Triglyceride-lowering agent and hyperinsulinism-ameliorating agent

The present invention is directed to a triglyceride-lowering agent, exhibiting excellent triglyceride-lowering effect and a hyperinsulinemia-ameliorating agent. The triglyceride-lowering agent and hyperinsulinemia-ameliorating agent are characterized by containing a pitavastatin compound, and amlodipine or a salt thereof.

Novel compounds with high therapeutic index

The present invention is directed to novel therapeutic compounds comprised of an amino acid bonded to a medicament or drug having a hydroxy, amino, carboxy or acylating derivative thereon. These high therapeutic index derivatives have the same utility as the drug from which they are made, and they have enhanced pharmacological and pharmaceutical properties. In fact, the novel drug derivatives of the present invention enhance at least one therapeutic quality, as defined herein. The present invention is also directed to pharmaceutical compositions containing same.

DERIVATIVES OF 1,4-DIHYDROPYRIDINE POSSESSING ANTIVIRAL EFFICACY

2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester type compounds having general formula I 112-. (canceled)17. A process for preparing a compound according to claim 13 , comprising the steps of:a) reaction of a derivative of formaldehyde with a derivative of acetoacetic acid ester and enamine in an appropriate solvent;b) treatment with sodium hydroxide in an appropriate solvent.18. The process according to claim 17 , wherein claim 17 , in step a) claim 17 , the derivative of formaldehyde is formaldehyde or glyoxylic acid.19. The process according to claim 17 , wherein claim 17 , in step a) claim 17 , the derivative of acetoacetic acid ester is 2-methoxycarbonyl methyl ester of acetoacetate or 2-ethoxycarbonyl methyl ester of acetoacetate.20. The process according to claim 17 , wherein claim 17 , in step a) claim 17 , the derivative of enamine is methyl-β-aminocrotonate claim 17 , ethyl-β-aminocrotonate or 2-ethoxycarbonyl methyl ester of β-aminocrotonate.21. The process according to claim 17 , wherein claim 17 , in step a) and b) claim 17 , the appropriate solvent is selected from methanol claim 17 , ethanol claim 17 , propanol and butanol.22. A pharmaceutical composition comprising as active ingredient a compound according to claim 13 , optionally together with one or more pharmaceutically acceptable excipients.23. A method of treating a condition requiring an antiviral agent in a subject in need thereof claim 13 , comprising administering an effective amount of a compound according to .24. A method of treating influenza in a subject in need thereof claim 13 , comprising administering an effective amount of a compound according to . The present invention relates to new 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester type compounds having general formula IwhereinNew 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester type compounds with general formula I possessing antiviral activity.Influenza, commonly called “the flu,” is an illness ...

ARYL DIHYDROPYRIDINONE AND PIPERIDINONE MGAT2 INHIBITORS

The present invention provides compounds of Formula (I): 3. A compound according to claim 2 , wherein:{'sup': 11', '15, 'sub': '1-4', 'Rand Rare independently selected from the group consisting of: H, Calkyl and halo;'}{'sup': 12', '14, 'sub': 1-4', '1-4, 'Rand Rare independently selected from the group consisting of: H, halo, Calkyl and Calkoxy; and'}{'sup': 13', 'i', 'f', 'j', 'j', 'e, 'sub': 1-4', '1-4', '1-4', '1-4', '2', 'm', '3-4', '2', '1-4', '2', '1-4, 'Ris independently selected from the group consisting of: H, halo, Calkyl substituted with 0-1 R, Calkoxy, Chaloalkyl, Chaloalkoxy, —(CH)—Ccycloalkyl, CN, NRR, SR, NHCO(Calkyl), NHSO(Calkyl), and a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR, O, and S.'}11. A pharmaceutical composition claim 1 , comprising: a pharmaceutically acceptable carrier and a compound of claim 1 , or a stereoisomer claim 1 , a tautomer claim 1 , or a pharmaceutically acceptable salt thereof.12. A pharmaceutical composition claim 9 , comprising: a pharmaceutically acceptable carrier and a compound of claim 9 , or a stereoisomer claim 9 , a tautomer claim 9 , or a pharmaceutically acceptable salt thereof.13. A pharmaceutical composition claim 10 , comprising: a pharmaceutically acceptable carrier and a compound of any one of claim 10 , or a stereoisomer claim 10 , a tautomer claim 10 , or a pharmaceutically acceptable salt thereof.14. The pharmaceutical composition according to claim 11 , further comprising one or more other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents claim 11 , anti-hyperglycemic agents claim 11 , anti-hyperinsulinemic agents claim 11 , anti-retinopathic agents claim 11 , anti-neuropathic agents claim 11 , anti-nephropathic agents claim 11 , anti-atherosclerotic agents claim 11 , anti-ischemic agents claim 11 , anti-hypertensive agents claim 11 , anti-obesity agents claim 11 , anti-dyslipidemic ...

Compounds And Compositions For Treating Cancer

The invention relates to compounds and composition for the treatment and prevention of cancer. The invention also covers all diseases that may be treated by selective modulation of levels of reactive oxygen species in diseased cells versus normal cells. Methods for the preparation and administration of such compositions are also disclosed. 4. A pharmaceutical composition comprising one or more compounds of claim 1 , or its pharmaceutically acceptable salt claim 1 , and a pharmaceutically acceptable carrier.5. The pharmaceutical composition of claim 4 , further comprising one or more chemotherapeutic agents.6. A kit comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound of or its salt or analog claim 1 , and instructions for preparation and/or administration of the pharmaceutical composition.7. The kit of claim 6 , further comprising one or more chemotherapeutic agents.8. A method for treating a cancer in a subject claim 1 , the method comprising: administering to a subject in need of such treatment a therapeutically effective amount of a compound of or its salt or analog claim 1 , to an individual in need thereof.9. The method of claim 8 , wherein treatment inhibits further growth of the cancer.10. The method of wherein the cancer is a carcinoma claim 8 , a sarcoma claim 8 , a melanoma claim 8 , a pancreatic cancer claim 8 , a breast cancer or a bladder cancer.11. The method of wherein the effective amount is from about 2.5 mg/kg to about 100 mg/kg of a compound of formula 1.12. A method for inhibiting cell proliferation claim 1 , the method comprising: contacting a cell with an effective amount of a composition comprising a compound of to inhibit the proliferation of the cell.13. A method for increasing apoptosis of a cell or in a population of cells claim 1 , the method comprising: contacting the cell or population of cells with an effective amount of a composition comprising a compound of to increase apoptosis in the ...

Small molecule inhibitors of necroptosis

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I)-(VIII) and by Compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), and (58)-(70). These necrostatins are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring necrostatins. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

METHOD FOR PURIFICATION OF CALCIUM CHANNEL BLOCKERS OF DIHYDORPYRIDINE TYPE AND PREPARATION OF NANOPARTICLES THEREOF

A method for purification calcium ion channel blocker medicament of dihydropyridine type and pharmaceutically acceptable salts thereof through the ultrasonic crystallization technology and direct preparation of nanoparticles thereof. 1. A method for purification of dihydropyridine-type calcium channel blockers and pharmaceutically acceptable salts thereof and direct preparation of nanoparticles thereof by ultrasonic crystallization technology.2. The ultrasonic crystallization method according to claim 1 , comprising the following steps: saturated or supersaturated solution of dihydropyridine-type calcium channel blockers and pharmaceutically acceptable salts thereof is initially formed by altering temperature or the polarity of solvent claim 1 , or by adding poor solvent claim 1 , and then nanoparticles with suitable size are obtained by ultrasound.3. Nanoparticles of dihydropyridine-type calcium channel blockers and pharmaceutically acceptable salts thereof obtained according to the method of claim 1 , wherein the size of the nanoparticles ranges from 20 nm to 2000 nm claim 1 , with the median size ranging from 200 nm to 1500 nm.4. The ultrasonic crystallization method according to claim 1 , wherein the temperature for ultrasonic crystallization ranges from −78° C. to 100° C. claim 1 , and preferably from −5° C. to 30° C.5. The ultrasonic crystallization method according to claim 1 , wherein the solvent for ultrasonic crystallization is selected from lower ketones claim 1 , lower alcohols claim 1 , lower ethers claim 1 , lower acids claim 1 , lower esters claim 1 , dichloromethane claim 1 , chloroform claim 1 , acetic anhydride and common small molecule solvents claim 1 , and preferably claim 1 , the solvent is a single common solvent selected from acetone claim 1 , ethanol claim 1 , methanol claim 1 , N claim 1 ,N-dimethyl formamide (DMF) claim 1 , acetonitrile claim 1 , diethyl ether claim 1 , dichloromethane claim 1 , dimethyl sulfoxide (DMSO) and water claim 1 ...

ARYL DIHYDROPYRIDINONES AND PIPERIDINONE MGAT2 INHIBITORS

The present invention provides compounds of Formula (I): 1. A compound of Formula (I):{'sup': 4', '16', '5', '16, 'x and y can be both a single bond; when x is a double bond, then y is a single bond and Rand Rare absent; when y is a double bond, then x is a single bond and Rand Rare absent;'}{'sup': 1', 'b', 'g', 'e', 'b', 'g', 'a, 'sub': 4-18', '2-8', '2', '1-8', '2', '2-8', '2', 'm', '3-10', '2', 'm', '1-12, 'Ris independently selected from the group consisting of: —CONH(Calkyl), —CONHChaloalkyl, —CONH(CH)Ph, —CONHCHCOCalkyl, —(CH)—(Ccarbocycle substituted with 0-2 Rand 0-2 R), —(CH)-(5- to 6-membered heteroaryl comprising: carbon atoms and 1-4 heteroatoms selected from N, NR, O and S; wherein said heteroaryl is substituted with 0-1 Rand 0-2 R), and a Chydrocarbon chain substituted with 0-3 R; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated;'}{'sup': '2', 'sub': 1-4', '3-4', '1-4, 'Ris independently selected from the group consisting of: Calkyl, Ccycloalkyl, and Chaloalkyl;'}{'sup': '3', 'sub': '1-4', 'Ris independently selected from the group consisting of: H, F, Cl, Calkyl and CN;'}{'sup': 4', '5, 'sub': '1-4', 'Rand Rare independently selected from the group consisting of: H, F, Cl, and Calkyl;'}{'sup': 3', '4, 'when x is a single bond, Rand Rmay be combined with the carbon atom to which they are attached to form a 3- to 6-membered carbocycle;'}{'sup': 6', 'c', 'c', 'j', 'j', 'j', 'j', 'j', 'f', 'j, 'sub': 1-4', '2', '2', 'n', 't', '2', 'm', '2', '1-6', '1', '2', '2', '2', '2, 'Ris independently selected from the group consisting of: H, halo, Calkyl, CN, NO, R, —(CH)—(X)—(CH)R, NH, —CONH(Calkyl), —NHCOXSOR, —NHCOCHPO(OEt), —NHCOCOR, —NHCOCH(OH)R, —NHCOCHCOR, —NHCONHR, and —OCONRR;'}X is independently selected from the group consisting of: O, S, NH, CONH, and NHCO;{'sub': 1', '1-4', '1-4', '3-4, 'Xis independently Chydrocarbon chain optionally substituted with Calkyl or Ccycloalkyl;'}{'sup': 5', '6, 'when y is a single bond, ...

Ketamine derivatives and compositions thereof

Ketamine derivatives and pharmaceutical compositions thereof are disclosed. When administered orally the ketamine derivatives provide increased bioavailability of ketamine in the systemic circulation. The ketamine derivatives can be used to treat neurological diseases, psychological diseases and pain.

COMPOUNDS USEFUL AS IMMUNOMODULATORS

The present disclosure generally relates to compounds useful as immunomodulators. Provided herein are compounds, compositions comprising such compounds, and methods of their use. The disclosure further pertains to pharmaceutical compositions comprising at least one compound according to the disclosure that are useful for the treatment of various diseases, including cancer and infectious diseases. 2. A compound of wherein Ris hydrogen.3. A compound of wherein Rand Rare selected from —CHand halo.4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein:{'sup': 2', '3', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b, 'sub': 2', 'm', '2', 'm', '2', 'n', '2', '2', 'n', '2', '2', 'n', '2', '2', 'm', '2', 'm', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', '1', '3', '1', '3', '1', '3', '1', '3', '3', '6', '2', 'm', '2', '2, 'one of Rand Ris hydrogen and the other is selected from —O(CH)Ph, —(CH)OPh, —O(CH)NRR, —S(O)NH(CH)NRR, —S(O)NH(CH)COH, —O(CH)pyridinyl, —(CH)NH(CH)NRR, —C(O)NH(CH)NRR, —NHC(O)(CH)NRR, —NHC(O)NH(CH)NRR; and —NHC(O)NH(CH)COH; wherein each piperidinyl group is optionally substituted with a C-Calkyl group; and wherein the pyridinyl group is optionally substituted with a cyano group; and wherein each Ph group is optionally substituted with one, two, or three groups independently selected from C-Calkoxy, C-Calkyl, C-Calkylcarbonyl, amino, carboxy, (C-Ccycloalkyl)alkoxy, cyano, halo, hydroxy, hydroxymethyl, —CHO, —C(O)NRR, —(CH)NRR, —OCHphenyl wherein the phenyl is optionally substituted with one or two halo groups, and —OCHpyridinyl optionally substituted with a cyano group, aminocarbonyl group, or a pyrazole ring; and'}{'sup': 6', '7', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b, 'sub': 2', 'm', '2', 'm', '2', 'n', '2', '2', 'n', '2', '2', 'n', '2', '2', 'm', '2', 'm', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', 'n', '2', '1', '3', '1', '3', '1', '3', ...

