SA04250273B1 - Pharmaceutical composition containing histone deacetylase inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a thin, space-saving electro-optical device with sounding body and to provide a method of manufacturing the device and an electronic unit. <P>SOLUTION: The electro-optical device is provided with: a display element part 10 having a liquid crystal display device 12 in which a picture display part 12a for displaying a picture is arranged; and a sounding part 20 having the sounding body 21. The display element part 10 and the sounding part 20 are arranged in such a way that the sounding part 20 is positioned at a rear face (heat sink 15) of the display element part 10, and a first air space A is constituted at least of the rear face of the display element part 10 and the sounding body 20. Thus, it is not necessary to arrange a sounding body frame 22 at the rear face of the display element part 10, and the thickness of the electro-optical device is saved by the thickness of the sounding body frame 22 and the height thereof is saved by the height obtained by adding the display element part 10 and the sounding part 20. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

Y

Pharmaceutical containing histone deacetylase inhibitor Aus

Pharmaceutical Composition Containing Histone Deacetylase Inhibitor Full Description BACKGROUND The present invention relates to a pharmaceutical composition or drug combination for the treatment of cancer; It contains a histone deacetylase inhibitor and another effective anti-cancer substance. Cancer is currently one of the most important causes of death. So far, I have done extensive research and invested a lot of money and time. However; Despite conducting research on ways to treat the disease, which touched on various fields such as surgery 80:86, radiotherapy, and thermotherapy ¢, cancer has not yet been overcome. Among these methods, chemotherapy is considered an essential sector, and research has been conducted on many anticancer drugs, for example, 0 drugs used to treat cancer chemically, Jie chemotherapy drugs, cisplatin ¢ and atoboside etoposide ¢ 5 0— S-fluorouracil; gemcitabine, 1-paclitaxel, docetaxel, carboplatin, oxaliplatin; And doxorubicin «vinblastine» etc. The pending Japanese patent application (Kokai) No. 01-157477 discloses a benzamide derivative 0 . Whereas, this derivative has an inductive differential effect and can be used for treatment or v

To alleviate malignant tumors ¢ and autoimmune diseases

disease; skin diseases; Parasitic infection, specifically

As an anticancer drug, it is effective in cases of hematopoietic leukemia

5 And esolid cancers have been disclosed in the aforementioned application for the Japanese patent.

01 - 167237 No. oe

General description of the invention

However, anti-cancer drugs have disadvantages when used in a single dose

Named for normal cells. With the exception of some cases of cancer, treatment with one drug may not be sufficient

to obtain the required degree of effectiveness. Z Ve This invention was developed to reduce toxicity, which is a problem in the field of chemical treatment.

And then get a good therapeutic effect.

Accordingly, the present invention presents a pharmaceutical composition or pharmaceutical combination of active substances

It includes:

(a) at least one of the benzamide derivatives represented by the general formula (5): E Z CH for CH, C (3)

Where:-

- “m” is an optionally substituted phenyl group or a heterocyclic group

Jan Ni has the optional substitution “; In which a group (or groups) is heterocyclic group

¢ : for the phenyl group or for the heterocyclic group is -1; Substitution groups chosen from a group consisting of a halogen atom ; a hydroxyl group ¢, an amino group ¢, and a nitro group; the cyano group ¢ and the alkyl group have 1-4 carbons; group © alkoxy-1 lgalkoxy; carbon atom and the alkyl amino group has 1-4 carbon atoms; and an alkylamine group in it = ; carbon atom and an acyl group with -1 ; carbon atom and an acylamino group sil has -1 ; carbon atom and an alkyl-thio group Lg alkylthio ; carbon atom the perfluoroalkyl group has -1 ¢)3 carbon; and the perfluoroalkyloxy group has -1; carbon atom A carboxyl group and an alkoxycarbonyl group have a 1-4 carbon atom, a phenyl group, and a heterocyclic group ¢ - 16 is an Aad) or a chemical moiety with the shape of Chosen from those forms shown in the general form (Y) (CHy)e— ' —(CH,)g—0—(CH,)e— » - R4 ‏ ,(CH,)g— N— (CH)e— y —(CH,)g—S—(CHy)e— 3 R50 0 I | 1 (CHy)m— , —(CHY)eg—N—C—(CH)m— , - - p (ml1])) - RS 0 (CH,)g—C—N— (CHy)m—sub o of which is an integer JSm' "g's ?; -1 where ©" is an integer between alkyl dc gana or hydrogen It is a hydrogen atom, Ry ranges from zero -?;, represented by acyl ; or an acyl carbons group; A carbon atom -1 optional substitution and has the general formula (©) verse: 0 ht | 3) -)--6 carbon; OR 4-1 is substitutively substituent and has an alkyl that is an alkyl group Re Cam ; or phenyl carbon atom; or a vinyl group 1-4 having a perfluoroalky group perfluoroalkyl hydrogen is a hydrogen atom Rss ; heterocyclic heterocyclic group 0 is optionally substituted and has -1; A carbon atom. An alkyl and an alkyl group is X which is an integer between 0-4; Provided that when it is 8 - bond then « is not equal to zero. (4):) is a chemical radical having a form selected from those represented by the general formula © - 0 R7 R7 | | i 1 E — C—N-— , -—-N—-C— , —=0-C—N— and —N—C—0— ,

Tear rir solution , —=C=N— , 0 for , —0-C-N— ,

I

—N—C—0— , —N—C—N——

where Ry and y each is a hydrogen atom or an optionally substituted alkyl group with 1-4 carbon atoms. - ,18 and each is a hydrogen atom; or a halogen atom or a hydroxyl group « or an amino sid group or an alkyl group with -1 ; carbon atom or the 0 alkoxy group has -1 ; carbon atom or an alkyl amino group with -1 ; carbon atom or an alkyl amino group with -1 ; carbon atom or an acyl group with -1 ; carbon atom or an acylamino group with -1 ; carbon atom or an alkylthio group with -1 ; carbon atom or a perfluoroalkyl group having -1 ; carbon atom or a perfluoroalkyl oxy group of -1 ; carbon atom or a carboxyl group or an alkoxycarbonyl group having 1-4 carbon atoms; Ry0 is a pharmaceutically acceptable hydroxyl group, amino group, or salt thereof that acts as an inhibitor of 2m170 (b) at least one other active anticancer substance selected from a group consisting of cisplatin; etoposide ¢ and ©-fluorouracil 5-fluorouracil ¢ gemcitabine ¢ and paclitaxel Jan Stas gall “paclitaxel docetaxel 0”; carboplatin, oxaliplatin ¢, doxorubicin, and vinblastine. The invention also provides a treatment kit for cancer that contains a pharmaceutical combination according to protective elements; It is characterized by: 0 -1 at least one of the components listed (a); It is an inhibitor of the enzyme histone deacetylase Z. histone deacetylase inhibiting substance. | 0

to

At least one Substance B which is another active anti-cancer substance.

*- Instructions for using the medicine in the larger package to take the medicine simultaneously or sequentially according to the type

Cancer (for consecutive use by the patient at intervals).

