EP1377291A2 - 1-butyric acid derivatives such as carbomethoxypropionyl cyanide or leflunomide derivatives, and the therapeutic use thereof - Google Patents
1-butyric acid derivatives such as carbomethoxypropionyl cyanide or leflunomide derivatives, and the therapeutic use thereofInfo
- Publication number
- EP1377291A2 EP1377291A2 EP02726161A EP02726161A EP1377291A2 EP 1377291 A2 EP1377291 A2 EP 1377291A2 EP 02726161 A EP02726161 A EP 02726161A EP 02726161 A EP02726161 A EP 02726161A EP 1377291 A2 EP1377291 A2 EP 1377291A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- cycloalkyl
- alkyl
- aryl
- formula
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical class O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 title claims description 5
- ZULHCBGKPZYNNU-UHFFFAOYSA-N methyl 4-cyano-4-oxobutanoate Chemical compound COC(=O)CCC(=O)C#N ZULHCBGKPZYNNU-UHFFFAOYSA-N 0.000 title description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical class CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title description 3
- 230000001225 therapeutic effect Effects 0.000 title description 3
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- 238000011282 treatment Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 35
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
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- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
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- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 abstract 1
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- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- AKRGLPCOXCYKNF-UHFFFAOYSA-N 5-chloro-5-oxopentanoic acid Chemical compound OC(=O)CCCC(Cl)=O AKRGLPCOXCYKNF-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Definitions
- the invention relates to butanoic acid derivatives, pharmaceutical compositions containing such derivatives and uses of such derivatives for the production of pharmaceutical compositions for the treatment of various diseases.
- Cancer is one of the leading causes of death these days and the number of cancer cases in industrialized countries is constantly increasing. This is mainly due to the fact that malignant tumors are a disease of old age and, thanks to the successful fight against infectious diseases, more people are reaching this age. Despite all the advances in the diagnostic and therapeutic fields, the prospects for a cure for the most common forms of internal cancer are rarely over 20%. A cancerous tumor can currently be destroyed or inhibited in its growth. A regression of a tumor cell into a normal cell cannot yet be achieved. The main therapeutic measures, surgery and radiation, remove cancer cells from the body. The cancer chemotherapeutics currently in use, the cytostatics, only lead to the destruction or damage of tumor cells.
- tumor cells have a metabolism that differs from that of healthy cells, in particular glycolysis.
- a change in the isoenzyme system involved in glycolysis and a change in the transport of NADH is typical for tumor cells.
- the activity of the enzymes of glycolysis is increased. This also allows high sales under the aerobic conditions typical of tumor cells.
- the present invention is based on the technical problem of providing active substances which are capable of proliferation, in particular of
- Cancer cells and thus to inhibit the growth of neoplastic tumors and inflammation as well as excessive defense reactions of the body, such as to inhibit septic shock, autoimmune diseases, graft rejection and acute and chronic inflammatory reactions, with at the same time having only little to no cytotoxicity towards normal cells of the blood, the immune system and the tissue cells.
- the invention teaches the use of a compound of formula I.
- compositions for the treatment and / or prophylaxis of diseases from the group consisting of
- Neoplastic tumors inflammatory diseases, autoimmune diseases, in particular systemic lupus erythematosus, degenerative joint diseases, diseases of the rheumatic type with cartilage degradation, all forms of arthritis, in particular rheumatoid and chronic polyarthritis, joint trauma, immobilization-related cartilage loss, septic shock, septic shock, septic shock shock, septic leukemia, Diseases caused by increased TNFalpha concentrations, cachexia, Crohn's disease, skin psoriasis, Wegener's granulatosis syndrome, rejection reactions after transplants, especially in the course of cell therapy or stem cell therapy ".
- Z phenyl, naphthyl, phenyl substituted with -Hai and / or -O-Hal and / or -C1-C8-alkyl, -cycloalkyl or -aryl or with -Hai and / or -O-Hal and / or C1-C8 alkyl,
- the invention teaches a pharmaceutical composition containing a compound of the formula
- At least one physiologically compatible auxiliary and / or carrier substance at least one physiologically compatible auxiliary and / or carrier substance.
- alkyl includes linear and branched alkyl groups.
- cycloalkyl also includes cycloalkyl groups with linear or branched alkyl substituents.
- aryl also includes aralkyl groups, where alkyl substituents can be alkyl or cycloalkyl.
- the antiproliferative effect of the compounds of the formula I according to the invention causes an immediate slowdown in the growth and a decrease in the So-called systemic inflammatory activity, namely in all processes of proliferation in the context of inflammation, wound healing or regeneration. Because of their pharmacological properties, the compounds according to the invention are therefore also outstandingly suitable for the treatment and prophylaxis of the other diseases listed above.
- the above medical definitions and terms can be found in the Röche Lexikon Medizin, 4th edition, Kunststoff, 1999.
- the invention further relates to a diagnostic agent containing at least one compound of the formula I for the detection of diseases, as mentioned above, by bringing a cell or cell culture to be examined into contact with such a compound and evaluating it appropriately. See example 2.
- a pharmaceutical composition according to the invention can contain several different compounds falling under the above definitions.
- a pharmaceutical composition according to the invention can additionally contain at least one active ingredient different from the compound of the formula I. Then it is a combination product.
- the various active ingredients used can be prepared in a single dosage form, i.e. the active ingredients are mixed in the dosage form.
- Preferred active substances in this context are so-called immunomodulators such as leflunomide (Arava®), methotrexate or anti-rheumatic drugs.
- R1 -H, methyl or ethyl
- R1 - H
- R2 -CH 2 -COO-methyl
- R3 -CN
- Counterions for ionic compounds of the formula I are, for example, Na +, K +, Li +, cyclohexylammmonium or basic amino acids (for example lysine, arginine, ornithine, glutamine).
- the medicaments produced with the compounds according to the invention can be administered orally, intramuscularly, peri-articularly, intra-articularly, intravenously, intraperitoneally, subcutaneously or rectally.
- the invention relates to processes for the production of medicaments, which are characterized in that at least one compound of the formula I is brought into a suitable dosage form with a pharmaceutically suitable and physiologically tolerable carrier and, if appropriate, other suitable active ingredients, additives or auxiliaries.
- Suitable solid or liquid pharmaceutical preparation forms or formulations are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositohen, syrups, juices, suspensions, emulsions, drops or injectable solutions, and preparations with a protracted active ingredient release, and conventional auxiliaries in their preparation such as carriers, explosives, binders, coating agents, swelling agents, lubricants or lubricants, flavoring agents, sweeteners and solubilizers can be used.
- Auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, Sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and mono- or polyhydric alcohols, such as glycerin.
- the medicaments are preferably produced and administered in dosage units, each unit containing as active ingredient a certain dose of the compound of the formula I according to the invention.
- this dose can be 1 to 1000 mg, preferably 50 to 300 mg, and in the case of injection solutions in ampoule form 0.3 to 300 mg, preferably 10 to 100 mg.
- daily doses of 20 to 1000 mg of active ingredient, preferably 100 to 500 mg, are indicated for the treatment of an adult patient weighing 50 to 100 kg, for example 70 kg. Under certain circumstances, however, higher or lower daily doses may also be appropriate.
- the daily dose can be administered both as a single dose as a single dose
- the compound carbomethoxypropionyl cyanide was prepared analogously to Q.Tang and S. Sen (Tetrahedron Letters 39 1998, p.2249-2252). Typically, 1.5 g (10 mmol) of carboxymethylpropionyl chloride was added to a solution of 1.79 g of CuCN (20 mmol) in 10 ml of acetonitrile. The mixture was heated under reflux for 30 min and, after cooling to room temperature, concentrated on a Rotavapor. The residue was dissolved in ether and the ether solution filtered. After removal of the solvent, a slightly yellow oil remained (yield 0.95 g, 67% of theory); IR (cm "1 ) 2225, 1727.
- Example 2 The Novikoff hepatoma cells used came from the tumor bank of the German Cancer Research Center, Heidelberg, (Cancer Research 1951, 17, 1010). 100,000 cells were sown per 25 cm 2 cultivation bottle.