Drp1-FILAMIN COMPLEX FORMATION INHIBITORS

Compounds represented by formula (I) below 5. The compound of or a pharmacologically acceptable salt thereof or a solvate of them claim 4 , wherein Rand Rare each independently H claim 4 , NO claim 4 , NH claim 4 , OH claim 4 , C-Calkyl claim 4 , C-Chaloalkyl claim 4 , or C-Calkoxyalkyl.9. The compound of claim 4 , or a pharmacologically acceptable salt thereof or a solvate of them claim 4 , wherein Ris NO.10. The compound of claim 4 , or a pharmacologically acceptable salt thereof or a solvate of them claim 4 , wherein Ris NH.11. The compound of claim 1 , or a pharmacologically acceptable salt thereof or a solvate of them claim 1 , wherein Ris H claim 1 , C-Calkyl claim 1 , C-Chaloalkyl claim 1 , or C-Calkoxyalkyl.12. The compound of claim 11 , or a pharmacologically acceptable salt thereof or a solvate of them claim 11 , wherein Ris C-Calkyl.13. The compound of claim 12 , or a pharmacologically acceptable salt thereof or a solvate of them claim 12 , wherein Ris CH.14. The compound of claim 1 , or a pharmacologically acceptable salt thereof or a solvate of them claim 1 , wherein Ris H claim 1 , C-Calkyl claim 1 , C-Chaloalkyl claim 1 , or C-Calkoxyalkyl.15. The compound of claim 14 , or a pharmacologically acceptable salt thereof or a solvate of them claim 14 , wherein Ris C-Calkyl.16. The compound of claim 15 , or a pharmacologically acceptable salt thereof or a solvate of them claim 15 , wherein Ris CH.17. The compound of claim 1 , or a pharmacologically acceptable salt thereof or a solvate of them claim 1 , wherein Ris C-Calkyl or C-Chaloalkyl.18. The compound of claim 17 , or a pharmacologically acceptable salt thereof or a solvate of them claim 17 , wherein Ris C-Calkyl.19. The compound of claim 18 , or a pharmacologically acceptable salt thereof or a solvate of them claim 18 , wherein Ris CH.20. The compound of claim 1 , or a pharmacologically acceptable salt thereof or a solvate of them claim 1 , wherein Ris phenyl which is unsubstituted or substituted with ...

COMPOSITIONS AND METHODS FOR THE TREATMENT OF GLIOBLASTOMA

Provided are compositions that include a platelet-activating factor antagonist, pharmaceutical compositions including the platelet-activating factor antagonist, methods of treating a modulating the proliferation of a glioma or a pathological condition resulting from patient having a glioma. 3. The composition of claim 1 , wherein the compound is an R-enantiomer claim 1 , an S-enantiomer claim 1 , or a combination thereof.4. The composition of claim 1 , wherein the compound or the pharmaceutically acceptable salt thereof is in an amount effective to inhibit the growth of a brain tumor or modulate a neurological activity induced by a brain tumor by antagonizing platelet-activating factor claim 1 , and the composition further comprises a pharmaceutically acceptable carrier.5. The composition of claim 4 , wherein the brain tumor is a selected from the group consisting of: a glioblastoma claim 4 , an astrocytoma claim 4 , an oligodendroglioma claim 4 , an ependymal tumor claim 4 , a neuronal tumor and a combination of glial tumors.6. The composition of claim 1 , wherein the pharmaceutically acceptable salt is an acid addition salt.9. The method of claim 7 , wherein the brain tumor is a selected from the group consisting of: a glioblastoma claim 7 , an astrocytoma claim 7 , an oligodendroglioma claim 7 , an ependymal tumor claim 7 , a neuronal tumor and a combination of glial tumors.10. The method of claim 7 , wherein the pharmaceutically acceptable salt is an acid addition salt.13. The method of claim 7 , wherein the therapeutic composition is formulated with an amount of the PAF receptor antagonist effective in reducing or inhibiting a pathological neurological condition associated with a brain tumor in a subject.14. The method of claim 13 , wherein the therapeutic composition is formulated with an amount of the PAF receptor antagonist effective in reducing or inhibiting a seizure associated with glioblastoma in a subject.15. (canceled)16. (canceled)17. (canceled) This ...

Compounds and methods for the treatment of neurodegenerative diseases

Novel compounds of formula (II) are disclosed. Compounds of formula (II) comprise ornithine derivatives or compounds that may metabolize to ornithine. Also disclosed are methods for the treatment of neurodegenerative diseases such as Alzheimer's Disease using compounds of formula (II).

Quaternary heteroatom containing compounds

The invention provides heterocyclic compounds with quaternary centers and methods of preparing compounds. Methods include the method for the preparation of a compound of Formula (II): comprising treating a compound of Formula (I): with a transition metal catalyst and under alkylation conditions as valence and stability permit.

Topical therapeutic formulations

The invention provides topical compositions and methods for using the compositions. The compositions can be used for the treatment of fibrotic or connective tissue disorders involving scarring, sub-dermal plaque accumulations, or fibrosis of muscle tissue. The disorders can be painlessly treated by the topical application of a composition described herein. One or more calcium channel blocker agents can serve as an active ingredient of the compositions, optionally in combination with, for example, one or more of emu oil and superoxide dismutase. The composition can further include pharmaceutically acceptable carriers that can facilitate the non-invasive transdermal delivery of the active(s) to subdermal sites.

TOPICAL THERAPEUTIC FORMULATIONS

The invention provides topical compositions and methods for using the compositions. The compositions can be used for the treatment of fibrotic or connective tissue disorders involving scarring, sub-dermal plaque accumulations, or fibrosis of muscle tissue. The disorders can be painlessly treated by the topical application of a composition described herein. One or more calcium channel blocker agents can serve as an active ingredient of the compositions, optionally in combination with, for example, one or more of emu oil and superoxide dismutase. The composition can further include pharmaceutically acceptable carriers that can facilitate the non-invasive transdermal delivery of the active(s) to subdermal sites. 1. A composition suitable for topical application to the skin and transdermal delivery, comprising: a calcium channel blocker active agent, superoxide dismutase, and emu oil, and one or more pharmaceutically acceptable carriers or gelling agents. This application is a continuation of U.S. application Ser. No. 14/981,167, filed on Dec. 28, 2015, which is a continuation in part of U.S. application Ser. No. 14/610,875, filed on Jan. 30, 2015, and a continuation in part of U.S. application Ser. No. 13/747,151, filed on Jan. 22, 2013, which claim priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 61/588,441, filed Jan. 19, 2012, and which are incorporated herein by reference.Peyronie's disease has been known as a distinct malady for hundreds of years. The plaque of Peyronie's disease may develop following trauma to the penis that causes localized internal bleeding. While the symptoms and severity of the disease can vary, a common manifestation is a lump, plaque or scar tissue in the non-erect penis. The condition can result in painful erections and penile disfigurement, and is often associated with impotence.Approximately one to ten percent of the male population experiences an incidence of Peyronie's disease in their lifetime. About 30 ...

ARYL DIHYDROPYRIDINONES AND PIPERIDINONE MGAT2 INHIBITORS

The present invention provides compounds of Formula (I): 2. A compound according to claim 1 , wherein:{'sup': 6', 'c', 'c, 'Ris independently R, OR, —CONHR, or —NHCOR;'}{'sup': '12', 'sub': 1-4', '1-4, 'Ris independently selected from the group consisting of: H, halo, Calkyl and Calkoxy;'}{'sup': '13', 'sub': 1-4', '1-4', '1-4', '1-4', '1-4', '2', 'm', '3-4', '1-4', '2', '2', '1-4', '2', '1-4, 'Ris independently selected from the group consisting of: H, halo, Calkyl substituted with 0-1 Calkoxy, Calkoxy, Chaloalkyl, Chaloalkoxy, —(CH)—Ccycloalkyl, CN, N(Calkyl), NHCO(Calkyl), NHSO(Calkyl), pyrazolyl, and morpholinyl;'}{'sup': 12', '13, 'alternatively, Rand R, together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic ring or a 5- to 6-membered saturated heterocyclic ring comprising: carbon atoms and 1-2 oxygen atoms;'}{'sup': '14', 'sub': '1-4', 'Ris independently selected from the group consisting of: H and Calkoxy; and'}{'sup': c', 'd', 'd', 'd, 'sub': 3-6', '2', 'm, 'Ris, at each occurrence, independently selected from the group consisting of: Ccycloalkyl substituted with 0-2 R, —(CH)-(phenyl substituted with 0-3 R), and a heteroaryl selected from: oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, and pyrazinyl; wherein said heteroaryl is substituted with 0-2 R.'}3. A compound according to claim 2 , wherein:{'sup': '6', 'sub': 3-6', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '2', '2', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '2', '2', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '1-4', '2', '1-4, 'Ris independently selected from the group consisting of: OPh, —CONH(Ccycloalkyl), —CONHPh, —CONH-(2-halo-Ph), —CONH-(3-halo-Ph), —CONH-(4-halo-Ph), —CONH-(4-Calkyl-Ph), —CONH(4-OH-Ph), —CONH-(3-Calkoxy-Ph), —CONH-(4-Calkoxy-Ph), —CONH-(4-Chaloalkyl-Ph), —CONH-(4-Chaloalkoxy-Ph), —CONH-(4-CN-Ph), —CONH-(4-tetrazolyl ...

ARYL DIHYDROPYRIDINONES AND PIPERIDINONE MGAT2 INHIBITORS

The present invention provides compounds of Formula (I): 3. A compound according to claim 2 , wherein:{'sup': 11', '15, 'sub': '1-4', 'Rand Rare independently selected from the group consisting of: H, Calkyl and halo;'}{'sup': 12', '14, 'sub': 1-4', '1-4, 'Rand Rare independently selected from the group consisting of: H, halo, Calkyl and Calkoxy; and'}{'sup': 13', 'i', 'f', 'j', 'j', 'e, 'sub': 1-4', '1-4', '1-4', '1-4', '2', 'm', '3-4', '2', '1-4', '2', '1-4, 'Ris independently selected from the group consisting of: H, halo, Calkyl substituted with 0-1 R, Calkoxy, Chaloalkyl, Chaloalkoxy, —(CH)—Ccycloalkyl, CN, NRR, SR, NHCO(Calkyl), NHSO(Calkyl), and a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR, O, and S.'}8. A compound according to claim 7 , wherein:{'sup': '2', 'sub': '3', 'Ris independently selected from the group consisting of: CFand Me;'}{'sup': '3', 'Ris independently selected from the group consisting of: H and F;'}{'sup': '4', 'Ris independently selected from the group consisting of: H and F;'}{'sup': '6', 'sub': 3', '3', '2', '2', '2', '2', '1-4', '1-5', '3, 'Ris independently selected from the group consisting of: OPh, —CONH(cyclopropyl), —CONH(cyclobutyl), —CONH(cyclopentyl), —CONH(cyclohexyl), —CONHPh, —CONH(4-F-Ph), —CONH(2-Cl-Ph), —CONH(4-Cl-Ph), —CONH(4-Me-Ph), —CONH(4-OH-Ph), —CONH(3-OMe-Ph), —CONH(4-OMe-Ph), —CONH(4-CF-Ph), —CONH(4-OCF-Ph), —CONH(1-Me-pyrazol-3-yl), —CONH(4-(1H-tetrazol-2-yl)-Ph), —CONH(4-(2H-tetrazol-5-yl)-Ph), —CONH(3-F-4-Me-Ph), —CONH(3-F-4-OMe-Ph), —CONH(CH)Ph, —CONH(5-OMe-pyrid-2-yl), —CONH(6-OMe-pyrid-3-yl), —CONH(5-OMe-pyrazin-2-yl), —CONH(6-OMe-pyridazin-3-yl), —NHCO(CH)SOMe, —NHCOPh, —NHCO(2-Me-Ph), —NHCO(3-Me-Ph), —NHCO(4-Me-Ph), —NHCO(2-Cl-Ph), —NHCO(3-Cl-Ph), —NHCO(2-C—F-Ph), —NHCO(2-C—F-Ph), —NHCO(isoxazol-5-yl), —NHCO(3-Me-isoxazol-5-yl), —NHCO(4-Me-isoxazol-5-yl), —NHCO(3-OMe-isoxazol-5-yl), —NHCO(3-Br-isoxazol-5-yl), —NHCO(3-(2-Cl-Ph)-isoxazol-5-yl), —NHCO(3-(3-F- ...

QUATERNARY HETEROATOM CONTAINING COMPOUNDS

The invention provides heterocyclic compounds with quaternary centers and methods of preparing compounds. Methods include the method for the preparation of a compound of Formula (II): 3. The method of claim 2 , wherein:{'sup': '1', 'Ris selected from halogen and an optionally substituted group selected from alkyl, carbocyclyl, carbocyclylalkyl, cyanoalkyl, aralkyl, heteroaralkyl, hydroxyalkyl, haloalkyl, acylalkyl, alkoxycarbonylalkyl, and aryloxycarbonylalkyl;'}{'sup': 2', '12', '7', '8', '11, 'R, R, R, R, and Rare independently selected at each occurrence from hydrogen, halogen, hydroxyl, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, and carbocyclyl;'}{'sup': 3', '4', '5', '13', '14', '15, 'R, R, R, R, R, and Rare independently selected at each occurrence from hydrogen, halogen, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, and aralkyloxy;'}{'sup': 6', '9', '10, 'R, R, and Rare independently selected at each occurrence from hydrogen, hydroxyl, and optionally substituted alkyl, alkoxy, alkylthio, aryloxy, carbocyclyl, aryl, arylcarbonyl, aralkylcarbonyl, heteroaryl, aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide.'}4. The method of claim 3 , wherein:{'sup': '1', 'Ris selected from halogen, alkyl, optionally substituted aralkyl, optionally substituted alkoxycarbonylalkyl, optionally substituted cyanoalkyl, and optionally substituted hydroxyalkyl; and'}{'sup': 6', '9', '10, 'R, R, and Rare independently selected at each occurrence from optionally substituted aralkyloxy, aralkoxycarbonyl, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, arylsulfonyl, alkoxycarbonyl, and aryloxycarbonyl.'}5. The method of claim 4 , wherein:{'sup': '6', 'X is —NR—;'}{'sup': 7', '7, 'Z is selected from —C(O)— and —CRR—;'}{'sup': 8', '8, 'A at each occurrence is —CRR—;'}{'sup': 10', '11', '11, 'W is selected from —NR ...

