Combinations that include methotrexate and a dihydroorotate dehydrogenase inhibitor
What is Al technical title?
Al technical title is built by PatSnap Al team. It summarizes the technical point description of the patent document.
A technology of dihydroorotic acid and hydrogen atoms, which can be used in drug combinations, anti-inflammatory agents, anti-toxic agents, etc., can solve problems such as hindering the development of compounds
Inactive Publication Date: 2011-12-21
ALMIRALL
View PDF5 Cites 0 Cited by
Summary
Abstract
Description
Claims
Application Information
AI Technical Summary
This helps you quickly interpret patents by identifying the three key elements:
Problems solved by technology
Method used
Benefits of technology
Problems solved by technology
Therefore, hepatotoxicity has been identified as an adverse effect directly arising from the mechanism of action of DHODH-inhibitors, which hampers the development of this class of compounds
Method used
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more
Image
Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
Click on the blue label to locate the original text in one second.
Reading with bidirectional positioning of images and text.
Smart Image
Examples
Experimental program
Comparison scheme
Effect test
example 1
[0347] Example 1 - Determination of Inhibition of Human DHODH Activity
[0348] DHODH activity and its inhibition were studied with 2,6-didichlorophenol-indophenol (DCIP) using a chromogen reduction assay. Combines substrate oxidation (dihydroorotate, L-DHO) and co-substrate reduction (coenzyme Q, CoQ) with chromogen reduction, thus enzymatic activity results in chromogen absorbance at 600 nm Loss.
[0349] Enzyme extracts (8 microliters, approximately 1.5 micrograms of human protein) were incubated in 96-well plates. Assay mix (200 μl) contained 200 μM CoQD, 100 μM L-DHO, 120 μM DCIP, and 2 μl Test compound. Compounds were dissolved in DMSO such that the stock concentration was 1 mM and tested at different concentrations ranging from 10 μM to 1 pM to calculate the IC 50 (inhibitor concentration required for 50% inhibition).
[0350] The reaction was initiated by the addition of enzyme, followed by incubation for 10 minutes at room temperature, followed by measurement of...
example 2
[0355] Example 2 - Reduced liver toxicity
[0356] Acute hepatotoxicity assays were performed on Swiss mice. Animals were administered either vehicle, or 100 mg / kg teriflunomide, or a compound of the invention (from the list shown above) alone by intraperitoneal route. After 24 hours, the animals were sacrificed and the levels of the liver markers AST (aspartate aminotransferase), ALT (alanine aminotransferase) and BIL (total bilirubin) in plasma were determined.
[0357] Table 2: After administration of 100 mg / kg compound, 100 mg / kg teriflunomide or vehicle Plasma levels (IU: International Units) of liver markers in mice after administration.
[0358] Compound number
[0359] As is clear from Table 2, compared to vehicle-treated mice, teriflunomide-treated mice showed a significant increase in three liver markers, clearly indicating high hepatotoxicity, whereas DHODH of the present invention Inhibitors did not cause significant increases in any of the parame...
example 3
[0360] Example 3: Determination of the efficacy of the combination product of the invention in adjuvant-induced arthritis.
[0361] The effect of DHODH inhibitor compounds in combination with methotrexate (0.05 mg / kg per day) was tested in a rat adjuvant-induced arthritis model (AIA) on animals with established disease (cure gender program). Briefly, Complete Freund's Adjuvant (CFA) was injected into the left hind paw of Wistar rats, and 10 days later, the organ plethysmometer (plethysmometer) was used to measure the Swelling condition. Rats exhibiting similar degrees of inflammation in both paws were randomized into treatment groups (n=7 per group). Compounds were administered orally once daily for 10 days and paw volume was measured every other day until day 21.
[0362] Table 3. Compound 20 (10 mg / kg per day), methotrexate (0.05 mg per day / kg) and their combination on the inhibition of paw inflammation in arthritic rats.
[0363] Results are expressed as percent ...