In this invention the term 'tel go combination' means that combination which includes component (a) which is a substance

© Histone deacetylase inhibitor © with ingredient (b) Bale Another anti-cancer active;

Where component (1) and component (b) are given simultaneously or at different times (sequentially).

The present invention includes a method for treating cancer; This method is based on giving component (a)

Mentioned and Component B mentioned to the patient simultaneously or at different times (sequentially). And in

In this case, the sequential manner in which component A and component B are taken depends 0 here on the type of cancer being treated and on the type of component A and component B. iy about it

The present invention also includes the use of said component (a) and component (b) to produce

a pharmaceutical formulation or drug combination for the treatment of cancer; and using the aforementioned component (a) and component (b)

mentioned for the production of the medical staff according to this invention. It is preferable to choose cbenzamide, which is the inhibitor of the enzyme histone deacetylase, chistone deacetylase Ve, or its pharmaceutically acceptable salts. This is one of the groups represented by the formulas

general (0) to (A) following:

A

0 . 1 b Cr Ww 2 8 NH,

H + a 1 5 0 0

I

Cr but H ¥ AO © 0 0 po 5 > eS Z NH, 8 H 0 = | AN 0 C 0 1

CHCHN

<> pg 2 1 NH, 6

AN

N 0 G 0

It is more preferable that the benzamide derivative be represented by the following general formula (0), or a pharmaceutically acceptable salt thereof: I CH, “OL i NH, 5 < J AO” and in the aggregate or The pharmaceutical composition in the present invention, the component (B), which is another active anti-cancer substance, is preferably from cisplatin; and it is more preferable to use the combination or combination to treat colon cancer or (Ua yu lung cancer) Which affects non-small cells; or ovarian cancer; or pancreatic cancer 0 In addition, the assembly or pharmaceutical composition in this invention is preferred to have the mentioned component (B), which is another substance. The active anti-cancer agent is iY! etoposide and it is more preferable to use the combination or combination for the treatment of ovarian cancer. Another active anti-cancer agent is camptothesine cisplatin 1°, the most preferred combination for the treatment of colon cancer; or non-small cell lung cancer; or ovarian cancer; or pancreatic cancer. In addition to that; The pharmaceutical combination or combination in this invention is preferred to have the mentioned (b) component in it; It is another active anti-cancer substance; It is 0--5-fluorouracil

1; It is more preferable that the collection or combination be for the treatment of fluorouracil cancer of the breast or colon cancer. In addition to that; The aggregate or pharmaceutical composition in this invention preferably contains the mentioned (b) component; It is another active anti-cancer substance; is gemcitabine; Most preferred would be the combination for the treatment of gemcitabine© non-small cell lung cancer; or colon cancer; or ovarian cancer. In addition, the pharmaceutical combination or combination in this invention preferably contains the mentioned (b) component; It is another active anti-cancer substance; is paclitaxel; It is most preferred to be the collection or combination for the treatment of breast cancer; Or paclitaxel cancer of the prostate or ovarian cancer

Le and moreover; The pharmaceutical aggregate or composition in this invention is preferably the aforementioned (b) ingredient; It is another active anti-cancer substance; is docetaxel; Most preferred would be the combination for the treatment of docetaxel non-small cell lung cancer; or ovarian cancer; or pancreatic cancer; Or prostate cancer. 0 In addition, the pharmaceutical assembly or composition in this invention preferably contains the mentioned (b) component; Another active antibody (ola pul) is carboplatin ¢ and is most preferred as an aggregate or combination for the treatment of non-small cell A carcinoma; or ovarian cancer; or pancreatic cancer. Shady about it; The pharmaceutical aggregate or composition in this invention preferably contains YH (component B) mentioned; It is another active anti-cancer substance” is oxaliplatin; The combination is most preferred for the treatment of colon cancer or ovarian cancer.

11

In addition, the aggregate or pharmaceutical composition in this invention preferably contains the mentioned (b) component; It is another active anti-cancer substance; is doxorubicin; The most preferred combination would be the combination for the treatment of ovarian cancer. In addition to that; The assembly or pharmaceutical composition in this invention is preferred to be in it

0 _ Component B mentioned; It is another active anti-cancer substance; Vinblastine is the most preferred combination or combination for the treatment of non-small cell lung cancer. In addition to that; The pharmaceutical compound or combination in this invention is a preferred combination or composition; In it, the component (1) gives the aforementioned, which is a substance that inhibits the enzyme histone de Olid.

0 and component (b) mentioned; It is another active anti-cancer substance; sequentially to the patient. In the pharmaceutical assembly, the aforementioned component (b); It is another active anti-cancer substance; preferably paclitaxel; And the sequence of its administration starts with the component paclitaxel, followed by the component (1) mentioned, which is an inhibitor of the enzyme histone deacetylase. It is more preferred that the pharmaceutical combination be for the treatment of breast cancer or ovarian cancer.

0 furthermore; and as a pharmaceutical assembly; The aforementioned (b) component; It is another substance, And anti-cancer; preferably cisplatin; The sequence of giving it starts with the aforementioned component (a); It is a histone deacetylase inhibitor; Then Alsis Platinum. Most preferably, the pharmaceutical combination for the treatment of non-small cell (A) cancer; It is preferable that the sequence of administering it be Tey with cis platinum, followed by the aforementioned component (A); It is material

Yo is an inhibitor of histone deacetylase. AS) AV anal collection is preferred for the treatment of colon cancer; or non-small cell lung cancer; or ovarian cancer; or pancreatic cancer.

VY

In addition to that; and as a pharmaceutical assembly; The aforementioned ingredient (b), which is another active anti-cancer substance; preferably gemcitabine; The sequence of administration of Teas is with component (a) SN, which is a histone deacetylase inhibitor; followed by gemcitabine. It is more preferred that the pharmaceutical combination be for the treatment of non-small cell lung cancer; It is preferable that the sequence of administration be followed by gemcitabine and then the aforementioned component (A), which is an inhibitor of the enzyme histone deacetylase. It is more preferred that the pharmaceutical assembly be for the treatment of colon cancer; or non-small cell lung cancer; or pancreatic cancer. In addition to that; and as a pharmaceutical assembly; The aforementioned (b) component; It is another active anti-cancer substance; preferably docetaxel; The sequence of administration is starting with docetaxel and then 0 mentioned (a) component; It is a histone deacetylase inhibitor. It is more preferred that the pharmaceutical combination be for the treatment of non-small cell lung cancer; or ovarian cancer; or pancreatic cancer; or prostate cancer. In addition to that; and as a pharmaceutical assembly; The aforementioned (b) component; It is another active anti-cancer substance; preferably carboplatin; The sequence of administering it will be starting with Carbo Platinum, then 1_ the aforementioned (a) component; Bale is a histone deacetylase inhibitor. It is more preferred that the pharmaceutical combination be for the treatment of non-small cell lung cancer; or ovarian cancer; or pancreatic cancer; or prostate cancer. In addition to that; and as a pharmaceutical assembly; The aforementioned (b) component; It is another active anti-cancer substance; preferably oxaliplatin; The sequence of administration is starting with oxaliplatin; ALY Component A; It is a histone deacetylase inhibitor. It is more preferable that the pharmaceutical assembly be for the treatment of colon cancer; or ovarian cancer.