SMALL MOLECULE INHIBITORS OF NECROPTOSIS

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I)-(VIII) and by Compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), and (58)-(70). These necrostatins are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring necrostatins. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role. 113-. (canceled)1539-. (canceled)4168-. (canceled)7092-. (canceled)100. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 14 , or any pharmaceutically acceptable salt or solvate thereof claim 14 , or any stereoisomer thereof.101. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 40 , or any pharmaceutically acceptable salt or solvate thereof claim 40 , or any stereoisomer thereof.102. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 69 , or any pharmaceutically acceptable salt or solvate thereof claim 69 , or any stereoisomer thereof.103. A method of treating a condition in a subject claim 14 , said method comprising the step of administering the compound of claim 14 , or any pharmaceutically acceptable salt or solvate thereof claim 14 , or any stereoisomer thereof claim 14 , to said subject in a dosage sufficient to decrease necroptosis.104. A method of treating a condition in a subject claim 40 , said method comprising the step of administering the compound of claim 40 , or any pharmaceutically acceptable salt or solvate thereof claim 40 , or any stereoisomer thereof claim 40 , to said subject in a dosage sufficient to decrease necroptosis.105. A method of treating a condition in a ...

Novel inhibitors of proliferation and activation of signal transducer and activator of transcription (stats)

Pyridine compounds effective in modulation STAT3 and/or STAT5 activation are provided that are useful in the prevention and treatment of proliferative disease and conditions including cancer, inflammation and proliferative skin disorders.

QUATERNARY HETEROATOM CONTAINING COMPOUNDS

The invention provides heterocyclic compounds with quaternary centers and methods of preparing compounds. Methods include the method for the preparation of a compound of Formula (II): 130-. (canceled)32. The compound of claim 31 , wherein Rand Rcombine to form a carbonyl group.33. The compound of claim 31 , wherein Rand Y combine to form a ring with Q claim 31 , the ring including between 3 and 12 ring atoms.34. The compound of claim 33 , wherein the ring includes between 4 and 7 ring atoms.37. The compound of claim 36 , wherein the compound comprises one of a (+) enantiomer of the compound or a (−) enantiomer of the compound in an enantiomeric excess of greater than 50%.39. The compound of claim 38 , wherein the compound comprises one of a (+) enantiomer of the compound or a (−) enantiomer of the compound in an enantiomeric excess of greater than 50%.40. The compound of claim 38 , wherein:{'sup': '1', 'Ris selected from halogen, alkyl, optionally substituted aralkyl, optionally substituted alkoxycarbonylalkyl, optionally substituted cyanoalkyl, and optionally substituted hydroxyalkyl; and'}{'sup': 6', '9', '10, 'R, R, and Rare independently selected at each occurrence from aralkyloxy, aralkoxycarbonyl, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, arylsulfonyl, alkoxycarbonyl, and aryloxycarbonyl.'}41. The compound of claim 40 , wherein:{'sup': '6', 'X is —NR—;'}{'sup': 7', '7, 'Z is selected from —C(O)— and —CRR—;'}{'sup': 7', '7, 'A at each occurrence is —CRR—;'}{'sup': 10', '11', '11, 'W is selected from —NR— and —CRR—; and'}n is 0-2.42. The compound of claim 41 , wherein n is 1.43. The compound of claim 38 , wherein:X is —O—;{'sup': 7', '7, 'Z is selected from —C(O)— and —CRR—;'}{'sup': 7', '7, 'A at each occurrence is —CRR—;'}{'sup': 10', '11', '11, 'W is selected from —NR—, and —CRR—; and'}n is 0-2.45. The method of claim 44 , wherein:{'sup': '6', 'X is —NR—;'}{'sup': 7', '7, 'A at each occurrence is —CRR—;'}{'sup': 10', '11', '11, 'W is selected from — ...

PARTIALLY SATURATED NITROGEN-CONTAINING HETEROCYCLIC COMPOUND

There are provided compounds having a superior PHD2 inhibitory effect that are represented by general formula (I′): 2. The compound according to wherein in the aforementioned general formula (I′) claim 1 ,{'sup': '4', 'Yis methanediyl,'}{'sup': '3', 'Ris a hydrogen atom,'}{'sup': '4', 'Ris —COOH,'}or a pharmaceutically acceptable salt thereof.5. The compound according to wherein in the aforementioned general formula (I′-2) claim 4 ,{'sub': 1-6', '1-6', '3-6, 'Y is a single bond or Calkanediyl (one of the carbon atoms in the Calkanediyl is optionally substituted by Ccycloalkane-1,1-diyl),'}{'sup': '2', 'sub': 3-8', '3-8', '1-6', '1-6', '1-6', '1-6', '1-6', '3-8', '1-6', '3-8', '1-6', '3-8', '1-6', '1-6', '3-8', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '1-6', '3-8', '1-6', '3-8', '1-6', '1-6', '1-6', '3-8', '1-6', '3-8, 'Ris Ccycloalkyl {the Ccycloalkyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of Calkyl (the Calkyl is optionally substituted by one phenyl), phenyl (the phenyl is optionally substituted by one halo-Calkyl), Calkoxy [the Calkoxy is optionally substituted by one group selected from the group consisting of Ccycloalkyl, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and Calkyl), and pyridyl (the pyridyl is optionally substituted by one halogen atom)], Ccycloalkoxy, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, Calkyl, Ccycloalkyl, and halo-Calkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, Calkyl, Ccycloalkyl, and halo-Calkyl)}, phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from the aforementioned group α3 of substituents), naphthyl, indanyl, tetrahydronaphthyl, pyrazolyl [the pyrazolyl is ...

PRODRUGS OF GLUTAMINE ANALOGS

The disclosure provides compounds having formula (I): 2. (canceled)3. (canceled)4. The compound of claim 1 , wherein Ris selected from the group consisting of methyl claim 1 , ethyl claim 1 , isopropyl claim 1 , cyclopentyl claim 1 , cyclohexyl claim 1 , trimethylammonium claim 1 , triethylammonium claim 1 , tri(hydroxyethyl)ammonium claim 1 , tripropylammonium claim 1 , and tri(hydroxypropyl)ammonium.5. (canceled)6. (canceled)7. (canceled)8. (canceled)9. (canceled)10. (canceled)11. (canceled)12. (canceled)13. (canceled)18. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier claim 1 , diluent claim 1 , or excipient.19. A method of treating cancer in a subject claim 1 , the method comprising administering to the subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.20. A method of treating cancer in a subject claim 17 , the method comprising administering to the subject in need thereof a compound of claim 17 , or a pharmaceutically acceptable salt thereof.21. The method of claim 20 , wherein the cancer is hepatocellular cancer claim 20 , brain cancer claim 20 , lung cancer claim 20 , breast cancer claim 20 , head and neck cancer claim 20 , pancreatic cancer claim 20 , prostate cancer claim 20 , melanoma claim 20 , colorectal cancer claim 20 , acute lymphoblastic leukemia claim 20 , acute myelogenous leukemia claim 20 , or chronic myelocytic leukemia.22. The method of claim 21 , wherein the cancer is colon cancer.23. The method of claim 21 , wherein the cancer is breast cancer.24. The method of claim 21 , wherein the cancer is brain cancer.25. The method of claim 21 , wherein the cancer is pancreatic cancer.26. The method of claim 21 , wherein the cancer is prostate cancer.27. The method of claim 20 , wherein the cancer is a solid tumor.28. The compound of claim 1 , wherein{'sub': '3', 'Ris H; and'}{'sub': '4', 'Ris methyl, iPr, or aryl.'}29. The compound of claim 1 , wherein{'sub': ...

1,4-Dihydropyridine Derivatives With HSP Modulating Activity

The invention provides 1,4-dihydropyridine derivatives of formula (I) wherein Ris optionally substituted Caryl group or 5 to 6 membered heteroaryl group comprising 1 to 3 nitrogen atoms or other heteroatoms like oxygen and sulphur, and combinations thereof; Rand Rare independently hydrogen or Calkyl group; Rand Rare independently hydrogen, Calkyl group optionally substituted with amino, mono- or di(Calkyl)amino, or with 5 to 24 membered optionally fused heterocyclic ring attached by nitrogen and optionally comprising additional 1 to 3 N, O, S heteroatoms and optionally substituted with Calkyl group or Calkoxy group; Ris Calkyl, Ccycloalkyl, CcycloalkylCalkyl or arylCalkyl group; and stereoisomers including enantiomers, diastereomers, racemic mixtures, mixture of enantiomers and combination thereof, as well as polymorphs, pharmaceutically acceptable salts, solvates, esters and prodrugs thereof for use in the therapeutic or prophylactic treatment of a disorder mediated by heat shock proteins. 124-. (canceled)26. The compound according to claim 25 , wherein{'sup': '1', 'sub': '1-6', 'Ris a phenyl group substituted with one or two halogens, or haloCalkyl groups;'}{'sup': 2', '3, 'sub': '1-6', 'Rand Rare independently a Calkyl group;'}{'sup': '4', 'sub': 1-6', '1-6', '1-6', '1-6, 'Ris a Calkyl group substituted with amino, mono- or di(Calkyl)amino, or with a 5 to 24 membered, optionally fused, heterocyclic ring attached by nitrogen, optionally comprising additional 1 to 3 N, O, or S heteroatoms, and optionally substituted with Calkyl or 1 to 3 Calkoxy group; and'}{'sup': '5', 'sub': 1-6', '1-6', '1-6', '1-6, 'Ris hydrogen; —CN; or a Calkyl group optionally substituted with amino, mono- or di(Calkyl)amino, or with a 5 to 24 membered, optionally fused, heterocyclic ring attached by nitrogen, optionally comprising additional 1 to 3 N, O, or S heteroatoms, and optionally substituted with Calkyl or 1 to 3 Calkoxy group; or'}{'sup': '4', 'sub': 1-6', '1-6', '1-6', '1-6, 'Ris ...

DIHYDROPYRIDINES FOR THE TREATMENT OF COGNITIVE IMPAIRMENT OR TRAUMATIC BRAIN INJURY

A genus of dihydropyridine chemical modulators of synaptojanin is disclosed. These modulators are selective inhibitors of synaptojanin 1 and may be used to treat cognitive impairment or traumatic brain injury, including promoting regeneration in cases of traumatic brain injury, or for treating neurodegenerative disorders. 2. The compound of claim 1 , wherein Ris isopropyl.3. The compound of claim 1 , wherein Ris hydrogen.4. The compound of claim 1 , wherein Ris selected from C-Calkyl claim 1 , C-Ccycloalkyl claim 1 , C-Calkoxy claim 1 , and nitro.5. The compound of claim 4 , wherein Ris selected from methyl claim 4 , methoxy claim 4 , t-butyl claim 4 , and nitro.6. The compound of claim 1 , wherein Ris selected from hydrogen and isopropyl; and Ris selected from methyl claim 1 , methoxy claim 1 , t-butyl claim 1 , and nitro.7. The compound of claim 6 , wherein Ris hydrogen.1419-. (canceled)20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the compound of .21. A method for treating cognitive impairment or traumatic brain injury in a patient claim 1 , comprising administering to the patient a therapeutically effective amount of the compound of .22. The method of claim 21 , wherein said cognitive impairment or traumatic brain injury is selected from Alzheimer's disease claim 21 , mild cognitive impairment claim 21 , Lewy body dementia (LBD) claim 21 , frontotemporal dementia (FTD) claim 21 , vascular dementia claim 21 , mixed dementia claim 21 , or Down Syndrome.23. The method of claim 22 , wherein said cognitive impairment or traumatic brain injury is Alzheimer's disease.24. The method of claim 21 , wherein said cognitive impairment or traumatic brain injury is traumatic brain injury.2531-. (canceled)32. The method of claim 21 , wherein Ris selected from hydrogen and isopropyl; and Ris selected from methyl claim 21 , methoxy claim 21 , t-butyl claim 21 , and nitro. This application is an International ...

Novel compounds and methods of treating or ameliorating an il-1r-mediated disease or disorder using same

The present invention provides compounds useful for treating or preventing an IL-1R-mediated disease or disorder. In certain embodiments, the disease or disorder comprises scleroderma.

2-OXO-3,4-DIHYDROPYRIDINE-5-CARBOXYLATES AND THEIR USE

The present invention is directed to novel compounds of Formula (I), pharmaceutically acceptable salts or solvates thereof, and their use. 7. The compound according to and pharmaceutically acceptable salts claim 1 , and solvates thereof claim 1 , wherein Ris methyl.8. The compound according to and pharmaceutically acceptable salts claim 1 , and solvates thereof claim 1 , wherein Land Rare taken together to form a moiety selected from the group consisting of cycloalkylmethyl claim 1 , heterocyclylmethyl claim 1 , heteroarylmethyl claim 1 , 2-alkoxyeth-1-yl claim 1 , 3-alkoxyprop-1-yl claim 1 , alkoxycarbonylmethyl claim 1 , said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl.9. The compound according to and pharmaceutically acceptable salts claim 1 , and solvates thereof claim 1 , wherein Ris tetrahydrofuranyl.10. The compound according to and pharmaceutically acceptable salts claim 9 , and solvates thereof claim 9 , wherein Lis CH.12. A pharmaceutical composition comprising a compound according to or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier claim 1 , diluent claim 1 , excipient and/or adjuvant.13. A medicament comprising a compound according to .14. A method for treating and/or preventing a TGR5 related disease comprising the administration of a therapeutically effective amount of a compound according to or pharmaceutically acceptable salt or solvate thereof claim 1 , to a patient in need thereof.15. The method according to claim 14 , wherein the disease is selected from metabolic and/or gastrointestinal diseases.16. The method according to wherein the disease is a metabolic disease selected from the group consisting of type II diabetes claim 15 , obesity claim 15 , dyslipidemia such as mixed or diabetic dyslipidemia claim 15 , hypercholesterolemia claim 15 , low HDL cholesterol claim 15 , high LDL cholesterol claim 15 , hyperlipidemia claim 15 , hypertriglyceridemia ...

