34 results about "Dihydrofolate reductase inhibitor" patented technology

Compounds of Formula I and Formula IA are inhibitors of dihydrofolate reductase and are suitable for use in compositions and methods for dihydrofolate reductase inhibition or, more specifically, treatment of a fungal infection, a bacterial infection or a protozoal infection, and, in specific embodiments, treatment of a fungal infection caused by C. albicans or C. glabrata:

wherein R, R₁, R₂, R₃, R₄, A, B, E, V, W, X, Y and Z are as defined herein.

The compositions and methods described herein discloses the design, synthesis and testing of compounds that act as inhibitors of DHFR. The basic scaffold of these inhibitors includes a 2,4-diaminopyrimidine ring with a propargyl linker to another substituted aryl, bicyclo or heteroaryl ring. These DHFR inhibitors are potent and selective for many different pathogenic organisms, including the DHFR enzyme from bacteria such as Bacillus anthracis and methicillin-resistant Staphylococcus aureus, fungi such as Candida glabrata, Candida albicans and Cryptococcus neoformans and protozoa such as Cryptosporidium hominis and Toxoplasma gondii. These compounds and other similar compounds are also potent against the mammalian enzyme and may be useful as anti-cancer therapeutics.

Compounds of the formula I: wherein R1, R2, R1' and R2' are independently hydrogen or a group releasing the free amine in vivo, R6 is a substituted phenyl or an optionally substituted, bicyclic or tricyclic aryl ring system or an optionally substituted mono, bi- or tricyclic heteroaryl ring system having utility as DHFR inhibitors with favourable pharmacokinetic properties.

Compounds of formula (I) or (II) are dihydrofolate reductase inhibitors, useful for the treatment of, for example, cell proliferative diseases:

wherein A and D are independently —CHR₇— or —NR₇—; E and G are independently ═CR₇— or ═N—; each R₆ independently represents hydrogen or —OR₇; R₇ is hydrogen or C₁-C₆ alkyl; R₁ is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; R₂ is the side chain of a natural or non-natural alpha amino acid which does not contain a carboxyl, or carboxyl ester group; Y is a bond, —C(═O)—, —S(═O)₂—, —C(═O)NR₃—, —C(═S)—NR₃, —C(═NH)NR₃ or —S(═O)₂NR₃— wherein R₃ is hydrogen or optionally substituted C₁-C₆ alkyl; L¹ is a divalent radical of formula -(Alk¹)_m(Q)_n(Alk²)_p- wherein m, n and p are independently 0 or 1, and Q, Alk¹ and Alk² are as defined in the claims; X¹ represents a bond; —C(═O); or —S(═O)₂—; —NR₄C(═O)—, —C(═O)NR₄—, —NR₄C(═O)NR₅—, —NR₄S(═O)₂—, or —S(═O)₂NR₄— wherein R₄ and R₅ are independently hydrogen or optionally substituted C₁-C₆ alkyl; and z is 0 or 1.

The invention provides a combined medicine having efficacy of antineoplastic drugs. The combined medicine consists of chlorogenic acid and a dihydrofolate reductase inhibitor of unit preparations in same or different specifications, and a pharmaceutically acceptable carrier, wherein the chlorogenic acid and the dihydrofolate reductase inhibitor are applied in a simultaneous or separated mode. According to the combined medicine, a synergistic effect can be developed when the chlorogenic acid and the DHFR (dihydrofolate reductase) inhibitor are used in a combined mode, and hematopoietic function injury and weight loss caused by the DHFR inhibitor can be relieved; toxic and side effects of the DHFR inhibitor can be effectively reduced; and the medicine, which combines the chlorogenic acid and the DHFR inhibitor is excellent in curative effect, low in toxicity and good in prospect of clinical application.

The present invention relates to a novel process for the preparation of the compound of formula I, a dihydrofolate reductase inhibitor

and to valuable intermediates in this process.

The present invention relates to pharmaceutical compositions containing a combination of reduced forms of folate, liver protectors, vitamins, and essential or non-essential amino acids, useful in preventing the adverse effects associated with prolonged use of dihydrofolate reductase inhibitors.

A method of controlling proliferation of fish parasites comprising the administration of 1 to 50 mg/kg fish body weight/day of an inhibitor of folate synthesis and/or an inhibitor of folate activation to fish continuously for 1 to 2 weeks. Using a combination preparation composed of an inhibitor of folate synthesis and an inhibitor of folate activation is preferable, and a sulfonamide is preferable for the inhibitor of folate synthesis. A dihydrofolate reductase inhibitor, a folate antagonist, etc., can be used as the inhibitor of folate activation. The antiparasitic agent is able to exterminate fish parasites via oral administration. It is particularly effective against parasites belonging to the ciliate group among fish parasites.

The invention provides a coupling compound which is a compound as shown in a formula (I) or a stereoisomer, a tautomer, a homologue, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound as shown in the formula (I), A is a linking group, and B is a dihydrofolate reductase inhibitor.

The invention provides novel compounds or the formula II: wherein R₁, R₂, R₃ and R₄ are independently hydrogen of a group that liberates the free amine in vivo, for example —CO-alkyl, preferably —CO—C₁-C₃ alkyl or pivalate; or —COhaloalkyl, preferably —CO—C₁-C₃ haloalkyl, most preferably —CO—C₁-C₃ chloroalkyl; wherein W is: and @ denotes the points of attachment and wherein the ester can be located in either direction; wherein n and m are independently 0-5; wherein one but not both or X and Y can be nitrogen, or X is C-A and/or Y is C—B; wherein A and B are independently selected from hydrogen, alkyl optionally substituted with a halogen, an electron donor group such as amino, alkylamino, dialkylamino or hydroxy, or an electron acceptor group such as nitro, cyano. trihaloalkyl or amido, alkoxy or halogen; and pharmacologically acceptable salts thereof. Provided that when R₁ to R₄ are hydrogen, both X and Y are C—H, n is 1 and —(CH₂)_n— is attached to the bridging oxygen of the ester group W, then m cannot be 0 or 1.

The invention relates to the use of an inhibitor of the dihydrofolate reductase enzyme selected from the group that consists of methotrexate, trimetrexate and pemetrexed; or a pharmaceutically acceptable salt thereof, for the preparation of a drug for the treatment or prevention of recurrences of a disease selected from the group that consists of cancer, psoriasis, psoriatic arthritis, juvenile polyarticular arthritis, rheumatoid arthritis, Crohn's disease, polymyositis, dermatomyositis and sarcoidosis, wherein said treatment or prevention includes administering to a patient, simultaneously, separately or sequentially, a lipophilic statin and the inhibitor of the dihydrofolate reductase enzyme. The invention also relates to a pharmaceutical composition which includes the inhibitor of the dihydrofolate reductase enzyme and the lipophilic statin together with pharmaceutically acceptable carriers and/or vehicles.