1 "In addition, as a pharmaceutical assembly, the aforementioned component (B), which is another active anti-cancer substance, is preferably Doxorubicin, and its administration sequence starting with Doxo is an inhibitor of histone deacetylase. Preferably sale Rubicin and then the aforementioned component (a), which is more likely to be a pharmaceutical assembly for the treatment of ovarian cancer. In addition, as a pharmaceutical assembly, the aforementioned component (b), which is another substance ©

anti-cancer active; preferably vinblastine; and that the administration sequence be starting with vinblastine followed by component (A); It is a histone deacetylase inhibitor. It is more preferred to be a pharmaceutical combination for the treatment of non-small cell lung cancer. In addition to that; and as a pharmaceutical assembly; the component (b); It is another active substance

0 anti-cancer; Preferably *- Fluorouracil; and that the administration sequence be starting with the component M0-fluorouracil; Then the off component) which is a histone deacetylase inhibitor. It is more preferable to have a pharmaceutical collection for the treatment of colon cancer. In the pharmaceutical formulation of the present invention said (a) ingredient and said (b) ingredient can be made in a pharmaceutical formulation using a specific compound of those active ingredients; 1 The pharmaceutical composition may be made using a preparation containing said (a) ingredient and said (b) ingredient as the active ingredients; or by using a compound by itself containing either (a) said component or (b) said component; With pre-preparation of the ingredient preparation now. Also, in a pharmaceutical combination according to this invention, preparations that are prepared separately (i.e., which contain ingredient (A) mentioned as an active ingredient and those containing ingredient (B) mentioned as an active ingredient) usually give

Yes to the patient simultaneously or at different times (or sequentially).

0

Brief description of the drawings

Figure: 10- It is a diagram showing the principle of judging the presence of synergistic action. Synergistic action

The present invention relates to a pharmaceutical composition or aggregate comprising a benzamide derivative of the formula

© (1); it is a histone deacetylase inhibitor; With another active ingredient

for cancer.

As used in this text, the term 1 to ; carbon atom" means the number of carbon atoms

in each substituent group; For example, do you mean substitution by a dialkyl? to + carbon atoms.

In a compound of general formula (1), the non-homocyclic ring is a monocyclic heterocyclic 0 with © or 76 atoms containing -1; nitrogen, oxygen, sulfur, or a non-homocyclic ring.

heterocycle 51070110-508©0. It includes a monomeric heterocyclic ring

monocyclic heterocycle is on

“pyridazine(y)a— yn ¢ pyrimidine and pyrimidine ¢ pyrazine and pyrazine” pyridine

thiophene; pyrroled sms « furang) ysis; pyrazoled ms; isoxazole Vo; isothiazole; and imidazole; And oxazole ¢

thiazole; piperidine; and piperazine; and pyrrolidine

quinuclidine; tetrahydrofuran; and morpholine

thiomorpholine; and the like. It includes a fused binary heterocyclic ring

bicyclic fused heterocycle on quinoline; isoquinoline; naphthyridine; J fe fused pyridines are fused pyridines

¢furopyridine, thienopyridine, pyrrolopyridine ¢ and oxazolo

Pyridine 022010117110106 and imidazolopyridine <imidazolopyridine and thiazolopyridine

1 ¢ benzothiophene; and Benzo Fisuran, you will threaten; The thiazolopyridine benzo-thiophene is a halogen and the like. The halogen may not be ¢ benzimidazole and benzimidazole and include an alkyl group. iodine, bromine, chlorine, or fluorine iodine; and «-propyl ethyl; and ethyl methyl on methyl carbons; carbon-1 atoms that have; isobutyl and n-butyl ; f#-butyl isopropyl dus and iso propyl © . tert-butyl; sec-butyl di ¢ ethoxy; ethoxy methoxy; carbon atoms on the 1-methoxy and including the alkoxy in it and the 6-alyloxy; an oxy allyl isopropoxy and ©-propoxy/0-0:000:7 ¢ and isopropoxy n-butoxy oS $i sn

J fue has 1 -؛ carbon atoms on the amino 3) aminoalkyl The amino alkyl group includes 0 and the like “2-aminopropyl sud -7” and “1-aminoethyl ethyl sud -1 and aminomethyl,

Ne ied Miguel N; carbon atoms on -1 that. And the alkyl amino group that has L-diethylamino «Ns» includes; ethyl —N methyl-”N35 ¢ N,N-diethylamino acetyl; and the like. The acyl group includes N,N-diisopropylamino isopropylamino Vo; propanoyl butanol; acetyl propanoyl; carbon atoms on the acetyl-1 in it; Atoms, -1 to contain acylamino ginal and the like. The acyl group includes <butanoyl and the butyl "propanoylamino sid"; Propanoyl is an acetylamino carbon on acetyl amino ¢ -1 which has alkylthio and the like. The alkyl group includes the cbutanoylamino amino cpropylthio ; and propyl te ethylthio; ethylthio has carbon atoms on methylthio Ye that have a -1; perfluoroalkyl carbon atoms and the like. The perfluoroalkyl group includes; and the like. Pentafluoroethyl; trifluoromethyl pentafluoroethyl on trifluoromethyl; Carbon atoms on -1 have il perfluoroalkyloxy and the perfluoroalkyloxy group includes 71 °

trifluoromethoxy; pentafluoroethoxy; and the like. The alkyl carbonyl group includes -1 alkoxycarbonyl; Carbon atoms on the cmethoxycarbonyl and the ethoxycarbonyl . and include the optionally substituted alkyl group having -1 ; carbon atoms on methyld—fual ; ethyldayly and «-propyl; isopropyldus x ; —ny butyl n-butyl ; isobutyl; sec-butyl and tert-butyl; with those contents having 1-4 Allg substituents consisting of halogen ; hydroxyl + and amino; nitro ¢, cyano ¢, and phenyl; The heterocycle 0 The pharmaceutically acceptable salt of the substance of this invention (1) that inhibits the enzyme histone deacetylase includes salts containing inorganic acid such as hydrochloric acid, chydrobromic acid, and sulfuric acid. sulfuric, phosphoric acid, and with organic acid such as acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and fumaric acid maleic acid, citric acid, cbenzoic acid, trifluoroacetic acid, p-toluenesulfonic acid = P-toluenesulfonic acid, and methanesulfonic acid. Component (A), which is the histone deacetylase inhibitory substance of this invention, is produced according to the process described in the pending Japanese patent application (Kokai) No. 01.0575477. Other active anti-cancer It is a commercially available ingredient that can be produced by known methods.

He wrapped

The combination or combination of this invention can be utilized as an anti-cancer drug; It may be used here

Generic pharmaceutical composition form.

The pharmaceutical composition comprising active ingredient (a) and (b) shall be prepared with any diluent or

excipients generally used in this field; such as AULA and the extended article; binder;

© and the binder; loose matter; surfactant; and lubricant. as it is done

Preparation of pharmaceutical aggregates from independent active ingredients using a diluent or an alkali excipient

filler extended material; binder; composite material; loose matter; and the reducing substance

to surface tension; and lubricant. The pharmaceutical composition may have different dosage forms, ie Nie

tablet, granule or powder form; or solution; or suspended; or an emulsion; or globule; or as a capsule; or Ve Injection (Solution or Suspension); or suppository.