ARYL DIHYDROPYRIDINONES AND PIPERIDINONE MGAT2 INHIBITORS

The present invention provides compounds of Formula (I): 1. A compound of Formula (I):{'img': {'@id': 'CUSTOM-CHARACTER-00003', '@he': '2.79mm', '@wi': '4.57mm', '@file': 'US20170216263A1-20170803-P00001.TIF', '@alt': 'custom-character', '@img-content': 'character', '@img-format': 'tif'}, 'designates a single or double bond;'}{'sup': 4', '16', '5', '16, 'x and y can be both a single bond; when x is a double bond, then y is a single bond and Rand Rare absent; when y is a double bond, then x is a single bond and Rand Rare absent;'}{'sup': 1', 'b', 'g', 'e', 'b', 'g', 'a, 'sub': 4-18', '2-8', '2', '1-8', '2', '2-8', '2', 'm', '3-10', '2', 'm', '1-12, 'Ris independently selected from the group consisting of: —CONH(Calkyl), —CONHChaloalkyl, —CONH(CH)Ph, —CONHCHCOCalkyl, —(CH)—(Ccarbocycle substituted with 0-2 Rand 0-2 R), —(CH)-(5- to 6-membered heteroaryl comprising: carbon atoms and 1-4 heteroatoms selected from N, NR, O and S; wherein said heteroaryl is substituted with 0-1 Rand 0-2 R), and a Chydrocarbon chain substituted with 0-3 R; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated;'}{'sup': '2', 'sub': 1-4', '3-4', '1-4, 'Ris independently selected from the group consisting of: Calkyl, Ccycloalkyl, and Chaloalkyl;'}{'sup': '3', 'sub': '1-4', 'Ris independently selected from the group consisting of: H, F, Cl, Calkyl and CN;'}{'sup': 4', '5, 'sub': '1-4', 'Rand Rare independently selected from the group consisting of: H, F, Cl, and Calkyl;'}{'sup': 3', '4, 'when x is a single bond, Rand Rmay be combined with the carbon atom to which they are attached to form a 3- to 6-membered carbocycle;'}{'sup': 6', 'c', 'c', 'j', 'j', 'j', 'j', 'j', 'f', 'j, 'sub': 1-4', '2', '2', 'n', 't', '2', 'm', '2', '1-6', '1', '2', '2', '2', '2, 'Ris independently selected from the group consisting of: H, halo, Calkyl, CN, NO, R, —(CH)—(X)—(CH)R, NH, —CONH(Calkyl), —NHCOXSOR, —NHCOCHPO(OEt), —NHCOCOR, —NHCOCH(OH)R, —NHCOCHCOR, —NHCONHR, and —OCONRR;'}X is ...

ARYLHYDRAZIDES CONTAINING A 2-PYRIDONE MOIETY AS SELECTIVE ANTIBACTERIAL AGENTS

The present invention belongs to the field of antibacterial agents, more specifically to antibacterials for treating infections. The invention provides arylhydrazides containing a 2-pyridone moiety, according to formula (I), which show selective antibacterial activity against . The invention also relates to their use as medicaments and specifically as antibacterials for the treatment of infections, as well as to a process for their preparation and to pharmaceutical compositions containing them. 2. A compound according to claim 1 , wherein Ris selected from Calkyl claim 1 , Calkenyl claim 1 , Calkynyl claim 1 , haloCalkyl claim 1 , hydroxyCalkyl claim 1 , Calkoxy claim 1 , CalkoxyCalkyl claim 1 , CcycloalkylCalkyl and PhCalkyl.3. A compound according to claim 1 , wherein A is A.4. A compound according claim 1 , wherein Rand Rare independently selected from hydrogen and Calkyl.5. A compound according to claim 4 , wherein Rand Rare hydrogen.6. A compound according to claim 4 , wherein one of Rand Ris hydrogen and the other is Calkyl.7. A compound according to claim 4 , wherein Rand Rare Calkyl.8. A compound according to wherein R claim 1 , R claim 1 , R claim 1 , Rand Rare independently selected from hydrogen claim 1 , halogen claim 1 , —OH claim 1 , Calkyl and Calkoxy.9. A compound according to claim 8 , wherein Ris selected from halogen claim 8 , —OH claim 8 , Calkyl and Calkoxy claim 8 , and R claim 8 , R claim 8 , Rand Rare independently selected from hydrogen and halogen.10. A compound according to claim 8 , wherein Ris selected from halogen claim 8 , —OH claim 8 , Calkyl and Calkoxy claim 8 , and R claim 8 , R claim 8 , Rand Rare hydrogen.11. A compound according to claim 1 , wherein Ris selected from Calkyl claim 1 , Calkynyl claim 1 , haloCalkyl claim 1 , CcycloalkylCalkyl and PhCalkyl.12. A compound according to claim 1 , wherein Ris selected from Calkyl claim 1 , Calkynyl claim 1 , haloCalkyl claim 1 , CalkoxyCalkyl claim 1 , CcycloalkylCalkyl claim 1 , ...

1,4- DIHYDROPYRIDINE DERIVATIVES WITH HSP MODULATING ACTIVITY

The invention provides 1,4-dihydropyridine derivatives of formula (I) wherein Ris optionally substituted Caryl group or 5 to 6 membered heteroaryl group comprising 1 to 3 nitrogen atoms or other heteroatoms like oxygen and sulphur, and combinations thereof; Rand Rare independently hydrogen or Calkyl group; Rand Rare independently hydrogen, Calkyl group optionally substituted with amino, mono- or di(Calkyl)amino, or with 5 to 24 membered optionally fused heterocyclic ring attached by nitrogen and optionally comprising additional 1 to 3 N, O, S heteroatoms and optionally substituted with Calkyl group or Calkoxy group; Ris Calkyl, Ccycloalkyl, CcycloalkylCalkyl or arylCalkyl group; and stereoisomers including enantiomers, diastereomers, racemic mixtures, mixture of enantiomers and combination thereof, as well as polymorphs, pharmaceutically acceptable salts, solvates, esters and prodrugs thereof for use in the therapeutic or prophylactic treatment of a disorder mediated by heat shock proteins. 124-. (canceled)26. The method claim 25 , according to wherein{'sup': '1', 'sub': '1-6', 'Ris a phenyl group substituted with one or two halogens, or haloCalkyl;'}{'sup': 2', '3, 'sub': '1-6', 'Rand Rare Calkyl group;'}{'sup': '4', 'sub': 1-6', '1-6', '1-6', '1-6, 'Ris Calkyl group optionally substituted with amino, mono- or di(Calkyl)amino, or with 5 to 24 membered, optionally fused, heterocyclic ring attached by nitrogen and optionally comprising additional 1 to 3 N, O, and/or S heteroatoms and optionally substituted with Calkyl or Calkoxy group; and'}{'sup': '5', 'sub': 1-6', '1-6', '1-6', '1-6, 'Ris hydrogen; —CN; Calkyl group optionally substituted with amino, mono- or di(Calkyl)amino, or with 5 to 24 membered, optionally fused, heterocyclic ring attached by nitrogen and optionally comprising additional 1 to 3 N, O, and/or S heteroatoms and optionally substituted with Calkyl or Calkoxy group; or'}{'sup': '4', 'sub': 1-6', '1-6', '1-6', '1-6, 'Ris hydrogen; —CN; Calkyl group ...

DIHYDROPYRIDINONE MGAT2 INHIBITORS

The present invention provides compounds of Formula (I): 110-. (canceled)12. The pharmaceutical composition according to claim 11 , wherein the additional therapeutic agents are selected from: anti-diabetic agents claim 11 , anti-hyperglycemic agents claim 11 , anti-hyperinsulinemic agents claim 11 , anti-retinopathic agents claim 11 , anti-neuropathic agents claim 11 , anti-nephropathic agents claim 11 , anti-atherosclerotic agents claim 11 , anti-ischemic agents claim 11 , anti-hypertensive agents claim 11 , anti-obesity agents claim 11 , anti-dyslipidemic agents claim 11 , anti-hyperlipidemic agents claim 11 , anti-hypertriglyceridemic agents claim 11 , anti-hypercholesterolemic agents claim 11 , anti-restenotic agents claim 11 , lipid lowering agents claim 11 , anorectic agents claim 11 , and appetite suppressants.13. The pharmaceutical composition according to claim 11 , further comprising one or more additional therapeutic agents selected from: a dipeptidyl peptidase-IV inhibitor claim 11 , a sodium-glucose transporter-2 inhibitor and a 11b-HSD-1 inhibitor. This application claims priority under 35 U.S.C. §119(e) to U.S. provisional application Ser. No. 61/828,219, filed May 29, 2013, and U.S. provisional application Ser. No. 61/982,574, filed Apr. 22, 2014; the entire contents of these applications are incorporated herein by reference.The present invention provides novel aryl and heteroaryl dihydropyridinone compounds, and analogues thereof, which are MGAT2 inhibitors, compositions containing them, and methods of using them, for example, for the treatment of diabetes, obesity, dyslipidemia and related conditions.The prevalence of obesity and diabetes is increasing at an alarming rate. According to WHO, in 2008, 70% of the U.S. adult population was overweight, and among them 33% were obese. Parallel to the explosive number of people becoming overweight and obese, in 2008, it was estimated that 12.3% of the U.S. population had elevated blood glucose [http://www ...

DIHYDROPYRIDINONE MGAT2 INHIBITORS

The present invention provides compounds of Formula (I): 2. A compound according to claim 1 , wherein:{'sup': 6', '7', '6', '7, 'ring A is independently selected from pyridyl, thienyl, thiazolyl, and pyrazolyl; wherein each ring moiety is substituted with 0-1 Rand 0-2 R; and alternatively, Rand R, together with the carbon atoms to which they are attached, combine to form a 6-membered carbocyclic ring.'}15. A pharmaceutical composition claim 1 , comprising a pharmaceutically acceptable carrier and a compound of claim 1 , optionally in combination simultaneously claim 1 , separately or sequentially with one or more additional therapeutic agents.16. The pharmaceutical composition according to claim 15 , wherein the additional therapeutic agents are selected from: anti-diabetic agents claim 15 , anti-hyperglycemic agents claim 15 , anti-hyperinsulinemic agents claim 15 , anti-retinopathic agents claim 15 , anti-neuropathic agents claim 15 , anti-nephropathic agents claim 15 , anti-atherosclerotic agents claim 15 , anti-ischemic agents claim 15 , anti-hypertensive agents claim 15 , anti-obesity agents claim 15 , anti-dyslipidemic agents claim 15 , anti-hyperlipidemic agents claim 15 , anti-hypertriglyceridemic agents claim 15 , anti-hypercholesterolemic agents claim 15 , anti-restenotic agents claim 15 , lipid lowering agents claim 15 , anorectic agents claim 15 , and appetite suppressants.17. The pharmaceutical composition according to claim 1 , further comprising one or more additional therapeutic agents selected from: a dipeptidyl peptidase-IV inhibitor claim 1 , a sodium-glucose transporter-2 inhibitor and a 11b-HSD-1 inhibitor.18. A method for the treatment of a disorder claim 1 , comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 , where said disorder is selected from: diabetes claim 1 , hyperglycemia claim 1 , impaired glucose tolerance claim 1 , gestational diabetes claim 1 , insulin resistance ...

Aryl dihydropyridinones and piperidinone mgat2 inhibitors

or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are monoacylglycerol acyltransferase type 2 (MGAT2) inhibitors which may be used as medicaments.

ARYL DIHYDROPYRIDINONES AND PIPERIDINONE MGAT2 INHIBITORS

The present invention provides compounds of Formula (I): 3. A compound according to claim 2 , wherein:{'sup': 11', '15, 'sub': '1-4', 'Rand Rare independently selected from the group consisting of: H, Calkyl and halo;'}{'sup': 12', '14, 'sub': 1-4', '1-4, 'Rand Rare independently selected from the group consisting of: H, halo, Calkyl and Calkoxy; and'}{'sup': 13', 'i', 'f', 'j', 'j', 'e, 'sub': 1-4', '1-4', '1-4', '1-4', '2', 'm', '3-4', '2', '1-4', '2', '1-4, 'Ris independently selected from the group consisting of: H, halo, Calkyl substituted with 0-1 R, Calkoxy, Chaloalkyl, Chaloalkoxy, —(CH)—Ccycloalkyl, CN, NRR, SR, NHCO(Calkyl), NHSO(Calkyl), and a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR, O, and S.'}11. A pharmaceutical composition claim 1 , comprising: a pharmaceutically acceptable carrier and a compound of claim 1 , or a stereoisomer claim 1 , a tautomer claim 1 , or a pharmaceutically acceptable salt thereof.12. A pharmaceutical composition claim 9 , comprising: a pharmaceutically acceptable carrier and a compound of claim 9 , or a stereoisomer claim 9 , a tautomer claim 9 , or a pharmaceutically acceptable salt thereof.13. A pharmaceutical composition claim 10 , comprising: a pharmaceutically acceptable carrier and a compound of any one of claim 10 , or a stereoisomer claim 10 , a tautomer claim 10 , or a pharmaceutically acceptable salt thereof.14. The pharmaceutical composition according to claim 11 , further comprising one or more other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents claim 11 , anti-hyperglycemic agents claim 11 , anti-hyperinsulinemic agents claim 11 , anti-retinopathic agents claim 11 , anti-neuropathic agents claim 11 , anti-nephropathic agents claim 11 , anti-atherosclerotic agents claim 11 , anti-ischemic agents claim 11 , anti-hypertensive agents claim 11 , anti-obesity agents claim 11 , anti-dyslipidemic ...