- CMPC carbomethoxypropionyl cyanide
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Transplantation (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Communicable Diseases (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Epoxy Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10112925 | 2001-03-13 | ||
DE10112924A DE10112924A1 (en) | 2001-03-13 | 2001-03-13 | 1-butanoic acid derivatives, pharmaceutical compositions containing such derivatives and uses of such derivatives |
DE10112925A DE10112925A1 (en) | 2001-03-13 | 2001-03-13 | Use of sugar phosphates, sugar phosphate analogs, amino acids, amino acid analogs for modulating transaminases and / or the association p36 / malate dehydrogenase |
DE10112924 | 2001-03-13 | ||
PCT/EP2002/002774 WO2002072527A2 (en) | 2001-03-13 | 2002-03-13 | 1-butyric acid derivatives such as carbomethoxypropionyl cyanide or leflunomide derivatives, and the therapeutic use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1377291A2 true EP1377291A2 (en) | 2004-01-07 |
Family
ID=26008808
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02726161A Withdrawn EP1377291A2 (en) | 2001-03-13 | 2002-03-13 | 1-butyric acid derivatives such as carbomethoxypropionyl cyanide or leflunomide derivatives, and the therapeutic use thereof |
Country Status (5)
Country | Link |
---|---|
US (1) | US20040152772A1 (en) |
EP (1) | EP1377291A2 (en) |
JP (2) | JP4382354B2 (en) |
CA (1) | CA2441088A1 (en) |
WO (1) | WO2002072527A2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10112925A1 (en) * | 2001-03-13 | 2002-10-02 | Erich Eigenbrodt | Use of sugar phosphates, sugar phosphate analogs, amino acids, amino acid analogs for modulating transaminases and / or the association p36 / malate dehydrogenase |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2905679A (en) * | 1959-09-22 | Process for the preparation of | ||
GB1091089A (en) * | 1965-08-20 | 1967-11-15 | Pierre Wirth | Organic base salts of n-carbamyl-aspartic acids |
FR2315916A2 (en) * | 1976-03-23 | 1977-01-28 | Univ Johns Hopkins | THERAPEUTIC MIXTURES INCLUDING ANALOGUES ALPHA HYDROXY ACIDS OF ESSENTIAL AMINO ACIDS AND THEIR ADMINISTRATION TO HUMANS FOR THE IMPROVEMENT OF PROTEIN SYNTHESIS AND THE SUPPRESSION OF UREA FORMATION |
GB2127809B (en) * | 1982-09-28 | 1986-03-12 | Ciba Geigy Ag | Certain b-oxo-a-carbamoyl-pyrrolepropionitriles |
US5200526A (en) * | 1987-04-27 | 1993-04-06 | The Governors Of The University Of Alberta | Syntheses of optically pure α-amino acids from 3-amino-2-oxetanone salts |
JPH06256184A (en) * | 1993-03-05 | 1994-09-13 | Morishita Roussel Kk | Amino acid preparation for cancer patient |
DE19610955A1 (en) * | 1996-03-20 | 1997-09-25 | Hoechst Ag | Combination preparation containing 5-methylisoxazole-4-carboxylic acid- (4-trifluoromethyl) -anilide and N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxycrotonic acid amide |
HUP9602024A3 (en) * | 1996-07-25 | 1999-05-28 | Toth Sandor | Pharmaceutical composition containing aminoacid for external use |
MXPA00010150A (en) * | 1998-04-17 | 2002-05-14 | Parker Hughes Inst | Btk inhibitors and methods for their identification and use. |
DE19857009A1 (en) * | 1998-12-10 | 2000-06-15 | Aventis Pharma Gmbh | Preparation with improved therapeutic range, containing nucleotide synthesis inhibitors |
-
2002
- 2002-03-13 CA CA002441088A patent/CA2441088A1/en not_active Abandoned
- 2002-03-13 EP EP02726161A patent/EP1377291A2/en not_active Withdrawn
- 2002-03-13 US US10/471,854 patent/US20040152772A1/en not_active Abandoned
- 2002-03-13 JP JP2002571444A patent/JP4382354B2/en not_active Expired - Lifetime
- 2002-03-13 WO PCT/EP2002/002774 patent/WO2002072527A2/en active Application Filing
-
2009
- 2009-08-03 JP JP2009181024A patent/JP2009292831A/en not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO02072527A2 * |
Also Published As
Publication number | Publication date |
---|---|
JP4382354B2 (en) | 2009-12-09 |
JP2009292831A (en) | 2009-12-17 |
CA2441088A1 (en) | 2002-09-19 |
WO2002072527A2 (en) | 2002-09-19 |
US20040152772A1 (en) | 2004-08-05 |
JP2005503333A (en) | 2005-02-03 |
WO2002072527A3 (en) | 2003-01-16 |
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