Tablets can be prepared using different types of carriers known in this field.

Such J gall carriers include excipients such as lactose: “16610 ¢ and glucose”;

and calcium carbonate 16 275002 calcium; and kaoline; And cellulose, crystalline Lill

6 » and salicylic acid 16?; binders such as water; ethanol J slag « 1 and propanol0008001; simple syrup of roux and glucose solution;

starch solution, Will; and gelatin solution 8618110; And carboxymethyl Obl a

carboxymethyl cellulose ¢ and shellac and methyl cellulose cmethyl cellulose and poly

dried starch La ll and loose materials such as ¢ polyvinyl pyrrolidone; sad ssn vinyl

sodium alginate ¢, powdered agar ¢, calcium carmelose 00 ¢, starch estarch and lactose; and dissociation inhibitors such as sucrose: ¢ and buffer cocoa butter 0 and hydrogenated oil; ¢

Ya

Sodium ¢ quaternary ammonium base and absorption enhancers such as quaternary ammonium bases, glycerin, Jie moisturizing agents; and the emollients sodium lauryl sulfate ¢ lactose; lactose; starch; Jie adsorbents; starch; glycerin colloidal silicic acid; colloidal salicylic acid; bentonite; bentonite; kaoline; choline; polyethylene glycol stearates; and stearates Talc, Jie glidants and lubricants © When necessary, the tablets can be coated with a common coating material, i.e. polyethylene glycol, or enterically coated with sugar or gelatin-coated tablet with Cilia in tablet form. Sia or film-coated tablet JSG or in centeric coated tablet Multilayer tablet or double-layer tablet 0 When forming granules, types can be used here Different from known carriers in this field These carriers include excipients such as lactose (s—SOU 4 ¢ crystalline cellulose ¢ starchlill; hydrogenated vegetable oil, choline, ckaoline, and talc; binders such as powdered oxides; and tragacanth powdered 0 seven tragacanth; and gelatin; and disintegrating materials, Jie disintegrators, calcium carmelo and agarwood. Capsules may be prepared by mixing the active substance with the different types of carriers mentioned above; Filling the resulting mixture (Sie) in a hard gelatin capsule or (And) or similar. When preparing injection materials, a solution is sterilized; emulsifier; suspended; With isotonic substance with blood. 0 The preparation here may be done using common diluents in this field; like water; ethanol ¢ and macrojoules; propylene glycol; ethoxylated isostearyl alcohol; And polyoxy alcohol iso and only

Ya

And stearic acid esters of polyoxyethylene sorbate “polyoxyisostearyl alcohol stearyl.” The pharmaceutical preparation may contain chloride. polyoxyethylene sorbitan fatty acid esters or ¢ isotonic solution required for the preparation of an isotonic solution sodium chloride suitable circuit materials solubilizers; Also, glycerin or glucose solvents. soothing agents and buffers | ©

Various Jt carriers are known in this field, and suppositories may be prepared using carrier materials; alcohols, cocoa butter, cocoa butter + semi-synthetic glyceride. polyethylene glycol; and, in addition, higher polyethylene glycol alcohols and/or coloring agentsiisla preservatives; The pharmaceutical composition may contain materials and/or perfumes and perfumes 0©:0 ; and/or flavorings: :2800 ; and/or preservatives and/or other sweeteners. In the pharmaceutical composition of this invention, the volumetric ratio between component (1) to component (b) is unspecified; such ratios are appropriately chosen within A wide range of volumetric ratios, and in the case of 0001 mee (preferably between 10001 meee) cisplatin, the molecular ratio ranges from benzamide derivative (component A mentioned). In the case of etoposide, the molecular ratio ranges from 1 0 of the benzamide derivative. 1 to 0001 mee) and the best is between dees meen and the best is between 00 meee). It is a benzamide derivative (component A mentioned). In the case of = fluorouracil 1 to 1 +, from 1 to 00001 = (and the best is between 0,000,000 mn) the molecular ratio ranges between the benzamide derivative. In the case of somicitabine, the molecular ratio ranges between almost 0 of the tanzamide derivative (component A mentioned). And in the case of 1 to 01 mre, and the best is between

Ye a, vee 1 and better between 1 1 -- 0 mg' 1 paclitaxel Molecular ratio ranges from 1 of the benzamide derivative (component A mentioned). 1 to 060 and best between 00 meen enn) and in the case of docetaxel the molecular ratio ranges between 1 of the benzamide derivative (component A mentioned). 1 to 1.1 1 and the best is between 00001 = e). 0 of the benzamide derivative (component A mentioned). 1 to 0.1 00011, and the best is between Y meres) and in the case of doxorubicin, the molecular ratio ranges between the aforementioned). Between 1-000001 and better between 1-00001 of a benzamide derivative (component A mentioned). They are chosen according to the “severity of disease” of the dosage form; the age of the patient » and the sex of the patient; And the severity of the disease, solutions, pills, granules, tablets, and other cases. For example, one of the 0 capsule tablets, granule capsules, emulsion pellets, emulsions, and suspensions 2 can be taken or taken intravenously orally; While injection materials are given either individually intravenously

Jie common infusion fluid given intramuscularly in conjunction - if necessary - with an infusion solution or similar; Or it may be given subcutaneously, amino acids glucose sole as a single preparation intraperitoneally or subcutaneously into the peritoneum Ye. .intrarectally it is given inside the rectum Suppository and for suppositories preparation

And the dosage of the pharmaceutical composition or assembly is chosen in this invention; This is based on form and usually ranges os ual dose; the patient's age; the sex of the patient; the severity of the disease; And cases of mg / kg / day, and it is preferable here to contain 0.00 - 0.00 101. The amount of active substance in the formula is between

Voor = e) The dose unit contains a quantity of the active ingredient(s) ranging from about mg. 5 Pharmaceutical combinations It is appropriate that the amount of the Alla derivative range in addition to; And in a kilogram weighing 1 mg per 0001 to 1,000 benzamide (component A mentioned) between about 1 mg per 50 to 11 cisplatin kg, this amount ranges A between about Alls the body. In 1 mg per 10 to 11 etoposides, this amount may range from about Alls body weight. In Campto-Thesin, this quantity may range appropriately from about Alla kg of body weight. and in 0 kg of body weight. 1 mg per 01 to 1 mg 001 to 0.1 fluorouracil the amount may range appropriately between about 0 —0 Alla and in kg of body weight. 1 per kg 1 mg per Foo to 1 and in the case of gemcitabine the quantity may range appropriately from about 1 05 mg per 100 to 100 11 In the case of paclitaxel, the amount may range appropriately between about 1 kg of body weight. 1 mg per 500 to 1.1, and in the case of docetaxel, the amount may range appropriately between about 1 kg of Body weight. 1 mg per 001 to 1.7, and in the case of carboplatinum, the amount may range appropriately between about Ye kg of body weight. 710:

YY

In the case of oxaliplatin, the amount may range appropriately from about 11 to 50 mg per 1 kg of body weight. In Alls doxorubicin the amount may range appropriately from about 11 to 50 mg per 1 kg of body weight. © And in Als vinblastine the amount may range appropriately from about 0 to 109 mg per 1 kg of body weight. And for giving drug combinations; In the case of simultaneous administration, the first active ingredient and the second active ingredient should be given without any time interval. And when administering drugs at different periods (sequentially), it is preferable here to give the first active ingredient and then give the second active ingredient after that, with a period ranging from 0 half a day to 10 days. Examples: The invention will be illustrated more preferentially through examples. Examples: Emphasis on the synergistic effect between the histone deacetylase inhibitor and known active anti-cancer substances 1 on the reproduction of dalle pull WAY The synergistic effect between the histone deacetylase inhibitor and known anti-cancer active substances was emphasized through examples on the proliferation of cancer cells. Test Substances: The histone deacetylase inhibitor was used in this invention; It is a substance 77-(7-amino 0phenyl)-;- [10-(pyridine =F ylmethoxycarbonyl)aminomethyl]benzamide (275 -048): which is represented by the formula (*): 171°

YY

<> CH, oN 0 0 1 1 2 “O © 0 a 0 In addition, known substances with anti-cancer activity have been used; This is in conjunction with MS- 275 Aley; such as paclitaxel (PTX), camptothecin (CPT), etoposide (16-77); cisplatin (CDDP), gemcitabine (EMG), or *-0(5)fluorouracil -20); or docetaxel (017); or carboplatin ((CBDCA) or oxaliplatin (070); or doxorubicin (DOX) or vinblastine (VBL) Tumor cells tested: strains used The following cellularity as carcinoma cells tested: - Colon cancer cell line 0 111-29 and/or HCT116 - Non-small cell lung cancer cell line: 2 «NCI-H and/or NCI- 11460 101-1123 4/5 4/5 and/or “Calou-3 s/s” Calu-1 and/or “A 549” ovarian cancer cell line: OVCAR-3 4/5 SK- OV. -3 - Pancreatic cancer cell line: Capan-1 l/s PAN-1 - Breast cancer cell line: PC-3 and/or LNcaP

Y¢ Concomitant use method: In these experiments, the conjugate effect of 148-275, which represents the inhibitor of histone deacetylase, was evaluated; other substances known to have anti-cancer activity; And that is as follows: On its own. MS-275 Effect (i) ° (n) The effect of other active substances known as anti-cancer substances. And other active substances known as anti-cancer substances. MS-275 Concomitant effect of (i) The following two types of methods were used: Simultaneous conjugate use: an hour in VY -177 In this method, cancer test cells were incubated for a period of 0 min containing a mixture of -148 275 and other known anti-cancer active substances; And then, Jan, the number of cancerous cells that remained alive was measured. Consecutive consecutive use: an hour in a medium containing one YE cancer test for a period of LOA In this method, __ of the test materials were incubated and the gas was withdrawn of that medium at that point in time; Then the 0 cells were incubated and gassed from this es AY hour in medium containing the YE test material for another 1 hour in no VY medium at that time point; Then the cells were then incubated for a period containing the test materials. The number of cancer cells that survived was then measured. It is noted here that when the sequential conjugate use was performed, each of the cases in which 148-275 works in the first twenty-four hours and the other active anti-cancer substance works in the next twenty-four hours; And also the situation in which this arrangement is reflected. In addition to that; In the control process

Yo One-time administration of drug within concomitant use; The test subject was only made to work in Ye Wad's first twenty-four hours or the next twenty-four hours. In another period, cells, axe gu Bye La, were last. The cells were incubated in the absence of dela VY, and in the a, which remained, Al. Method of measuring the number of remaining cancer cells: © Using test materials, the number of Ala pull after the completion of the previous treatment (incubation) of the cells, by one of the following two methods: da The cells that remained Red neutral color test: - This method of measurement is based on the use of the property that only the remaining cells can Absorption of neutral red color dissolved in water into cells. The method includes treating 0 cancer cells with any of the aforementioned test substances in cavities; Then add the color solution to the cavities after the end of treatment (incubation); And conduct (PBS mg / ml in 1) Neutral Red for one hour to get the cells to absorb a TV incubation process under temperature

NaH,PO4s ethanol 7001 from solution to which Sad is added as neutral red; Then it is still in the hollows; This is to extract the neutral red color that was absorbed into the cells and measure (01M) 0 Then the neutral red color that was extracted; This is done by a micro-plate reader with a distance of nanometers. ©0506 Value: 1115 Test This method is to test the viability of cells; It is based on the use of the fact that:

MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenol)-2-(4-sulfonyl)-2H- Ye.tetrazoliumm)

YYyo

It is metabolized or metabolized to metachondria dehydrogenase, which is present in the remaining cells. This test is performed using a Cell Titer®96 to measure cell proliferation according to the instructions included with the reagents. © Conjugate ratio of test materials and synergism evaluation :

The conjugate ratio of the test subjects (CYS) is determined in the graph shown in Figure 1- The x-ordinate shows the logarithm (log M) of the concentrations of the test subjects; the y-coordinate shows the relative survival rate in a state of reference for the remaining cancer cells that were tested At a concentration of the test materials of zero, graphs were made

0 for concentration of test subjects and relative survival rate of cancer cells tested in Alla Using test subjects alone concentrations of 109 test subjects in Alla were found to have relative survival rates of Jon Lexie would like to be, and 16 for subjects Test A 33 is synergistic in the sense that the ICs of test substance M is 1 µM and the value of test substance 3 is vo)

Ve micromolar, the anticancer effect of test substance 3 is equivalent to 100 times the effect of test substance A, and the correlation ratio between test sale A and test substance 8 is Vee 1, and this ratio is kept constant for different total concentrations of the test materials. However, the ICsp value varies

of the test material according to the tested cancer cells; So that the cross-ratio must be specified for both

Test subjects and each type of cancer cells tested.

Yo in the form, Y = The concentration curve shows 1- The survival of the test substance, A, represented by the solid line; while the dashed line represents 3. Besides, assuming that test sale A and test substance 8 are used in a fixed ratio (ie, in a ratio of 1:001) under varying total concentrations; and that the crossover effect

Yv of test subjects is an additive effect; Here, the concentration-survival ratio curve can be found by cross-use calculations. For example, this is shown as Y= with successive black dots. On the other hand, the actual curve of the concentration-survival ratio can be found from the values that were actually measured in Alls using test material M and test material B in a fixed ratio (i.e. Nia in a ratio of 1:001 ©, but with varying total concentrations). . And when the curve is located on the left side of the concentration-survival ratio curve, which was found mathematically assuming the additive effect as shown - for example - by the set of black squares in Figure -1, then it is possible here to judge the concomitant effect of test material A and test material B. It is a synergistic effect. On the other hand, Laie, the actual concentration-survival rate curve is located on the right side of the concentration-survival rate curve for 10-5777173 6006002 0 which is found mathematically assuming the additive effect as shown by the set of black triangles in the figure - 1; Here the synergistic effect of test substance A and test substance B can be judged to be an opposite effect. In practice, the association index (01) is calculated from the results of the measurements in the method described in the following reference:

Chou TC et Millah Adv. Enzyme Regul. 22: 27-55 (1984) (Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors). Vo In this case, when the conjugate effect of test substance A and test substance 8 is additive, then V=CT, and when !© is less than 1, the effect here is a synergistic effect, and when CT is more than 1 0 The effect will be the opposite. In addition, the lower the value is than 1, the higher the degree of synergy; However, the higher the value than 1, the higher the degree of contrast.

Ya

And the degree of synergy or permeability is as follows: CT The relationship between the value range of (1) can be expressed in a table

I EE TT

Results: Lah following ratios between 275-148 and other active anti-la pull materials in different Agtapu© cells tested in Ala simultaneous concomitant use:

Ya (Y) Table in Concurrent Conjugated Use (X) to Other Active Anticancer Substances MS-275 Ratio (MS- 275: X) Cancer Cell Strain Time Ratio - No as ove) Yeo by NCI-H522 | lung cancer that

Youd £0 2 70 Ovarian Cancer 777/000 05|" pe 7:1 a I Yee) [eee pf SK-OV-3 Ovarian Cancer 7:1 01 vee [oven VY.

Vir 1 Yee: 1:1 Youd | L Ni PANC- 1 Pancreatic Cancer 101 You i 101 Eee 2) 01001 2 YY. 011 A 7 MCF-7 Breast Cancer 1:1 fae ny YY £00) 0011 L PC-3 Prostate Cancer 2:1 011 VY. Here are the results in simultaneous conjugated use:

Ye. (¥) Table with Other Active Anticancer Substances in MS- 275 Synergistic Effect of Concomitant Use of Concomitant Concomitant Use: Ami 3 = [=] | w | ue eel Le for the colon except | for pain | 6600 + VY NCI-H522 | Lung cancer _— 1 that affects any person other than "brother" *#

Te Tn] +++ for Calu- 1 +++ vy Calu-3 7m Tn_ +++ VY NCT- H23 + for NCT- H358 +++ for 1101-0 ++ + ++ for SK-0OV-3 cancer — + YY. bleach for | the the | w [overs ++ ++ ++ for PANC- 1 Cancer ++ —_ 1 Pancreas +++ VY MCF- 7 Breast Cancer Grandfather AY. _— VY PC-3 Cancer ++ YY. prostate

As explained by ale, there was a concomitant effect of 148-275 and with another well-known anti-cancer drug such as PTX, CPT, 16 VP-, GEM, or 5-FU. The conjugate effect of CDDP 5 MS-245 has been observed in a wide range of tumor cells. Shows schedule -? Results in Ala sequential cross-use of 275 MS-with PTX and shows © Table -- Results for 275 MS-with “GEM” shows Table = Results for 275 -1458, with “CDDP Table Y= shows the results for the MS-275 with CPT, Table A= shows the results for the MS-5 with DTX, and Table 4 shows the results for the MS-275 with CPT. “CBDCA Table Vom Shows Results for 275 MS-with 0707; Table -11 shows the results for 275 -148 with DOX, Table -?1 shows the results for MS-275 with VBL, and Table Y = results for MS-275 1 0 With .5-FU It is noted in these tables that the ratio between 275 XS: means the ratio between MS-275 and another active anti-cancer substance (X) while List Wu "refers to the treatment of MS-275 For an initial treatment period of YE an hour, and treatment with the other active anti-cancer substance during a subsequent period of 1 hour, then incubation in a medium that does not contain the test substance for a period of 275->X->F indicates Ve to treatment with the other active anticancer substance in an initial treatment period of YE hour; treated with MS-275 over a subsequent dallas period of YE hour; Then, the incubation is done in a medium that does not contain the test material for a period of 5 hours. In addition, the numerical values show the synergistic effect, and here the values of (Cl

YY

(4) Table of PTX with MS-275 Sequential conjugation of Alla Synergistic effect on cancerous cell line Hourly time | Ratio: 275 | Order of consecutive conjugation

X

X->275->F | 275->X->F 1 <1,) Yess :) | VY C ivory | SK-OV- Cancer ++ — 3 Ovarian 1l 0... 7 ave +ve | 1-470 | Breast cancer ++ (°) table ‎| GEM: with MS-275 the synergistic effect of sequential combinational use of a cancerous cell, hourly time | Ratio: 275 | Concurrent cross-use order ADL

X->275->F | 275->X->F X

EA <1 You vy +ve +ve | 111-29 | Colon cancer +++ — <1 M Yoo VY +YE +4 NCI-

H522 for ++

VY 01001 2d YY +4 +4 NCI- 118122: ++ lung cancer that affects

RET <1 You: VY +Y§ Neither A 549 Cells other than the lowercase +++ B 'of Y,) Eon) vy P | OVCAR | Ovarian cancer +++ — 3 "51 Suva) | + pancreas yy (1) Schedule: CDDP with MS-275 Synergistic effect of sequential concomitant use of 275: cancer cell time per hour | ADL ratio of Adcsan es 6 IY Ac) vy +ve+ve | 1101116 | colon cancer

Tmt 'AS 01 VY +7 + HT rt

RET. 00 1:1 vy +ve +ve | 00111522 | lung cancer nme

OEY 0:1 VY +YE + A 549 Non-cell mYa ovarian cancer | SK-OV3 | + am VEY 1:1 vy l a a 1 lal 1:11 heb b +v¢ | OVCAR-3 te. 0' 41 Ao) YY YE + PANC-1 | pancreatic cancer

Tt

AY 1p. 1:1 vY +v¢ +v¢ | Capan-l pp et

Table (V) Synergistic effect of sequential conjugate use of MS-275 with simultaneous conjugate CPT: X ~>F —>F Colon cancer | 1161116 |74+74+ (‘,AO 41 You) | YY sec hen [en [re] ree for lung cancer | 110111522 | 74+ 74 Yeo) | YY 01 ,74" that affects +++ + cells other than 59 740+ 74+ YY | died | Ld 71 small _— ++ ha der 7 + YY + 1 +76 SK-OV3 | riba VY [renee cancer v, 64 >, Yeo:Y | VY +YE +YE | Capan-l pancreas B +++ Table (A) effect 5,500) for consecutive concomitant use of MS -275 with DTX (Docetaxel): Synchronized Hourly DDA X 275 Lung Cancer | “AY 0.0... | #YE YE | A549 Infecting VY++ Non-Cancer Cells 1 | +76 HY SK- ... No TEE Cancer «AY Fou 2) +Y¢ +Y¢ | Capan-1 A Cr Tee Cancer Food +Y¢ +Y¢ | Pc -3 B A Cr Imre

Yo (1) Table (Carboplatinum): CBDCA with MS-275 Synergistic Effect of Consecutive Concomitant Use of 275: Cancer Cell Strain | time in hours | Synchronous ratio X

X 275->X an | [een] ee++ that infects T" (Y VY +7) +74 | NCI-HS522 | Non-AKAD A7 cells: YY +Y¢ +Y¢ | SK-OV3 Cancer | meme] a VEY Yi) | VY +7) +6 cancer [me OY 101 VY +74 +Y¢ | PANC-1 an [mee] (V+) Schedule (oxaliplatin): OXP with MS- 275 Synergistic effect of sequential covalent use of concurrent covalent X