Small molecule inhibitors of necroptosis

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I)-(VIII) and by Compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), and (58)-(70). These necrostatins are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring necrostatins. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

SOLID BETALAIN COMPOSITIONS AND METHODS

Solid, free-flowing, and substantially completely dissolvable preparations with high betalain content are presented. Most typically, the betalain profile of the preparations is near natural and includes betalains in an amount of between 10-40 wt %. As the preparations of the inventive subject matter maintain chemical stability and flowability over extended periods of time, it should be noted that the betalain preparations are now amenable to compounding in small and measured quantities. Furthermore, new biological activities of betalains are shown, and especially include significant induction of SIRT and reduction of serum triglyceride. 134-. (canceled)35. A method of producing a free-flowing and substantially completely dissolvable powder with a total betalain content of at least 2 wt % , comprising:preparing or providing a liquid containing a plurality of chemically distinct betalains and sugar;applying the liquid to a hydrophobically modified silica resin or a hydrophobically modified styrene resin under conditions effective to bind at least some of the total betalains; andeluting the bound betalains from the resin with an aqueous eluent under conditions effective to produce an elution fraction having a betalain to sugar ratio of at least 1.0; andremoving water from the elution fraction to form a solid, and grinding the solid to form the free-flowing and substantially completely dissolvable powder.36. The method of wherein the liquid is a beet juice.37. The method of wherein the hydrophobically modified silica or styrene resin comprise a hydrophobic group that is covalently coupled to the resin.38. The method of wherein the hydrophobic group is covalently coupled to the resin via a linking moiety having a length equivalent to at least 3 carbon-carbon bonds.39. The method of wherein the hydrophobic group has a structure effective to bind the betalains via pi-stacking.40. The method of wherein the hydrophobic group has multiple rings with planar configuration and ...

Oligomer-calcium channel blocker conjugates

The invention provides small molecule drugs that are chemically modified by covalent attachment of a water soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from the characteristics of the small molecule drug not attached to the water soluble oligomer.

ARYL DIHYDROPYRIDINONES AND PIPERIDINONE MGAT2 INHIBITORS

The present invention provides compounds of Formula (I): 4. A compound according to claim 3 , wherein:{'sup': '2', 'sub': '3', 'Ris independently selected from the group consisting of: CFand Me;'}{'sup': '3', 'Ris independently selected from the group consisting of: H and F;'}{'sup': '4', 'Ris independently selected from the group consisting of: H and F;'}{'sup': '6', 'sub': 3', '3', '2', '2', '2', '2', '1-4', '1-5', '3, 'Ris independently selected from the group consisting of: OPh, —CONH(cyclopropyl), —CONH(cyclobutyl), —CONH(cyclopentyl), —CONH(cyclohexyl), —CONHPh, —CONH(4-F-Ph), —CONH(2-Cl-Ph), —CONH(4-Cl-Ph), —CONH(4-Me-Ph), —CONH(4-OH-Ph), —CONH(3-OMe-Ph), —CONH(4-OMe-Ph), —CONH(4-CF-Ph), —CONH(4-OCF-Ph), —CONH(1-Me-pyrazol-3-yl), —CONH(4-(1H-tetrazol-2-yl)-Ph), —CONH(4-(2H-tetrazol-5-yl)-Ph), —CONH(3-F-4-Me-Ph), —CONH(3-F-4-OMe-Ph), —CONH(CH)Ph, —CONH(5-OMe-pyrid-2-yl), —CONH(6-OMe-pyrid-3-yl), —CONH(5-OMe-pyrazin-2-yl), —CONH(6-OMe-pyridazin-3-yl), —NHCO(CH)SOMe, —NHCOPh, —NHCO(2-Me-Ph), —NHCO(3-Me-Ph), —NHCO(4-Me-Ph), —NHCO(2-Cl-Ph), —NHCO(3-Cl-Ph), —NHCO(2-C—F-Ph), —NHCO(2-C-F-Ph), —NHCO(isoxazol-5-yl), —NHCO(3-Me-isoxazol-5-yl), —NHCO(4-Me-isoxazol-5-yl), —NHCO(3-OMe-isoxazol-5-yl), —NHCO(3-Br-isoxazol-5-yl), —NHCO(3-(2-Cl-Ph)-isoxazol-5-yl), —NHCO(3-(3-F-Ph)-isoxazol-5-yl), —NHCO(3-OBn-isoxazol-5-yl), 1H-imidazol-1-yl, —NHCO(5-Me-1,3,4-oxadiazol-2-yl), —NHCO(1-Me-1,2,3-triazol-4-yl), —NHCO(6-OMe-pyrid-3-yl), —NHCO(6-Cl-pyridazin-3-yl), 5-CF-1,3,4-oxadiazol-2-yl, 1H-tetrazol-1-yl, 1H-tetrazol-3-yl, and 2H-tetrazol-5-yl;'}{'sup': 11', '15, 'Rand Rare independently selected from the group consisting of: H, Me, F, and Cl;'}{'sup': '12', 'Ris independently selected from the group consisting of: H, F, Cl, Me and OMe;'}{'sup': '13', 'sub': 2', '3', '2', '3', '2', '3', '2, 'Ris independently selected from the group consisting of: H, F, Cl, Br, Me, OMe, OEt, CHOMe, CF, CHCF, OCHF, OCF, CN, N(Me), cyclopropyl and cyclopropylmethyl;'}{'sup': 12', '13, ' ...

PRODRUGS OF GLUTAMINE ANALOGS

The disclosure provides compounds having formula (I): 2. The compound of claim 1 , wherein X is —CH—.3. (canceled)4. The compound of claim 1 , wherein Ris selected from the group consisting of methyl claim 1 , ethyl claim 1 , isopropyl claim 1 , cyclopentyl claim 1 , and cyclohexyl.5. The compound of claim 1 ,wherein:m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; and{'sub': 3', '4', '1', '6', '1', '6, 'each Rand Ris independently H, C-Calkyl or substituted C-Calkyl, aryl or substituted aryl;'}{'sub': '10', 'Ris selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.'}6. The compound of claim 5 , whereinm is 1.713-. (canceled)17. (canceled)18. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier claim 1 , diluent claim 1 , or excipient.20. (canceled)21. The method of claim 19 , wherein X is —CH—.22. The method of claim 19 , wherein Ris selected from the group consisting of methyl claim 19 , ethyl claim 19 , isopropyl claim 19 , cyclopentyl claim 19 , and cyclohexyl.23. The method of claim 19 , wherein Ris an amino acid.24. The method of claim 23 , wherein the amino acid is tryptophan.25. The method of claim 19 , wherein Ris a N-acyl amino acid.26. The method of claim 25 , wherein the amino acid is tryptophan.31. The method of claim 19 , wherein the cancer is selected from the group consisting of hepatocellular carcinoma claim 19 , glioblastoma claim 19 , lung cancer claim 19 , breast cancer claim 19 , head and neck cancer claim 19 , prostate cancer claim 19 , melanoma claim 19 , and colorectal cancer. This application is a continuation-in-part of PCT/US2016/044767, filed Jul. 29, 2016, that claims the benefit of U.S. Provisional Application No. 62/199,566, filed Jul. 31, 2015, which is incorporated herein by reference in its entirety.The prodrug approach is a well-established ...

PRODRUGS OF GLUTAMINE ANALOGS

The disclosure provides compounds having formula (I): 2. The compound of claim 1 , wherein X is —CH—.3. (canceled)4. The compound of claim 1 , wherein Ris selected from the group consisting of methyl claim 1 , ethyl claim 1 , isopropyl claim 1 , cyclopentyl claim 1 , and cyclohexyl.516-. (canceled)18. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier claim 1 , diluent claim 1 , or excipient.19. A method of treating cancer in a subject claim 1 , the method comprising administering to the subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris selected from the group consisting of Cstraight-chain alkyl claim 1 , a substituted Cstraight-chain alkyl claim 1 , a Cbranched alkyl claim 1 , and a substituted Cbranched alkyl.20. (canceled)21. The compound of claim 4 , wherein Ris selected from the group consisting of methyl claim 4 , ethyl claim 4 , and isopropyl.22. The compound of claim 1 , wherein:{'sub': 2', '3', '4', 'm', '5', '6, 'Ris —C(═O)—Y—(CRR)—NRR;'}Y is a bond;each m is independently 1, 2 or 3;{'sub': 3', '1', '6', '3', '4', 'm', '5', '6, 'each Ris independently H, C-Calkyl, or —(CRR)—NRR;'}{'sub': '4', 'each Ris H; and'}{'sub': 5', '3', '4', 'm', '5', '6', '3', '4', 'm', '5', '6, 'each Ris independently H, —C(═O)—(CRR)H, —C(═O)—(NRR), or —C(═O)—(CRR)—NRR;'}23. The compound of claim 22 , wherein:m is 1; and{'sub': 5', '6, 'Rand Rare each H.'}24. The compound of claim 1 , wherein:{'sub': 2', '3', '4', 'm', '5', '6, 'Ris —C(═O)—Y—(CRR)—NRR;'}{'sub': '5', 'Ris H;'}{'sub': 6', '3', '4', 'm, 'Ris —C(═O)—(CRR)H.'}25. The compound of claim 1 , wherein:m is 1;{'sub': '5', 'Ris H;'}{'sub': 6', '3', '4', 'm', '5', '6, 'Ris —C(═O)—(CRR)—NRR.'}26. The compound of claim 1 , wherein:{'sub': 2', '7', 'n', '9', 'o, 'Ris —P(═O)(OR)(NHR); and'}n is 2 and o is 0;n is 1 and o is 1; orn is 0 and o is 2.27. The compound of claim 1 , wherein:{'sub': 2', '3', '4', 'm', '8', '3', ...

COMPOSITIONS AND METHODS FOR THE TREATMENT OF GLIOBLASTOMA

Provided are compositions that include a platelet-activating factor antagonist, pharmaceutical compositions including the platelet-activating factor antagonist, methods of treating a modulating the proliferation of a glioma or a pathological condition resulting from patient having a glioma. 16.-. (canceled)9. The method of claim 7 , wherein the brain tumor is a selected from the group consisting of: a glioblastoma claim 7 , an astrocytoma claim 7 , an oligodendroglioma claim 7 , an ependymal tumor claim 7 , a neuronal tumor and a combination of glial tumors.10. The method of claim 7 , wherein the pharmaceutically acceptable salt is an acid addition salt.13. The method of claim 7 , wherein the therapeutic composition is formulated with an amount of the PAF receptor antagonist effective in reducing or inhibiting a pathological neurological condition associated with a brain tumor in a subject.14. The method of claim 13 , wherein the therapeutic composition is formulated with an amount of the PAF antagonist effective in reducing or inhibiting a seizure associated with glioblastoma in a subject.1517.-. (canceled)18. The method of claim 7 , wherein the compound is an R-enantiomer claim 7 , an S-enantiomer claim 7 , or a combination thereof. This application is a division of U.S. patent application Ser. No. 15/556,719, filed on Sep. 8, 2017, which is a § 371 national stage entry of PCT/US2016/021429, filed Mar. 9, 2018, which claims priority to U.S. Provisional Patent Application Ser. No. 62/130,221 entitled “COMPOSITIONS AND METHODS FOR THE TREATMENT OF GLIOBLASTOMA” and filed Mar. 9, 2015, and to U.S. Provisional Patent Application Ser. No. 62/253,533 entitled “COMPOSITIONS AND METHODS FOR THE TREATMENT OF GLIOBLASTOMA” and filed Nov. 10, 2015, the entireties of which are hereby incorporated by reference.This invention was made with government support under P30 GM103340 awarded by the National Institutes of Health. The government has certain rights in the invention.The ...

Quaternary heteroatom containing compounds

with a transition metal catalyst and under alkylation conditions as valence and stability permit.

DRUG-INDUCED ACTIVATION OF THE REELIN SIGNALING SYSTEM

Disclosed herein are compounds for activating the Reelin signaling system for the treatment of neurological disorders. Further provided are compounds and methods for activating a lipoprotein receptor, such as ApoER2 or VLDLR. 1. A method of treating a disease or disorder in a subject in need thereof , the method comprising administering to the subject an agonist of a lipoprotein receptor.2. A method of improving cognitive function in a subject in need thereof , the method comprising administering to the subject an agonist of a lipoprotein receptor.3. A method of increasing dendritic spine density in a subject in need thereof , the method comprising administering to the subject an agonist of a lipoprotein receptor.4. A method of improving associative learning in a subject in need thereof , the method comprising administering to the subject an agonist of a lipoprotein receptor.5. A method of improving spatial learning in a subject in need thereof , the method comprising administering to the subject an agonist of a lipoprotein receptor.6. A method of improving long-term potentiation of neurons in a subject in need thereof , the method comprising administering to the subject an agonist of a lipoprotein receptor.7. The method of any one of - , wherein the lipoprotein receptor is selected from ApoER2 and VLDLR.8. The method of claim 1 , wherein the disease or disorder is of the central nervous system.9. The method of claim 8 , wherein the disease or disorder is a developmental disorder claim 8 , a cognitive disorder claim 8 , a degenerative disorder claim 8 , a neuropsychiatric disorder claim 8 , or brain injury.10. The method of claim 9 , wherein the developmental disorder is Lissecephaly.11. The method of claim 9 , wherein the cognitive disorder is selected from Angelman Syndrome and schizophrenia.12. The method of claim 9 , wherein the degenerative disorder is Alzheimer's disease.13. The method of claim 9 , wherein the neuropsychiatric disorder is selected from ...

