ^ 4sn en Tue n n Na 228 Ί 13 4-C 4 N C 6 H 4 sun 3n n CH 3n Na 7350 114 4-C t H 5 C 6 H 4 sun 3n CF 3n n Na > 360 115 4- (0 ς Η 5 Ο) 0 t H4sn en CF 3n n Na 338-342 116 4-C t H s C 6 H 4 sn en sun 3C1 n Na > 360 117 4- (C t H a O} C 6 H 4 sn en CH e01 n Na 318-320 118 4-C4H 5 C 6 H 4 sun 3n Vg n Vg Na 340-345 1 19 4-0 έ Η 5 0 έ Η 4 sun 3n F C1 n Na 7 360 120 4-C f H 5 , 2-CH 3 C t H 3 OH 3 n F n n Na 7360 121 4-C b N 5 C 4 H 4 sun 3n CH 3 S n n Na > 350 122 4-C ( H 5 C4H 4 sun 301 n n n Na > 360 123 4-C 6 H 5 C 6 H 4 he 3C1 n C1 n Na > 350 124 4 — C Λ H 4sun 3ci sun 5n n Na > 340 125 4- (2-FC t H 4 ) C D H 4 sun 3C1 F n n Na 330-335, - (decomp.). 126 4- (4-CH s C b N. 4 ) C 4 H4sun 3C1 F n n Na 7 345 127 4-cC t H „C t H 4 sun 3n F n n TO 350-360(decomp.) 128 4-0 ^ 0 ^ 4sun 3n F n n TO > 350
    1 452480
    Continuation of table.Z
    —--.g - -R- ΣΣΕΞΞΞ ’ 129sun 3n 01 n n to / 350 130 4- (C i H y 0) C 4 H 4sun 3n 01 N n to 164-171 131Ch j n 01 n n to 310-325 132 4- (4-8 ^ 0 ^^) 0 ^ 4 sun 3n F n n to 370 133 4- (4-ВГС € Н 4 ) С 6 Н 4sn en 01 n n to ^ 360 134 4- (2-FC 6 H 4 ) C t H 4CH n F n n to 339-346 135 4- (4-EU 6 H 4 ) C 4 H 4sun 3n F n n to 270-275 136 4-C 6 H ^ H 4sn en F n n Lysine 222-231 137 4-C 6 N, C 6 N 4CH n F n n 1-amino-2-butanol ** 128-134 138 4-nC 6 H (i C t H 4CH 5n F n n Lysine 205-212 139 4-0-0 ^ ,, C 4 H 4CH en F n n Lysine 226-231 140 4-C 6 H 5 O 6 H 4n n F n n TO 326-329 141 4- (4-BrC ^ H 4 ) 0 6 H 4sun 5n F n n Lysine 253-258 142 4- (4-NO 2 C 6 H 4 O) C fc H 4sun 3n F n n Na 7360 143 4-Ο ς Η 5 Ο 6 Η 4sun 3n I n n Na 7360 144 4-C t H 5 C t H 4sun 3n N F n Na 360 145 4- (2-FC fe H 4 ) C t H 4sn eC1 F n n Na 330-335 (decomp.) 146 4- (3-FC fc H 4 ) C fc H 4sun 3n N n n Na 7360 147 4- (4-NOS ^ H 4 ) C e H 4sun 3n F n n Na > 360
    * Lysine - Η 3 Ν0Η ^ CH / IH ^ CH ^ CHCO ^ H
    NH g
    1-amino-2-butanol - HjN HHCCH1CCH 3 /
    HE
    23 1452480 24
    Table 4: Compounds Prepared in Examples 148-154
    Example R R <,R 5T.plo, ° C 148 4- (2-FC t H 4 ) C 6 H 4CHjCH 2 N (CH 3 ) 2H F 146-149 149 4- (2-FC 6 H 4 ) C t H 4CH 2 CH 1 N (CH 3 ) 1 - HC1 H F 238 (decomp.) 150 4- (2-FC fe H 4 ) C fe H 4(CH 2 ) 3 N (CH 3 ) 2H F 88-92 151 4- (2-FC fe H 4 ) C ^ H 4(CH 2 ) 3 N (CH 3 ) 2 HC1 H F 118-123 (decomp.) 152 4- (2-FC t H 4 ) C £ H 4'CH 2 CH g s (CH 2 CH e ) iH F 63-68 153 4- (2-FC 4 H 4 ) C ^ H 4CH ^ CH ^ NiCH ^ CH 3 ), HC1 H F 90-95 (decomp.) 154 4-C 6 H 5 C 6 H 4ch 2 ch 2 n (ch 3 ) 2 HC1 H F 80-84
    Tables 5 a
    Antitumor effect of phenylquinoline carboxylic acids
    - Example compound L 1210 bleeding (dosage in In vitroHCT-15 ID so, μ g / ml mg / kg) 111About 1H 111 1 Ί 5 3 (25) 128 <0.50 1 (25) 191 <0.50 4 Not tested 71.00 5 Not tested 71.00 6 Not tested <0.1 7 -<1.0 and 70.1 2 (175) 153 <5.0 and> 0.50 8 (100) 146 <0.50 148 (fifty) 179 <0.01
    '25
    I 4 5248 ()
    Continuation of the table, 5
    1 7 3 149 (100) 178 4ίθ ~ 3 Adriamidine Not tested 0.01 Cisplatin Not tested 0, 66 5-fluorouracil0.27
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    同族专利:
    公开号 | 公开日
    NO842969L|1985-01-23|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BE502610A|1950-04-18|
    US2888346A|1955-08-22|1959-05-26|Gen Aniline & Film Corp|Ultra-violet absorbing compounds|US4889862A|1986-08-28|1989-12-26|E. I. Du Pont De Nemours And Company|Freeze-dried pharmaceutical compositions of phenylquinoline carboxylic acids|
    AU611255B2|1987-12-28|1991-06-06|Dowelanco|Phenoxyphenoxypropionates, intermediates thereof and methods of preparation|
    US4861783A|1988-04-26|1989-08-29|E. I. Du Pont De Nemours And Company|4-quinoline carboxylic acid derivatives useful for treating skin and muco-epithelial diseases|
    US4968702A|1989-01-17|1990-11-06|American Cyanamid Company|Substituted quinolinecarboxylic acids|
    US4918077A|1989-01-25|1990-04-17|E. I. Du Pont De Nemours & Co., Inc.|3-phenyl-5,6-dihydrobenzacridine-7-carboxylic acids and related compounds as cancer chemotherapeutic agents|
    DE3905339A1|1989-02-22|1990-09-06|Basf Ag|CHINOLINE-4-CARBONATEURED DERIVATIVES AND THEIR USE|
    US5393891A|1993-06-08|1995-02-28|The Du Pont Merck Pharmaceutical Company|Immunoassay reagents and methods for detecting brequinar and analogs|
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    AU2003099A|1997-12-19|1999-07-12|Eli Lilly And Company|Method for treating diabetes|
    JPWO2004002484A1|2002-06-26|2005-10-27|協和醗酵工業株式会社|Phosphodiesterase inhibitor|
    US8232310B2|2006-12-29|2012-07-31|Georgetown University|Targeting of EWS-FLI1 as anti-tumor therapy|
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    US9604927B2|2014-10-09|2017-03-28|Oncternal Therapeutics, Inc.|Indolinone compounds and uses thereof|
    WO2017172368A1|2016-03-31|2017-10-05|Oncternal Therapeutics, Inc.|Indoline analogs and uses thereof|
    KR102282794B1|2016-07-29|2021-07-27|온크터널 테라퓨틱스, 인코포레이티드.|Uses of Indolinone Compounds|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US51631983A| true| 1983-07-22|1983-07-22|
    US60510484A| true| 1984-04-30|1984-04-30|
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