X ->X 275 [|e [ee jean ++ «AY Yo YY +76 +Y¢ SK-Cancer] Here V1 (VY) Table (Doxo Rubicin): DOX with MS -275 Synergistic Effect of Consecutive Concomitant Use of Cancer Cell Line Hourly Time | Ratio: 275 | Concurrent cross-use order X ->275->F | —>X—>F

X 275 l ye | VY +4 +4 SK-OV3 cancer + ovary (VY) schedule (vinblastine): VBL for sequential conjugate use of 275 -145 with so ul effect cancer cell time ratio 275: Concurrent ADL Cross-Use Order X Hourly ->275->F | 275->X->F

X

+, Ad 011 +76 0+4 A549 | Non-Small Cell Lung Cancer 3 Fluorouracil): —0) 5-FU with MS-275 Synergistic Effect of Recurrent Concomitant Use of Carcinogen | hourly time ratio | simultaneous conjugation order dda) strain X->275->F | 275->X->F | 275:X

V4 voy VY +74 +Y¢ HT- 29 Cancer ++ colon In each of the cases of the active anti-cancer substances that were tested, it was noted that there was an effect

MS- 275 results from concomitant use with sb ° Industrial use: As explained above, there was a synergistic effect in laboratory tests between histone enzyme inhibitors and various other known active substances against MS 275 D. Estelesis is represented in cancer. Therefore, it is hoped that a synergistic effect will be obtained when treating cancer that also affects human patients.

Claims (1)

Yv protective elements from active substances that include: A apa pharmaceutical formula or combination 1-1 which is a histone de-benzamide inhibitor Gata (a)-: (#) represented by the following formula histone deacetylase inhibiting substance Salad v CH CH 2 A 4 NH, H 1 ; ~N 0 (b) at least one other active anticancer substance selected from the 5,000+ group consisting of cisplatin ¢ and etoposide; camptothecin; 7 and *- 5-fluorouracil; And gemcitabine, paclitaxel A ¢, docetaxel ¢, carboplatin ¢, oxaliplatin q ¢, doxorubicin ¢, and vinblastin. 1 "- A pharmaceutical composition or combination according to claim number (V), where the substance selected from a group containing component (B), which represents another active anti-cancer substance, is cisplatin 1. - A pharmaceutical composition or combination according to claim No. (7); used for the treatment of “Y” lung cancer of “non-small cell lung” or deep WAN cancer. YA; colon cancer or colon cancer ¢ ovarian cancer 7-pancreatic cancer ¢ the substance Cian ¢ (1) is a pharmaceutical formulation or combination according to Claim 6-1 selected from a group containing On component (B), which represents another active anti-substance. etoposide for cancer The term etoposide | ¥ and used in the treatment of (o£) the pharmaceutical composition or assembly according to the claim — 0 1 . ovarian cancer Y; Where the selected substance is (1) a pharmaceutical composition or combination according to claim 1 1 l from a group containing component (B), which represents another active anti-cancer substance. camptothecin is camitothecin ¥ the pharmaceutical composition or combination According to Claim No. (1); it is used in the treatment of “1-7” or “non-small cell lung cancer” or “colon cancer” or “ovarian cancer” Ovarian cancer 7. pancreatic cancer ub sill ¢, where the selected substance (V) is a pharmaceutical composition or combination according to claim A 1 from a group containing component (B) which represents another active anti-cancer substance Y .5-fluorouracil is 0--1-fluorouracil Yq and used in the treatment of cancer, A, the pharmaceutical composition or assembly, according to the protection element, + 1. colon cancer breast cancer Y a pharmaceutical formulation or combination according to claim (1); Where the selected substance is 0-1 from a group containing component (B), which represents another active anti-cancer substance. gemcitabine is gemcitabine 7 of the pharmaceutical composition or assembly according to claim (10); It is used in the treatment of 11-1 or non-small cell lung cancer, lung cancer that affects non-small cells, Y; Colon cancer, ovarian cancer, or ovarian cancer. pancreatic cancer. Pancreas ¢ A composition or pharmaceutical combination according to claim (1), where the selected substance is 1-1 from a group containing component (B), which represents another active anti-cancer substance Y paclitaxel is paclitaxel and is used In the treatment of (VY) the pharmaceutical composition or assembly according to the element of protection 0-1-01 or “ovarian cancerar-all” or “breast cancer,” (sal) Y prostate cancer ¥ or A pharmaceutical group according to claim (1), where the selected substance, 2S 5-0 E 1, is from a group containing component (B), which represents another active anti-cancer substance, Y. docetaxel is docetaxel 7 stood up 0m 1 - the pharmaceutical composition or assembly according to protection element 06 and is used in the treatment of non-small cell lung cancers sa Ve + or v ovarian cancer anal cancer or v cancer pancreatic cancer ub Sad) ¢ or cancer ,. prostate cancer Bliu 5 ul ¢ 1 7- A pharmaceutical composition or combination according to claim element (1), where the selected substance Y is from a group containing component (B), which represents another active anti-cancer substance 7, which is carbohydrate Carboplatin-11.1, the pharmaceutical composition or assembly according to the protection element (11); it is used in the treatment of non-small cell lung cancer, or ,. pancreatic cancer_sb Sul or cancer + ovarian cancerana cancer v = A 1 pharmaceutical composition or combination according to claim (\ 0), where the selected substance (Y) is from a group containing component (b) that represents a substance Another active anti-cancer agent ¥ is oxaliplatin. .ovarian cancer or ovarian cancer colon cancer Y YS 1 pharmaceutical formulation or assembly according to claim (1); where the selected substance, Y, is from a group containing component (b) that represents Another active anti-cancer substance 7 is doxorubicin -71 1 Pharmaceutical composition or combination according to claim (10); used in the treatment of Y ovarian cancer. YY 1 Pharmaceutical composition or combination according to claim (1); where it is sald) selected Y from Ae sana contains component (b) which represents another active anti-cancer substance 7 is vinblastine YY 1 pharmaceutical formulation or assembly according to claim (77); It is used in the treatment of Y lung cancer (A) that affects non-small cell lung cancer - Y¢ \ a pharmaceutical group according to the protection element ( \ ) in which the patient is given sequentially Y component 0) The aforementioned, which is a histone alti ul deacetylase inhibiting substance 1, and the aforementioned active ingredient (b), which is another ¢ anti-cancer active substance, and all of the two components are given ° to patients in a form sequentially administered to patients. paclitaxel .paclitaxel ¥: 1 7- An assembly (Ana) of Lane according to the protection element (Yo) 6 where the sequence is (Lac) on assembly Y starting with paclitaxel and then the aforementioned component (A) that Represents a substance that inhibits the enzyme vo histone deacetylase. histone deacetylase inhibiting substance -71-1 Pharmaceutical assembly according to claim (77); It is used in the treatment of ovarian cancer or breast cancer. =-YA 1 Pharmaceutical assembly according to claim (4) Y ¢ where the component (B), which Y represents another active anti-cancer substance, is cisplatin -Y4 1 Pharmaceutical assembly according to the element Protection (Y A) (' and in it the sequence of giving assembly Y starts with component 0) which Jia is a substance that inhibits histone deacetylase enzyme “inhibiting substance v” and then cisplatin 0 cisplatin 0 1 The catch collection ay according to protective element (1) ¢ and is used in the treatment of lung cancer y that affects non-small cell lung.©:©6806 non-small cell lung ¢ or ovarian cancer ¥ » or carcinoma colon cancers sill or pancreatic cancer .pancreatic cancer ¢ 1 1?- a pharmaceutical assembly according to claim element Y A) 1 in which the sequence of giving the assembly Y is replaced by cisplatin and then component 0 (which contains a substance that inhibits histone enzyme ¥ deacetylase histone deacetylase inhibitihg substance ¢Y It is used in the treatment of lung cancer 10 1) Pharmaceutical assembly according to protection element 7-1 or ovarian cancer “non-small cell lung cancer” or pancreatic cancer “colon cancer” Or colon cancer (ovarian cancer v. pancreatic cancer ¢) and in which the component (B) representing (YE) has a pharmaceutical assembly according to the protection element =F). The sequence of giving the assembly (YY) is a pharmaceutical assembly according to the protection element: - 1 histone deacetylase with component 0 (which represents a substance that inhibits the enzyme histone deacetylase le Y. camptothecin and then camptothecin “inhibiting substance v the assembly Pharmaceutical according to the protective element (; "); and used in the treatment of lung cancer ~Yo 1 non-small cell lung cancer. Which affects non-small cell lung cancer and in which the sequence of giving the assembly (YY) is a pharmaceutical assembly according to the protective element - 1 1 Then component 00 (which represents a camptothecin inhibitor substance starting with camptothecin Y. histone deacetylase inhibiting substance deacetylase 1 ¢¢ 1 1?- pharmaceutical grouping according to claim (77); It is used in the treatment of lung cancer (Sal Y affecting WAN other than non-small cell lung cancers_pxaall) or ovarian cancer 3 or colon cancer s—s&l or pancreatic oda Pancreatic cancer ¢ 1 - Pharmaceutical assembly according to the claim) ¢ In which the component (B) that Jia Y sells other active anti-cancer drugs is gemcitabine. 1 4- The pharmaceutical assembly according to the protection element (YA), in which the sequence of giving the assembly is “ - starting with component (A), which represents a substance that inhibits the enzyme histone deacetylase inhibiting substance 3; then gemcitabine 1 6- The pharmaceutical combination according to the protection element (q ¥)” and is used in the treatment of lung cancer that affects WAY non-small cell lung cancer. 1 1;- The pharmaceutical combination According to the protection element (FA) and in which the sequence of giving the assembly is “- starting with gemcitabine and then the aforementioned component (A), which represents an inhibitor of the enzyme 1 histone deacetylase. histone deacetylase inhibiting substance ¢o Pharmaceutical pooling according to protection element (¢ 1) and used in the treatment of lung cancer —¢v \; or non-small cell lung cancers of the ovaries other than WAY affecting Y; or pancreatic cancer gsb sill or ¢ ovarian cancer 3 .colon cancer. ¢ The pharmaceutical pool of claim ($3) and in which the component (b) which is 1-1 .5-fluorouracil represents another active anti-cancer substance is 0 = fluorouracil Y The pharmaceutical pool of claim (¥ ¢ In it, the sequence of giving the assembly -1 is an inhibitor sale; Then the component (1) that represents S-fluorouracil starting with the substance ©— fluorouracil Y histone deacetylase inhibiting substance for the enzyme histone deacetylase 7m) - the pharmaceutical assembly according to the protection element ($4) and is used in the treatment of cancer 1 .colon cancer colon Y in which the aforementioned (b) component ¢ ( Y ¢ ) is the pdaloid assembly according to claim - 71 1 which represents another active anti-cancer substance that is docetaxel A*0060613. - " The pharmaceutical assembly according to the protection element (£7) » and in it the sequence of giving the assembly is -?;;1/1; then the aforementioned component (A), which represents the inhibitory substance docetaxel lescatesodela, starting with the substance Y histone deacetylase inhibiting substance for the histone enzyme deacetylase 3 1 8 ;- Pharmaceutical grouping according to claim (97;); It is used in the treatment of non-small cell lung cancer, s yall, or ovarian cancer: ovarian cancer; or pancreatic cancer, of ¢ pancreatic cancer, prostate cancer ,. prostate cancer ¢ 1 4- The pharmaceutical assembly according to the protective element (VE) in which the component (B), which Y represents another anti-cancer active substance, is 3 carboplatin. 1 6 0- The fishing group is according to the protection element (4L) and in it the sequence of giving the group Y starts with carboplatin. carboplatin, then the aforementioned component (A), which represents an enzyme inhibitor ,. histone deacetylase inhibiting substance Histone deacetylase v -51 1 Pharmaceutical assembly according to claim element (00) and used in the treatment of lung cancer y that affects non-small cell lung cancer; or ovarian cancer .pancreatic cancer (wl Sill or covarian cancer v oY) Pharmaceutical assembly according to Claim (TE) in which Component B is mentioned .oxaliplatin, which is another active anti-cancer substance, is oxaliplatin Y –oY 1 Pharmaceutical assembly according to the claim element (AM), in which the sequence of giving the assembly is “0, starting with oxaliplatin CEILS YI, then the aforementioned component (a), which represents an inhibitory substance, v, for the enzyme histone deacetylase deacetylase inhibiting substance. . 1 4- The pharmaceutical assembly according to the protection element (¥ °) ‘and is used in the treatment of colon cancer’ or ovarian cancer? 1 85 - Pharmaceutical assembly according to the claim element (¢) and in which the aforementioned (b) component Y, which represents another active anti-cancer substance, is doxorubicin. 1 7- The pharmaceutical assembly according to claim element (00), in which the sequence of giving the assembly d en is with cdoxorubicin, then the aforementioned component (A), which represents substance 7, histone deacetylase inhibiting substance. ‏ 1<1 Pharmaceutical grouping according to the claim). It is used in the treatment of Y ovarian cancer. – 0A 1 Pharmaceutical assembly according to claim element (YE) in which component (B), which Y represents another active anti-cancer substance, is vinblastine. FD 1>- The pharmaceutical assembly according to the protection element (OA), where the sequence of administering the assembly is 0, starting with vinblastine. 001800 Then the aforementioned component (A), which represents a deacetylase inhibiting substance, Asmaqt. Pharmaceutical grouping according to the protective element (OA) is used in the treatment of lung cancer. Non-small cell lung cancer. From: T at least one of said component (A) that is a histone deacetylase inhibiting substance ¢ histone deacetylase inhibiting substance « © At least one of said component (B) that is another active anti-cancer substance ‎anti- cancer active substance 1 ¢ Instructions for taking the formulation, in order to take the formulation simultaneously or sequentially according to the type of cancer (for consecutive administration to a patient at intervals between them). To (YY), in which the patient is given sequentially the aforementioned component (A), which is a substance that inhibits histone v enzyme, histone deacetylase inhibiting substance Sala J, and the aforementioned active ingredient (B), which is another substance Active anti-cancer and all the two components are given to the patients sequentially.