Optionally condensed dihydropyridine, dihydropyrimidine and dihydropyrane derivatives acting as late sodium channel blockers

The present invention relates to novel heterocyclic compounds and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula (I): wherein Q1, Q2, R2, R3, R4, R5, and R6 are as described herein. The invention also relates to methods for the preparation of the compounds, and to pharmaceutical compositions containing such compounds.

Dihydropyridine derivatives useful as protein kinase inhibitors

This invention provides novel dihydropyridine derivatives of the formula (I) having protein tyrosine kinase inhibitory activity, to process for the manufacture thereof and to the use thereof for the treatment of c-Met-mediated diseases or c-Met-mediated conditions.

PRODUCTION METHOD

PROCESS FOR THE PRODUCTION OF AMLODIPINMALEAT

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Process for preparing (s)-(-)-felodipine

본 발명은 이하, "S-(-)-펠로디핀"로 표기되는 S-(-)-에틸메틸 4-(2,3-디클로로페닐)-1,4-디히드로-2,6-디메틸-3,5-피리딘-디카르복실레이트의 제조방법에 관한 것으로서, 키랄성 분리화합물을 포함하는 펠로디핀 유도체를 합성하여 (S)-이성질체를 분리한 후 베타히드록시에스테르의 선택적인 에스테르 교환반응을 통해 S-(-)-펠로디핀을 합성하는 효율적인 제조방법에 관한 것이다. 상기 키랄성 분리물질은 (R)-글리시돌(Glycidol) 또는 (S)-글리시돌로부터 다양한 친핵체와 에폭사이드와의 반응을 통해 합성한다. In the present invention, S-(-)-ethylmethyl 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-, which is hereinafter referred to as "S-(-)-felodipine" The present invention relates to a method for preparing 3,5-pyridine-dicarboxylate, wherein a (S) -isomer is isolated by synthesizing a felodipine derivative including a chiral separation compound and then selectively transesterified with betahydroxyester. An efficient method for synthesizing S-(-)-felodipine is provided. The chiral separation material is synthesized by reaction of various nucleophiles with epoxides from (R) -glycidol or (S) -glycidol. (R)-글리시돌, (S)-글리시돌, (S)-(-)-펠로디핀 (R) -glycidol, (S) -glycidol, (S)-(-)-felodipine

Esters of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid possessing antimetastatic activity

Esters of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid of a general formula: (FORMULA) where "R" is a substituted alkyl or terpenyl. The method of obtaining the said esters consisting in subjecting the esters of the acid of a general formula: CH<u3>uCOCH<u2>uCOOR, where "R" is a substituted alkyl or terpenyl, to reaction with the hexamethylenetetramine in the presence of the ammonium acetate in the medium of the ethylic alcohol at its boiling temperature, whereas the esters of the acetoacetic acid of the abovementioned general formula, the hexamethylenetetramine and the ammonium acetate may be taken in stoichiometric proportion.

制备氨氯地平马来酸盐的工艺、所制得的氨氯地平马来酸盐、其药物组合物和用途

一种制造氨氯地平马来酸盐的工艺，它包括使氨氯地平或其酸加成盐在酸性环境下与马来酸反应以形成氨氯地平马来酸盐产物。这种工艺可制得基本上不含氨氯地平天冬氨酸的氨氯地平马来酸盐。

A process for the preparation of lercanidipine hydrochloride.

Method for preparing 1,4-dihydropyridinecarboxylic esters or their salts

Process for preparing 2-(4-(4,4-dialkyl-2,6-piperidindion-1-yl)butyl)piperayinyl)pyrimidines

Pyrimidine derivs. of formula(I) and their pharmaceutically acceptable acid addition salts are prepd. by reacting a glutaric anhydride with II in hydrocarbon solvent at 60-150≰C. In (I) R1 and R3 are each C1-4 alkyl; Z is H, hydroxy, halo, pseudohalo; W is =O, =NH or =N-(CH2)4-X(X=Cl, Br, I, sulfate or phosphate);r is H2N-(CH2) 4-,X-(CH2)4- or H. (I) have selective CNS activity. They have no meuroleptic effect but otherwise have an anxiolytic profile similar to buspiron.

Производные дигидропиридинов и стабилизированная полимерная композиция

Использование: стабилизация полимеров. Сущность: поливинилхлорид и полипропилен стабилизируют эффективным количеством производных дигидропиридинов общей формулы: [(CH 3 ) 2 (R 1 )NC 5 H 5 (CH 3 ) 2 XOC(CH 3 ) 2 NC 5 HOCX(CH 3 ) 2 NC 5 H 5 (R 1 )(CH 3 ) 2 ] n X где n = 1, 2; R 1 = H, CH 3 ; x = 0, N-R 2 , R 2 -H, C 4 H 9 ; причем если n = 1, y = H, если n = 2, y = -/CH 2 / 6 . 2 с.п. ф-лы, 10 табл. ЗЕЕ оСс пы Го (19) РОССИЙСКОЕ АГЕНТСТВО ПО ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ 13) ВИ “” 2081 115 Сл 50° С 070 401/14, С 08 К 5/34, С 08 Е 23/00 12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ РОССИЙСКОЙ ФЕДЕРАЦИИ (21), (22) Заявка: 4831038/04, 06.08.1990 (30) Приоритет: 02.10.1989 ЕК 8913053 (46) Дата публикации: 10.06.1997 (56) Ссылки: Патент Франции М 2239496, кл. С 081 271/06, 1982. (71) Заявитель: Рон-Пуленк Шими (ЕК) (72) Изобретатель: Луи Карет[ЕН], Мишель Гай[ЕК], Сильви Лаво[ЕК], Жиль Мюр[ЕК] (73) Патентообладатель: Грейт Лейкс Кемикал Франс С.А. (ЕК) (54) ПРОИЗВОДНЫЕ ДИГИДРОПИРИДИНОВ И СТАБИЛИЗИРОВАННАЯ ПОЛИМЕРНАЯ КОМПОЗИЦИЯ (57) Реферат: Использование: стабилизация полимеров. Сущность: поливинилхлорид и полипропилен стабилизируют эффективным количеством производных дигидропиридинов общей формулы: (СНз)2(В МС5Н(СНз)2 ХОС(СНЗ)2МС5 НОСХ(СНз)> МС5Н(В ')(СНз)2] их где п =1, 2; В! =Н, СНз; х=0, М-В?, В2-Н, С „Но; причем если п = 1, у = Н, если п = 2, у = -/СН.№. 2 с.п. ф-лы, 10 табл. 2081115 С1 КО (19) 13) ВИ” 2081 115. (51) 1пЕ. С1.6 СЛ С 070 401/14, С 08 К 5/34, С 08 Е 23/00 ЕЕ 0с ПЧ Го КУЗЗАМ АСЕМСУ ГОК РАТЕМТ$ АМО ТКАОЕМАКК$ 12) АВЗТКАСТ ОЕ 1МУЕМТОМ (21), (22) АррИсаНоп: 4831038/04, 06.08.1990 (30) Рпогйу: 02.10.1989 ЕВ 8913053 (46) Рае о! рибИсаНоп: 10.06.1997 (72) |пуетог: (71) АррИсапе: Коп-Рщепк эпити (ЕК) [иг КагейЕН], Мэре! СаЛЕН], ЗИ!м Гауо[ЕК], 2! Ми[[ЕК] (73) Ргорпеюг: Сгей тек$ Кетка! Егап$ 5.А. (ЕК) (54) ПНУОКОРУКОМЕ ОЕКМАТМЕ$ АМО ЭТАВИЕО РОУМЕКС СОМРОЗГОМ (57) АБзГасЕ: НЕЕО: слеп гу ог роутегз. ЗИВЗТАМСЕ: роууопу| спопае апа роургоруепе аге Зар!хея МИ еНесНуе аточпе ©] ...

Method for preparing 1,4-dihydropyridinecarboxylic esters or their salts

Method of preparing 4-aryl-1,4-dihydroperidines or salts thereof

Method of preparing phellodipine

FIELD: chemical industry. SUBSTANCE: 2,3-dichlorobenzylideneacetoacetic acid methyl ester is reacted with 3-aminocrotonic acid ethyl ester in boiling alcohol in the presence of pyridine as catalyst, and the resulting product is then crystallized from acetone. Method makes it possible to prepare phellodipine of high purity in the from of crystals which are readily filtered off. EFFECT: more efficient preparation method. 8 cl ребра с ПЧ с» (19) РОССИЙСКОЕ АГЕНТСТВО ПО ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ ВЦ ”’ 2 171 251 6 МК’ С 070 211/90 (13) С2 (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ РОССИЙСКОЙ ФЕДЕРАЦИИ (21), (22) Заявка: 98112386/04, 13.12.1996 (24) Дата начала действия патента: 13.12.1996 (30) Приоритет: 10.01.1996 ЗЕ 9600086-4 (43) Дата публикации заявки: 27.03.2000 (46) Дата публикации: 27.07.2001 (56) Ссылки: Ч$ 5310917 А, 10.05.1994. ЕР 0007293 АЛ, 23.01.1980. $Ц 431671 А, 05.06.1974. (85) Дата перевода заявки РСТ на национальную фазу: 08.07.1998 (86) Заявка РСТ: ЗЕ 96/01649 (13.12.1996) (87) Публикация РСТ: М/О 97/25313 (17.07.1997) (98) Адрес для переписки: 193036, Санкт-Петербург, а/я 24, "НЕВИНПАТ", Поликарпову А.В. (71) Заявитель: АстраЗенека АБ ($Е) (72) Изобретатель: ГУСТАВССОН Андерс (ЗЕ), КЕЛЬСТРЕМ Оке (ЗЕ), ПАЛЬМЕР Свен (5Е) (73) Патентообладатель: АстраЗенека АБ (5Е) (74) Патентный поверенный: Поликарпов Александр Викторович (54) СПОСОБ ПРОИЗВОДСТВА ФЕЛОДИПИНА (57) Изобретение относится К усовершенствованному способу получения фелодипина, который заключается в том, что метиловый эфир 2,3-дихлорбензилиденацетоуксусной кислоты подвергают взаимодействию с этиловым эфиром — З-аминокротоновой кислоты в кипящем спирте в присутствии пиридина в качестве катализатора с последующей кристаллизацией полученного продукта из ацетона. Способ позволяет получить фелодипин с высокой степенью чистоты в виде кристаллов, которые легко отфильтровываются. 7 з.п.ф-лы. 2171251 С2 Ко ребра с ПЧ с» КОЗЗАМ АСЕМСУ ГОК РАТЕМТ$ АМО ТКАШОЕМАКК$ 1 АВЗТКАСТ ОЕ 1МУЕМТОМ (19) ВО ^”2 171 251 (51) п ...

The method of obtaining asymmetric 1,4-dihydropyridines

Amlodipiinbenseensulfonaadi valmistamise meetod

Novel dihydropyridines with hindered amine groups

METHOD OF OBTAINING NON-SYMMETRIC ETHERS OF 1,4-DIHYDROPYRIDINDICARBONIC ACIDS

Resolution method of S---amlodipine

본 발명은 설포란하에서 D-(-)-타르트레이트를 이용하여, 라세미 암로디핀으로부터 순수한 (S)-(-)-암로디핀을 분리하는 방법을 제공한다. D-(-)-타르트레이트, S-(-)-암로디핀, 설포란 The present invention provides a method for separating pure (S)-(-)-amlodipine from racemic amlodipine using D-(-)-tartrate under sulfolane. D-(-)-tartrate, S-(-)-amlodipine, sulfolane

Piperazine derivatives

FIELD: organic chemistry. SUBSTANCE: invention relates to derivatives of piperazine of the formula (I) where Q - phenyl, naphthyl, pyridyl, pyrimidyl, furyl, isoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzyl, diphenylmethyl possibly substituted with 1 or more substituents taken from alkyl, alkoxyl, trifluoromethyl, dialkylamino, halogen, cyano- and ethylenedihydroxy-group; R - groups of the formula (a) and (b) where R 1 and R 2 are C 1-6 -alkoxyl or methylenedihydroxy-group; G is C 3-6 -cycloalkyl, phenyl, benzoyl, benzylcarbonyl, alpha-hydroxybenzyl, pyrrolyl where nitrogen atom has hydrogen atom or alkyl or takes part in binding with R, alkyl group substituted with heterocyclic group (thienyl, imidazolyl); alkanoylamino-group, morpholinoalkyl, 1-alkylindole-2-yl-group, phenylalkyl. Compounds of the formula (I) can be used as a drugs at different diseases of circulation organs or cerebral region, in part, that's caused by an excessive activation of calmodulin. EFFECT: improved method of synthesis, enhanced effectiveness of compounds. 13 cl, 6 tbl, 123 ex ЕРЗУСТЬС ПЧ Го (19) РОССИЙСКОЕ АГЕНТСТВО ПО ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ ВИ” 2 124 511 (51) МПК (13) СЛ 405/04, 405/14, А 61 К 31/495 С 070 403/04, 403/06, 403/14, 12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ РОССИЙСКОЙ ФЕДЕРАЦИИ (21), (22) Заявка: 94016183/04, 12.05.1994 (30) Приоритет: 14.05.1993 УР 5-112771 (46) Дата публикации: 10.01.1999 (56) Ссылки: МО 0103022, 1981. СН 637391, 1983. 1$ 4761411, 1988. СВ 1554215, 1979. ОЕ 3507983, 1985. ЕР 039190, 1981. Ц$ 4775673, 1988. (98) Адрес для переписки: 103735 Москва, ул.Ильинка 5/2, Союзпатент (71) Заявитель: Фармасьютикал Ко., Лтд (/Р) (72) Изобретатель: Кендззиро Ямамото (+Р), Атсуси Хасегава ()Р), Хидеки Кубота (УР), Масахиро Андо (УР), Хитоси Ямагути (/Р) (73) Патентообладатель: Фармасьютикал Ко., Лтд (/Р) (54) ПРОИЗВОДНЫЕ ПИПЕРАЗИНА (57) Реферат: Производные пиперазина формулы |, где О - фенил, нафтил, пиридил, пиримидил, ИЗОХИНОЛиИНИЛ, фурил, бензофуранил, ...

