Process for the preparation of linagliptin

The present invention relates to processes for the preparation of 8-(3R)-3-aminopiperidinyl)-7-butyn-2-yl-3 -methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione and novel intermediates useful in its synthesis.

A2B ADENOSINE RECEPTOR ANTAGONISTS

Disclosed are novel compounds that are Aadenosine receptor antagonists, useful for treating various disease states, including asthma and diarrhea. 2. The method of claim 1 , wherein the disease state is chosen from atherosclerosis claim 1 , and angiogenesis.39.-. (canceled)10. A method of treating a cardiovascular disease by inhibition of an adenosine receptor characterized as A claim 1 , comprising administering to a human in need thereof a therapeutically effective dose of the compound 3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1 claim 1 ,3 claim 1 ,7-trihydropurine-2 claim 1 ,6-dione.11. The method of claim 1 , wherein the disease state is chosen from atherosclerosis claim 1 , and angiogenesis.1218.-. (canceled) This application is a Continuation of U.S. patent application Ser. No. 11/950,740, filed Dec. 5, 2007, which is a Divisional of U.S. patent application Ser. No. 11/189,202, filed Jul. 25, 2005, now U.S. Pat. No. 7,317,017, which is a Continuation of U.S. patent application Ser. No. 10/431,167, filed May 6, 2003, now U.S. Pat. No. 6,977,300, which is a Continuation in Part of U.S. Non-Provisional patent application Ser. No. 10/290,921, filed Nov. 8, 2002, now U.S. Pat. No. 6,825,349, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/401,408, filed Aug. 5, 2002 and U.S. Provisional Patent Application Ser. No. 60/348,222, filed Nov. 9, 2001 the complete disclosure of which is hereby incorporated by reference.The present invention relates to Aadenosine receptor antagonists, and to their use in treating mammals for various disease states, such as gastrointestinal disorders, immunological disorders, neurological disorders, and cardiovascular diseases due to both cellular hyperproliferation and apoptosis, and the like. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.Adenosine is a naturally occurring nucleoside, which exerts its ...

SOLID STATE FORMS OF LINAGLIPTIN

The present invention provides solid state forms of Linagliptin, processes for preparing the solid state forms, and pharmaceutical compositions thereof. 1. Crystalline Form X of Linagliptin , characterized by data selected from: a powder XRD pattern having peaks at 8.3° , 9.6° , 13.0° , 17.6° , and 18.9°±0.2 degrees 2θ; a powder XRD pattern as shown in ; and any combinations thereof.2. The crystalline Form X according to claim 1 , characterized by a powder XRD pattern having peaks at 8.3° claim 1 , 9.6° claim 1 , 13.0° claim 1 , 17.6° claim 1 , and 18.9°±0.2 degrees 2θ claim 1 , further characterized by one claim 1 , two claim 1 , three claim 1 , four claim 1 , or five peaks selected from 8.8° claim 1 , 10.6 13.6° claim 1 , 16.2° claim 1 , and 17.0°±0.2 degrees 2θ.3. The crystalline Form X of any one of and claim 1 , which is anhydrous.4. The crystalline Form X of any one of to claim 1 , which is non-hygroscopic.5. Crystalline Form XXII of Linagliptin claim 1 , characterized by data selected from: a powder XRD pattern having peaks at 9.8° claim 1 , 10.6° claim 1 , 12.3° claim 1 , 20.1° claim 1 , and 23.7°±0.2 degrees 2θ; a powder XRD pattern as shown in ; and any combinations thereof.6. The crystalline Form XXII according to claim 5 , characterized by a powder XRD pattern having peaks at 9.8° claim 5 , 10.6° claim 5 , 12.3° claim 5 , 20.1° claim 5 , and 23.7°±0.2 degrees 2θ claim 5 , and further characterized by one or more powder XRD peaks selected from 7.1° claim 5 , 14.1° claim 5 , 15.7° claim 5 , 21.8° claim 5 , and 27.2°±0.2 degrees 2θ.7. The crystalline Form XXII of any one of and claim 5 , having a total solvent content of about 5000 ppm to about 20 ppm claim 5 , as measured by GC.8. The crystalline Form XXII of any one of to claim 5 , which is non-hygroscopic.98. The use of the solid state forms of Linagliptin according to any one of to for the preparation of a different solid state form of Linagliptin.108. The use of the solid state forms of Linagliptin ...

PROCESS FOR THE PREPARATION OF CHIRAL 8-(3-AMINOPIPERIDIN-1-YL)-XANTHINES

The invention relates to an improved process for preparing enantiomerically pure 8-(3-aminopiperidin-1-yl)-xanthines. 2. The compound of formula (II) according to claim 1 , wherein{'sup': '1', 'sub': 'a', 'claim-text': {'sub': 'a', 'Ris a hydrogen, fluorine or chlorine atom or a cyano, methyl, ethyl, methoxy or ethoxy group,'}, 'Ris a phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl, pyrimidinylmethyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl or naphthyridinylmethyl group wherein the aromatic or heteroaromatic moiety is in each case mono- or disubstituted by R, where the substituents may be the same or different, and'}{'sup': '2', 'Ris a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl group, and'}{'sup': '3', 'Ris a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl group.'}3. The compound of formula (II) according to claim 2 , wherein{'sup': '1', 'Ris a cyanobenzyl, (cyanopyridinyl)methyl, quinolinylmethyl, (methylquinolinyl)methyl, isoquinolinylmethyl, (methylisoquinolinyl)methyl, quinazolinylmethyl, (methylquinazolinyl)methyl, quinoxazinylmethyl, (methylquinoxalinyl)methyl, (dimethylquinoxalinyl)methyl or naphthyridinylmethyl group,'}{'sup': '2', 'Ris a methyl, cyclopropyl or phenyl group, and'}{'sup': '3', 'Ris a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-chlorobenzyl, 2-bromobenzyl or 2-cyanobenzyl group.'}4. The compound of formula (II) according to claim 3 , wherein{'sup': '1', 'Ris a (4-methylquinazolin-2-yl)methyl, (3-methylisoquinolin-1-yl)methyl or (3-cyanopyridin-2-yl)methyl group,'}{'sup': '2', 'Ris a methyl group, and'}{'sup': '3', 'Ris a 2-butyn-1-yl group.'}9. The method according to claim 8 , wherein the phthalyl protecting group is detached in the presence of ethanolamine.10. The method according to claim 8 , wherein the phthalyl protecting group is detached in ...

Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions

The present invention relates to substituted quinazolines of formula (I): 2. The compound of formula (I) according to claim 1 , in whichR1 and R2 are the same or different and are independently selected from 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino and (2-(S)-amino-propyl)-methylamino;or a tautomer, enantiomer, diastereomer, mixture or salt thereof.3. The compound of formula (I) according to claim 1 , in which X and Y are the same claim 1 , or a tautomer claim 1 , enantiomer claim 1 , diastereomer claim 1 , mixture or salt thereof.6. Physiologically acceptable salt of the compound according to with an inorganic or organic acid or base.7. Pharmaceutical composition containing a compound of formula (I) according to claim 1 , or a physiologically acceptable salt thereof with an inorganic or organic acid or base claim 1 , optionally together with one or more pharmaceutically acceptable excipients.8. Use of a compound according to for preparing a pharmaceutical composition which is suitable for treating type II diabetes mellitus or obesity.9. Process for preparing a pharmaceutical composition according to claim 7 , characterised in that the compound of formula (I) or a physiologically acceptable salt thereof with an inorganic or organic acid or base is incorporated in one or more pharmaceutically acceptable excipients.10. A method of treating or preventing type II diabetes mellitus or obesity claim 1 , the method comprising administering the compound according to claim 1 , and optionally one or more other active substances claim 1 , to a patient.11. The method according to claim 10 , wherein the one or more other active substances is selected from metformin claim 10 , metformin; sulphonylureas claim 10 , nateglinide claim 10 , repaglinide claim 10 , thiazolidinediones (e.g. pioglitazone) claim 10 , PPAR-gamma agonists claim 10 , alpha-glucosidase blockers claim 10 , insulin or insulin analogues claim 10 , and GLP-1 and GLP-1 analogues.12. ...

COMPOUNDS AND COMPOSITIONS FOR TREATING CHEMICAL WARFARE AGENT-INDUCED INJURIES

Compounds and compositions for treating injuries caused by exposure to chemical warfare agents are described herein. 122-. (canceled)24. The compound of claim 23 , wherein{'sup': '2', 'sub': 1', '6, 'a. Ris H or C-Calkyl;'}{'sup': '6', 'b. L is C(O)NR;'}{'sup': 3', '7, 'sub': 4', '14, 'c. Ris C-Ccyclyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with R;'}{'sup': '6', 'd. each Ris H;'}{'sup': 7', '8, 'sub': 1', '6', '2', '6', '2', '6, 'e. Ris C-Calkyl, C-Calkenyl, C-Calkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, halo, hydroxyl, alkoxy, thiol, alkylthio, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, thioyl, alkylthioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea, hydroxyl alkoxyl, alkoxy alkoxyl, acyl, nitro, or cyano, each of which is optionally substituted with 1-3 R;'}{'sup': '8', 'sub': 1', '6', '2', '6', '2', '6', '3, 'f. each Ris independently C-Calkyl, C-Calkenyl, or C-Calkynyl, halo, hydroxyl, alkoxy, thiol, alkylthio, aryloxy, amino, alkylamino, dialkylamino, thioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea acyl, nitro, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl, wherein said heterocyclyl can be substituted at one or more positions with halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF, and —CN;'}{'sup': '9', 'g. Ris H;'}{'sup': 11', '12', '8, 'sub': 1', '6', '2', '6', '2', '6, 'h. each of R-Ris, independently, H, C-Calkyl, C-Calkenyl, or C-Calkynyl, halo, hydroxyl, alkoxy, amino, alkylamino, thiol, alkylthiol, nitro, or cyano, each of which is optionally substituted with 1-2 R;'}i. m is 1 andj. n is 0.25. The compound of claim 24 , wherein{'sup': '2', 'sub': 1', '6, 'a. Ris C-Calkyl;'}{'sup': 3', '7, 'b. Ris aryl or heteroaryl, substituted with R;'}{'sup': 7', '8, 'c. Ris aryl or ...

INHIBITORS OF P75 RECEPTOR AND THEIR USES

Novel p75 receptor antagonist compounds and compositions and uses thereof for the prevention and treatment of p75-associated disorders, such as neurodegenerative diseases, are described. 8. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.10. A method for inhibiting p75 receptor in a subject comprising administering the compound of to the subject claim 1 , such that p75 receptor is inhibited in said subject.11. The method of claim 10 , wherein p75 receptor activation is inhibited in said subject.12. The method of claim 10 , wherein p75 receptor function is inhibited in said subject.13. A method for preventing or treating a disease or condition characterized by p75 activation in a subject claim 1 , comprising administering an effective amount of the compound of to the subject.14. The method of claim 13 , wherein p75 receptor activation is inhibited in said subject.15. The method of claim 13 , wherein p75 receptor function is inhibited in said subject.16. The method of claim 13 , wherein the disease or condition is a neurodegenerative disease.17. The method of claim 16 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease claim 16 , Down's syndrome claim 16 , Creutzfeldt-Jacob disease claim 16 , kuru claim 16 , scrapie claim 16 , transmissible mink encephalopathy claim 16 , Riley-Day familial dysautonomia claim 16 , multiple system atrophy claim 16 , amyotrophic lateral sclerosis (ALS) claim 16 , glaucoma claim 16 , neuropathy claim 16 , ischemia claim 16 , hypoxia claim 16 , neural injury claim 16 , Huntington's disease claim 16 , epilepsy claim 16 , Parkinson's disease claim 16 , spinal cord injury and neuroblastoma.18. The method of claim 16 , wherein the neurodegenerative disease is a disease which can be treated with agents that activate a Trk receptor claim 16 , with neurotrophins claim 16 , and/or with neurotrophin-derived peptides or peptidomimetics.19. The method ...

XANTHINE DERIVATIVES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

The present invention relates to substituted xanthines of general formula 2. The Compound according to claim 1 , wherein{'sup': '1', 'claim-text': (1) a hydrogen atom,', {'sub': '1-6', '(2) a C-alkyl group,'}, {'sub': '3-6', '(3) a C-alkenyl group,'}, {'sub': 3-4', '1-2, '(4) a C-alkenyl group which is substituted by a C-alkyloxy-carbonyl group,'}, {'sub': '3-6', '(5) a C-alkynyl group,'}, {'sub': 3-6', '1-3, '(6) a C-cycloalkyl-C-alkyl group,'}, '(7) a phenyl group which may be substituted by a fluorine, chlorine or bromine atom or by a methyl, trifluoromethyl, hydroxy or methoxy group,', {'sub': '1-4', 'sup': 10', '12, 'claim-text': [{'sup': '10', 'claim-text': (i) a hydrogen atom, a fluorine, chlorine or bromine atom,', {'sub': 1-4', '3-6, '(ii) a C-alkyl, trifluoromethyl, hydroxymethyl, C-cycloalkyl, ethynyl or phenyl group,'}, {'sub': 1-4', '1-2', '1-2', '1-3', '1-3', '1-3', '1-3', '1-2', '1-3', '1-2', '1-3', '1-3', '1-3', '1-3', '3-6', '3-6', '1-2, '(iii) a hydroxy, C-alkyloxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, phenoxy, benzyloxy, 2-propen-1-yloxy, 2-propyn-1-yloxy, cyano-C-alkyloxy, C-alkylsulphonyloxy, phenylsulphonyloxy, carboxy-C-alkyloxy, C-alkyloxy-carbonyl-C-alkyloxy, aminocarbonyl-C-alkyloxy, C-alkyl-aminocarbonyl-C-alkyloxy, di-(C-alkyl)aminocarbonyl-C-alkyloxy, pyrrolidin-1-yl-carbonyl-C-alkyloxy, piperidin-1-ylcarbonyl-C-alkyloxy, morpholin-4-ylcarbonyl-C-alkyloxy, methylsulphanylmethoxy, methylsulphinylmethoxy, methylsulphonylethoxy, C-cycloalkyloxy or C-cycloalkyl-C-alkyloxy group,'}, {'sub': 1-3', '1-3', '1-3', '1-3', '1-2', '1-2, '(iv) a carboxy, C-alkyloxycarbonyl, carboxy-C-alkyl, C-alkyloxy-carbonyl-C-alkyl, aminocarbonyl, C-alkylaminocarbonyl, di-(C-alkyl)aminocarbonyl or cyano group,'}, {'sub': 1-2', '1-2', '1-2', '1-2', '1-2', '1-2', '1-2', '1-2', '1-2', '1-3', '1-2', '1-2', '1-2', '1-2', '1-2', '1-2', '1-2, '(v) a nitro, amino, C-alkylamino, di-(C-alkyl)amino, cyano-C-alkylamino, [N-(cyano-C-alkyl)-N—C-alkyl-amino ...

SMALL MOLECULES FOR THE TREATMENT OF PRIMARY CANCER AND CANCER METASTASIS

Certain embodiments are directed to non-hydrolysable ATP analogs and adenosine receptor antagonists that inhibit migration and growth of cancer cells. 2. The compound of claim 1 , wherein R1 is selected from hydrogen claim 1 , cyano claim 1 , C1 to C3 alkyl claim 1 , halo claim 1 , or heteromethyl claim 1 , and R2 is a hydrogen or halogen.3. The compound of claim 2 , wherein R1 is a hydrogen claim 2 , fluoro claim 2 , methyl claim 2 , cyano claim 2 , or trifluoromethyl.4. The compound of claim 1 , wherein R1 is cyano and R2 is hydrogen claim 1 , R1 is hydrogen and R2 is hydrogen claim 1 , R1 is trifluoromethyl and R2 is hydrogen claim 1 , R1 methyl and R2 is hydrogen claim 1 , and R1 is fluoro and R2 is fluoro.5. A method for treating a cancer patient comprising administering to the patient an effective amount of a one or more compounds of .6. The method of claim 5 , wherein the cancer is breast cancer.7. The method of claim 5 , wherein one or more compounds of are administered intravenously.8. The method of claim 5 , wherein one or more compounds of are administered orally.10. The compound of claim 9 , wherein R3 is difluoro methyl claim 9 , cyclopropyl claim 9 , cyclobutyl claim 9 , or β-tetrahydrofuran.11. A method for treating a cancer patient comprising administering to the patient an effective amount of one or more compounds of . This application claims priority to U.S. Provisional Application Ser. No. 62/104,705 filed Jan. 17, 2015, which is incorporated herein by reference in its entirety.The bone is the most common site of metastasis in patients with advanced cancers including breast and prostate cancers (Jin et al. (2011) 128, 2545-2561; Kohno, (2008) 13, 18-23). Bone metastases are major, potentially fatal complications in patients with advanced cancers. Almost all patients with skeletal metastases have significantly decreased quality of life due to intense pain, pathological fractures, spinal cord compression, and metabolic complications (Welch et al. ( ...

POLYMORPHS

The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament. 1. A method of preparing polymorph C of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine , the method comprising:(a) refluxing a solution of 1-[(4-methyl-quinazolin-2-Amethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in methanol to provide a hot methanolic solution,(b) cooling the hot methanolic solution to a temperature of 40-60° C. to provide a cooled methanolic solution,(c) adding tert-butylmethylether to the cooled methanolic solution to form a suspension,(d) cooling the suspension first to a temperature of 15-25° C. and then to a temperature of 0-5° C. to provide crystals,(e) suction filtering the crystals, and(f) drying the crystals obtained in step (e) in vacuo at a temperature of 70° C. to provide Polymorph C,wherein Polymorph C loses water at a temperature of 30-100° C. and exhibits further thermal effects at a temperature of about 150° C. and about 175° C. in a differential scanning calorimetry (DSC) analysis.2. The method according to claim 1 , wherein the X-ray powder diagram of Polymorph C has characteristic reflections at the following d values: 12.90 Å claim 1 , 11.10 Å claim 1 , 6.44 Å claim 1 , 3.93 Å and 3.74 Å.3. The method according to claim 1 , wherein the hot methanolic solution obtained in step (a) is filtered before cooling in step (b). This Application claims priority of EP 06 009 202, which is hereby incorporated by reference in its entirety.1. Field of the InventionThe invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament.2. Description of the Prior ArtThe enzyme DPP-IV, also known by the name CD26, is a serine protease which promotes the cleaving of dipeptides in proteins with a proline or alanine ...

PROCESS FOR THE PREPARATION OF CHIRAL 8-(3-AMINOPIPERIDIN-1-YL)-XANTHINES

The invention relates to an improved process for preparing enantiomerically pure 8-(3-aminopiperidin-1-yl)-xanthines. 3. The first compound according to claim 2 , wherein the phthalyl protecting group of the second compound is detached in the presence ethanolamine.4. The first compound according to claim 2 , wherein the phthalyl protecting group of the second compound is detached in the presence of i) ethanolamine and ii) in the presence of toluene or a mixture of tetrahydrofuran and water.5. The first compound according to claim 2 , further comprising crystallizing the first compound from ethanol or methanol.6. The first compound according to claim 2 , further comprising crystallizing the first compound from ethanol.7. The first compound according to in a form pure for medicament production.8. The first compound according to in a form pure for medicament production.10. A process for preparing a medicament comprising the first compound according to claim 1 , the process comprising combining the first compound with one or more inert carriers and/or diluents.11. A process for preparing a medicament comprising the first compound according to claim 2 , the process comprising combining the first compound with one or more inert carriers and/or diluents.12. A process for preparing a medicament comprising the first compound according to claim 9 , the process comprising combining the first compound with one or more inert carriers and/or diluents. The invention relates to an improved process for preparing chiral 8-(3-aminopiperidin-1-yl)-xanthines, their enantiomers and their physiologically tolerated salts.8-(3-aminopiperidin-1-yl)-xanthines of the following general structurein which Ris, for example, an optionally substituted arylmethyl group or an optionally substituted heteroarylmethyl group, Ris, for example, an alkyl group and Ris, for example, an optionally substituted benzyl group or a straight-chain or branched alkenyl or alkinyl group are already known from the ...

SUBSTITUTED XANTHINE DERIVATIVES

The present invention relates to compounds of formula (I) a process for their manufacture, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment of conditions having an association with TRPC5 containing ion channels. R, R, R, Rand Rhave meanings given in the description. 4. A pharmaceutically acceptable salt of the compound according to .5. (canceled)6. A pharmaceutical composition comprising the compound according to .7. (canceled)8. (canceled)9. A method for treating a TRPC5 mediated disorder in a subject claim 1 , the method comprising administering to the subject an effective amount of the compound of .10. The method according to claim 9 , wherein the TRPC5 mediated disorder is a psychiatric claim 9 , neurological or neurodegenerative condition.11. The method according to claim 10 , wherein the psychiatric claim 10 , neurological or neurodegenerative condition is selected from the group consisting of diseases associated with dysregulated emotional processing (e.g. borderline personality disorder or depressive disorders like major depression claim 10 , major depressive disorder claim 10 , psychiatric depression claim 10 , dysthymia claim 10 , and postpartum depression claim 10 , and bipolar disorders) claim 10 , anxiety and fear-related disorders (e.g. post-traumatic stress disorder claim 10 , panic disorder claim 10 , agoraphobia claim 10 , social phobias claim 10 , generalized anxiety disorder claim 10 , panic disorder claim 10 , social anxiety disorder claim 10 , obsessive compulsive disorder claim 10 , and separation anxiety) claim 10 , memory disorders (e.g. Alzheimer's disease claim 10 , amnesia claim 10 , aphasia claim 10 , brain injury claim 10 , brain tumor claim 10 , chronic fatigue syndrome claim 10 , Creutzfeldt-Jakob disease claim 10 , dissociative amnesia claim 10 , fugue amnesia claim 10 , Huntington's disease claim 10 , learning disorders claim 10 , sleeping disorders claim 10 , multiple personality ...

ADENOSINE RECEPTOR ANTAGONISTS AND USES THEREOF

Disclosed herein are compounds, compositions, formulations, and methods for modulating the Aadenosine receptor. 2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein:{'sup': '4', 'sub': 1', '6, 'Ris C-Calkyl;'}{'sup': '6', 'sub': 1', '6, 'Ris selected from hydrogen, and C-Calkyl.'}3. (canceled)4. (canceled)5. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein:{'sup': 1', '2, 'sub': 1', '6, 'Rand Rare each independently selected from substituted or unsubstituted C-Calkyl;'}{'sup': '3', 'Ris selected from substituted or unsubstituted phenyl.'}6. (canceled)7. The compound of claim 5 , or a pharmaceutically acceptable salt or solvate thereof claim 5 , wherein:{'sup': '1', 'Ris ethyl;'}{'sup': '2', 'Ris n-propyl; and'}{'sup': '3', 'Ris 3-(trifluoromethyl)phenyl.'}8. (canceled)9. (canceled)10. (canceled)11. (canceled)12. (canceled)14. The compound of claim 13 , or a pharmaceutically acceptable salt or solvate thereof claim 13 , wherein:{'sup': 1', '2, 'sub': 1', '6, 'Rand Rare each independently selected from substituted or unsubstituted C-Calkyl;'}{'sup': '3', 'Ris selected from substituted or unsubstituted phenyl.'}15. (canceled)17. The compound of claim 16 , or a pharmaceutically acceptable salt or solvate thereof claim 16 , wherein:{'sup': '4', 'Ris methyl or ethyl;'}{'sup': 5', '7', '7', '7', '8', '7', '9, 'sub': '2', 'Ris hydrogen, R′, —C(═O)R, —C(═O)—OR, —C(═O)N(R)(R), —C(═O)—SR, or —P(═O)(OR);'}{'sup': 7', '10', '11', '11', '11', '11, 'sub': 1', '6', '1', '6', '3', '8', '5', '10', '2', '8', '5', '10', '2', '2', '2', '2', '8', '2', '2', 'n', '2', 'p, 'Ris C-Calkyl, substituted or unsubstituted C-Cheteroalkyl, substituted or unsubstituted monocyclic C-Ccycloalkyl, substituted or unsubstituted bicyclic C-Ccycloalkyl, substituted or unsubstituted monocyclic C-Cheterocycloalkyl, substituted or unsubstituted bicyclic C-Cheterocycloalkyl, substituted or unsubstituted ...

SUBSTITUTED XANTHINE DERIVATIVES

This invention relates to novel deuterated compounds that are substituted xanthine derivatives and pharmaceutically acceptable salts thereof. In particular, this invention relates to novel substituted xanthine derivatives that are deuterated derivatives of a pentoxifylline metabolite. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed deuterated compounds and compositions in methods of treating diseases and conditions for which pentoxifylline and related compounds are beneficial. The compounds of the invention are represented by the following structural formula: 122-. (canceled)24. The compound of claim 23 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.25. The compound of claim 23 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6000.26. The compound of claim 23 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6600.27. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.28. A method of treating a disease or condition in a patient in need thereof claim 24 , comprising administering to the patient an effective amount of a compound of claim 24 , wherein the disease is selected from diabetic nephropathy and hypertensive nephropathy.29. A method of treating chronic kidney disease in a patient in need thereof claim 24 , comprising administering to the patient an effective amount of a compound of .30. The method of wherein the chronic kidney disease is glomerulonephritis claim 29 , focal segmental glomerulosclerosis claim 29 , nephrotic syndrome claim 29 , reflux uropathy claim 29 , or polycystic kidney disease.31. A method of treating chronic disease of the liver in a patient in need thereof claim 24 , comprising administering to the patient an effective amount of a compound of .32. The method of wherein the chronic disease of the ...

AMORPHOUS FORM OF LINAGLIPTIN AND PROCESS FOR PREPARATION THEREOF

The present invention relates to an amorphous form of linagliptin and processes for the preparation thereof. The invention also relates to a pharmaceutical composition comprising therapeutically effective amount of an amorphous form of linagliptin and use of said composition for treatment of diabetes especially type-I or type-II, prediabetes or reduction of glucose tolerance. 2. The amorphous form of linagliptin according to claim 1 , having a water content less than 0.5% wt/wt.3. An improved process for the preparation of an amorphous form of linagliptin according to claim 1 , the process comprising:(a) providing a solution of linagliptin in a suitable solvent or mixture of solvents;(b) obtaining the amorphous form of linagliptin by removal of solvent.4. The process according to wherein suitable solvent comprises water; alcohols such as methanol claim 3 , ethanol claim 3 , isopropanol and the like; ketones such as acetone claim 3 , butanone and the like; esters such as ethyl acetate claim 3 , butyl acetate and the like; halogenated hydrocarbons like methylene dichloride claim 3 , ethylene dichloride claim 3 , chlorobenzene claim 3 , and the like claim 3 , nitriles like acetonitrile; polar aprotic solvents like dimethylformamide claim 3 , dimethylacetamide claim 3 , N-methyl pyrrolidone claim 3 , dimethyl-sulfoxide claim 3 , tetrahydrofuran or mixtures thereof.5. The process according to wherein removal of solvent comprises using a rotational distillation device like a Buchi Rotavapor claim 3 , spray drying claim 3 , agitated thin film drying (“ATFD”) claim 3 , freeze drying (lyophilization) claim 3 , and the like.6. An improved process for the preparation of an amorphous form of linagliptin according to claim 1 , the process comprising:(a) suspending linagliptin in a suitable organic solvent and removing the solvent to obtain residue;(b) adding a suitable anti-solvent to the residue; and(c) obtaining the amorphous form of linagliptin.7. The process according to ...

8-[3-AMINO-PIPERIDIN-1-YL]-XANTHINES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

The present invention relates to substituted xanthines of general formula 2. 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine.3. 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine.5. The process according to claim 4 , wherein the tert.-butyloxycarbonyl group is cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with bromotrimethylsilane or iodotrimethylsilane claim 4 , optionally using a solvent such as methylene chloride claim 4 , ethyl acetate claim 4 , dioxane claim 4 , methanol claim 4 , isopropanol or diethyl ether at temperatures between 0 and 80° C. This application is a continuation of application Ser. No. 12/143,128, filed Jun. 20, 2008, which is a continuation of application Ser. No. 10/639,036, filed, Aug. 12, 2003. This application claims the benefit of U.S. provisional application Ser. Nos. 60/409,312, filed Sep. 9, 2002 and 60/461,752, filed Apr. 10, 2003, and German application Nos. DE 102 38 243.3, filed Aug. 21, 2002 and DE 103 12 353.9, filed Mar. 20, 2003.The present invention relates to compounds having valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).The present invention relates to new substituted xanthines of general formulathe tautomers, the stereoisomers, the mixtures, the prodrugs thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV), the preparation thereof, the use thereof for the prevention or treatment of diseases or conditions associated with an increased DPP-IV activity or capable of being prevented or alleviated by reducing the DPP-IV ...

XANTHINE DERIVATIVES, THEIR USE AS A MEDICAMENT, AND PHARMACEUTICAL PREPARATIONS COMPRISING THE SAME

The invention relates to a xanthine derivative defined by chemical formula I or a salt thereof, its use as a medicament, especially for use in the treatment of serotonin-related diseases or disorders, and a pharmaceutical preparation comprising the xanthine derivative. 2. Xanthine derivative according to claim 1 , wherein at least one of Rand Ris not hydrogen.3. Xanthine derivative according to claim 1 , wherein Ris selected from an optionally substituted linear claim 1 , branched or cyclic (C1-C5)-alkyl group claim 1 , from the group consisting of methyl claim 1 , ethyl claim 1 , n-propyl claim 1 , isopropyl claim 1 , cyclopropyl claim 1 , cyclobutyl and cyclopentyl.4. Xanthine derivative according to claim 1 , wherein Ris selected from an optionally substituted (C5-C12)-aryl claim 1 , (C5-C12)-heteroaryl claim 1 , (C6-C12)-alkyl-aryl claim 1 , (C6-C12)-alkyl-heteroaryl claim 1 , (C6-C12)-alkenyl-aryl claim 1 , (C6-C12)-alkenyl-heteroaryl claim 1 , (C6-C12)-alkynyl-aryl claim 1 , (C6-C12)-alkynyl-heteroaryl claim 1 , (C6-C12)-aryl-alkylene claim 1 , (C6-C12)-heteroaryl-alkylene claim 1 , (C6-C12)-aryl-alkenylene claim 1 , (C6-C12)-heteroaryl-alkenylene claim 1 , (C6-C12)-aryl-alkylylene and (C6-C12)-heteroaryl-alkylylene.5. Xanthine derivative according to claim 1 , wherein Ris a group defined by chemical formula (Ia){'br': None, 'sup': '5', '—R-Ar\u2003\u2003(Ia),'}{'sup': '5', 'wherein Ris (C0-C3)-alkylene, and'}Ar is an optionally substituted (C5-C12)-aryl or (C5-C12)-heteroaryl.6. Xanthine derivative according to claim 1 , wherein Ris hydrogen claim 1 , flour claim 1 , chlorine claim 1 , brome claim 1 , amine claim 1 , amide claim 1 , carbonitrile optionally substituted (C1-C10)-alkyl claim 1 , optionally substituted saturated or unsaturated (C5-C6)-heterocyclic claim 1 , optionally substituted (C2-C10)-alkenyl claim 1 , optionally substituted (C1-C5)-alkoxy claim 1 , wherein the alkyl and alkenyl groups optionally comprise one or more bivalent groups as ...

POLYMORPHS

The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament. 1. Anhydrous polymorph A of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine , characterised in that it melts at 206±3° C.2. Polymorph A according to claim 1 , characterised in that in the X-ray powder diagram it has inter alia characteristic reflexes at the following d values: 11.49 Å claim 1 , 7.60 Å claim 1 , 7.15 Å claim 1 , 3.86 Å claim 1 , 3.54 Å and 3.47.3. Anhydrous polymorph B of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine claim 1 , characterised in that at a temperature of 10-40° C. it transforms reversibly into the polymorph A of .4. Polymorph B according to claim 3 , characterised in that in the X-ray powder diagram it has inter alia characteristic reflexes at the following d values: 11.25 Å claim 3 , 9.32 Å claim 3 , 7.46 Å claim 3 , 6.98 Å and 3.77 Å.5. Polymorph C of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine claim 3 , characterised in that it loses water at a temperature of 30-100° C. and in the DSC diagram it exhibits further thermal effects at approx. 150° C. and 175° C.6. Polymorph C according to claim 5 , characterised in that in the X-ray powder diagram it has inter alia characteristic reflexes at the following d values: 12.90 Å claim 5 , 11.10 Å claim 5 , 6.44 Å claim 5 , 3.93 Å and 3.74 Å.7. Anhydrous polymorph D of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine claim 5 , characterised in that it melts at 150±3° C.8. