4-(7'-halo-2-quino (xa-) linyloxy)phenoxy propionic acid derivatives as antineoplastic agents

UKRAINE

(19) and A (11) 79293 (13) C2

(51) IPC (2006)

007 U 215/22 (2007.01) A61K 31 / 47A61K 31 / 498A61R 35 / 00A61R 35/02 (2007.01) A61R 43/00

007 ı 215/227 (2007.01) 007 ı 241/44 (2007.01)

MINISTRY OF EDUCATION SCIENCE OF UKRAINE

STATE DEPARTMENT OF INTELLECTUAL PROPERTY

DESCRIPTION

TO THE INVENTORY PATENT

(54) DETERMINATION OF 4- (7-HALO-2-CHINO (CSA-) LINYOLOXY) PHENOXYPROPYLIC ACID AS ANTIPRY-LINES

(21) а200500921

(22) 03.07.2003

(24) Jun 11, 2007

(86) PCT / and32003 / 021062, 03.07.2003

(31) 60 / 393,858

(32) 03.07.2002

(33) from

(46) Jun 11, 2007, Bul. No. 8, 2007

(72) Horvitz Jerome P., of, Corbett Thomas X, of, Palomino Eduardo, of, Pauline Liza, of, Haysdaline Stewart T., of

(73) VAYNE STEET UNIVERSITY, from

(56) SORVETT T.N. ET AB: "RESBIKPSAB

(2) [4- (7-CHNOBORENE) -2-THALATO-HYDROCHLORIC ACID] ​​RENNOX] RPROPYLENE "INVESTMENT OF NON-MEMBRANEOUS, MAY ™ FROM MGNORP RIVISNERES, VOZTMC, FROM, VI. 16, PO. 2 , 1998, P. 129-139. N. Ebju. E.T. ET B.B .: "Yuyavid, Zupiyevov apbioioiodisai E \ 'aiiiaiiiopi Afaideiyev Af Aiiiito Agadiy, 2- {4 - [(7-Cyano-2-

Dipokhaiaipuu) ohu] rpepochu} rgoriopis Ascis (HK469) "b.MeuuSNem., ναΙ. 44, - 28 ArhiI 2001, R. 1758-1776y, 6 197 728, B1.2001

from, 4,629,493, A, 1986

(57) 1. A compound of formula (I):

CH3

the heterocycle binds to carbon atomic carbonyl, to which Z is joined through the atomization of a monocyclic, fused bicyclic or bridged bond of a bicyclic saturated or unsaturated heterocyclic ring system containing 5 to 12 ring atoms, which may additionally contain 1-4 hetero atoms selected from the group consisting of non-peroxide oxygen, sulfur or nitrogen, wherein the heterocyclic system may be unsubstituted or substituted;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein Y is H.

3. The compound of claim 1, wherein Y is -OH.

4. The compound of claim 1, wherein Y is -OMe.

5. A compound according to any one of the preceding claims. 1-4, in which X is -Ci.

6. A compound according to any one of the preceding claims. 1-4, in which X is -Ag.

7. A compound according to any one of the preceding claims. 1-6, in which Z is an amino acid.

8. A compound according to any one of the preceding claims. 1-6, in which Z is 4 \ IN- (CH2) 2-SO3.

9. A compound according to any one of the preceding claims. 1-6, in which Z is 4MN-CH2-CO2N.

10. A compound according to any one of the preceding claims. 1-6, in which Z is 4 \ IN-CH (CH3) -CO2H.

11. A compound according to any one of the preceding claims. 1-6, in which Z is a pyrrolidine, piperidine, morpholine, 1,3-benzodiazepine, 1,4-benzodiazepine or 1,5-benzodiazepine group coupled to nitrogen.

12. A compound of formula (I):

HHHCH N.

iA (11) 79293 (13) C2

σ>

C-C (= O) -2

(AND)

CH3

where A is CH;

X is E, SI or Bg;

X

where A is CH or N;

X is E, SI or Bg;

Y is hydrogen, hydroxy or (C1-

C7) alkoxy; and

Z is a α- or β-

an amino acid coupled through the nitrogen atom to the α- or β-

aminosulfonic acid or heterocycle,

3

79293

4

Y is hydroxy or (C 1 -C 7) alkoxy; and Z is a -IchRaR;

wherein R a and R b independently represent hydrogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkanoyl, aryl, aryl (C 1 -C 7) alkyl, or wherein R a and R 3 together with the atom atom to which they are attached, form a pyrrole-din, piperidine, morpholine, 1,3-benzodiazepine, 1,4-benzodiazepine or 1,5-benzodiazepine group;

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, wherein Y is -OH.

14. The compound of claim 12, wherein Y is -OMe.

<tr><td><p>15. Compound for any</p></td><td><p>with</p></td><td><p>points</p></td><td><p>12-14,</p></td><td><p>in</p></td><td><p>which one</p></td><td><p>X</p></td><td><p>show</p></td></tr><tr><td><p>Laying itself-CI.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>16. Compound for any</p></td><td><p>with</p></td><td><p>points</p></td><td><p>12-14,</p></td><td><p>in</p></td><td><p>which one</p></td><td><p>X</p></td><td><p>show</p></td></tr><tr><td><p>lays down -Vg</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>17. Compound for any</p></td><td><p>with</p></td><td><p>points</p></td><td><p>12-16,</p></td><td><p>in</p></td><td><p>which one</p></td><td><p>Z</p></td><td><p>show</p></td></tr>

is -ICHRaR1, wherein Ra and P1 are each independently from each other hydrogen, (C1-C7) alkyl, (C1-C7) alkanoyl, aryl, or aryl (C1-C7) alkyl.

18. The compound according to any one of the preceding claims. 12-16, in which Z represents -NH2.

19. A compound according to any one of the preceding claims. 12-16, in which Z is the number of NHS.

20. A compound according to any one of the preceding claims. 12-16, in which Z is linked with 1,3-benzodiazepine nitrogen,

1,4-benzodiazepine or 1,5-benzodiazepine group.

21. A compound of formula (I):

CHs

where A is CH;

X is P, CI or Bg;

Y is hydrogen, hydroxy or (C1-C7) alkoxy; and Z is a πρ_andP;

Ra and R1 independently of one another are an aqueous, (C1-C7) alkyl, (C1-C7) alkanoyl, aryl,

aryl (C1-C7) alkyl, or wherein both Ra and P3, together with the atomomase to which they are attached, form a pyrrole-din, piperidine, morpholine, 1,3-benzodiazepine, 1,4-benzodiazepine or 1,5-benzodiazepine group; or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21, wherein R a and R 1 independently of one another are (C 1 -C 7) alkanoyl, aryl, aryl (C 1 -C 7) alkyl, or wherein R a and R 1 together with the atom atomic mixtures to which they are attached form pyrrolidone, piperidine, morpholine, 1,3-benzodiazepine, 1,4-benzodiazepine or 1,5-benzodiazepine group.

23. The compound of claim 21 or 22, wherein Y is H.

24. The compound of claim 21 or 22, wherein Y is -OH.

25. The compound of claim 21 or 22, wherein Y is -OMe.

<tr><td><p>26. Compound for any</p></td><td><p>with</p></td><td><p>points</p></td><td><p>21-25,</p></td><td><p>in</p></td><td><p>which one</p></td><td><p>X</p></td><td><p>show</p></td></tr><tr><td><p>Laying itself-CI.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>27. Compound for any</p></td><td><p>with</p></td><td><p>points</p></td><td><p>21-25,</p></td><td><p>in</p></td><td><p>which one</p></td><td><p>X</p></td><td><p>show</p></td></tr><tr><td><p>lays down -Vg</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>28. Compound for any</p></td><td><p>with</p></td><td><p>points</p></td><td><p>21-27,</p></td><td><p>in</p></td><td><p>which one</p></td><td><p>Z</p></td><td><p>show</p></td></tr>

one from each other are hydrogen, (C1-C7) alkyl, (C1-C7) alkanoyl, aryl, or aryl (C1-C7) alkyl.

29. A compound according to any one of the preceding claims. 21-27, in which Z represents a pyrrolidine, piperidine or morpholine group linked to nitrogen.

30. A compound according to any one of the preceding claims. 21-27, in which Z is a nitrogen-bound 1,3-benzodiazepine,

1,4-benzodiazepine or 1,5-benzodiazepine group.

31. A compound of formula (I):

CH3

where

It is N;

X is P, CI or Bg;

Y is hydroxy; and Z is a πρ_andWhere R a and R b independently represent hydrogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkanoyl, aryl, aryl (C 1 -C 7) alkyl, or wherein R a and R together with an atom atom, to which they are attached to form a pyrrole-din, piperidine, morpholine, 1,3-benzodiazepine, 1,4-benzodiazepine or 1,5-benzodiazepine group;

or a pharmaceutically acceptable salt thereof.

32. The compound of claim 30, wherein R a and R 1 are independently from each other hydrogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkanoyl, aryl, aryl (C 1 -C 7) alkyl, or R a and R r az with a nitrogen atom to which they are attached form a pyrrolidine, piperidine, morphol-new group.

33. The compound of claim 31 or 32, wherein X is -CH.

34. The compound of claim 31 or 32, wherein X is -Ag.

35. A compound according to any one of the preceding claims. 31-34, in which Z represents -A ^ R aR, wherein R a and R b are each independently from each other hydrogen, (C1-

<tr><td><p>C7) alkyl, (C1-C7) alkanoyl</p></td><td><p></p></td><td><p>ar</p></td><td><p>il ab</p></td><td><p>at</p></td><td><p>aryl</p></td><td><p>C1-</p></td></tr><tr><td><p>C7) alkyl.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>36. Compound for any</p></td><td><p>with</p></td><td><p>points</p></td><td><p>31-34</p></td><td><p>in</p></td><td><p>which one</p></td><td><p>Z</p></td><td><p>show</p></td></tr><tr><td><p>It's called -NH2.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>37. Compound for any</p></td><td><p>with</p></td><td><p>points</p></td><td><p>31-34</p></td><td><p>in</p></td><td><p>which one</p></td><td><p>Z</p></td><td><p>show</p></td></tr><tr><td><p>It is a number of NHS '3.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>38. Compound for any</p></td><td><p>with</p></td><td><p>points</p></td><td><p>31-34</p></td><td><p>in</p></td><td><p>which one</p></td><td><p>Z</p></td><td><p>show</p></td></tr><tr><td><p>Lays itself -CHSH'3) 2.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>39. Compound for any</p></td><td><p>with</p></td><td><p>points</p></td><td><p>31-34</p></td><td><p>in</p></td><td><p>which one</p></td><td><p>Z</p></td><td><p>show</p></td></tr>

It is a nitrogen-linked pyrrolidine, piperidine or morpholine group.

40. A compound according to any one of the preceding claims. 31-34 in which Z is linked to a 1,3-benzodiazepine, 1,4-benzodiazepine or 1,5-benzodiazepine group of nitrogen,

pou

41. A compound of formula (I):

^CH3

(I)

where A is N;

X is P, CI or Bg;

Y is hydrogen, hydroxy or (C1-

C7) alkoxy; and Z is a πρ_andP;

It contains -NRaR, where Ra and P are each independently

5

where R_and and R1 independently of one another represent a (Ci-C7) alkanoyl, aryl, aryl (C 1 -C 7) alkyl, (C 1 -C 7) alkyl, with Ra and P together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, morpholine, 1,3 benzodiazepine, 1,4-benzodiazepine or 1,5-benzodiazepine group, or a pharmaceutically acceptable salt thereof.

42. The compound of claim 41, wherein Y is H.

43. The compound of claim 41, wherein Y is -OH.

44. The compound of claim 41, wherein Y is -OMe.

45. A compound according to any one of the preceding claims. 41-44, in which X is-CI.

46. ​​A compound according to any one of the preceding claims. 41-44, in which X appears to be -Vg.

47. A compound according to any one of the preceding claims. 41-46, in which Ra and Rn independently represent (C1-C7) alkanoyl, aryl, or aryl (C1-C7) alkyl.

48. A compound according to any one of the preceding claims. 41-46, in which Ra and Rraz with the nitrogen atom to which they are attached form pyrrolidine, piperidine, morpholine, 1,3-benzodiazepine, 1,4-benzodiazepine or a 1,5-benzodiazepine group.

49. Compounds 2- {4 - ((7-bromo-2-

quinolinyl) oxy) phenoxy} propionylamide;

2- {4 - ((7-chloro-2-

quinolinyl) oxy) phenoxy} propionimethylamide;

(2- (4- (7-chloro-2-

quinoxalinyl) oxy) phenoxy) propionylamino ethanesulfonic acid;

(2- (4- (7-bromo-2-

quinolinyl) oxy) phenoxy) propionylamino ethansoal -

Background acid;

{2- {4- (7-Bromo-quinolin-2-

yl) phenoxy} propionylamino} acetic acid {2- {4- (7-chloro-quinoxalin-2-yloxy) -phenoxy} -propionylamino} acetic acid; (P) 2- (4- (7-bromo-2-

quinolinyl) oxy) phenoxy) propionylamino ethansoal -

Background acid;

(P) {2- [4- (7-Bromo-quinolin-2-yloxy) -phenoxy] -propionylamino} acetic acid or

(P) {2- {4- (7-chloroquinoxalin-2-yloxy) phenoxy} propionylamino} acetic acid; or pharmaceutically acceptable salts thereof.

79293 6

50. A compound according to any one of the preceding claims. 1-49, which is a co-fusion (P) -enantiomer.

51. A compound according to any one of the preceding claims. 1-49, which is a co-fusion (C) -enantiomer.

52. A compound according to any one of the preceding claims. 1-51, while the compound is isolated and purified.

53. The compound of claim 52, wherein the compound is a solid substance.

54. The compound of claim 52, wherein the compound is a cosolvent crystalline solid.

55. The compound of claim 1, wherein A is CH.

56. The compound of claim 7 or 11, wherein A is N.

57. A pharmaceutical composition comprising a compound according to any one of the preceding claims. 1-56 and a pharmaceutically acceptable solvent or carrier.

58. The pharmaceutical composition of claim 57, is formulated as a unit dosage form.

59. The pharmaceutical composition of claim 58, wherein said unitary dosage form is formulated for oral administration.

60. The pharmaceutical composition of claim 58, wherein the unit dosage form is formulated for injection by injection.

61. A compound according to any one of the preceding claims. 1-56 for use in medical therapy.

62. The use of a compound according to any one of the preceding claims. 1-56 for the manufacture of a medicament for the treatment of cancer in mammals.

63. A therapeutic method for treating cancer in mammals comprising administering to a mammal in need of such therapy an effective amount of a compound for any of the claims. 1-56.

64. A therapeutic method for treating cancer in mammals comprising administering to a mammal in need of such therapy an effective amount of a pharmaceutical composition according to any one of the preceding claims. 57-60.

65. A therapeutic method for treating cancer in mammals comprising administering to a mammal in need of such therapy an effective amount of a mixture of two or more compounds of any of claims 1 to 5. 1-56.

66. A therapeutic method for treating cancer in mammals comprising administering to a mammal in need of such therapy an effective amount of a mixture of two or more pharmaceutical compositions according to any one of the preceding claims. 57-60.

The invention described here has been made part of the government grant in the form of the grant ΝΟΙ-ΝΙΗΝSА82341, issued by the National Institute of Cancer Diseases. The United States Government has certain rights in the present invention.

This application confirms the priority of the United States Patent Application No. 60 / 393,858, registered on July 3, 2002, and is incorporated herein by reference.

US Pat. Nos. 5,364,831 and 6,197,728 describe herbicidal compounds of the formula:

where X is a halogen atom, R includes -C (= O) P¹, where R¹ is different

substituted alkoxy radicals, -5P³Radicals and MNN⁴-radicals, while P.⁴ is a group of C1-4 alkoxycarbonylalkyl, hydroxyalkyl, phenyl, C1-4 alkoxyalkyl or di-C1-4alkylamino.

US Pat. No. 4,629,493 describes herbicides

A is CH or N;

7 79293 8

X is halogen; n = 0, 1, or 2;

I¹ is hydrogen or lower alkyl; and

I² is -OH, -O-alkyl, -OM (inorganic or organic salt),

-NP³P⁴, where am I³ and I⁴, respectively, represent a hydrogen atom or lower alkyl.

One of these compounds is now serially released to fight against perennial and perennial herbaceous weeds of broad-leaved crops. This compound has the following formula:

Sohi is there! ai, ipouzijidaiiopai yugid, 16,

129-139 (1998), evaluated a series of kinokalinovyh compounds on activity against solid tumors in mice. The next connection

(hereinafter referred to as HK469) has been described as having a broad spectrum of activity against transplanted tumors of mice. This compound has also been described as having relatively low efficacy and several undesirable side effects, including toxicity and νίνο, which includes, for example, paralytic intestinal obstruction, damage to the epithelium of the CSF (gastrointestinal tract), brain toxicity, neuromuscular toxicity, muscle toxicity and weight loss.

Naii siipe e ai b Messi Spet., 2001, 44, 1758-1776, describe antitumor compounds of the formula:

No. may be H or SI;

X may be H, C1, I, or NO2;

Y may be H, I, C1, Bg, I, methoxy or N3;

Z may be H, C1 or methoxy; and

I may represent OH, alkoxy or NAYA, where I and I represent H, methyl, NH2 or OH, see. tabl. 5 of this publication.

Naii siipe e ah [b. Me Spet., 2002, 45, 3130] describe bioisosters and coagents of the antitumor compound (HK469).

In the United States provisional application, Serial No. 60 / 309,144, registered July 7, 2001, now the application RST / 302/24442, entitled "Antitumor Bases", describes a compound of the formula:

tumor medications.

The present invention relates to compounds that are effective anti-tumor agents. Accordingly, the compounds of the invention are compounds of formula (I):

A is CH or N;

X is I, SI or Vg;

Y is hydrogen, hydroxy or (C1-C7) alkoxy; and

Z is an amino acid or heterocycle, or a pharmaceutically acceptable salt thereof.

Some embodiments of the invention also relate to the compounds of the invention having the formula (I) as defined above:

where

A is CH;

X is I, SI or Vg;

Y is hydroxy or (C1-C7) alkoxy; and Z is ^ I_andI_ı;

wherein the Yaa and Ya independently of each other are hydrogen, (C1-C7) alkyl, (C1-C7) alkanoyl, aryl, aryl (C1-C7) alkyl, or Yaa and Ya together with the azo atom to which they are attached , form pyrrolidone-new, piperidine, morpholine, 1,3-benzodiazepine, 1,4-benzodiazepine or 1,5-benzodiazepine group;

or a pharmaceutically acceptable salt thereof.

Some embodiments of the invention also relate to compounds of the invention having the formula (I) as defined above:

where

A is CH;

X is I, SI or Vg;

Y is hydrogen, hydroxy, or (C1-C7) alkoxy; and

Z is -NP₃P ^

where Yaa and Ya are independently from each other (C1-C7) alkanoyl, aryl, aryl (C1-C7) alkyl, or Yaa and Ya, together with the nitrogen atom to which they are attached, form pyrrolidine, piperidine, morpholine, 1,3-benzodiazepine, 1,4-

benzodiazepine or 1,5-benzodiazepine group;

or a pharmaceutically acceptable salt thereof.

Some embodiments of the invention also relate to compounds of the invention having the formula (I) as defined above:

where

It is N;

X is I, SI or Vg;

Y is hydroxy; and

Z is -NP₃P ^

wherein the Yaa and Ya independently of each other are hydrogen, (C1-C7) alkyl, (C1-C7) alkanoyl, aryl, aryl (C1-C7) alkyl, or Yaa and Ya together with the azo atom to which they are attached , form pyrrolidone-new, piperidine, morpholine, 1,3-benzodiazepine, 1,4-benzodiazepine or 1,5-benzodiazepine group;

or a pharmaceutically acceptable salt thereof.

Some embodiments of the invention relate to

also compounds of the invention having the formula

(I) above:

or a pharmaceutically acceptable salt thereof.

Currently, there is a need for new counter-

9

where

It is N;

X is P, CI or Bg;

Y is hydrogen, hydroxy or (C 1 -C 10) alkoxy; and

Z is -IMRaR1 ,;

wherein R a and R b are independently from each other (C 1 -C 7) alkanoyl, aryl, aryl (C 1 -C 7) alkyl, or R a and R 3, together with the nitrogen atom to which they are attached, form pyrrolidine, piperidine, morpholine, 1,3-benzodiazepine, 1,4-

a benzodiazepine or a 1,5-benzodiazeptoic group;

or a pharmaceutically acceptable salt thereof.

The invention also relates to a therapeutic method for inhibiting the growth of tumor cells in mammals which involves administering an mammal in need of such treatment an effective amount of the conjugate compound.

The invention also relates to a therapeutic method for treating cancer in mammals which involves administering to an mammal in need of such treatment an effective amount of a compound of the invention.

The invention also relates to a therapeutic method for treating cancer in mammals which involves the joint administration of an mammal in need of such an effective amount of a mixture of two or more compounds of the invention, for example, the precursors of the compounds of formula (I).

The invention also relates to the use of the compound of the invention in medical therapy.

The invention also relates to the use of the compound of the invention for the manufacture of a medicament for treating cancer in mammals.

The inventors have found that compounds of formula (I), as well as products of precursors of the compounds of formula (I) according to the invention, which are metabolized ipνίνο, applied alone or in combination, may be useful as antitumor agents and agents for the treatment of cancer.

The following terms, unless otherwise indicated, mean the following:

"Halogen" means fluorine, chlorine, bromine or iodine. "Alkyl", "alkoxy" and. etc. means unbranched and branched groups; but the reference to a particular radical, for example, "propyl", means only a non-branched radical, and a branched isomer, such as isopropyl, will be mentioned separately. If the alkyl may be partially unsaturated, this alkyl chain may have one or more (for example, 1.2, 3, or 4) double or triple bonds in the chain.

The term "aryl" means a phenyl radical or an ortho-fused bicyclic carbocyclic radical containing ~ 9-10 ring atoms in which at least one ring is aromatic.

The term "arylalkyl" or "aryl (C1-C7) alkyl" refers to a group of the formula aryl (C1-C7) alkyl, dearyl, and (C1-C7) alkyl are as defined herein.

The term "amino acid" refers to the residues of the native amino acids (e.g., AiA, Agd, Avp, Avr, Souv, Ciy, Sip, Siu, Niv, NuI, Nur, Ii, Ii, Iuu, Mits, Rie, Rgo, Zeg, Thr , Tgr, Tug, and WaI) in the U- or I-form, as well as unnatural amino acids (e.g., ta-urine, phosphoserine, phosphotreonine, phosphotyrozin, hydroxyproline, gamma carboxy-glutamate,

79293 10

hypochloric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, citrulline, α-methyl-alanine, para-

benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). This term also includes natural and non-naturally occurring amino acids containing a common amino protecting group (for example, acetyl or benzyloxycarbonyl), as well as natural and non-naturally occurring amino acids protected by carboxy terminals (for example, such as C1-C7) alkyl, phenyl, benzyl ether or amide, or such as α-methylbenzylamide). Other pri-date amino and carboxy-protecting groups are also known to specialists [see, for example, T. Sch. Segepa, Rhoiseispid Sgoriv Ip Ohdpis Zupiyev; Mieu: ICead Wohk, 1981, and the link you will bring there]. The amino acids may be coupled to the other part of the compound of Formula (I) via carboxy-termination, amino-termination, or through any other convenient site, for example, via cysteine ​​sulfur.

The term "heterocycle" means a Z-radical which is attached or bonded to carbon atom carbonyl through a ring nitrogen atom of a monocyclic, fused bicyclic or bridged bond bicyclic saturated or unsaturated ring system containing five or two hundred and fifty ring atoms, including carbon and 1-4 heteroatoms independently of one another in the group consisting of non-peroxide oxygen, sulfur and at least one N (X), wherein X is absent or is H, O, (C1-C4) ) alkyl, phenyl, or benzyl. Peroxide heterocycles can for example, pyrrolidine, piperidine, morpholine, 1,3-benzodiazepine, 1,4-benzodiazepine, or

1,5-benzodiazepine groups.

A "isolated" compound means a compound which is isolated from an environment in which it may be present at normal conditions. For example, the compound can be isolated from the environment to obtain the isolated compound.

The term "partially unsaturated", for example, (C1-C7) alkyl, which may be partially unsaturated, means that said substituent has one or more unsaturated bonds, for example, one or more double bonds, one or more triple bonds, or both of these links.

A "purified" compound means a compound which in a given amount of a substance has a concentration of at least 50%, 60%, 70%, 80%, 90%, and intermediate concentrations. For example, the isolated compound may have a concentration of 51%, 52%, 53%, 54%, etc. It is of interest that the compound has a concentration of 90% -95% and intermediate values. More preferably, the compound has a concentration of 95% -99% and intermediate values. More preferably, the compound has a concentration of 99% -99.9% and intermediate values. Most preferably, the compound has a concentration of more than 99.9% of this amount.

"Possible" or "possibly" means that event

or states that are described, do not necessarily have to

have a place and that the description contains cases when the event

11

or the condition is present, and cases where they do not occupy the place. For example, "optionally substituted" means that said substituent may be present, but may not be present, and that the description contains instances when said substituent is present, and instances where said substituent is not present.

Expressions "including", "for example", "such as" etc. are used for illustrative purposes and do not limit the scope of the invention.

The nouns in the singular in this application should be classified as "at least one" or "one or more", including the claims in the claims, unless otherwise indicated.

It will be appreciated by those skilled in the art that compounds with a chiral center may exist in optically active and racemic forms and may be isolated in these forms. Some compounds may exhibit polymorphism. It is to be understood that this invention contains all the racemic, optically active, lymphatic or stereoisomeric forms, or mixtures thereof, the compounds of the invention having the beneficial properties described herein, as well known in the art of obtaining optically active forms (on -example, by separating the racemic form by various methods of recrystallization, by synthesizing a target compound from optically active starting materials, by chiral synthesis, or by way of a chromatographic separation using a chiral stationary phase) and methods for detecting, apryklad, antitumor activity,

Specific and preferred values ​​of the radicals, substituents and ranges listed below are for illustrative purposes only and do not exclude other indicated values ​​or other values ​​within the indicated ranges for radicals and substituents. The compounds of the invention contain compounds of formula (I) a combination of values, specific values, more specific values ​​and superior values, which are described here.

In particular, (C 1 -C 7) alkyl may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, hexyl or heptyl; (C 1 -C 7) alkoxy may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy, and -methylhexyloxy or heptyloxy; (Cu-C7) alkanoyl may be acetyl, propanoyl, butanoyl, pentanoyl, 4-methylpentanoyl, hexanoyl or hepta-noil; aryl may be phenyl, indene or naphthyl.

When (C 1 -C 7) alkyl is unsaturated or partially saturated, it can in particular be a vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1- 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexen-1-inyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl.

The specific value for X is B, SI or Vg.

Another specific value for X is SI.

79293 12

Another specific value for X is Sr. Specific value for Y is hydrogen, hydroxy or (C1-C7) alkoxy.

Another specific value for Y is hydrogen

(-N).

Another specific value for Y is hydroxy (-OH).

Another specific value for Y is (C1-C7) alkoxy.

Another specific value for Y is the mark-sy (-OMe).

A specific value for Z is -YP_andP

Another specific value for Z is -NH2. Another specific value for Z is -YNSNa.

Another specific value for Z is -N (OH3) 2

Another specific value for Z is the pyrrole-din radical.

Another specific value for Z is the piper radical.

<tr><td><p>Another specific value</p></td><td><p>for</p></td><td><p>Z</p></td><td><p>is</p></td><td><p>sea</p></td></tr><tr><td><p>folic radical.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>Another specific value</p></td><td><p>for</p></td><td><p>Z</p></td><td><p>is</p></td><td><p>1,3-</p></td></tr><tr><td><p>benzodiazepine radical.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>Another specific value</p></td><td><p>for</p></td><td><p>Z</p></td><td><p>is</p></td><td><p>1,4-</p></td></tr><tr><td><p>benzodiazepine radical.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>Another specific value</p></td><td><p>for</p></td><td><p>Z</p></td><td><p>is</p></td><td><p>1.5-</p></td></tr>

benzodiazepine radical.

Another specific value for Z is amino acid.

Another specific value for Z is the alpha-amino acid.

Another specific value for Z is an amino acid containing an alpha-carbon atom, which is a non-water substituent in (I _) configuration.

Another specific value for Z is the amino acid containing the alpha-carbon atom, which is an non-water substituent in (O) -configuration.

<tr><td><p>The other one</p></td><td><p>specific</p></td><td><p>meaning</p></td><td><p>for</p></td><td><p>Z</p></td><td><p>is -NH-</p></td></tr><tr><td><p>(OH 2) 2 -δθ 3 H.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>The other one</p></td><td><p>specific</p></td><td><p>meaning</p></td><td><p>for</p></td><td><p>Z</p></td><td><p>is -NH-</p></td></tr><tr><td><p>CH2-CO2N.</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>The other one</p></td><td><p>specific</p></td><td><p>meaning</p></td><td><p>for</p></td><td><p>Z</p></td><td><p>is 4MN-</p></td></tr>

CH (CH3) -CO2H.

A specific group of compounds of formula (I) containscompounds in which the carbon carrying the metal group is in (O) -configuration.

A preferred group of compounds of formula (I) containscompounds in which the carbon carrying the metal group is in the (I_) configuration.

The preferred compounds of the invention comprise, as follows:

2- {4 - ((7-bromo-2-

quinolinyl) oxy) phenoxy} propionylamide;

2- {4 - ((7-chloro-2-

quinolinyl) oxy) phenoxy} propionylamide;

(2- (4- (7-chloro-2-

quinoxali

nil) oxy) phenoxy) propionylaminoethanesulfonic acid

acid;

(2- (4- (7-bromo-2-

quinolin

nil) oxy) phenoxy) propionylaminoethanesulfonic acid

acid;

{2- {4- (7-Bromo-quinolin-2-

13 79293

ylxy) phenoxy} propionylamino} acetic acid;

{2- {4- (7-chloro-quinoxalin-2-yloxy) -phenoxy} -propionylamino} acetic acid;

(P) (2- (4- (7-Bromo-2-

quinolin

nil) oxy) phenoxy) propionylaminoethanesulfonic acid;

(P) {2- [4- (7-Bromo-quinolin-2-

xloxy) phenoxy] protonamino} acetic acid; and

(R) {2- {4- (7-chloro-quinoxalin-2-

ylxy) phenoxy} propionylamino} acetic acid; or pharmaceutically acceptable salts thereof.

Preferred compounds of the invention include, for example, compounds of the formula:

where

X is SI,

Y is hydrogen or (C 1 -C 7) alkoxy, and Z is -I / I R_andP or amino acid; and a compound of the formula:

N

where

X is SI or B,

Y is hydrogen (C 1 -C 7) alkoxy, and Z is -I / I R_andP or amino acid; or pharmaceutically acceptable salts thereof.

More preferably, the compounds of the invention

X is SI or B,

Y is hydrogen or methoxy, Z is amino acid, or pharmaceutically acceptable salts thereof. Most preferably, the compounds of the invention

contain compounds of the formula:

14

according to the invention, provides for the joint administration of various compounds of formula (I) according to the invention, for example, a mixture of two or more compounds of formula (I).

In cases where the compounds are substantially essential or acidic for the formation of stable non-toxic salts with acids or bases, it may be desirable to introduce a compound as a salt. Examples of pharmaceutically acceptable salts of malt salts obtained by reaction with organic acids formed physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Perhaps also formed acceptable inorganic salts, for example, hydrochloride, sulfate, nitrate, bicarbonate and carbonate.

Pharmaceutically acceptable salts can be obtained using standard techniques well known in science, for example, by the reaction of the parent compound, such as an amine, with a suitable acid that forms a physiologically acceptable anion. It can also be obtained salts of alkali metals (for example, sodium, potassium or lithium), or of the ground metals (for example, calcium) with carboxylic acids.

The compounds of formula (I) may be used in a pharmaceutical composition composition and administered to a male, such as a human, in various forms adapted to the selected route of administration, i.e., oral or parenteral, in particular intravenous, intravenous, intramuscular, locally or subcutaneous.

Thus, the described compounds can be administered systemically, for example, orally, in combination with a pharmaceutically acceptable carrier, such as an organic solvent or digestible food carrier. They can be placed in solid or soft gelatin capsules, can be compressed tablets or can be administered directly to the intestine taken by the patient. For oral or therapeutic use, the active compound can be mixed with one or more of the filler-like and is used in the form of swallow tablets, buccal tablets, chewable tablets, capsules, elixirs, suspensions, syrups, pills, and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage composition of compositions and drugs, of course, can vary and can be from ~ 2 to ~ 60% by weight. of a given unit dosage form.

Tablets, lozenges, pills, capsules, etc. It may also contain the following components: binding substances such as tragacanth gum, gum arabic, corn starch gelatin; fillers, such as dicalcium phosphate; Renners such as corn-styrenic starch, potato starch, alginic acid, and the like; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose or aspartame; or flavoring tori, such as peppermint, gaule terrier oil and an aromatic flavor. If the unit dosage form is a capsule, it may contain, in addition to the substances listed above, a liquid carrier,

X is SI or B,

Y is hydrogen or methoxy,

Z is an amino acid in the form of a

(II) -enantiomer (enantiomers) or their pharmaceutically acceptable salts.

The invention also relates to therapeutic

cancer treatment in mammals, which involves the introduction of

A mammal in need of such treatment, ephi-

amount of the compound of the invention,

for example, compounds of formula (I) in which Z represents

It is taurine or glycine. Another way to treat

15

for example, vegetable oil or polyethylene glycol. Different other substances may also be present, for example, to cover or otherwise modify the physical form of a solid drug. For example, tablets, pills or capsules may have coatings of gelatin, wax, shellac or sugar, etc. The syrup or elixir may contain active ingredient, sucrose or fructose as sweetener, methyl and propylparabens as preservatives, coloring agent and flavoring, for example, cherry or orange. Of course, any substance that is used for the manufacture of medicinal forms should be pharmaceutically acceptable and non-toxic in the amounts used. In addition, the active compound can be introduced into the formulation of preparations and devices for delayed elimination.

The active compound may also be administered intravenously or intraperitoneally by injection or injection. Solutions of the active compound or its salts can be made in water, muzhvly, in a mixture with non-toxic surfactant. Dispersions can also be produced in glycerol, liquid polyethylene glycols, triacetate and mixtures thereof, as well as in oils. Under the conditions of preservation and use, these drugs contain preservative, which prevents the growth of microorganisms.

The dosage forms for injection or infusions may contain sterile water dispersions or dispersions or sterile powders containing the active ingredient and are adapted for the extemporal preparation of sterile solutions for dispersions for injections or infusions, possibly encapsulated in liposomes. In all cases, the final dosage form should be sterile, fluid and stable in the manufacturing and preservation conditions. The liquid carrier can be a solvent-nickel or liquid dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycols, etc.), vegetable oils, non-toxic glycerol esters and their suitable mixtures. The corresponding fluidity can be suppressed, for example, by the formation of liposomes, by maintaining the required particle size of the dispersion case or by using surfactants. Prevention of the influence of microorganisms can be achieved through various antibacterial and fungicidal agents, such as parabens, chlorobutanol, phenol, co-carbic acid, tymerosal, and the like. In many cases, the use of isotonic agents, such as sugars, buffers, or chloridunatria, is preferable. Prolonged absorption of injectable compositions may be effected by using in these compositions a means for slowing suction, for example, alumina monostearate, iZelatin. In many cases, the use of isotonic agents, such as sugars, buffers, or chloridunatria, is preferable. Prolonged absorption of injectable compositions may be effected by using in these compositions a means for slowing suction, for example, alumina monostearate, iZelatin. In many cases, the use of isotonic agents, such as sugars, buffers, or chloridunatria, is preferable. Prolonged absorption of injectable compositions may be effected by using in these compositions a means for slowing suction, for example, alumina monostearate, iZelatin.

Sterile injectable solutions are prepared by administering an actual compound in an appropriate amount to a suitable solvent, together with various other ingredients as defined above, as necessary, followed by filtration sterilization.

In the case of sterile powders for cooking

sterile injectable solutions, predominant

cooking methods are vacuum drying and sub-

79293 16

dry drying, resulting in a powder of the active ingredient, together with an additional desired ingredient present in the sterile but filtered solutions described above.

In the case of a local application describedcompounds may be applied in pure form, that is, if they are liquids. However, it is generally preferable to apply them to the skin in the form of positions or compositions, in combination with a dermatologically acceptable carrier, which can be solid and liquid.

Suitable solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Suitable liquid carriers include water, dimethylsulfoxide (MI3), alcohols, glycols, or water-alcohol / water-glycol mixtures, in which the described compounds may be dissolved or dispersed in effective amounts, possibly by means of non-toxic surfactants. Intermediate supplements, such as flavors and additional anti-microbial agents, may be added to optimize the properties of the composition for this application. The resulting liquid compositions can be worn from absorbing pads, used for impregnation of bandages and other loose or sprayed into the affected area using spray or aerosol dispensers.

Also, in the form of liquid carriers, thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral substances may be used in the form of pastes, gels, ointments, soaps, etc. easy to spread, for nano-tion directly on the skin of the patient.

Examples of suitable dermatological compositions that can be used for the application of the compounds of formula (I) onto the skin are known by the pharmacists; for example, look at the Bastion of Jesus Christ. [U.S. Patent No. 4,608,392], Segia [U.S. Patent No. 4,992,478], U.S. Pat. [U.S. Patent No. 4,559,157], and Mogkapte [US Patent No. 4,820,508].

Relevant doses of the compounds of formula (I) may be determined by comparing their activity in the model animal animals. Methods of extrapolation of effective doses in mice and other animals in people are known in science; for example, see U.S. Patent No. 4,938,949.

The amount of the compound, its active salt or its derivative, which is necessary for use in the treatment, will vary not only depending on the specific salt selected, but also on the method of application, the nature of the disease to be treated, and age and I will become a patient, and, in the final sub-bag, will be determined by a doctor-curator.

The compound is preferably used in the form of a single dosage form; for example containing 5-1000 mg / m², preferably 10-750 mg / m, is most prominently 50-500 mg / m² active ingredient on unitary dosage form.

The chosen dose may be presented in the

looking at a single dose or in the form of a split

The total dose is repeated through defined

intervals of time, for example, two, three, four or

more subdoses per day. The sub-dose itself can be

17

is also divided, for example, into a number of individual pri-joms that are freely distributed in time.

The compounds of the invention are active anti-tumor agents and have high efficacy and / or reduced toxicity compared to HK469.It is preferred that the compounds of the invention are more effective and less toxic than HK469 (P), and / or do not reach the potential The place of the catabolic stage of metabolism, which is characteristic of HK469, ie, has a metabolic profile that is different from HK469.

The present invention relates to therapeutic methods for treating cancer in mammals which involve administering to a mammal having a cancer, an effective amount of a compound, or a composition for the invention. The term "mammal" means primates, humans, rodents, canine, cat, cattle, sheep, horses, pigs, goats, etc. The term "cancer" encompasses any type of malignant neoplasms, for example, colon cancer, breast cancer, melanoma and leukemia, and that in general is characterized by undesirable proliferation of cells, for example, non-regulated growth, lack of differentiation, local tissue invasion and metastases.

The ability of the compound of the invention to cure can be determined using analytical techniques that are well known in science. For example, the development of treatment programs, assessment of toxicity, data analysis, quantitative evaluation of tumor cell kill and the biological significance of screening using transplantable tumors are described in the literature. In addition, the ability of the compound of the invention to treat cancer can be determined using the tests described below.

In order to evaluate the compounds of the invention and known pro-typing compounds, the following advanced techniques were used:

In the studies, adenocarcinoma-03 strains of the pancreas, adenocarcinoma-16 / C of the mammary gland, adenocarcinoma-17 / ASG of the mammary gland and human melanoma I-OX were used in the initial strain of mice (C57B1 / 6 for tumors of the pancreas 03 and For Neoplasms of the Breast Cancer). Mice VAI / s SUY (deficient in B- and T-cells) were used to support tumors and chemotherapy trials of human melanoma I-OX. Tumors were transplanted into a suitable hybrid Re (B6I32P1 = C57B1 / 6 female / female) or in the source strain for a chemotherum -curricular exams. Individual values ​​of bodyweight weight for each experiment differed within 5g, and all mice at the beginning of treatment weighed more than 17g. Mice received food and water without any restrictions.

The animals were grouped, subcutaneously implanted with 30-60 mg of tumor fragments using a trocar 12 calibres per day 0, and again grouped by nonviolent distribution into different treatment groups and control groups. In the early stages of treatment, chemotherapy-peyos began within 1-3 days after implantation of the tumor, when the number of cells was relatively small

79293 18

(10⁷-10⁸) For the study of later stages or stages of progression, the tumors were allowed to grow within 5 days or more before treatment began. The bouts were measured with a calciner two times a week. Mice were killed when the weight of the tumor reaches a gall of 1500 mg. Weight of the tumor was estimated on the basis of two-dimensional measurements:

Weight of the tumor (in mg) = (and χ b²) / 2, where a and b represent the length and width of the down-line (mm), respectively.

Endpoints for evaluation of antitumor activity in relation to solid tumors

a) Tumor growth retardation (T-C value), where T is the mean time (in days) required to reach tumors in the treatment group for a predetermined amount (eg 1000 mg), and C is the mid-day (in days) , necessary to reach the fluff lines in the control group of the same size. Survived mice with missing tumors were excluded from these calculations (for a case-by-case treatment, a separate table). This value is an important criterion for antitumor activity, because it provides an opportunity to quantify the tumor cell tumor.

b) The calculation of tumor cell killing for subcutaneous (AF) tumors increases. Logarithmization of cells was calculated on the following formula:

Iodine of total killing of cells (in mass) = (ve-number of T-S in days) / (3,32) (TC),

where T-S is the growth retardation of the tumor, as described above, and TS is the time of doubling the volume of the tumor (veins), which is estimated by the optimally adjusted linear logarithmic schedule of exponential tumor growth in the control group (in the range from 100 to 800 mg). Transmission of T-S values ​​into the decimal log-rhyme of cell death is possible due to the fact that the TB tumors that have restored growth after treatment (meaning Px) is approaching the values ​​of the TS-fold in untreated control mice.

In some cases, both for the evaluation data for the past period and for the data presented in the present invention, it is important to compare log-rhythmic killing values ​​in studies that significantly differ in the methodology. To this end, a table of activity was compiled, which is given below. It should be noted that an activation rating is required in the range from +++ to ++++ in order to trigger a partial regression (RR) or full remission (SR) of most of the transplanted solid tumors of 100-300 mg mice. Thus, a compound with a rating of activity + or ++ can not considered as active under the usual clinical criteria. PP is a reduction in the weight of the down line of less than 50% of the size before treatment. The SR is the reduction in the mass of the tumor to a magnitude less than the palpable size (that is, reduction to the smallest detected mass).

19th

Translating the decimal logarithm for killing the cells in the activity evaluation

Groups were administered when the size of the tumors in the control group reached about 700-1200 mg (mean value in the group). The T / C percentage is based on the anti-tumor efficacy: T / C = 0% means no tumor growth. T / C = 100% means no antitumor activity, i.e., treated and control tumors grew one by one. The T / C value &lt;42% is considered to be a significant anti-tumor activity according to the criteria for the treatment of cancer of the National Institutes of Invasive Diseases (UTI). The T / C value &lt;10% is considered to be a very significant antitumor activity, and this level is used by the H1S1 to confirm the success of the clinical examinations in the case of compliance with the requirements of toxicity, composition and somewhat different requirements (so-called activity level NN-2).

Making medicines for injectable mice

Compounds in the form of their sodium salts were prepared in a 1% solution of sodium bicarbonate, in water or in a buffered phosphate salt solution (pH3), with pH adjusted to 7.0-7.5 by hydrochloric acid, and administered intravenously (IV) or orally (RO), in a volume of 0.2 ml per injection.

Amide compound - data of the η-νίνο test

The following are the characteristics for the compounds obtained by the invention (Table A), as compared to KHK469 (Tables 1-10).

Table 1. These data comprise a comparison of the activity of HK469 and compound 14a with respect to the early stage adenocarcinoma of the pancreas 03 in the B0P1 males.

Cell 5: Compound 14a was injected IV at a dose of 120 mg / kg / injection, once daily at days 3-6, 9-11, and duplicates per day at 7-8 days to a total dose of 1320 mg / kg. The weight loss was -0 , 8 g (-3.6%). The dose toxicity has not been reached. Compound 14a was active and provided T / C = 7.3% and the log-killing of cells 1.9 (activity rating -H-). This was a high non-toxic dose (HTHN).

Cell 6: Compound 14a was injected IV at a dose

60 mg / kg / injection, once daily for days 3-6, 9-11 and two

79293 20

times a day at 7-8 days to a total dose of 660 mg / kg. The weight loss was -0.4 g (-1.8%), and drug death -0.5. This dose showed a minimum activity and provided T / C = 40% and the logarithm of killing cells0.7 (activity rating +).

Cell 7: Compound 14a was injected IV at a dose of 30 mg / kg, once daily at days 3-6, 9-11 and twice daily at 7-8 days to a total dose of 330 mg / kg. The losers were 0.4 g (-1.8%), there were no lethal results. This dose was inactive and showed T / C = 74% and the logarithm of killing the cells is 0.3 (the rating is negative (-)).

Cell 8: Compound HK469 was injected IV at a dose of 60 mg / kg once daily at day 3-5 up to a total dose of 180 mg / kg. Treatment was stopped in advance due to the condition of mice and weight loss -3.6 g (-15.5%), lowering the value on day 8. There were no deaths from medications, and the mice restored weight on the 13th day. It is known that MTU (maximum admissible dose) for HK469 is 450-480 mg / kg IV. However, this sub-total dose of 180 mg / kg was active and ensured T / C = 11% and the log-killing of cells was 1.43 (activity rating ++).

Table 2. These data comprise a comparison of the activity of HK469 and compound 14b with respect to the early stage adenocarcinoma of the pancreas 03.

Compound 14b, mono-methylamide HCl469, was evaluated for the adenocarcinoma of the pancreas duct of early stage 03. It should be noted that this compound was insoluble in water, and therefore it was administered orally.

Cage 2: Control experience HK469: HK469 IV was administered once daily at days 3-6, 10 up to a total dose of 300 mg / kg. This caused a loss of body weight of -15%; Below is the value of day 8, full recovery -day 12 (approximately). This dose was highly active (1/5 of cure, the logarithm of mortality in untreated, 3.3, activity rating ++++).

Cage 3: 14b was injected with PO at a single dose of 150 mg / kg twice daily for the 3rd day. The dose was increased to 250 mg / kg twice daily at day 4-7 up to a total dose of 2300 mg / kg. This led to a weight loss of 9%, below the value of day 8, a complete recovery of the 10th day. This dose was moderately active (T / C = 39%, logging rate 0.8, rating +).

Cells 4 and 5: Treatment stopped in advance to save the compound.

Table 3. These data comprise a comparison of the activity of XK469 and compound 14c with respect to the adenocarcinoma of the mammary gland (M17 / Abg), which has multi-cardic resistance.

Compound 14c (dimethylamide derivative of 8-methoxy-HK469) was active (Cell 5).

Cell 1 (control trial without treatment): Time to 1000mg = 8.5 days (Tb 1.1 day). Tumor growth corresponded to the expected.

Cage 2 (negative control): Ad-rimycin was administered once daily in the IV dose of 7.5 mg / kg / injection at days 1, 7 up to a total dose of 15 mg / kg. It is known that this dose is as high as possible. The compound was inactive (T / C = 90%).

Cell 4: HK469 was administered once daily IV

dose of 56 mg / kg / injection at days 1-5 and 10 to total

doses of 336 mg / kg. The dose was very active:

21

T / C = 9%, the logging rate is 4.2, the active rating is ++++.

Cell 5: Compound 14z is dimethyl-carboxylic acid of compound 13a. Compound 14 was injected with PO once daily, I45 mg / kg at days 1-3 and 7-9 at a total dose of 870 mg / kg. Toxicity was not achieved. This dose was active (T / C = 20%, kill rate 1.5, activity rating ++). It is worth paying attention to this plan of treatment. If an adaptation had to take place before the treaty, it would have happened exactly under such a scheme treatment. Then one would expect a significant reduction of antitumor activity (compared with 13a for a short, high dose treatment). In addition, it could be expected that subsequent, lower doses would, in fact, be inactive for this scheme. In reality, activity has not decreased, and subsequent, lower doses were still active. In short, the dose-intensive scheme (twice a day, days 1-3),

Cage 6: 14c was injected PO once a day at 90 mg / kg at days 1-3 and 7-9 to a total dose of 540 mg / kg. This dose was active: T / C = 31%; logarithm 1.4, activity rating ++.

Cell 7: 14c was injected PO once a day, 55.8 mg / kg at days 1-3 and 7-9 to a total dose of 334.8 mg / kg. This dose was active: T / S = 31%, kill log 1.0, activity rating +.

Cell 8: 14c was injected PO once a day34.6 mg / kg at days 1-3 and 145 mg / kg at the bottom of 7-9 to a total dosage of 538.8 mg / kg, which corresponds to the total dose in Cell 6. This dose was moderately active -garmin killing 0.9, activity rating +). If there was no adaptation to the drug, the kill log should have been the same as in Cell 6. Activity was reduced (compared to Cell 6), but the fact that activity was present obviously means that there was no significant adaptation .

Table 4: These data include a comparison of the activity of XK469 and compound 14e (dimethylamide 11b) with a pancreatic pancreatic adenocarcinoma (P03). The region 14e was active (Cell 2) and improved with respect to HK469 (Cell 5). The need for a higher dose for compound 14e can be considered a disadvantage when compared to compound 11b (Cell 14).

This experiment was planned for a separate assessment of compounds 11b, 14e and XK469 (R-enantiomer).

Cell 1 (control trial without treatment): Time up to 1000mg = 12.5 days (TB 2.0 days). It was a sub-line of Rapse-03, which grew rapidly. It is worse treatment-treated than previous lines that grow slower. Handling and growth were in line with expectations.

Cage 2: Compound 14e was administered RO with a single dose of 120 mg / kg twice daily at days 3-9 up to a total dose of 1680 mg / kg. Apparent toxicity was not there, and the mouse gained weight. This dose (although very large) was very active (T / C = 8.3%, logarithm of 2.5, activity rating +++).

Cage 3: Compound 14e was injected with RO for a one-

zoo 60mg / kg twice a day, from day 3-9 to the total

79293 22

dose of 840 mg / kg. This dose was almost as active as the next higher dose. The fact that the next lower dose (Cell 4) was almost inactive indicates that the higher dose (Cell 2) was poorly absorbed from the gastrointestinal tract (GIT). This often occurs at very high doses of compounds that do not dissolve in water. However, the dose used in Cluster 3 was also very high (total dose of 840 mg / kg). Although she showed some activity (logging killing 2.2), she did not exceed the compound 11b.

Cell 4: Compound 14e was injected with PO for a single dose of 30 mg / kg twice daily, at day 3-9 to a total dosage of 420 mg / kg. This dose was minimal acting on the T / C index and inactive on the logarithm of dipping.

Cell 5: HK469 (P) IV was injected once a day with a dose of 57 mg / kg / injection, at the bottom of 3-9 to a total dose of 399 mg / kg. This is an adequate dose for this syndrome. She showed a weight loss of -6.7%, with a lower value on the 8th day, a complete recovery on the 11th day. The dose was active (T / C = 4.1%, logging rate of 1.7, activity rating ++).

Cell 6: HK469 (P) IV was injected once a day with a dosage of 38 mg / kg / injection, at the bottom of 3-9 to a total dose of 266 mg / kg. The dose was active (T / C = 8.3%, log-rhyme killing 1.4, activity rating ++).

Cell 14: Compound 11b (racemic) was injected IV once a day at a dose of 48 mg / kg / injection at the bottom of 3-9 total dose of 336 mg / kg. This led to a loss-weight of -8.9% (below the value - day 11). Unfortunately, the mice were not weighed on days 12, 13, 14, 15, 16, and on the 17th day, weight gain was more than a gram of nutmeg in comparison with weight before treatment. This canconsidered as a complete restoration of weight about 15 days. The dose was active (T / C = 0%, logging rate 2.6, activity rating +++). This is a higher activity compared with HK469 and several more activity compared with compound 14e. It should be noted that compound 11b requires a lower dose than HK469.

Table 5. These data include a comparison of the activity of XK469 (P) and the racemic compound 14T in relation to the pancreatic adenocarcinoma (P03). Sponge 14a (Cell 3) showed activity similar to the activity of HK469 (P) (Cell 2). Thus, sporadic bowel 14β was found to be better tolerated at the dose used and did not lead to loss of weight or other negative symptoms. However, toxicity was not achieved, and the need for a higher dosage indicates that the racemic mixture that you tried in this experiment has a less vivacity, while the 3-form was inactive (see Table 6 below).

Cell 2: HK469 (P) IV was injected once a day with a dosage of 45 mg / kg / injection at 3-10 days to a total dose of 360 mg / kg. Losing weight was 7%, below value came on day 11, and complete recovery at 14days. This dose has proven to be active and provides T / C = 21% and the log killing killing of cells is 1.84 (rating activity ++).

Cage 3: Compound 14β was injected IV at the bottom of 3-8 with

following doses 60 mg / kg / injection (once daily -

days 3-5, twice a day - day 6), 80 mg / kg (twice

day - day 7, once a day - day 8). Then

23

For some mice, the route of administration was changed to the subcutaneous (subcutaneous) damage due to damage to the caudal vein. Another part of the treatment was carried out with the following method: 80 mg / kg / injection (once daily, the AS - days 9-11, with 3 mice received IV injection in day 11). The final total dose was 780 mg / kg. There was no loss. This dose was active (T / C = 10%, log cell count = 1.67, activity retention ++).

Table 6. These data relate to the comparison of the activity of HK469 (P) and each of the P- and Z-enantiomers of the compound 14ß in relation to human melanoma (I_OX) of the WSSW worm.

The enantiomer of Compound 14a was inactive (Cell 3) and did not show significant toxicity, except for mild short-term disruption during the last day of injection. Compound 14β (P) (Cell 2) is an active form of co-activity, and its activity is comparable to the activity of HK469 (P) (Cell 4). P-form showed some kind of toxicity, which was characterized by weight loss (-13.5%) and whitening of the paws (a sign of leukopenia) that went through 4 days after onset. However, the greatest interest is that both enantiomers appeared as those that are better tolerated than could be expected. Significantly, the comparison of the corresponding total doses of HK469 and compound 14ί, which is shown in Table. 5 for this experiment. It should be noted that ZSU mice tolerated a higher dose of compound 14β compared with HK469. Known

Cage 2: Compound 14β (P) was injected IV, once daily at day 1-6 and twice daily at day 7 of the total dose of 700 mg / kg. This dose showed a minimal anti-tumor activity (T / C = 47%, log-rhyme kill = 0.8). Weight loss was -2.8 g (-13.5%; below the value on the 13th day) and the absence of deaths from drugs. On the 14th day, there was a breakdown of paws in mice (a sign of leukopenia). These symptoms passed on the 18th day.

Cage 3: Compound 14ß (Z) was injected IV, once daily at day 1-6, twice daily for the 7th day of a total dose of 700 mg / kg. This dose showed a minimal anti-tumor activity (T / C = 71%, log-rhyme kill = 0.3). Symptoms present in the use of the R enantiomer (see above) were not detected in the introduction of the Z-form of the drug. S-treated enzymers were scored during treatment (+ 2.0% on day 8) and showed a moderate excitation / hyperactive behavior last day of treatment.

HK469 (P) was administered IV once daily at day 1-7 up to a total dose of 175 mg / kg. This dose showed anti-tumor activity (T / C = 34%, logarithm of 0.8). It is known that ZSJ mice carry about 50% of the usual mouse MTU (360 mg / kg).

Table 7. These data comprise a comparison of the activity of racemic compound 14d, compounds XK469 (P) and 2- {4 - ((7-bromo-2-quinolinyl) oxy) phenoxy} propionic acid of compound 11z (P) with respect to adenocarcinoma -momans of the mammary gland 16 / From the early stage. The supplementary course of injections (after a day x7 injections) could provide better comparisons by preventing excessive weight loss. This assessment was repeated on the basis of an elongated injecting

79293 24

using the P-form of compound 14d to confirm its enantiomeric activity and was compared with compound 11z (P), see. Tabl. 9 below. Alternatively, racemic compound 14d was active and provided 1/5 (20%) of non-tumor animals (day 161). Animals were then implanted by Mat6 / C / 71. Tumor implants are very successful, which shows the lack of participation of immunological factors in the previous treatment. It should be borne in mind that the racemic compound 14d was reversible at dual dose (moderate weight loss -11%), indicating either P- or S-enantiomer is inert, as in the case of 14ß, of the taurine derivative XK469 .

Racemic compound 14d: dual dose was administered at a dose of 60 mg / kg IV, day 1-5, with a 4-hour interval between injections. Injections were stopped due to damage to the caudal vein. The losers were 11% (below the value on the 4th day), with a complete restoration on the 10th day (the restoration time of the owner for 6 days). This course of treatment shows-all active (T / C = 14%, the log-rate of killing a cli-tin = 0.9, activity rating +). One mouse had a tumor, and this condition was preserved until the 161st day. The animal again implanted Mat16 / C / 71 to confirm that it was a cure. Fungal implants grew successfully, which shows the dependence of the participation of immunological factors in pre-treatment.

Compound HK469 (P): The compound was administered at a dose of 50 mg / kg / IV IV once daily at day 1-5 to a total dose of 250 mg / kg. Injections were interrupted by weight loss and poor appearance of animals (weight loss -15.3% on day 6, shaggy appearance). Animals started diarrhea (observed on day 7), ivag continued to fall (below the morning- you weight -21.2% on the 7th day). Recovery of weight began on day 8, and the value corresponding to the vazido of the onset of injection was achieved on the 12th day. Although deadly results were not available, this dose can be considered toxic due to excess weight loss (&gt; 20%). The C3H strain is not extremely long-lasting, and the usual MTU is 360-450 mg / kg. However, the compound ХК469 was active (T / C = 4%, log cell count = 1.6, activity rating ++).

Compound 11c (P): This compound was administered once daily at a dose of 48 mg / kg / IV IV at a dose of 1-5 to a total dose of 240 mg / kg. Injections were stopped due to the weight of tomorrow and bad appearance of animals (losers -17,5% on the 6th day and shaggy appearance). The weight continued to fall, and some animals were labeled with diarrhea on the 8th and 9th day. One animal was taken in for 10 days, and the result of the autopsy confirmed the death of the drug (diarrhea at the time of death, softening of the walls of the gastrointestinal tract, reduced liver and spleen). This dose can be considered toxic because of over-losing weight (below the value is -29.4% on Day 9), although the surviving mice recovered the weight of the pre-injection weighting on the 13th day. Compound 11c was active toxic dose (T / C 0%, log loss of cells = 1.8, activity rating ++).

Other compounds were evaluated by νίνο, as described

It is also shown in Tables 8-10.

Table 8. P-enantiomers of compound 11c, compound

25

KIK469 and compounds 14β were evaluated separately, on the basis of an extended course of injections, for the mammary adenocarcinoma of the mammary gland 16 / C from an early stage. This experiment confirms the activity of the P-component 14T. It should be noted that similar features of 11c (P) (Cell 2), HK469 (P) (Cell 3), and 14y (P) (Cell 4), in addition to the need for a higher dose for 14? R enantiomers revealed substantially equivalent-valent activity and provided a logarithm of cell kill&gt; 4.0 (activity rating ++++) with an extended periodic injection rate. All three drugs were well tolerated, while for HK469was marked moderate weight loss (-7,4%). 14? 1111 (P) showed less weight loss (-3.0% and -4.3%, respectively). For all values ​​of weight loss, complete restoration came within 2-4 days from the moment-lower value, which means the rapid restoration of the owner.

11c (P): Animals in the Cell 2 received an injection of 60 mg / kg / injection a day, beginning on day 1, with a total dose of 480 mg / kg. At the same time, the graphic compound 11c (P) was well poreno-sim, and no adverse effects were noted. Weight loss was moderate -1,14 g (-4,3%), below the value occurred on the 14th day, with full restoration on the 17th day. This dose was highly active (T / C 0%, logging rate of killing 4.8, activity rating ++++), but there was no cure.

HK469 (P): Animals in Cellet 3 received injections of 60 mg / kg / day, only 8 injections from day 1 to a total dose of 480 mg / kg. In this extended schedule, the compound HK469 (P) was also well tolerated and led to loss of weight -2.0 g (7.4%); the value is lowered on the 17th day, with full restoration of weight on the 20th day. Compound ХК469 (Р) under such scheme appeared highly active (T / C = 0%, log factor of killing of cells = 5.4, activity rating ιιιι and). There was no kick-up.

14S (P): Animals in the Cell 4 received doses with such an increase: 80 mg / kg / injection (day 1), 100 mg / kg (day 3), 120 mg / kg (day 4), 160 mg / kg (day 5), 200 mg / kg (days 7, 9) and 250 mg / kg (days 11, 13, 15) to a total dose of 160 mg / kg. Compound 14ß (P) was found to be well tolerated at such doses and schedule, and led to a moderate weight loss of -0.8 g (-3.0%). Below, the weight loss occurred on the 14th day, with complete restoration on the 16th day. The R-enantiomer of Compound 14a was highly active (T / C = 0%, log cell death = 4.2, activity rating +++ +). No negative symptoms were observed after injection of Compound 14 (P), and there was no cure either.

Animals in the Celtic 5 received doses with the following increase: 50 mg / kg / injection (day 1), 65 mg / kg (day 3), 75 mg / kg (day 4), 100 mg / kg (5th day) and 125 mg / kg (days 6, 7, 9) to a total dose of 665 mg / kg. This injection was discontinued to save medicine. This, lower, the dose of 14? (P) was also active (T / C = 14%, the logarithm of killing the cli-tin 1.8, activity rating ++).

Table 9. This assessment confirmed the activity

R-enantiomer of compound 14d. Estimates of 14d (P)

The lower limit of solubility of this compound was disturbed

at iv IV introduction, so in this case application

79293 26

Shapes of IR (intraperitoneal) injections. Except for the need for a higher dose for 14d (P), thiscomparison showed the effectiveness (Cluster 3, ratingactivity ++), which is equivalent to the efficiency of the parent compound (11c (P)) (cell 5, active-steal ++), with such a method of administration and a short intensive treatment schedule.

P-enantiomers 14d and 11c were injected with each other directly against the adenocarcinoma of the pancreas in the early stage. IP input was used for two reasons. First, the R-form 14d has an intermediate solubility of 25 mg / kg (0.2 ml / injection). This is about 40% of the dose administered IV for the racemic mixture (60 mg / kg, see Table 7). The low solubility of the R-form makes ^ -injection technically unacceptable by administration due to the excessive amount of injections needed to deliver an adequate total dose. Second, although this drug series is active in oral administration, the RO-method in this experiment was not used because of the possibility of cleavage of the amide bond with strong gastric acids. For the same reason, 14d (P) was prepared without acid or base, in order to minimize the possibility of splitting with the restoration of the initialcompound (11 s (P)).

14d (P): Animals in Celiac 2 injected it with a dose of 75 mg / kg / injection twice a day (2 days) at the bottom of 3-5 to a total dose of 450 mg / kg. It was noted that increased volume of urination and low-level appearance of animals, which means a possible diuretic effect of the drug. The dose was toxic, with one death of the counts on the 10th day. The results of the autopsy revealed the normal size of the stomach and the liquid filling of the upper and lower parts of the gastrointestinal tract (diarrhea). On the sere day the weight loss value of 23.4% was achieved on the 9th day, while other surviving animals restored to the initial preincentive value by 17 days. Although this dose was toxic, compound 14d (P) was active (T / C = 0%, cell death log = 1.52, activity rating ++). Looking back, now we can say that the subordinate schedule of in '

Animals in Cellet 3 injected this compound with an IP dose of 45 mg / kg / twice a day, at a dose of 3-7 times the total dose of 450 mg / kg. Then the injections were stopped, as these animals also showed signs of a diuretic effect. The average weight loss of 6.7% was achieved on the 9th day, and complete restoration of weight on the 12th day. This dose was active in this schedule of administration and provided T / C = 12.6%, the logarithm of cell kill = 1.72, activity retention ++.

11c (P): Animals in Cellet 4 were injected with this dosage spray at the following doses: 50 mg / kg / injection at days 3-5, 7 and 60 mg / kg / injection per day 6 to a total dose of 250 mg / kg. Injections were stopped due to weight loss (ne-zhche value -16.7% with full restoration on the 17th day) and poor appearance of animals (shaggy, perceived appearance, large amounts of urine output). One drug death occurred on the 11th day. The results of the autopsy revealed normal spleen, fluid filling of the upper and lower parts of the PIKT and the shaking of the paws. Looking at the back, now we can say that an elongated schedule

27

injections through the day would be better tolerated.

Animals in Cellet 5 injected this compound at 30 mg / kg / day (days 3-5, 7) and 37.5 mg / kg / day (day 6) to a total dose of 157.5 mg / kg. At this dose there were no weight loss or external signs of exhaustion. The dosage was active (T / C = 26%, logarithm of cells = 1,58, activity rating ++).

Table 10. The I-enantiomers of 14b (I), 14i (I), 11z (I) and XK469 (I) were evaluated on the basis of long-term injection schedules for the early stage adenocarcinoma of the parietal gland. The low viscosity of compound 14b (I) (this experiment) and the previously tested compound 14d (I) (see Table 9), does not allow for ν-introduction for technical reasons (too many injections). Oral (RO) method of administration, which is the best alternative way for this series of drugs, was recognized as unsuitable for the possible splitting of amide bonds 14b and 14i (I) in the acidic environment of the stomach. Thus, in this test, the compounds were initially administered by an IR in order to detect an acceptable alternative route of administration. However, after the first IR injection of compound 14i (I), the appearance of prolonged pain-induced hearing was noted. Since this compound retains good water solubility, for the subsequent injections, the method of administration was changed to IV (Cell 4). At a total dose of 455 mg / kg, which is administered according to the elongated graph, 14i (I) showed T / C = 10%, the killing log 1.6 (activity rating ++), which confirms the activity of the I-form of this compound. In view of the considerable loss of weight, it can be assumed that higher doses may be administered (apparently with greater efficacy).

However, 14i (I) requires a higher dose than the starting compound, HK469 (I). Animals in Hematopoietic Cluster 7 were administered HK469 (I) to a total dose of 350 mg / kg, using IP injections in the same schedule, and received 5% T / C, the logarithm of killing 2.2 corresponding to the activity rating of +++.

14b (I): Injections of IR also caused pain. In contrast to 14i (I), this compound has much lower water solubility. So, in order to achieve an adequate overall dose, the method of administration for the subsequent injections was changed to the subcutaneous (subcutaneous) (AF in the posterior part of the neck, the tumors were implanted on the sides of the arm, on the sides of the mouse, in the middle between the anterior and hind legs) . In the extended schedule of injections to the total dose of 615 mg / kg, compound 14b (I) showed T / C = 3%, the killing log of 1.9 (rating activity ++), which confirms the activity of the Y-form of the compound. However, compound 14b (I) was less active and required a larger total dose than the starting compound 11z (I) (total dose 400 mg / kg) administered by the IR in the same schedule for the animals in the Cell 11 (T / C = 0%, the logarithm of killing3.3 , 1/5 cure for tumor on day 148).

14i (I): Cage 2: A dose of 135 mg / kg was administered by the IR only

day 3. More injections were not due to prolonged periods

pain response caused by this method

administration and dose. The mice pulled the hind limbs and

79293 28

sprained for up to 1 hour after injection - a classic pain response. There was an apparent weight loss of -1.6 g (-6.7%) on day 7 (negligible) with complete recovery on day 9. Despite the low total administered dose administered, the compound 14i (I) at The IP-introduction was active and provided T / C = 10% and log-rhyme cell kill 1.1 (activity rating +).

Cage 3: dose of 80 mg / kg was injected IR only in 3 days. As for animals in Celtic 2, after this injection stopped due to prolonged pain (for an hour). On the 4th day there was one death from the injection (inflammation of the upper gastrointestinal tract, which was revealed at the autopsy). Despite the low entry dose, 14i (I) in this group also proved to be active, albeit very moderately (T / C = 37%, log-rhyme kill 0.7, activity rating +).

Cell 4: The initial dose of 50 mg / kg of IP administered on day 3 did not cause any adverse reactions after the injection. The method of administration has been changed to Much because of significant pain caused by higher doses, and injections continued from day to day (totaling 7) to the 15th day of the general dose of 455 mg / kg. A moderate weight loss below the value of -0.8g (-3.4%) occurred at 7-day, with complete restoration on the 11th day (acupuncture during treatment). This dose was moderately active (T / C = 8%, 1.6 killing log, activity rating ++). Given the moderate loss, it can be assumed that it can be introduced a much higher doses of this substance (obviously, with greater efficiency).

HK469 (I): Cell 5: Injection AU 80 mg / kg / injection administered at the bottom of 3-5 to a total dose of 240 mg / kg. Injection was stopped due to a significant weight loss -16.7% (below the value occurred on the 9th day, complete renewal on day 14). One death from drugs occurred on the 10th day (opening: diarrhea, fluid inflammation of the excited gastrointestinal tract, showing epithelial damage to the gastrointestinal tract). This method and schedule of administration were selected to determine whether the compound XK469 (and this series) is active in the AF-administration. Looking back, it's now possible to say that a lower dose of a schedule administered would be better off. However, the compound ХК469 (albeit at the dose І_Ю20 on this schedule) at ЗС-introduction was found to be active and provided T / С = 9% and logarithm of 1.6, activity rating ++.

Cage 6: IP injection of 80 mg / kg / injection was injected at drops 3 and 5. Sporadic extraction of the posterior extremities (withdrawal pain) was noted, which lasted 1-2 minutes after injection. At day 7 and 9, the mice did not receive injections due to poor external vision and weight loss (-11.6%, below the magnitude of the 9th day). Complete recovery occurred on the 11th day, and injections were restored on days 11 and 13 at a total dose of 320 mg / kg. Compound HK469 was very active in the method of introduction of this graph (T / C = 5%, log counts 2.0, activity rating +++).

Cage 7: IR injection of 50 mg / kg / injection was administered following day x7 injections from day 3 to a total dose of 350 mg / kg. This dose was good ne-renosome, without negative symptoms of post-injection. Below the value of weight loss -0.8g (-3.0%) occurred on the 8th day, and complete recovery - on

29

11th day (weight gain during treatment). Compound HK469 proved to be very active in the IP of the method of the elongation of the periodic graph and provided T / S = 5% and the logarithm of killing-2.2 (activity rating +++).

14b (P): Cell 8: Initial dose of 135 mg / kg was injected on day 3. It was marked by passing on bareness and pain after injection, therefore, injected injections were injected into the Armed Forces. 14b (P) were injected with 5C and 5 and 7 (135 mg / kg), with no post-injection reactions noted. On the 9th day, an interruption in injections was made through a slightly shaggy form of animals and weight loss (below the value on day 9) -2.8 g (-11.6%). Although until the 20th day of the mouse did not recover fully their original weight, they were stably weighed and their appearance improved, starting from the 11th day, so the treatment was restored from the 11th day (50 mg / kg) and continued at the bottom 13 and 15 (80 mg / kg) to a total dose of 615 mg / kg. Compound 14b (P) at this dose was active and provided T / C = 3% and the logarithm of cell killing was 1.9 (rating activity ++).

Cage 9: IP injection at a dose of 80 mg / kg / injection was administered at days 3, 5 and 7. Sporadic withdrawal of the hind limbs (withdrawal pain) was continued, which lasted 1-2 minutes after injection. At 9th day, they took a break in injections through a shaggy mice look and weight loss (below -13.3% on the 10th day). Although until the 20th day of the mouse did not reset completely their initial weight, they gradually gained weight and their appearance improved, starting from the 11th day, therefore, the injections were resumed on days 11, 13 and 15 to a total dose of 480 mg / kg . Compound 14b (P) also appeared to be very active at this dose and provided T / C = 6% and the logarithm of killing cells 1.7 (activity rating⁺⁺⁾.

Cage 10: IP injection at a dose of 50 mg / kg / injection was injected every other day x7, starting at 3-day, up to a total dose of 350 mg / kg. This dose is well-tolerated, without any negative symptoms after injection. Loss of weight was moderate, a lower level of -1.6 g (-6.6%) on day 8, complete restoration on day 15 (weight gain during treatment). Compound 14b (P) was moderately active in the introduction of IP using this periodic graph, and provided T / C = 16.5% and logarithm of 1.0 (activity rating +).

11z (P): Cell 11: IP injection at a dose of 80 mg / kg / injection was administered at the bottom of 3 and 5. There were noted sporadic extraction of the posterior limbs (passing blisters), which lasted 1-2 minutes after injection. At days 7 and 9, they took a break in the injections through a slaughtered form of mice and an expressive weight loss of -18% (below the value on the 9th day). Although the 16-year-old mouse did not fully restore their initial weight, they steadily gain weight and their appearance improved from the 11th day, so injections were restored at days 11.13 and 15 to a total dose of 400 mg / kg. Although postponed weight loss in the trained treatment group means almost the BIO10 dose (at 20% body weight, the dose is considered to be extremely toxic according to the standards of GCSI), CompoundIce (P) was highly active in the administration of IP and provided T / C = 0% and the logarithm of killing cells3. 3 (activity rating ++++). One mouse disappeared

79293 30

a tumor, and this condition was preserved until the 148th day when the animals were again implanted P03 / 142. Tumple implants grew successfully, indicating the absence of frequent immunological factors in the previous cure-bath.

Cage 12: IR injection at a dose of 50 mg / kg / injection was injected every other day x7, starting at 3-day, up to a total dose of 350 mg / kg. This dose is well-tolerated, without any negative symptoms after injection. Weight loss was moderate, lower -0.8g (-3.2%) occurred on day 8, out-of-recovery on the 11th day (weight gain during treatment). Compound 11c (P) was active in IR method of introduction using such an extended periodic schedule, and provided T / C = 3% and the log of killing 1.4 (activity rating ++).

General manufacturing techniques

Production of {4 - ((7-Substituted-2-

quinolinyl) oxy) phenoxy} propionic acid compounds (Schemes I-II)

As shown in Scheme I, the one-step production of trans-3-ethoxy acryloyl chloride (3) by reaction of ethylvinyl ether (1) and oxalyl chloride (2) followed by decarboxylation described

The amidation of the meta-substituted anilines (4a-e) with the 3-ion, i.e., conversion to 5a-i, was modeled on the basis of the methodology described by SATRIIiI and RoBeGs (U.S. Patent No. 4,710,507) for the preparation of trans-KI (4- bromo-3-methylphenyl) -3-

ethoxypropenamide. The latter cyclization in the mixture of 5- (7a-e) and 7-substituted quinoline-2-tin (6a-e) was carried out in concentrated sulfuric or in hydrochloric acid [SartriiI and Ro'Egov]. This mixture, in turn, was converted to the corresponding derivatives of 2-chloroquinoline (8a-e) and (9a-e), by heating with a reverse refrigerator with chlorophyll phosphorus [Saccharomyces et al.]. Most of the 7-substituted derivatives (8a-e) were separated from the regionisomer (9a-e) by fractionated crystallization. From the residue, additionally, compound 8a-with column chromatography raffia on silica gel was added. As shown in Scheme II, 2-chloroquinolines 8a-e were coupled with 2- (4-

31

79293

32

hydroxyphenoxy) propionic acid (20) with the use of I \ Ian or K2CO3 in the form of a NiMr (N, N-dimethylformamide) with a reflux condenser with acidification (21a-e) with the use of the following procedure. To a solution of 7-substituted-2-chloroquinoline and 2- (4-hydroxyphenoxy) propionic acid (1 equiv.) Which was dissolved in YMR (5 ml / mmol), 60% Nα (3 eq.) Was added and the mixture was carefully heated to a rotary refrigerator for 2 hours. After cooling, the mixture was concentrated to give a solid, to which water was added, and the solution filtered through celite, then washed with water. The filtrate was extracted with ether, the water layer was alkylated with 1M HCl to pH 3-4.

2- (4-hydroxyphenoxy) propionic acid (1eq) dissolved in YMR (5ml / mmol) was added with 60% Nα (3 equiv.) Portions and the mixture was carefully heated to reflux for 2 hours. After cooling, it was concentrated to give a solid, to which water was added and the solution was filtered through celite and then washed with water. The filtrate was extracted with ether, the aqueous layer was acidified with IM HCl to pH3-4. After cooling, the solid was collected, dried, dissolved in LSOEI and filtered through a silica gel. The filtrate was concentrated to reduce the volume, the solid was collected and recrystallized from LSOEI-heptane to give compounds of propionic acid (11 a-i). Alternatively, the reaction can be carried out using K2CO3 (2.5 eq.) In place of Nα ^ but the reaction time usually increases, for example, to ~ 12 hours.

Compound HK469 having one stereogenic center in the position of P-2 propionic acid is naturally obtained in the form of a racemic mixture. E - (+) - forms 11b and 11c were prepared by the esterification of E - (+) - 2- (4-hydroxyphenoxy) propionic acid, which is serially released from 8i and 8c. The chiral HPRI (High Performance Liquid Chromatography) of the E-forms 11b and 11c showed that these compounds were obtained with a purity&gt; 99% of it (enantiomeric excess). The HPI-C separation of racemic compounds 11b and 11 was carried out using the column AZTES Smoo-thioiis T250x4.6mm, 65% H2O, 35% CH3OH, 20mMN4NO3 at 1 ml / min, detection at 250 nm. The so-called column, solvent system and spectral parameters were used to determine the enantiomers

moderate purity (E -) - 11b and (E -) - 11s.

The invention will now be described by way of non-limiting examples:

Production of {4 - ((7-substituted-2-

quinolinyl) oxy) phenoxy} propionamide compounds (AN) and {4 - {(7-substituted-2-quinoxalinyl) oxy} phenoxy} propionamide compounds (A = ^ (Scheme III)

The following is a description of the conversion of one of 2- {4 - ((7-bromo and 7-chloro-2-quinolinyl) oxy) phenoxy} -propionic acid to the corresponding mono- and diamidescidinopropionamide derivatives. The compound of formula 14 is obtained from the corresponding compounds of formula 13a-6 using the reaction conditions as described below. The definition of the specific substituents X, Y, A, Z, Ea, and EB in the final compounds of formula 14a-i of the presentations of Table. AND.

As a result of the reaction of 2- {4 - {(7-bromo-2-quinolinyl) oxy} phenoxy} propionic acid 11c (A = CH) (Scheme II) with thionyl chloride, intermediate chlorohydrin was obtained, after treatment with methylamine in THP (tetrahydrofuran) have been converted into monomethylamide 146 (Table A) with a good yield. In the same way, as a result of the reaction of chloranhydride of the compound III (X = SI, Y = H, L = CH) in THP (tetrahydrofuran) with dimethylamine, N , N'-dimethylamide 14e (Table A).

Treatment of chlorine hydrates (EZ) -, (E +) - or (3 -) compounds XK469 (A = H) and compounds 11c (A = CH), respectively, amino acid taurine ^ H2SH2SH23O3H) in the TNR and in the presence of 1 M NaOH received corresponding {(EZ) -, (E +) - or (3 -) -} taurine compounds with goodexcitation in the form of sodium salt (14? and 14d) with goodexercise. The same reactions with the amino acid glycine ^ H2SH2SO2H) can provide N-amino acid derivatives (14I and 14i, Table A).

Scheme 111

IZa-b

33

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34

<tr><td><p>Output</p><p>compound</p></td><td><p>Conditions of reaction</p></td><td><p>Ultimate</p><p>compound</p></td></tr><tr><td><p>HAVE</p></td><td><p>ΜΟΟΗ / ΝΗ₃</p></td><td><p>14a</p></td></tr><tr><td><p>HK469</p></td><td><p>5ОС1₂, IN₂CHP / THP</p></td><td><p>14b</p></td></tr><tr><td><p>HAVE</p></td><td><p>5ОС1_2i INCHSN / TNR</p></td><td><p>14s</p></td></tr><tr><td><p>From</p></td><td><p>5ОС1₃, NN₂Ooh₃/ THP</p></td><td><p>144</p></td></tr><tr><td><p>11b</p></td><td><p>5years₂, MN (CH₃)₂/ THR</p></td><td><p>14th</p></td></tr><tr><td><p>HK469</p></td><td><p>"OS, SHON 7 TNG, NN, THIRD, AO, 'I, H *</p></td><td><p>14H</p></td></tr><tr><td><p>13a</p></td><td><p>COSI, N * OOH / TNG, INGSSGYGZOIA, N *</p></td><td><p>1 + 8</p></td></tr><tr><td><p>And for</p></td><td><p>spit; хаон / тнр imsns₃C (= O) Oh, n *</p></td><td><p>14H</p></td></tr><tr><td><p>HK + 69</p></td><td><p>ZOSG, NIOSH / TNR, ICHNSN₂C (= O) SM N '</p></td><td><p>14i</p></td></tr>

Mi-i

Table A. Compounds obtained by the PI Scheme.

<tr><td><p>Connections</p></td><td><p>X</p></td><td><p>Υ</p></td><td><p>AND</p></td><td><p>Z</p></td></tr><tr><td><p>14a</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>N</p></td><td><p>sh₂</p></td></tr><tr><td><p>14b</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>N</p></td><td><p>NNSSnz</p></td></tr><tr><td><p>14s</p></td><td><p>SI</p></td><td><p>FONT</p></td><td><p>N</p></td><td><p>wives)</p></td></tr><tr><td><p>144</p></td><td><p>Hr</p></td><td><p>N</p></td><td><p>CH</p></td><td><p>NNSSnz</p></td></tr><tr><td><p>14th</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>CH</p></td><td><p>wives,),</p></td></tr><tr><td><p>I4G</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>N</p></td><td><p>Ischsng ızm</p><p>salt taurine</p></td></tr><tr><td><p>1 + 8</p></td><td><p>Hr</p></td><td><p>N</p></td><td><p>CH</p></td><td><p>1CHN {CH₂) 25OzM</p><p>salt taurine</p></td></tr><tr><td><p>14H</p></td><td><p>Hr</p></td><td><p>N</p></td><td><p>CH</p></td><td><p>MNSN₂CO₂M</p><p>glycine salt</p></td></tr><tr><td><p>14i</p></td><td><p>SI</p></td><td><p>N</p></td><td><p>N</p></td><td><p>KSNN₂CO₂M</p><p>glycine salt</p></td></tr>

Example 12- {4 - ((7-Bromo-2-

quinolinyl) oxy) phenoxy} propionylamide (146) A mixture of 2- {4 - [(7-bromo-2-quinolinyl) oxy] phenoxy}

propionic acid 11c (0.20 g, 0.52 mmol) and ZOSI2 (0.40 mL, 0.66 g, 5.4 mmol) was heated for 1 hour, then solid obtained by evaporation to a yellow towat. This substance was dissolved in THD (10 ml); added methylamine (2M in TIIR) until the mixture became basic, and by evaporation obtained a yellowish solid. Addition (10 ml) and saturated NNOSO to pH8 and extraction of a mixture of AcOEI (2x25 ml). The combined extractspromated with saturated CHClC (10 mL) and after drying (MgSO4) were filtered through silica gel and evaporated to yield a crude white solid. This material was recrystallized with EYUN-heptane to give the title compound

146 (0.20 g, 95%) as white crystals; mp 150-151 ° C;¹H NMR (400 MHz, CDCl3)? 8.06 (6, J = 8.8, HZ, 1H), 7.93 (6, J = 1.6 Hz, 1H), 7.59 (6, J = 9.2Hz, 1H), 7.48 (66, = 8.4, 1.6 Hz, 1H), 7.19-7.14 (t, 2H), 7.07 (6, J = 8.8, HZ, 1H), 6.97-6.91 (t, 2H), 6.56 (bv, 1H), 4.68 (i, J = 6.4 Hz, 1H), 2.87 (6, J = 5.2 Hz, 3H), 1.60 (6, J = 6.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl3)? 173.0, 162.6, 154.2, 148.0, 147.3, 139.8, 130.4, 128.8, 128.4, 124.4, 124.2, 123.1, 116.5, 113.3, 75.9, 26.2, 19.1. (MI) t / ζ (%) 400 (M +, 33), 342 (40), 328 (6), 316 (22), 298 (7), 206 (17), 189 (5), 149 ( (19), 55 ( 21), 45 (7). NRMZ (mass spectroscopy of high separation capacity) (EI) (electronic ionization), t / ζ 400.0426 (calculation for ^ ππΙΦΒ ^ 400.0423).

Example 2

2- {4 - ((7-Chloro-2-quinolinyl) oxy) phenoxy} propionimethylamide (14e)

A mixture of 2- {4 - [(7-chloro-2-quinolinyl) oxy] phenoxy} propionic acid 13c (0.45g, 1.3mmol) and ZOSI2 (0.48ml, 0.78g, 6.6mmol) was heated to reflux within 1 hour. After cooling, the solution was evaporated under reduced pressure with evaporation of a yellow liquid dissolved in THP (15 ml). Add dimethylamine (2M in THP) until the mixture failed to become basic and evaporated to give a light brown solid. Water (15 ml) and saturated I / NaHCO3 were added to pH 8, a mixture of extra-cooled AcOEI (2x25 ml). The combined extracts were diluted with saturated IIAcI (2x10 mL) and after drying (MdO4), by evaporation, they received zoloturine. This liquid was purified by flash column chromatography (1: 4 hexane and: AsOEI) (P1 = 0.44 (1: 4 hexanes: AsOEI)) to give a white solid, which crystallized with EUN-heptane to give the title compound 14e (0.42 g, 87%) in the eyes of a dirty white solid, m.p. 148-150 ° C;¹H NMR (400 MHz, CDCl3)? 8.05 (6, J = 9.2Hz, 1H), 7.75 (6, J = 2.4 Hz, 1H), 7.65 (6, J = 9.2 Hz, 1H), 7.34 (66, (T, 2H), 4.96 , 3.14 (c, 3H), 2.97 (c, 3H), 1.62 (6, J = 7.2.2H, 3H). ¹³C NMR (100 MHz, CDCl3)? 171.3, 162.8, 154.6, 147.6, 147.2, 139.6, 135.9, 128.7, 127.2, 125.8, 124.1, 122.9, 115.9, 113.0, 74.5, 36.8, 36.6, 17.9. IR (infrared spectroscopy) (KBr) 1650, 1605, 1590, 1570, 1485, 1435, 1420, 1410,

1395, 1370, 1365, 1340, 1295, 1280, 1250, 1225,

1190, 1160, 1140, 1115, 1100, 1080, 1065, 1030,

1005, 990, 960, 940, 875, 850, 825, 805, 790, 770,

730, 625, 605, 505, 480, 450, 360 cm '¹. M3 (E1) m / z (%) 370 (M +, 30), 298 (48), 270 (21), 254 (15), 236 (3), 220 (3), 191 (8), 135 ( 3), 127 (11), 105 (3), 100 (100), 91 (4), 72 (47), 69 (6), 57 (6), 55 (8), 44 (6), 28 15). A similar calculation for C20H19Ii2CI3: C, 64.78; H, 5.16; N, 7.55. Found: C, 64.55; H, 5.15; N, 7.47.

Example 3

Sodium (2- (4- (7-chloro-2-

quinoxalinyl) oxy) phenoxy) propionylamino-ethanesulfonate (141)

A mixture (HK469) (0.49 g, 1.4 mmol) and 3 CO 2

(0.52 mL, 0.85 g, 7.1 mmol) was heated at 1

hours, and then by evaporation got

yellow liquid dissolved in THP (1.5 ml). Otri-

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35

The manic solution and 1M NaOH (1.6 ml, 1.6 mmol) added in drops at an even speed to a solution of sodium beta-aminoethyl sulfonate (taurine) (0.17 g, 1.3 mmol) in 1M NaOH (1.4 ml, 1.4 mmol) at 0 ° C. After stirring for 0.5 h at room temperature, the mixture was diluted with water (10 ml) and added to the IM H2O4 to pH3. The mixture was washed with ether (2x25 mL), and the NaOH layer was added to the pH of a pH of 7, and then evaporated and dried to give a yellow tow solid. This substance was poured by frying CH3OH, the insoluble material was filtered off, the filtrate was evaporated and recrystallized from CH3OH-EUN to give the title compound; (0.47 g, 74%) in the form of white crystals, m.p.250-252 ° C.;¹H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.99 (C, 6 = 8.8 Ni, 1H), 7.71 (C, J = 1.6 Ni, 1H), 7.61 (C, J = 8.8 N, 1H ), 7.21 (C, J = 9.2 N, 2H), 7.06 (C, J = 8.8 N, 2H), 4.72 (ς, J = 6.4 N, 1H), 3.74-3.58 (t, 2H), 3.03-2 . 88 (t, 2H), 1.57 (C, J = 6.8 N, 3H). IA (KBG) 3260, 1650, 1565, 1550, 1500, 1485, 1440, 1395, 1370, 1330, 1290, 1260, 1230, 1195, 1140, 1105, 1090, 1055, 1000, 915, 835, 820, 805, 770.695, 665, 635, 610, 530, 500, 430 cm '¹; MZ (EI, non-negative ion) t / z (%) 450 (M ''^and. 100), 343 (3).

Distribution by chiral HPII-C (Z-enantiomer 19.6 minutes, I-enantiomer 23.2 minutes) with the use of the column Yeedis (Y, Y) -NPe1k-O1 250x4.6mm, 75% hexanes, 25% 2-Phon, 15mm A ^ NN at 1.5 mL / min, detection at 245 nm.

The same series of reactions was carried out with compound ХК469 (Я +) or (С-) to obtain the corresponding enantiomer of compound 14; (I +), mp 250-252 ° C, [α] ο = + 20.2 ° (c = 0.50, H2O); or (C-) 251-253 ° C, [a] 0 = -20.0 ° (c = 0.50, H2O).

Example 4

A. Racemic. Sodium (2- (4- (7-bromo-2-quinolinyl) oxy) phenoxy) propionylamino-ethanesulfonate (14d)

A mixture of the compound 11c ^ I-Bg; A = CH) (which was obtained according to J. S. Sp. 2002, 45, 3130, 3135, see Compound 11C) (0.23 g, 0.59 mmol) and ZOSI2 (0.45 mL, 0.73 g, 6 , 2 mmoles) was heated for 1 hour, and then by evaporation, obtained a yellow solid, which was dissolved in THF (2.0 ml). This solution and 1M NaOH (0.7 mL, 0.7 mmol) were added dropwise to a solution of taurine (0.07 g, 0.55 mmol) in 1M NaOH (0.6 mL, 0.6 mmol) at 0 ° C. After stirring for 0 , 5 hours at room temperature, the mixture was diluted with water (5 mL) and 1M H2O4 to pH3. The mixture was washed with ether (2x10 mL), in a water layer, 1M NaOH was added to pH7, then evaporated and dried to give the title compound 14d as a dirty-white solid. This substance was mixed with hot CH3OH, the insoluble material was filtered, and the filtrate was evaporated and recrystallized from CH3OH to give the title compound (0.21 g, 75%) in the form of dirt-white crystals. T.p. 231-233 ° C;¹H NMR (400 MHz, CDCl3) δ 8.26 (C, J = 9.2 Hz, 1H), 7.87 (C, J = 1.6 Hz, 1H), 7.76 (C, J = 8.0 Hz, 1H), 7.55 = 8.8, 1.6 Hz, 1H), 7.18-7.10 (t, 3H), 7.08-7.02 (t, 2H), 4.72 (η, γ = 6.4 Hz, 1H), 3.71-3.60 (t, 2H), 3.04- 2.90 (t, 2H), 1.57 (C, J = 7.6 Hz, 3H).

B. (H) -enantiomer. Sodium (2- (4- (7-bromo-2-quinolinyl) oxy) phenoxy) propionylamino-ethanesulfonate {14d (I)}

36

They were prepared according to the procedure described above (A Racemic), with the exception that the compound was obtained by the esterification of 8c and 11 - (+) - 2- (4-hydroxyphenoxy) propionic acid 10, which is commercially available.

(I) -anantiomer: mp 251-253 ° C, [a] D = + 20.0 °

(c = 0.25, CH3OH). Distribution by chiral HPII-C (Z-enantiomer 21.8 minutes, I-enantiomer 25.7 mm -line) using column Yeedis (Y, Y) -NePeK-O1 250x4.6mm, 75% hexanes, 25% 2-PhpOn, 15mMaFNN at 1.5ml / min, detection at 230nm.

Example 5

A racemic. {2- [4- (7-Bromo-quinolin-2-yloxy) -phenoxy] -propionylamino} acetic acid (14P)

They were prepared according to the procedure of Example 4 with the consequence that the glycine solution was replaced with soluble taurine to obtain a compound of the formula that corresponds to 14P, wherein Y = H, i.e., Z = -NnsH2SO2N, mp 157-159 ° C. or its salts.

B. (I) -anantiomer. {2- [4- (7-Bromo-quinoline-2-yloxy) -phenoxy] -propionylamino} acetic acid (14P (H)).

They were made according to the procedure described above (A. Racemic), with the exception that the compound 11c was obtained by the esterification of 8c and H - (+) - 2- (4-hydroxyphenoxy) propionic acid 10, which is serially released.

(I) -anantiomer: mp 172-174 ° C, [a] D = +8.6 ° (c = 0.50, CH3OH). Distribution of chiral nRi_C (Z-enantiomer 24.0 min, I-enantiomer 29.0 w-lin) using a column Yeedis (Y, Y) -NePeK-O1 250x4.6mm, 65% hexanes, 35% 2-Phon, 15mA ^ NN at 1 ml / min, detection at 220 nm.

Example 6

Α Racemic {2- {4- (7-Chloro-quinoxalin-2-yloxy) -phenoxy} -propionylamino} acetic acid (14i).

They were prepared according to the procedure of Example 3, with the consequence that the glycine solution was replaced with soluble taurine to obtain a compound of the formula which corresponds to 14I, wherein Y = H, i.e., Z = -Nη ^ 2 ^ 2 U.sub.188-190.degree. C. or its salts .

B. (I) -anantiomer. {2 {4- (7-chloro-quinoxalin-2-yloxy) -phenoxy} -propionylamino} acetic acid (14i (I)).

They were prepared according to the procedure described above (A. Racemic), with the exception that HK469 was obtained by the esterification of serially released H - (+) - 2- (4-hydroxyphenoxy) propionic acid.

(I) -anantiomer: mp 190-192 ° C, [a] d = + 19.0 °

(c = 0.50, 0.1 M NaOH). Distribution by chiral HPII-C (Z-enantiomer 21.7 minutes, I-enantiomer 26.7 mm -line) using column Yeedis (Y, Y) -NePeK-O1 250x4.6mm, 65% hexanes, 35% 2-PhpOn, 15mMa4NN4 at 1ml / min, detection at 240nm.

Example 7

The following are examples of pharmaceutical pharmaceutical forms containing a compound of the formula I ("Compound X") for therapeutic or prophylactic use in humans.

37

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38

<tr><td><p>(i) Tablet 1</p></td><td><p>mg / pill</p></td></tr><tr><td><p>"Connection"</p></td><td><p>100.0</p></td></tr><tr><td><p>Lactose</p></td><td><p>77.5</p></td></tr><tr><td><p>Povidon</p></td><td><p>15.0</p></td></tr><tr><td><p>Sodium croscalliosis</p></td><td><p>and 2.0</p></td></tr><tr><td><p>Microcrystalline cellulose</p></td><td><p>92.5</p></td></tr><tr><td><p>Magnesium stearate</p></td><td><p>12</p></td></tr><tr><td><p>(ii) Tablet 2</p></td><td><p>300.0</p><p>mg / pill</p></td></tr><tr><td><p>"Compound X"</p></td><td><p>20.0</p></td></tr><tr><td><p>Microcrystalline cellulose</p></td><td><p>410.0</p></td></tr><tr><td><p>Starch</p></td><td><p>50.0</p></td></tr><tr><td><p>Sodium starch glycollate</p></td><td><p>15.0</p></td></tr><tr><td><p>Magnesium stearate</p></td><td><p>12</p></td></tr>

500.0

(iii) capsule mg / capsule

"CompoundX" 10.0

<tr><td><p>Colloidal silicon dioxide</p></td><td><p>1.5</p></td></tr><tr><td><p>Lactose</p></td><td><p>465.5</p></td></tr><tr><td><p>Peptized starch</p></td><td><p>120.0</p></td></tr><tr><td><p>Magnesium stearate</p></td><td><p>12</p></td></tr><tr><td><p></p></td><td><p>600.0</p></td></tr>

(Ιν) Solution for injection 1

"Compound X" (in the form of free acid)

Bicomponent of sodium phosphate

Monobasic sodium phosphate

Sodium chloride

how much it takes to bring the pH to 7.0-7.5

Water for injections

(ν) Injectable solution 2 (10 mg / mol)

"Compound X" (in the form of free acid)

Monobasic sodium phosphate

Bicomponent sodium titanium phosphate grout sip

wide ιχαύιςβ »тгл тсвсккиш Ъц в и * О-Уй

th] oh^-leighlsch^-laa^-l C'N)

(νA) Aerosol

"Compound X"

Oleic acid

mg / mol

1.0

12.0

0.7

4.5

as much as 1 mlm / ml

10.0

0.3

1.1

ПШИИМАМ иисЬ§сяО ТЮ 1 "в

ZDO'O

mg / vial

20.0

10.0

Trichlormonofluoromethane 5000.0

Dichlorodifluoromethane 10000.0

Dichlorotetrafluoroethane 5000.0

The above-mentioned compositions may be obtained by conventional methods known in pharmaceutical technology.

All publications, patents, and patent documents are included in this application as a reference, so that each of them was included in this application in the link. The invention is described on the appendix of various specific and best embodiments and methods. However, it is worthwhile to understand that multidisciplinary modifications and modifications can be made in the regions of the invention.

39

79293

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Table I. Evaluation of compounds 14a and XK469 with respect to the early stage adenocarcinoma of the pancreas 03 in male biceps,

<tr><td><p>Cage</p></td><td><p>Treatment/</p><p>method of input</p></td><td><p>G rafik</p></td><td><p>Total dose</p><p>mg / kg</p></td><td><p>Average loss</p><p>body weight</p><p>g / miip</p></td><td><p>in</p><p>!</p></td><td><p>The day is lower</p><p>the value of the loss</p><p>balance</p></td><td><p>Number</p><p>drug deaths</p><p>(days of death)</p></td><td><p>Medium</p><p>tumorous</p><p>load in</p><p>mg on the 14th day ·</p><p>(range)</p></td><td><p>T / C,%</p><p>1</p></td><td><p>Absence</p><p>tumors on the 21st</p><p>day</p></td><td><p>Time up to 1000 mg ¹</p><p>days (range)</p></td><td><p>T-S (in days)</p></td><td><p>&gt; 1</p><p>In there is »</p><p>and</p></td><td><p>Comments</p></td></tr><tr><td><p>1</p></td><td><p>None</p><p>Xh</p></td><td><p></p></td><td><p></p></td><td><p>-0.4</p></td><td><p>-1.8</p></td><td><p>5</p></td><td><p>0/5</p></td><td><p>1724 (580-2932)</p></td><td><p></p></td><td><p>0/5</p></td><td><p>11 (11-16)</p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>5</p></td><td><p>14a (RO)</p></td><td><p>003 and 9-th and</p><p>I'm 7-8</p></td><td><p>1.32</p></td><td><p>-0.8</p></td><td><p>-3.6</p></td><td><p>8</p></td><td><p>0/5</p></td><td><p>126 (63-385)</p></td><td><p>7.3</p></td><td><p>0/5</p></td><td><p>23 (21-35)</p></td><td><p>12</p></td><td><p>1.9</p></td><td><p>Active</p><p>(++)</p></td></tr><tr><td><p>6</p></td><td><p>14a (RO)</p></td><td><p>003-6,9-11VY 7-8</p></td><td><p>660</p></td><td><p>-Ol</p></td><td><p>-1.8</p></td><td><p>5</p></td><td><p>0/5</p></td><td><p>695 (342-1389)</p></td><td><p>40</p></td><td><p>0/5</p></td><td><p>15.5 (13-</p><p>18.5)</p></td><td><p>4.5</p></td><td><p>0.7</p></td><td><p>Active (+)</p></td></tr><tr><td><p>7</p></td><td><p>14a (RO)</p></td><td><p>003-6,9-11VY 7-8</p></td><td><p>330</p></td><td><p>-0.4</p></td><td><p>-1.8</p></td><td><p>6</p></td><td><p>0/5</p></td><td><p>1273 (343-1975)</p></td><td><p>74</p></td><td><p>0/5</p></td><td><p>13 (11.5-22)</p></td><td><p>2</p></td><td><p>oz</p></td><td><p>Inactive</p><p>&lt;-)</p></td></tr><tr><td><p>8</p></td><td><p>HK469</p><p>(IV)</p></td><td><p>003-5</p></td><td><p>180</p></td><td><p>-3.6</p></td><td><p>-15.5</p></td><td><p>8</p></td><td><p>0/5</p></td><td><p>189 (126-297)</p></td><td><p>11</p></td><td><p>0/5</p></td><td><p>20 (18.5-23)</p></td><td><p>9</p></td><td><p>1.4</p></td><td><p>Active</p><p>(++)</p></td></tr>

&lt;&gt; О - once a day, ВЮ - 2 times a day

Mice * males B1) (■ ';; à () β (date of birth): 6/14/99; OOA (date of acquisition): 7/27/99; Source: N111' SKI. cotton wool - 22.8 g

Tumor; Adenocarcinoma of the pancreas ROS / 215; OOT (transplantation date): 8/2/99, time to 1 (U0mg = 1] days; GHS - 1,9 days

Preparation: Compound 14a: light yellow powder + 3% EION + 1% Tether-80 + dst. Nio - "suspension; pH 5.5; 0.2 ml / mouse / injection, compound XC469: (NIH: O697887, series K518-140-1): 90 mg / kg of the liquid stock solution was diluted to a bol / kg dst. NZO- * solution; pH 8.0-&gt; 6.5 using 1.0 N HCl; 0.2ml / min / inject.

Table 2. Evaluation of compound 14b in relation to early stage pancreatic duct adenocarcinoma

<tr><td><p>5</p><p>N</p><p>I</p><p>I"</p></td><td><p>Kh / way</p><p>introduction</p></td><td><p>Schedule</p></td><td><p>Total dose</p><p>mg / kg</p></td><td><p>Average body loss, g / mouse</p></td><td><p>% body weight loss</p></td><td><p>The day is the lowest value of the loss</p><p>balance</p></td><td><p>In the deaths from</p><p>1 medication</p></td><td><p>Average tumorload in mga 18th day (range)</p></td><td><p>T / C,%</p></td><td><p>23 Eeyore 8</p><p>How from</p><p>З □ д ор 3</p><p>- SG</p><p>E</p><p>£</p><p>Where</p></td><td><p>Time to time (range)</p></td><td><p>Slow growth (in days)</p></td><td><p>Logarithmation of cells</p></td><td><p>Rating</p><p>activity</p></td></tr><tr><td><p>1</p></td><td><p>None of them</p></td><td><p></p></td><td><p></p></td><td><p>0</p></td><td><p>0</p></td><td><p>5</p></td><td><p>-</p></td><td><p>1713 (1295-2486)</p></td><td><p>-</p></td><td><p>0/5</p></td><td><p>13 (11-14)</p></td><td><p>-</p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>2</p></td><td><p>HK469</p><p>(IV)</p></td><td><p>OBZ-b, 10</p></td><td><p>300</p></td><td><p>-3.2</p></td><td><p>15</p></td><td><p>8</p></td><td><p>0/5</p></td><td><p>64 (32-126)</p></td><td><p>4</p></td><td><p>1/5</p></td><td><p>41.1 (36.6-</p><p>44.3)</p></td><td><p>28.1</p></td><td><p>3.3</p></td><td><p>Highly active (++++)</p></td></tr><tr><td><p>3</p></td><td><p>14b (RO)</p></td><td><p>I'm 3-7</p></td><td><p>2300</p></td><td><p>-2.0</p></td><td><p>9</p></td><td><p>8</p></td><td><p>0/5</p></td><td><p>671 (203-748)</p></td><td><p>39</p></td><td><p>0/5</p></td><td><p>21 (19.5-38)</p></td><td><p>7.0</p></td><td><p>0.8</p></td><td><p>Moderately active {+}</p></td></tr><tr><td><p>4</p></td><td><p>14b (RO)</p></td><td><p>YOU 3.4</p></td><td><p>480</p></td><td><p>-0.8</p></td><td><p>4</p></td><td><p>5</p></td><td><p>0/5</p></td><td><p>1266 (895-1600)</p></td><td><p>74</p></td><td><p>0/5</p></td><td><p>15 (14.5-15)</p></td><td><p>2.0</p></td><td><p>0.2</p></td><td><p>Inactive (-)</p></td></tr><tr><td><p>5</p></td><td><p>14 of her (RO)</p></td><td><p>joining</p></td><td><p>108</p></td><td><p>+0.4</p></td><td><p>0</p></td><td><p>5</p></td><td><p>0/5</p></td><td><p>1312 (756-1387)</p></td><td><p>77</p></td><td><p>0/5</p></td><td><p>15.7 (13.8-</p><p>19.8)</p></td><td><p>2.7</p></td><td><p>0.3</p></td><td><p>Inactive (-)</p></td></tr>

C) O - once a day, VU - 2 times a day

Mice: female VO1; Source: SKG-KAIeitsiy, OOI: 1/24/00; ΠΟΑ: 2/29/00; Compared weight-21.6 g / mouse;

Tumor: ROS / 229; YOUTH: 4.14.00; TD = 2.6 days

Preparation: compound HK.469 (racemic, series K8 18-140-1, N01): white powder + 1% niacin, + solution PB5 (polybutadiene sterin); pH adjusted to 7.0 with the help of NSI; 0.2ml / min / injection; Compound 14b: white powder + 5% EUN, 3% suspension ORE (polyoxyethylene) + PV5; pH 7; 0.2 ml / milia / injections.

41 79293 42

Table 3. Evaluation of Compound 14c for Adult Mammary Adenocarcinoma 17 / AR of the Early Stage

<tr><td><p>Cage</p></td><td><p>Compound for KH (method</p><p>introduction)</p></td><td><p>Number of injections</p></td><td><p>Total dose, mg / hr</p></td><td><p>% body weight loss at</p><p>lower meaning</p></td><td><p>The day is the lowest value ¹</p><p>__</p></td><td><p>and. IA inⁱⁿ 8</p><p>3</p><p>at</p><p>X</p><p>1</p><p>η</p><p>5 &lt;</p><p>"</p><p>5 '</p></td><td><p>»Lit.</p><p>G ° "§</p><p>8 5th and</p><p>ee e</p><p>2 = i vv</p></td><td><p>% t / s</p></td><td><p>Slow growth (in</p><p>days)</p></td><td><p>Logarithm of killing</p><p>1</p></td><td><p>k »n&gt;</p><p>T e d o</p><p>II</p><p>* with</p><p>IG</p><p>X</p><p>X</p><p>and"</p></td><td><p>Activity rating</p></td></tr><tr><td><p>1</p></td><td><p>No kh</p></td><td><p>0</p></td><td><p>0</p></td><td><p>+ 1.4%</p></td><td><p>7</p></td><td><p>-</p></td><td><p>1201 (1044-2220)</p></td><td><p>-</p></td><td><p>-</p></td><td><p>-</p></td><td><p>0/5</p></td><td><p>-</p></td></tr><tr><td><p>2</p></td><td><p>Adriamycin</p></td><td><p>2</p></td><td><p>15</p></td><td><p>-1.4%</p></td><td><p>7</p></td><td><p>0/5</p></td><td><p>1086 (863 1506)</p></td><td><p>90%</p></td><td><p>0</p></td><td><p>no</p></td><td><p>0/5</p></td><td><p>-</p></td></tr><tr><td><p>4</p></td><td><p>HK469 (1U)</p></td><td><p>6</p></td><td><p>336</p></td><td><p>-7.1%</p></td><td><p>8</p></td><td><p>0/5</p></td><td><p>108 (63-270)</p></td><td><p>9%</p></td><td><p>15.5</p></td><td><p>4.2</p></td><td><p>0/5</p></td><td><p>++ - ++</p></td></tr><tr><td><p>5</p></td><td><p>14, (RO)</p></td><td><p>6</p></td><td><p>870</p></td><td><p>-5.8%</p></td><td><p>9</p></td><td><p>0/5</p></td><td><p>243 (126-385)</p></td><td><p>20%</p></td><td><p>5.5</p></td><td><p>1.5</p></td><td><p>0/5</p></td><td><p>++</p></td></tr><tr><td><p>6</p></td><td><p>14z (RO)</p></td><td><p>6</p></td><td><p>540</p></td><td><p>+ 1.4%</p></td><td><p>9</p></td><td><p>0/5</p></td><td><p>369 (234-466)</p></td><td><p>31%</p></td><td><p>5.0</p></td><td><p>1.4</p></td><td><p>0/5</p></td><td><p>++</p></td></tr><tr><td><p>7</p></td><td><p>14 »(RO)</p></td><td><p>6</p></td><td><p>334.8</p></td><td><p>+ 0.0%</p></td><td><p>9</p></td><td><p>0/5</p></td><td><p>368 (239-878)</p></td><td><p>31%</p></td><td><p>3.5</p></td><td><p>1.0</p></td><td><p>0/5</p></td><td><p>+</p></td></tr><tr><td><p>8</p></td><td><p>14a (RO)</p></td><td><p>6</p></td><td><p>538.8</p></td><td><p>-1.4%</p></td><td><p>11</p></td><td><p>0/5</p></td><td><p>660 (271-835)</p></td><td><p>55%</p></td><td><p>3.3</p></td><td><p>0.9</p></td><td><p>0/5</p></td><td><p>+</p></td></tr>

Mice: Females SWD / No, source N01 SKK-Kip £ sion, ÏÎΒ = 12/13/99, ÏΟΑ = 1/25/00, lorivn. weight = 27, bg

The tumor is the adenocarcinoma of the mammary gland 17 / A (1 g, p-glycoprotein-postive tumor with multicellular resistance / passage-194, OOT = 3/20/2000, TÜ 1.1 days, file = 2586

Tables »4. Evaluation of compounds 11b, 14e and XK469 for adenocarcinoma of the early stage pancreatic duct in females

mice ΒΑΡΙ

<tr><td><p>Cage</p></td><td><p>X (method</p><p>introduction)</p></td><td><p>Number</p><p>injections</p></td><td><p>General</p><p>dose, mg / kg</p></td><td><p>% loss of body weight</p><p>lower</p><p>meanings</p></td><td><p>Day</p><p>LOWER</p><p>value</p></td><td><p>5 С '5, Вη 2 ^and "</p><p>1 + and</p><p>~ "1</p><p>G &lt;</p></td><td><p>Average</p><p>mass</p><p>tumor on '</p><p>14th day (range) ¹</p></td><td><p>£</p></td><td><p>1 ea</p><p>".3 5'D have *</p><p>£</p></td><td><p>Logarithm</p><p>killing</p></td><td><p>£ 11§ | 1.</p><p>. £ p</p></td><td><p>P)</p><p>■ 5 y</p><p>15^andwith §V</p></td></tr><tr><td><p>¹</p></td><td><p>No how</p></td><td><p>0</p></td><td><p>0</p></td><td><p>+ 12%</p></td><td><p>10</p></td><td><p></p></td><td><p>1513 (681-2149)</p></td><td><p>-</p></td><td><p>-</p></td><td><p>•</p></td><td><p>0/5</p></td><td><p>*</p></td></tr><tr><td><p>2</p></td><td><p>14e (RO)</p></td><td><p>14</p></td><td><p>1680</p></td><td><p>+ 4.3%</p></td><td><p>9</p></td><td><p>0/5</p></td><td><p>126 (63-264)</p></td><td><p>8.3%</p></td><td><p>16.5</p></td><td><p>2.5</p></td><td><p>0/5</p></td><td><p>+++</p></td></tr><tr><td><p>3</p></td><td><p>14e (RO)</p></td><td><p>14</p></td><td><p>840</p></td><td><p>+ 3.3%</p></td><td><p>10</p></td><td><p>0/5</p></td><td><p>234 (75-333)</p></td><td><p>15%</p></td><td><p>14.5</p></td><td><p>2.2</p></td><td><p>0/5</p></td><td><p>+++</p></td></tr><tr><td><p>4</p></td><td><p>14s (RO)</p></td><td><p>14</p></td><td><p>420</p></td><td><p>0</p></td><td><p>9</p></td><td><p>0/5</p></td><td><p>567 (446-1200)</p></td><td><p>37%</p></td><td><p>3.5</p></td><td><p>0.5</p></td><td><p>0/5</p></td><td><p>±</p></td></tr><tr><td><p>5</p></td><td><p>HK469 (IV)</p></td><td><p>7</p></td><td><p>399</p></td><td><p>-6.7%</p></td><td><p>8</p></td><td><p>0/5</p></td><td><p>63 (0-214)</p></td><td><p>4.1%</p></td><td><p>11.5</p></td><td><p>1.7</p></td><td><p>0/5</p></td><td><p>++</p></td></tr><tr><td><p>6</p></td><td><p>HK.469 (IV)</p></td><td><p>7</p></td><td><p>266</p></td><td><p>-6.7%</p></td><td><p>5</p></td><td><p>0/5</p></td><td><p>126 (0-234)</p></td><td><p>8.3%</p></td><td><p>9.5</p></td><td><p>1.4</p></td><td><p>0/5</p></td><td><p>■ n-</p></td></tr><tr><td><p>14</p></td><td><p>NO (IV)</p></td><td><p>7</p></td><td><p>336</p></td><td><p>-8.9%</p></td><td><p>1!</p></td><td><p>0/5</p></td><td><p>0 (0-126)</p></td><td><p>0%</p></td><td><p>17.5</p></td><td><p>2.6</p></td><td><p>0/5</p></td><td><p>+++</p></td></tr>

Mice: females VIRI, source SKK-KaIeI £ Іi, ООВ = 3/27/00, ПОА - 5/9/00, пор ун. weight = 18,2 gPukhlin - adenocarcinoma of the pancreas duct 03 / passage-231, VOT = 5/19/00 TU = 2, some

File = 2606 This tumor is highly sensitive to taxol (activity rating ++++) It is also quite sensible to adriamycin (activity +++). Sensitively sensitive to UR-16, cytotoxane, SiZORRi (activity rating ++). Moderately sensual to 5-RP (activity (+). Not sensual knowledge of the blast

Preparation: Compound HK469 (K): white solid: 1% bicarb. + РВ8 with a solution, pH 7.5; 0.2 ml / injection IV, once daily at day 3-9, compound 14e: white solid + 6% ethanol + 3% ROE 80 + diet. H; O to obtain a suspension, pH 4.5; 0,2 ml / sec. OR twice a day at days 3-9; and Compound 11b: white solid + 1% bicarbonate. + РВ8 with a solution, pH - 7,5; 0.2 ml / IV injection, once daily for days 3-9,

43 79293 44

Table 5. Evaluation of compound 141 "for early adenocarcinoma of the pancreas duct 03

<tr><td><p>£</p><p>3 '</p><p>X</p><p>you</p></td><td><p>Compound for</p><p>treatment (method |</p><p>introduction)</p></td><td><p>• "</p><p>¼</p><p>»</p><p>X</p></td><td><p>2 from-ι &amp;&gt;</p><p>¿£</p><p>Β</p><p>9</p><p>P »</p><p>M</p><p>1</p></td><td><p>Average loss</p><p>body weight, g / mouse</p></td><td><p>% body weight loss</p><p>at lower</p><p>meanings</p></td><td><p>The day is lower</p><p>the value of the loss</p><p>balance</p></td><td><p>Number of deaths</p><p>from drugs (day</p><p>death)</p></td><td><p>Average tumor</p><p>load in mg</p><p>on the 17th day</p><p>(range)</p></td><td><p>£</p><p>N</p><p>AT</p></td><td><p>Absence</p><p>tumors on the 35th</p><p>day</p></td><td><p>and t</p><p>η °</p><p>^X AND</p><p>5 §</p><p>In δ§ I</p><p>'' '' ¿</p></td><td><p>N</p><p>P.</p><p>AND</p></td><td><p>Logarithmization </p></td><td><p>Comments</p></td></tr><tr><td><p>1</p></td><td><p>None of them</p></td><td><p></p></td><td><p></p></td><td><p>+0.8</p></td><td><p>+3.5</p></td><td><p>11</p></td><td><p></p></td><td><p>1202 (235-1666)</p></td><td><p></p></td><td><p>0/5</p></td><td><p>16 (14-22)</p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>2</p></td><td><p>HK469 (IV)</p></td><td><p>OOP-Y</p></td><td><p>360</p></td><td><p>-1.6</p></td><td><p>-1.6</p></td><td><p>11</p></td><td><p>0/5</p></td><td><p>256 (216-554)</p></td><td><p>21</p></td><td><p>0/5</p></td><td><p>27 (20-30)</p></td><td><p>11.0</p></td><td><p>1.84</p></td><td><p>Active</p><p>(++)</p></td></tr><tr><td><p>3</p></td><td><p>14G (vi-BS)</p></td><td><p>90 3-5, 8-11, BIO 6.7</p></td><td><p>780</p></td><td><p>+0.0</p></td><td><p>+0.0</p></td><td><p>11</p></td><td><p>0/5</p></td><td><p>126 (63-322)</p></td><td><p>10</p></td><td><p>0/5</p></td><td><p>26 (24-31)</p></td><td><p>10.0</p></td><td><p>1.67</p></td><td><p>Active</p><p>(++)</p></td></tr><tr><td><p>4</p></td><td><p>&amp; lt; 4 &amp; gt; (vi-5O</p></td><td><p>1</p></td><td><p>390</p></td><td><p>+0.8</p></td><td><p>+3.5</p></td><td><p>11</p></td><td><p>0/5</p></td><td><p>600 (108-726)</p></td><td><p>50</p></td><td><p>0/5</p></td><td><p>19.5 (18-</p><p>26)</p></td><td><p>3.5</p></td><td><p>0.58</p></td><td><p>Inactive</p><p>on(-)</p></td></tr><tr><td><p>5</p></td><td><p>14G (IU)</p></td><td><p>00 3.4</p></td><td><p>30</p></td><td><p>+1.6</p></td><td><p>+7.1</p></td><td><p>11</p></td><td><p>0/5</p></td><td><p>1420 (446-</p><p>1574)</p></td><td><p>&gt; 100</p></td><td><p>0/5</p></td><td><p>16 (14-23)</p></td><td><p>0.0</p></td><td><p>0.0</p></td><td><p>Inactive</p><p>on(-)</p></td></tr>

C) P - once a day, SBU - 2 times a day

Mice: Females Set, Source: N01 RGeagis, PO C: 10/22/01, ICHE: 12/4/01 compar. weight = 22g / mnshaPukhlin: Rapeseed 03/124, POT: 2/1/02 T4 = 1.8 days

Preparation: compound XK469 (K): concentrated 99.4% solution (K) + 0.5% SNSO) + PBO - * solution (pH 7.5); 0.2 ml / mlia / injection; compound 14I: dirty white solid + dil. N₂O - solution (pH 5.5), 0.2 ml / mil / inject.

Table 6. Estimation of compound 14G (K) and 14G (5) in relation to human melanoma of early stage BPH in females of mice BAB / c

<tr><td><p>Cage</p></td><td><p>Compound</p><p>(configuration)</p><p>(way</p><p>introduction)</p></td><td><p>Schedule</p></td><td><p>Total dose</p><p>mg / kg</p></td><td><p>Average body loss, g / mouse</p></td><td><p>Percentage loss of weightlifted weight</p></td><td><p>The day is the lowest value of the loss</p><p>balance</p></td><td><p>Number of deaths from drugs (day of death)</p></td><td><p>Medium tough non-loading IMG for the 9th day (range)</p></td><td><p>£</p><p>N</p><p>p</p></td><td><p>Absence of tumors on the 13th day</p></td><td><p>Time to time (range)</p></td><td><p>T-S {in days)</p></td><td><p>Logarithm</p><p>killing</p></td><td><p>Comments</p></td></tr><tr><td><p>¹</p></td><td><p>No kh</p></td><td><p></p></td><td><p></p></td><td><p>+1.2</p></td><td><p>+5.9</p></td><td><p>7</p></td><td><p></p></td><td><p>1394 (1057-1674)</p></td><td><p></p></td><td><p>0/5</p></td><td><p>8.0 (8.0-</p><p>9.0)</p></td><td><p></p></td><td><p></p></td><td><p>Inactive</p><p>(-)</p></td></tr><tr><td><p>2</p></td><td><p>NGSVD (IU)</p></td><td><p>&lt;зш-6, ув</p><p>7</p></td><td><p>700</p></td><td><p>-2.8</p></td><td><p>13.5</p></td><td><p>13</p></td><td><p>0/5</p></td><td><p>651 (63-1114)</p></td><td><p>47</p></td><td><p>0/5</p></td><td><p>11.0 (8.5-</p><p>23.5)</p></td><td><p>3.0</p></td><td><p>0.8</p></td><td><p>Active</p><p>&lt;+)</p></td></tr><tr><td><p>3</p></td><td><p></p></td><td><p>90 ı-ı, ış</p><p>7</p></td><td><p>700</p></td><td><p>+0.4</p></td><td><p>2.0</p></td><td><p>8</p></td><td><p>0/5</p></td><td><p>994 (734-1200)</p></td><td><p>71</p></td><td><p>0/5</p></td><td><p>9.0 (8.0-10.0)</p></td><td><p>1.0</p></td><td><p>0.3</p></td><td><p>Inactive</p><p>(-)</p></td></tr><tr><td><p>4</p></td><td><p>HK469 (K) (IV)</p></td><td><p>90 1-7</p></td><td><p>(P. 75)</p></td><td><p>-1.6</p></td><td><p>8.0</p></td><td><p>7</p></td><td><p>0/5</p></td><td><p>467 (234-1067)</p></td><td><p>34</p></td><td><p>0/5</p></td><td><p>11.3 (9.0-</p><p>13.0)</p></td><td><p>z.z</p></td><td><p>0.8</p></td><td><p>Active</p><p>(+)</p></td></tr>

OP - once a day, VU - 2 times a day

Mice: Va1 / s8SJ, source: N01 Ragebiscus, POV 11/26/01 - 12/3/01, POA: 1/8/02 cfp. Weight: 20.3 g / mouse

Tumor: human melanoma LOX / 398, POT: 4/8/02 Tue: 1.2 days

Preparation: compound ХК469 (К): {98.4 enanthus, excess); 0.5% SNSO₃ + РВ8 - "solution (pH 9 + 1Н НС! -» рН 7); 0.2 ml / mouse / инъекция; compound 14G (K); white solid + dist. N₂O -► solution (pH 5.5); 0.2 mL / mouse / injection; and compound 143 (5): white solid + dil. N₂O - * solution (pH 5.5); 0.2ml / min / inject.

45

79293

46

Table 7. Estimation of racemic I4u compound, XK469 (K) and 11 c (K) for early breast adenocarcinoma 161c

<tr><td><p>£</p><p>1</p><p>that's it</p></td><td><p>00</p><p>B</p><p>X</p><p>£</p></td><td><p>Way</p><p>introduction</p></td><td><p>Schedule</p></td><td><p>Total dose</p><p>mg / kg</p></td><td><p>Average loss</p><p>body weight</p><p>g / mouse</p></td><td><p>and·*</p><p>and</p><p>X</p><p>u</p><p>X</p></td><td><p>The day is lower</p><p>value</p><p>weight loss</p></td><td><p>oh oh oh</p><p>2 J · P ·</p><p>Λ O. Gy Ya</p><p>41 ·</p><p>2 »p</p><p>IS'</p></td><td><p>K ζ and 'Ζ ^p</p><p>And And And I.</p><p>1 &amp; i</p><p>3rd 3rd</p><p>with</p></td><td><p>£</p><p>N</p><p>AT</p></td><td><p>Absence</p><p>tumors on the 161-</p><p>th day</p></td><td><p>Time to YUOmg</p><p>in days</p><p>(range)</p></td><td><p>T-S (in days)</p></td><td><p>Logarithm</p><p>killing</p></td><td><p>Comments</p></td></tr><tr><td><p></p></td><td><p>None</p><p>Them</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p>+0.8</p></td><td><p>0.0</p></td><td><p>4</p></td><td><p></p></td><td><p>1656 (1418-2526)</p></td><td><p></p></td><td><p>0/5</p></td><td><p>8 (7-8)</p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>2</p></td><td><p>14c</p><p>raiyimich</p></td><td><p>IV</p></td><td><p>wow</p><p>1-5</p></td><td><p>600</p></td><td><p>'²'³</p></td><td><p>-11.0</p></td><td><p>4</p></td><td><p>0/6</p></td><td><p>230 (0-728)</p></td><td><p>14</p></td><td><p>1/6</p></td><td><p>11.5 (9.5-13)</p></td><td><p>3.5</p></td><td><p>0.9</p></td><td><p>Assets</p><p>on (+)</p></td></tr><tr><td><p>3</p></td><td><p>HK469</p><p>(I)</p></td><td><p>IV</p></td><td><p>OO</p><p>1-5</p></td><td><p>250</p></td><td><p>-4.4</p></td><td><p>-21.2</p></td><td><p>7</p></td><td><p>0/5</p></td><td><p>63 (0-365)</p></td><td><p>4</p></td><td><p>0/5</p></td><td><p>14.5 (12.5-</p><p>19)</p></td><td><p>6.5</p></td><td><p>1.6</p></td><td><p>Toxin</p><p>on</p></td></tr><tr><td><p>4</p></td><td><p>No (b)</p></td><td><p>IV</p></td><td><p>oh</p><p>1-5</p></td><td><p>240</p></td><td><p>-6.0</p></td><td><p>-29.4</p></td><td><p>9</p></td><td><p>1/5 (10)</p></td><td><p>0 (all zeros)</p></td><td><p>0</p></td><td><p>0/5</p></td><td><p>15.2 (13-17)</p></td><td><p>7.2</p></td><td><p>1.8</p></td><td><p>Toxin</p><p>on</p></td></tr>

&lt;) О - once a day, ВЮ - 2 times a day

Mice: Females; Source: SKJ - Knierzion, UL: 3-18-02, OOA: 4-22-02; equally Weight = 20.6 g / mouse Swollen: Breast gland 16/3/204; UT: 5-6-02; T4 = 1.2 days

Preparation: compound 14 {· racemic: white solid + dist. N₂O + heating -&gt; solution (pH 7); 0.2ml / mouse / iye; Compound HK469 (K) white solid + O, 5% (vol.) IaSPO, + dist. NgO - ♦ solution (pH 10 -&gt; 7 using 1 H HCl); 0.2 ml / mouse / injection; Compound 11c (B): white solid + 0.5% (v / v) NaHCO3 + dist. N_;O - ♦ solution; (pH 10-&gt; 7 with the help of 1 H HCl); 0.2ml / wash / injection.

T a and 8. Evaluation of compounds 14G IIC), 11c (K) and HK.469 (K) for adenocarcinoma of the mammary gland 16 / from the early stage

<tr><td><p>£</p><p>N</p><p>X</p></td><td><p>Treatment</p></td><td><p>Method of input</p></td><td><p>Schedule</p></td><td><p>ω ω</p><p>■ D-</p><p>ζ and</p><p>and</p><p>I"</p><p>ı</p><p>8</p><p>R</p></td><td><p>Average body loss, g / mouse</p></td><td><p>% body weight loss</p></td><td><p>LOW LINE mark of loss</p><p>balance</p></td><td><p>Number of deaths from drugs (death of death)</p></td><td><p>Average tumorload in Mgna 7th day (range)</p></td><td><p>WR</p><p>AT⁴</p><p>N</p><p>and</p></td><td><p>Lack of tumors on the 28th day</p></td><td><p>Time up to 1000mg (range)</p></td><td><p>T-S (in days)</p></td><td><p>Logarithm</p><p>killing</p></td><td><p>Comments</p></td></tr><tr><td><p>1</p></td><td><p>None</p><p>Xh</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p>+1.6</p></td><td><p>+5.8</p></td><td><p>7</p></td><td><p></p></td><td><p>1820 (1286-2736)</p></td><td><p>0</p></td><td><p>0/5</p></td><td><p>6 (all on the 6th day)</p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>2</p></td><td><p>11IU</p></td><td><p>IV</p></td><td><p>&lt;} 20x8</p></td><td><p>480</p></td><td><p>4.2</p></td><td><p>-4.3</p></td><td><p>14</p></td><td><p>0/5</p></td><td><p>0 (all zeros)</p></td><td><p>0</p></td><td><p>0/5</p></td><td><p>22 (20-24)</p></td><td><p>16</p></td><td><p>4.8</p></td><td><p>Active</p><p>(++++)</p></td></tr><tr><td><p>3</p></td><td><p>HK469</p><p>(Yu</p></td><td><p>IV</p></td><td><p>ò? 2Î "8</p></td><td><p>480</p></td><td><p>-2.0</p></td><td><p>-7.4</p></td><td><p>18</p></td><td><p>0/5</p></td><td><p>0 (all zeros)</p></td><td><p>0</p></td><td><p>0/5</p></td><td><p>24 (19-26)</p></td><td><p>18</p></td><td><p>5.4</p></td><td><p>Active</p><p>(++++)</p></td></tr><tr><td><p>4</p></td><td><p>14th (K)</p></td><td><p>IV</p></td><td><p>Days 1, 3-5, 7,</p><p>At 11, IZ, 15</p></td><td><p>І6І0</p></td><td><p>4), 8</p></td><td><p>oh, oh</p></td><td><p>14</p></td><td><p>0/5</p></td><td><p>O (0-151)</p></td><td><p>0</p></td><td><p>0/5</p></td><td><p>20 (16.5-</p><p>22)</p></td><td><p>14</p></td><td><p>4.2</p></td><td><p>Active</p><p>(++++)</p></td></tr><tr><td><p>5</p></td><td><p>I4G (K)</p></td><td><p>IV</p></td><td><p>Days 1-7, 9</p></td><td><p>665</p></td><td><p>• 0.8</p></td><td><p>-2.9</p></td><td><p>5</p></td><td><p>0/5</p></td><td><p>260 (0-523)</p></td><td><p>14</p></td><td><p>0/5</p></td><td><p>12 (10-</p><p>16.5)</p></td><td><p>6</p></td><td><p>1.8</p></td><td><p>Active</p><p>&lt;++&gt;</p></td></tr>

02O after a day

Mice: females C) N / A M'GU (-); Source: ISI-RheseIghisk; YOU 8-19-02; IZOA: 10-1-02; cf. weight = 27, bh / mouse

Tumor: Math I6 / C73; OOT: and 1-04-02; T4 = 1.0 day

Preparation: Compound 11c (H) white solid + 3% E (OH + 1% ROE + 0.25% (vol.) MnSOz + dilute NHO - * solution (pH 9 - * 7 using 1 H HCl); OXYML / Mouse / IV injection; Compound XK469 (K) white solid + 3% EION + 1% ROE + 0.25% (v / v) IANOSO + dilution H_gO - »solution (pH 7,5); 0.2 ml / mnshaII Lection IV; Compound 14G (B): white solid + dil NIO - "solution (pH 5); O ^ ml / mouse / IV injection

47

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48

Table 9. Evaluation of 14β (I) and 11c (I) compounds in the early stage of the pancreas duct adenocarcinoma adenocarcinoma 03

<tr><td><p>3 '</p><p>I</p><p>No.</p></td><td><p>AND</p><p>I</p><p>η</p><p>and</p><p>ε</p></td><td><p>1 Method of Input</p></td><td><p>Schedule</p></td><td><p>Total dose</p><p>mg / kg</p></td><td><p>Average loss</p><p>body weight, g / mouse</p></td><td><p>% weight loss</p><p>body</p></td><td><p>⁵ 1 5</p><p>the same</p><p>From 5</p></td><td><p>Number of deaths</p><p>from drugs (day</p><p>death)</p></td><td><p>Average tumor</p><p>load in</p><p>mg on the 14th day</p><p>(range)</p></td><td><p>% t / s</p></td><td><p>Absence</p><p>tumors on the 31st</p><p>day</p></td><td><p>Time to UOOmga</p><p>days (range)</p></td><td><p>£</p><p>&lt;?</p><p>AND</p></td><td><p>Logarithm</p><p>killing</p></td><td><p>Comments</p></td></tr><tr><td><p>1</p></td><td><p>None</p><p>Xh</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p>+2.0</p></td><td><p>+10.0</p></td><td><p>9</p></td><td><p></p></td><td><p>1004 (550-1093)</p></td><td><p></p></td><td><p>0/5</p></td><td><p>14 (13-18)</p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>2</p></td><td><p>NK (B)</p></td><td><p>1P</p></td><td><p>NU-5</p></td><td><p>450</p></td><td><p>4.4</p></td><td><p>-23.4</p></td><td><p>9</p></td><td><p>1/5 (10)</p></td><td><p>0 (0-63)</p></td><td><p>0</p></td><td><p>0/5</p></td><td><p>24.75 (23-27)</p></td><td><p>10.75</p></td><td><p>1.52</p></td><td><p>B20</p></td></tr><tr><td><p>3</p></td><td><p>I4k (N)</p></td><td><p>IP</p></td><td><p>WGH-7</p></td><td><p>450</p></td><td><p>-1,2</p></td><td><p>-6.7</p></td><td><p>9</p></td><td><p>0/5 '</p></td><td><p>126 (100-252)</p></td><td><p>12.6</p></td><td><p>0/5</p></td><td><p>26 (20-27)</p></td><td><p>12</p></td><td><p>1.72</p></td><td><p>Active (++)</p></td></tr><tr><td><p>4</p></td><td><p>111 (s)</p></td><td><p>IP</p></td><td><p>003-7</p></td><td><p>260</p></td><td><p>-3.2</p></td><td><p>-16.7</p></td><td><p>10</p></td><td><p>1/5 (14)</p></td><td><p>126 (0-298)</p></td><td><p>12.6</p></td><td><p>0/5</p></td><td><p>24.5 (19-26)</p></td><td><p>Y.5</p></td><td><p>1.5</p></td><td><p>B "20</p></td></tr><tr><td><p>5</p></td><td><p>YES</p></td><td><p>IP</p></td><td><p>003-7</p></td><td><p>157.5</p></td><td><p>-0.0</p></td><td><p>-0.0</p></td><td><p>9</p></td><td><p>0/5</p></td><td><p>260 (75-351)</p></td><td><p>26</p></td><td><p>0/5</p></td><td><p>25 (22.5-26)</p></td><td><p>11</p></td><td><p>1.58</p></td><td><p>Active (++) and</p></td></tr>

01) - once a day, SBU - 2 times a day

Mice: female C "; Source: LISI-Egebegisk; OOP: 7-29-02; IZOA: 9-17-02; cf. weight "18.5g," mouse

Tumor; Rape 03/135; OOT: 9-27-02, TI = 2.1 days

Preparation: Compound 14d (K): white solid + 3% EUN + 1% ROE + diet. ІІ, О - "solution (pH 7); 0.5 ml / mouse / IP injection; Compound Ne (K): white solid + 3% EUN + 1% ROE + 0.25% (v / v) NaOHO₃ + will give. N₂O -, solution (pH 9.5 - »7 with the help of 1 N HCI); 0.5 ml / min / injection of 1P

Table 10. Evaluation of compounds 14b (I), 14i (I), 1 Is (I), and XK469 (I) in relation to adenocarcinoma of the pancreatic duct of the early stage

49

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50

<tr><td><p>9</p></td><td><p>and</p></td><td><p>IP</p></td><td><p>days 3.5, 11,</p><p>13, 15</p></td><td><p>480</p></td><td><p>-3.2</p></td><td><p>-13.3</p></td><td><p>10</p></td><td><p>0/5</p></td><td><p>108 (0-171)</p></td><td><p>6</p></td><td><p>0/5</p></td><td><p>27 (26-</p><p>44)</p></td><td><p>12</p></td><td><p>1.7</p></td><td><p>Active</p><p>(++)</p></td></tr><tr><td><p>10</p></td><td><p>1</p></td><td><p>1</p></td><td><p>020: 3-15</p></td><td><p>350</p></td><td><p>-1.6</p></td><td><p>hb, 6</p></td><td><p>8</p></td><td><p>0/5</p></td><td><p>304 (63-427)</p></td><td><p>16.5</p></td><td><p>0/5</p></td><td><p>22 (21.5-</p><p>28)</p></td><td><p>7</p></td><td><p>1.0</p></td><td><p>Active</p><p>(+)</p></td></tr><tr><td><p>η</p></td><td><p>PIC)</p></td><td><p>IP</p></td><td><p>days 3, 5, 11,</p><p>13, 15</p></td><td><p>400</p></td><td><p>4.4</p></td><td><p>-18.0</p></td><td><p>9</p></td><td><p>0/5</p></td><td><p>0 (0-108)</p></td><td><p>0</p></td><td><p>1/5</p></td><td><p>38 (36-</p><p>50)</p></td><td><p>^and</p></td><td><p>3.3</p></td><td><p>Active</p><p>(++++)</p></td></tr><tr><td><p>12</p></td><td><p>1</p></td><td><p>1</p></td><td><p>&lt;&gt; 20: 3-15</p></td><td><p>350</p></td><td><p>-0.8</p></td><td><p>-3.2</p></td><td><p>8</p></td><td><p>0/5</p></td><td><p>63 (0-309)</p></td><td><p>3</p></td><td><p>0/5</p></td><td><p>25 (22.5-30)</p></td><td><p>10</p></td><td><p>1.4</p></td><td><p>Active</p><p>(++)</p></td></tr>

I) I - once a day, (2) - every other day

Mice: males BORI; source: SKI-RaIeI ^ N; OOP: 8/26/02; G) OA: 10/8/02; steaming weight = 23.5g / mouse

Tumor: P03 / 135; OOP: 10/18/02; Tb - 2.1 days

Preparation:

Compound 14b (K): white solid + 3% EUN + 1% ROE + 0.25% of manso, + saline solution - suspension (pH 8.0), 0.5 ml / mouse / injection, IR; 0.2 mL / mouse, 8C;

Compound 14i (K): white solid + 3% EUN + 1% ROE + 0.25% IANSO₃ + saline solution - »solution (pH 8.0), 0.5 ml / mouse / inject, IP; 0.2 mL / mouse / inject, IV;

Compound HK469 (K): white solid + 3% EUN + 1% ROE + 0.5% 1UansO₃ + saline solution - * solution (pH 9 -&gt; 7 using 1 N HCl); 0.2 ml / mouse / inject, 5C; 0.5 ml / micia / inject, IR;

Compound 11c (II) white solid + 3% EUN + 1% ROE + 0.25% IanSO2 + saline solution - * solution (pH 9 - ♦ 7 using 1 H HCl); 0.5 ml / mouse / injection, IP.

Computer layout V. Matsele Signature Circulation 26 copies.

Ministry of Education and Science of Ukraine

State Department of Intellectual Property, st. Uritskogo, 45, Kyiv, Ukraine, 03680

State Enterprise "Ukrainian Institute of Industrial Property", st. Glazunova, 1, m. Kiv - 42, 01601