Method of preparing 1,4-dihydropyridinecarboxylic acid aralalkyl esters

Amlodipine gentisate, and process for preparing it

본 발명은 암로디핀 겐티세이트 염과 이의 제조방법에 관한 것으로서, 더욱 상세하게는 암로디핀과 겐티스산(gentisic acid)을 반응시켜 제조한 결정성 산부가염으로서 낮은 독성과 충분한 안정성이 확보되고 약효가 증진됨은 물론 투여 후 장시간 유효혈중 농도를 유지하므로 고혈압을 비롯한 심장혈관계 질환의 치료제로서 유효한 다음 화학식 1로 표시되는 암로디핀 겐티세이트 염과 이의 제조방법에 관한 것이다. The present invention relates to amlodipine gentisate salt and a method for preparing the same, and more particularly, as a crystalline acid addition salt prepared by reacting amlodipine and gentisic acid, low toxicity and sufficient stability are secured, and drug efficacy is improved. Of course, since the effective blood concentration is maintained for a long time after administration relates to the amlodipine gentisate salt represented by the following formula (1) effective as a therapeutic agent for cardiovascular diseases, including hypertension, and a preparation method thereof. 암로디핀, 겐티세이트 염, 결정성 산부가염, 고혈압, 심장혈관계 질환 Amlodipine, Gentisate Salt, Crystalline Acid Addition, Hypertension, Cardiovascular Disease

The method of obtaining 2,6-diamino-dihydropyridines

DIHYDROPYRIDINE DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF

METHOD FOR PRODUCING 6- (ARIL) -4-AMINOPICOLINATES

1. Способ получения 6-(арил)-4-аминопиколината формулыгде Q представляет собой Cl или Br;R представляет собой С-Салкил; иW представляет собой H, F или Cl;X представляет собой H, F, Cl или С-Салкокси;Y представляет собой галоген; иZ представляет собой H или F;включающий нагревание эфира 3-галоген-6-(арил)-4-иминотетрагидропиколиновой кислоты формулы (I)где R представляет собой С-Салкил;Rпредставляет собой -OS(O)R, -OC(O)Rили -OC(O)OR;Rпредставляет собой С-Салкил или незамещенный или замещенный фенил;Q представляет собой Cl или Br; иW представляет собой H, F или Cl;X представляет собой H, F, Cl или С-Салкокси;Y представляет собой галоген; иZ представляет собой H или F;при температуре от 25°С до 150°С в присутствии полярного растворителя и выделение продукта.2. Способ по п.1, в котором полярным растворителем является С-Салкановой кислотой.3. Способ по п.1, в котором эфир 3-галоген-6-(арил)-4-иминотетрагидропиколиновой кислоты получают хлорированием или бромированием сульфонилированного, ацилированного или карбонатсодержащего оксима формулыгде W, X, Y, Z, R, Rи Rимеют значения, указанные выше, хлорирующим или бромирующим агентом. РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (51) МПК C07D 213/79 (13) 2011 154 176 A (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ЗАЯВКА НА ИЗОБРЕТЕНИЕ (21)(22) Заявка: 2011154176/04, 08.06.2010 (71) Заявитель(и): ДАУ АГРОСЕЙЕНСИЗ ЭлЭлСи (US) Приоритет(ы): (30) Конвенционный приоритет: 08.06.2009 US 61/184,874 (85) Дата начала рассмотрения заявки PCT на национальной фазе: 10.01.2012 R U (43) Дата публикации заявки: 20.07.2013 Бюл. № 20 (72) Автор(ы): РЕНГА Джеймс (US), УАЙТЕКЕР Грегори (US), АРНДТ Ким (US), ЛОУ Кристиан (US) (86) Заявка PCT: (87) Публикация заявки PCT: WO 2010/144380 (16.12.2010) R U (54) СПОСОБ ПОЛУЧЕНИЯ 6-(АРИЛ)-4-АМИНОПИКОЛИНАТОВ (57) Формула изобретения 1. Способ получения 6-(арил)-4-аминопиколината формулы A 2 0 1 1 1 5 4 1 7 6 A Адрес для переписки: 129090, Москва, ул. Б. Спасская, 25, стр.3, ООО "Юридическая ...

Synthetic process of manidipine hydrochloride

本发明公开了一种盐酸马尼地平的合成工艺。该方法以N-羟乙基哌嗪为起始原料，经双乙烯酮酰化，再与间硝基苯甲醛、3-氨基丁烯酸甲酯缩合得马尼地平，经氯化氢有机溶剂成盐后得到盐酸马尼地平。本发明经过改进1-二苯甲基-4-(2-羟基乙基)哌嗪的合成工艺，双乙烯酮酰化反应引入催化剂，成盐过程采用氯化氢有机溶剂等新方法，确保了产品质量，提高了收率，更有利于工业化生产。

Substituted indeno[2,1-c] pyridines useful as calcium channel blockers

Novel substituted indeno[2,1-c] pyridine compounds useful as calcium channel blockers, pharmaceutical compositions thereof, and methods of treatment are disclosed.

New method for producing 4-substituted 1,4-dihydropyridines

An organic acid salt of amlodipine

본 발명은 물리화학적 성질이 우수한 암로디핀의 신규 유기산염, 그의 제조방법 및 그를 포함하는 약제학적 조성물에 관한 것이다. The present invention relates to a novel organic acid salt of amlodipine having excellent physicochemical properties, a preparation method thereof, and a pharmaceutical composition comprising the same.

Topical therapeutic formulations

The invention provides topical compositions and methods for using the compositions. The compositions can be used for the treatment of fibrotic or connective tissue disorders involving scarring, sub-dermal plaque accumulations, or fibrosis of muscle tissue. The disorders can be painlessly treated by the topical application of a composition described herein. One or more calcium channel blocker agents can serve as an active ingredient of the compositions, optionally in combination with, for example, one or more of emu oil and superoxide dismutase. The composition can further include pharmaceutically acceptable carriers that can facilitate the non-invasive transdermal delivery of the active(s) to subdermal sites.

Topical therapeutic formulations

Levamlodipine besylate crystal, its preparation method and application

本发明提供一种苯磺酸左旋氨氯地平晶体，分子式是：(C 20 H 25 ClN 2 O 5 )·(C 6 H 6 O 3 S)·(H 2 O) 1.5 ，分子量是：594.07，晶体学测量参数是：单斜晶系，P2 1 手性空间群，手性绝对构型由晶体学Flack参数为0.08(6)确定；单胞大小是 β＝95.817(4)°，V＝2880.1(11)。X-射线粉末衍射谱图(Cu-Kα)中特征峰在2θ为：6.70°，10.12°，12.40°，13.36°，13.68°，17.04°，22.46°，24.16°显示。还提供相关制备方法和应用。本发明的苯磺酸左旋氨氯地平晶体具有明确的晶型及其结晶水个数，明确的晶体学主要参数及确切的原子空间位置，改善了现有苯磺酸左旋氨氯地平的溶解性及稳定性，有利于苯磺酸左旋氨氯地平片剂稳定性的提升及生物利用度的改善，制备简单，成本较低，所制得的晶体晶型规则，粒径尺寸均匀，适于大规模推广应用。

Dihydropyridine derivative

Dihydropyridine derivatives of the following formula, analogs thereof and pharmaceutically acceptable salts thereof have an activity of selectively inhibiting the action of N-type calcium channel. They are used as remedies for various diseases relating to the N-type calcium channel.

Dihydropyridine derivative

Dihydropyridine derivatives of the following formula, analogs thereof and pharmaceutically acceptable salts thereof have an activity of selectively inhibiting the action of N-type calcium channel. They are used as remedies for various diseases relating to the N-type calcium channel such as encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage or the like, Alzheimer's disease, etc.

Dihydropyridine derivatives

Dihydropyridine derivatives represented by the following formula: analogs thereof and pharmaceutically acceptable salts thereof have an activity of selectively inhibiting the action of N-type calcium channel, and they are used as therapeutic agents for various diseases relating to N-type calcium channel.

Dihydropyridine derivatives

Compounds having a selective N-type calcium channel antagonistic activity are provided. Dihydropyridine derivatives represented by the following formula: analogs thereof and pharmaceutically acceptable salts thereof have an activity of selectively inhibiting the action of N-type calcium channel, and they are used as therapeutic agents for various diseases relating to N-type calcium channel.

Dihydropyridine derivative

Dihydropyridine derivatives of the following formula, analogs thereof and pharmaceutically acceptable salts thereof have an activity of selectively inhibiting the action of N-type calcium channel. They are used as remedies for various diseases relating to the N-type calcium channel such as encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage or the like, Alzheimer's disease, etc.

Method of synthesis of dihydropyrimidine derivatives

FIELD: organic chemistry. SUBSTANCE: product: derivatives of dihydropyrimidine of the formula (I) where n=1 or 2; R 1 hydrogen or methyl; X oxygen or NR 2 ; R 2 hydrogen or butyl; if n=1 then Y hydrogen and if n=2 then Y hexamethylene group. Reaction conditions: interaction of acetoacetic ester or acetacetamide of the formula II with aldehyde of the formula (III) Y-(CHO) n and ammonia. Compounds of the formula I show thermo-andphotostabilizing agents for polymers. EFFECT: improved method of synthesis. ОС9З0ОУО0сС ПЧ Го РОССИЙСКОЕ АГЕНТСТВО ПО ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ (19) (51) МПК ВИ” 2 040 520‘ С 070 211/44, 211/58, 211/90, 401/14, С 08 К 5/3435 13) СЛ 12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ РОССИЙСКОЙ ФЕДЕРАЦИИ (21), (22) Заявка: 4895177/04, 29.04.1991 (30) Приоритет: 02.10.1989 ЕК 8913053 (46) Дата публикации: 25.07.1995 (56) Ссылки: Патент Франции М 2239496, кл. С 08К 5/34, 1918. (71) Заявитель: Рон-Пуленк Шими (ЕК) (72) Изобретатель: Луи Карет[ЕН], Мишель Гай[ЕК], Сильви Лаво[ЕК], Жиль Мюр[КК] (73) Патентообладатель: Рон-Пуленк Шими (ЕК) (54) СПОСОБ ПОЛУЧЕНИЯ ПРОИЗВОДНЫХ ДИГИДРОПИРИДИНОВ (57) Реферат: Сущность изобретения: продукт производные дигидропиридинов Фф-лы | (см. чертеж), где п 1 или 2; В. водород или метил; Х кислород или МВК К> водород или бутил, причем, если М 1, то \У водород; если М 2, то У гексаметиленовая группа. Условия реакции: взаимодействие ацетоуксусного эфира или ацетацетамида Фф-лы | (смчертеж) с альдегидом Ф-лы Ш У-(СНО)- и аммиаком. Соединения Фф-лы | являются термо- и фотостабилизаторами для полимеров. 1 ил. СН. СН Н. у Н З В, -М хХ-ОС | | 0-Х М-К. Т СН СН СЯ. Н.С Н. С з З З | Н п СН З Н З СН -СО-СН -60-Х М-В Г З 2 1 СН З 2040520 С1 КО ОС9З0ОУО0сС ПЧ Го КУЗЗАМ АСЕМСУ ГОК РАТЕМТ$ АМО ТКАОЕМАКК$ 7 ВО”” 2 040 520” С1 т б 070 211/44, 211/58, 211/90, 401/14, С 08 К 5/3435 12) АВЗТКАСТ ОЕ 1МУЕМТОМ (21), (22) АррИсаНоп: 4895177/04, 29.04.1991 (30) Рпогйу: 02.10.1989 ЕВ 8913053 (46) Рае ог рибИсаНоп: 25.07.1995 (71) АррИсапе: Коп-Рщепк эпити (ЕК) ...

Substituted 2-pyridones and pyrid-2-thiones processes for their preparation and their use in medicaments

For inhibiting HMG-CoA reductase and cholesterol synthesis, the novel 2-pyridones and pyrid-2-thiones of the formula <IMAGE> in which A is optionally substituted aryl or heterocyclic, B is optionally substituted alkyl, cycloalkyl or aryl, D and E independently are optionally substituted aryl or heterocyclic, H, nitro, cyano, optionally substituted alkyl, alkenyl or imino, amino, alkoxy or acyl, or forms a ring with B, G is O or S, X is -CH2-CH2- or -CH=CH-, and R represents a group of the formula <IMAGE> and salts thereof. [US5032602A]

Substituted dihydroazepines useful as calcium channel blockers

Substituted dihydroazepines, their preparation, and the use thereof as calcium channel blockers are disclosed.