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more
PUM
Login to view more
Abstract
The present invention provides a combination comprising (a) methotrexate and (b) a non-hepatotoxic dihydroorotate dehydrogenase (DHODH) inhibitor of formula (I): wherein: R1 consists of a hydrogen atom, a halogen atom, C1-4 alkyl, C3-4 cycloalkyl, -CF3 and -OCF3; R2 is selected from the group consisting of hydrogen atom, halogen atom and C1-4 alkyl; R3 Selected from the group consisting of -COOR5, -CONHR5, tetrazolyl, -SO2NHR5 and -CONHSO2R5 groups, wherein R5 is selected from the group consisting of hydrogen atoms and straight-chain or branched C1-4 alkyl groups; R4 is selected from the group consisting of a hydrogen atom and a C1-4 alkyl group; R9 is selected from a group consisting of a hydrogen atom and a phenyl group; G1 represents a group selected from N and CR6, wherein R6 is composed of a hydrogen atom, Halogen atom, C1-4 alkyl, C3-4 cycloalkyl, C1-4 alkoxy, -CF3, -OCF3, N-containing monocyclic C5-7 heteroaryl, N-containing monocyclic C3-7 heterocyclic And selected from the group consisting of C6-10 aryl groups, said C6-10 aryl groups may be optionally substituted by one or more substituents selected from halogen atoms and C1-4 alkyl groups; G2 means selected from the following Groups in the group: hydrogen atom, hydroxyl, halogen atom, C3-4 cycloalkyl, C1-4 alkoxy and -NRaRb, wherein Ra represents C1-4 alkyl and Rb consists of C1-4 alkyl and C1 - selected from the group consisting of 4 alkoxy-C1-4 alkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 6 to 8 which may optionally contain an oxygen atom as another heteroatom membered heterocyclic ring; monocyclic or bicyclic 5 to 10 membered heteroaryl ring containing one or more nitrogen atoms, which may be optionally replaced by one or more members selected from halogen atoms, C1-4 alkyl, C1-4 alkoxy Substituents of radical, C3-4 cycloalkyl, C3-4 cycloalkoxy, -CF3, -OCF3 and -CONR7R8, wherein R7 and R8 are independently selected from hydrogen atom, straight chain or branched chain C1-4 alkane group, C3-7 cycloalkyl group, or R7 and R8, together with the nitrogen atom to which they are attached, form a group of the following formula: wherein n is an integer from 0 to 3; and phenyl, which may optionally be replaced by one or more One selected from halogen atom, C1-4 alkyl, hydroxyl, C1-4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, cyano, -CF3, -OCF3, -CONR7R8, oxadiazole Substituents of diazolyl, triazolyl, pyrazolyl and imidazolyl, said diazolyl, triazolyl, pyrazolyl and imidazolyl can be optionally replaced by C1-4 alkyl or C3-7 cycloalkyl Substituted and wherein R7 and R8 are independently selected from a hydrogen atom, a straight or branched C1-4 alkyl group, a C3-7 cycloalkyl group, or R7 and R8 together with the nitrogen atom to which they are attached form a group of the following formula: wherein n is an integer from 0 to 3; or, when G' represents CR6, G2 together with R6 forms a non-aromatic C5-10 carbocyclic group or a C6-10 aryl group, and its pharmaceutical Pharmaceutically acceptable salts and N oxides.
Description
【Technical field】 [0001] The present invention relates to novel combinations of methotrexate and dihydroorotate dehydrogenase (DHODH) inhibitors. These combinations are suitable for the treatment, prevention or inhibition of diseases and conditions known to be ameliorated by methotrexate and / or by inhibition of dihydroorotate dehydrogenase, such as autoimmune diseases, immune and inflammatory diseases, destructive Destructive bone disorder, malignant neoplastic disease, angiogenic-related disorder, viral disease, and infectious disease. 【Background technique】 [0002] Methotrexate (MTX) is an antimetabolite and immunomodulator that affects many intracellular pathways of purine metabolism. It is effective in reducing the signs and symptoms of rheumatoid arthritis (RA) and slowing or stopping radiation damage. Due to its efficacy, ease of administration, and relatively low cost, MTX has become the first-line oral therapy in most RA patients. In patients with an incomplete r...
Claims
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more
Application Information
Patent Timeline
Application Date:The date an application was filed.
Publication Date:The date a patent or application was officially published.
First Publication Date:The earliest publication date of a patent with the same application number.
Issue Date:Publication date of the patent grant document.
PCT Entry Date:The Entry date of PCT National Phase.
Estimated Expiry Date:The statutory expiry date of a patent right according to the Patent Law, and it is the longest term of protection that the patent right can achieve without the termination of the patent right due to other reasons(Term extension factor has been taken into account ).
Invalid Date:Actual expiry date is based on effective date or publication date of legal transaction data of invalid patent.
Login to view more 
Login to view more