Method for synthesizing paroxetine chiral intermediate

本发明公开了一种合成帕罗西汀手性中间体的方法，包括：将N‑甲基丙二酸单酯与手性的氟代肉桂酸酯衍生物在碱性条件下反应，反应结束，后处理得到帕罗西汀手性中间体。本发明的优点主要体现在：以手性氨基醇化合物合成的氟代肉桂酸酯为手性底物，与N‑甲基丙二酸单酯进行加成环化反应，得到富含需要构型的手性哌啶二酮，同时回收手性的氨基醇，对于生产帕罗西汀过程中的无用对映体加以充分利用，减少了环境的压力，同时反应产率高，操作简单，原料廉价易得，反应条件温和，后处理简便。本发明的反应条件也能应用于大量制备，适合工业化生产，因而具有较高的实用价值和社会经济效益。

Dihydropyridone MGAT2 inhibitor

本发明提供式(I)的化合物或其立体异构体或药用盐，其中所有变量如本申请所定义。这些化合物为II型单酰基甘油酰基转移酶(MGAT2)抑制剂，其可用作药物。

A kind of preparation method of CV-4093

本发明公开了一种盐酸马尼地平的制备方法，属于医药制备技术领域。以哌嗪为起始原料合成N‑(2‑羟乙基)哌嗪的合成，再合成1‑二苯甲基‑4‑(2‑羟乙基)哌嗪，然后再合成2‑(4‑二苯甲基‑1‑哌嗪基)乙基乙酰乙酸乙酯，将2‑(4‑二苯甲基‑1‑哌嗪基)乙基乙酰乙酸乙酯、间硝基苯甲醛和β‑氨基巴豆酸甲酯溶于异丙醇中，加热回流，蒸除溶剂，剩余物溶于三氯甲烷中，用无水硫酸钠干燥后过滤，滤液减压回收溶剂，剩余物加入甲醇至完全溶解，冰浴下通入氯化氢，蒸除溶剂，剩余物加入甲醇，再加入活性炭脱色过滤，滤液冷却得到盐酸马尼地平。本发明的一种盐酸马尼地平的制备方法，工艺简单，收率高，成本低，得到的产品纯度高。

Process for preparing diaryl compounds

내용 없음. No content.

Amlodipine-losartan disulfonate, process for preparing the same, and pharmaceutical composition including the same

본 발명은 신규 복합염인 암로디핀-로자탄 다이술폰산염, 이의 제조방법 및 이를 포함하는 약제학적 조성물에 관한 것이다. 본 발명에 따른 암로디핀-로자탄 다이술폰산염은 암로디핀과 로자탄의 동시 투여시 암로디핀의 용해도가 급격히 낮아지는 문제점을 해소하고, 암로디핀과 로자탄을 동일 투약 단위에 포함시키는 과정에서 균질하게 혼합하여 제제화하는데 어려웠던 문제점을 해결하여 고혈압의 치료를 위한 약제학적 조성물에 효과적으로 사용될 수 있다. The present invention relates to a novel complex salt, amlodipine-rozatan disulfonate, a preparation method thereof, and a pharmaceutical composition comprising the same. Amlodipine-Rozatan disulfonate according to the present invention solves the problem that the solubility of amlodipine is sharply lowered when amlodipine and rozatan are simultaneously administered, and is formulated by homogeneously mixing in the process of including amlodipine and lozatan in the same dosage unit. It can be effectively used in pharmaceutical compositions for the treatment of hypertension by solving problems that were difficult to do. 암로디핀-로자탄 다이술폰산염, 암로디핀, 로자탄 Amlodipine-Rozatan Disulfonate, Amlodipine, Lozatan

Method for preparing 1,4-dihydropyridinecarboxylic esters or their salts

Method of producing 5-methyl 3 beta-(n-benzyl-n-methylamino)-ethyl ether 2,6-dimethyl-4-(3 prime-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid or hydrochloride thereof

Изобретение касаетс  замещенных пиридинов, в ч стностн получени  5-метилового 3/i-(N-бeнзил- -мeтилaми- но)-этилового эфира 2,6-диметил-4- г(3 -нитрофенил)-1,4-дигидропирнцин- -3,5-дикарбоновой кислоты или его сол нокислой соли,  вл ющегос  церебральным и коронарным возод л тором, используемым в медицине. Цель - повышение выхода целевого продукта и упрощение процесса. Последний ведут частичным гидролизом диметилового эфира 2,6-диметил-4-(3 -нитрофенип)- -1,4-дигидропиридин-З,5-дикарбоновой кислоты в присутствии NaOH в среде метанола при кип чении с последующей обработкой М-(2-хлорэтил)-К-бёнзил- метипамином в среде инертного органического растворител  в присутствии акцептора протонов - триэтиламина при 120 С. Целевой продукт вьдел ют в виде основани  или сол нокислой соли. Эти услови  позвол ют исключить необходимость очистки, т.к. получаетс  целевой продукт с т.пл. 202-206&amp;deg;С и выходом 66% (основание) или с т.пл. 129-132&amp;deg;С и выходом 70% (соль). i а ;о ел The invention relates to substituted pyridines, in the preparation of the 5-methyl 3 / i- (N-benzyl-methyl-2-methyl) ethyl ester 2,6-dimethyl-4-g (3-nitrophenyl) -1,4-dihydropyrncin- -3,5-dicarboxylic acid or its hydrochloric acid salt, which is a cerebral and coronary carrier used in medicine. The goal is to increase the yield of the target product and simplify the process. The latter is carried out by partial hydrolysis of 2,6-dimethyl-4- (3-nitrophenip) -1,4-dihydropyridine-3 dimethyl ester, 5-dicarboxylic acid in the presence of NaOH in methanol medium at boiling, followed by treatment with M- (2- chloroethyl-K-benzonylmethipamine in an inert organic solvent medium in the presence of a proton acceptor, triethylamine at 120 C. The target product is added as a base or as a hydrochloric acid salt. These conditions eliminate the need for cleaning, since the target product is obtained with a mp. 202-206 ° C and a yield of 66% (base) or with m.p. 129-132 ° C and 70% yield (salt). i a; o ate

COMPOUNDS AND COMPOSITIONS AS MODULATORS OF STEROID RECEPTORS AND ACTIVITY OF CALCIUM CHANNELS

ÐÎÑÑÈÉÑÊÀß ÔÅÄÅÐÀÖÈß RU (19) (11) 2007 126 551 (13) A (51) ÌÏÊ C07D 213/84 (2006.01) ÔÅÄÅÐÀËÜÍÀß ÑËÓÆÁÀ ÏÎ ÈÍÒÅËËÅÊÒÓÀËÜÍÎÉ ÑÎÁÑÒÂÅÍÍÎÑÒÈ, ÏÀÒÅÍÒÀÌ È ÒÎÂÀÐÍÛÌ ÇÍÀÊÀÌ (12) ÇÀßÂÊÀ ÍÀ ÈÇÎÁÐÅÒÅÍÈÅ (21), (22) Çà âêà: 2007126551/04, 13.12.2005 (71) Çà âèòåëü(è): ÀÉÐÌ ËËÊ (BM) (30) Êîíâåíöèîííûé ïðèîðèòåò: 13.12.2004 US 60/635,760 11.02.2005 US 60/652,248 (85) Äàòà ïåðåâîäà çà âêè PCT íà íàöèîíàëüíóþ ôàçó: 13.07.2007 (87) Ïóáëèêàöè PCT: WO 2006/066011 (22.06.2006) R U (54) ÑÎÅÄÈÍÅÍÈß È ÊÎÌÏÎÇÈÖÈÈ, ÊÀÊ ÌÎÄÓËßÒÎÐÛ ÑÒÅÐÎÈÄÍÛÕ ÐÅÖÅÏÒÎÐÎÂ È ÀÊÒÈÂÍÎÑÒÈ ÊÀËÜÖÈÅÂÛÕ ÊÀÍÀËΠ(57) Ôîðìóëà èçîáðåòåíè 1. Ñîåäèíåíèå ôîðìóëû I: A 2 0 0 7 1 2 6 5 5 1 A Àäðåñ äë ïåðåïèñêè: 101000, Ìîñêâà, Ì.Çëàòîóñòèíñêèé ïåð., 10, êâ.15, ÅÂÐÎÌÀÐÊÏÀÒ, ïàò.ïîâ. È.À.Âåñåëèöêîé, ðåã. ¹ 11 â êîòîðîé R1 âûáðàí èç ãðóïïû, âêëþ÷àþùåé Ñ6-Ñ10àðèë è Ñ5-Ñ10ãåòåðîàðèë; ãäå ëþáîé àðèë èëè ãåòåðîàðèë íåîá çàòåëüíî çàìåùåí 1-3 ðàäèêàëàìè, íåçàâèñèìî âûáðàííûìè èç ãðóïïû, âêëþ÷àþùåé ãàëîãåí, C1-Ñ6àëêèë, C1-Ñ6àëêîêñèãðóïïó, ôåíèë, ãàëîãåíçàìåùåííûé-Ñ1-Ñ 6àëêèë è ãàëîãåíçàìåùåííóþ-C1-Ñ6àëêîêñèãðóïïó; Rx âûáðàí èç ãðóïïû, âêëþ÷àþùåé öèàíîãðóïïó è -C(O)R2; ãäå R2 âûáðàí èç -NR6R7 è -OR7; ãäå R6 âûáðàí èç ãðóïïû, âêëþ÷àþùåé âîäîðîä, C1-Ñ6àëêèë è 1-ãèäðîêñèâèíèë; è R7 âûáðàí èç ãðóïïû, âêëþ÷àþùåé C1-Ñ6àëêèë, ãàëîãåíçàìåùåííûé-Ñ1-Ñ6àëêèë, Ñ3-Ñ12öèêëîàëêèë, Ñ6-Ñ10àðèë è Ñ5-Ñ10ãåòåðîàðèë; ãäå ëþáîé öèêëîàëêèë, àðèë èëè ãåòåðîàðèë íåîá çàòåëüíî çàìåùåí 1-3 ðàäèêàëàìè, íåçàâèñèìî âûáðàííûìè èç ãðóïïû, âêëþ÷àþùåé ãàëîãåí, Ñòðàíèöà: 1 RU 2 0 0 7 1 2 6 5 5 1 (86) Çà âêà PCT: US 2005/045449 (13.12.2005) R U (43) Äàòà ïóáëèêàöèè çà âêè: 20.01.2009 Áþë. ¹ 2 (72) Àâòîð(û): ÌÈØÅËËÈ Ïüåð-Èâ (US), ÏÝÉ Âýé (US), ÓÈÒßÊ Äæîí (US) A 2 0 0 7 1 2 6 5 5 1 A R U 2 0 0 7 1 2 6 5 5 1 Ñòðàíèöà: 2 R U íèòðî, C1-Ñ6àëêèë, C1-Ñ6àëêîêñèãðóïïó, ôåíèë, ôåíîêñèãðóïïó, ãàëîãåíçàìåùåííûé-Ñ1-Ñ6àëêèë è ãàëîãåíçàìåùåííóþ-Ñ1-Ñ6àëêîêñèãðóïïó; èëè R6 è R7 ñîâìåñòíî ñ àòîìîì àçîòà, ê êîòîðîìó îíè îáà ïðèñîåäèíåíû, îáðàçóþò Ñ5-Ñ10ãåòåðîàðèë èëè Ñ3-Ñ8ãåòåðîöèêëîàëêèë; R3 ...

Patent SU431671A3

1,4-dihydropyridines

(57)【要約】本公報は電子出願前の出願データであるた め要約のデータは記録されません。

Dihydropyridines and new uses thereof

The invention provides a method of treating benign prostatic hyperplasia in a subject which comprises administering to the subject a therapeutically effective amount of a compound having the structure: ##STR1## wherein Y is --(CH 2 ) n --, where n is 1, 2, 3, 4 or 5; --(CH 2 ) h --O--(CH 2 ) k --, where h and k are independently the same or different and are 2, 3 or 4; --(CH 2 ) h --CH═CH--(CH 2 ) k --; or --(CH 2 ) h --C.tbd.C--(CH 2 ) k --, where h and k are independently the same or different and are 1, 2, 3 or 4; wherein Z is O, NH, or CH 2 ; wherein R 1 is a linear or branched chain alkyl, alkoxyalkyl or arylalkyl group; wherein R 2 and R 4 are independently the same or different and are H, or a linear or branched chain alkyl group; wherein R 3 is H, a linear or branched chain alkyl, alkoxy, alkoxyalkyl or acyl group; and wherein R 5 and R 6 are independently the same or different and are H, OH, Cl, Br, F, NO 2 , CN, CF 3 , or NH 2 , or a linear or branched chain alkyl, alkoxy, alkoxycarbonyl, acyl, alkylsulfoxide, alkylsulfone, or mono- or dialkylamino group. Other active compounds containing one, two or three rings are also disclosed as well as pharmaceutical compositions prepared therefrom and methods of use in the treatment of BPH, inhibition of cholesterol synthesis, and reduction of intraocular pressure.

Substituted anilinic piperidines as MCH selective antagonists

This invention is directed to compounds which are selective antagonists for melanin concentrating hormone-1 (MCH1) receptors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention provides a pharmaceutical composition made by combining a therepeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.

The method of obtaining 1,4-dihydropyridines or their salts

Method of producing derivatives of 1,4-dihydropyridine or acid-additive salts thereof

Dihydropyridines of the formula:- …<CHEM>… and their pharmaceutically acceptable acid addition salts… wherein Y is -(CH2)2-, -(CH2)3-, -CH2CH(CH3)- or -CH2C(CH3)2-;… R is aryl or heteroaryl;… R<1> and R<2> are each independently C1-C4 alkyl or 2-methoxyethyl; and… R<3> is hydrogen, C1-C4 alkyl, 2-(C1-C4 alkoxyl) ethyl, cyclopropylmethyl, benzyl, or -(CH2)mCOR<4> where m is 1, 2 or 3 and R<4> is hydroxy, C1-C4 alkoxy or - NR<R>5<6> where R<5> and R<6> are each independently hydrogen or C1-C4 alkyl, pharmaceutical compositions containing them, and processes for their production. …<??>The compounds are particularly useful in the treatment or prevention of a variety of cardiac conditions, e.g, angina pectoris.

Process for the preparation of 6-(aryl)-4-aminopicolinates

与极性溶剂一起加热3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯以制备6-(芳基)-4-氨基皮考啉酸酯。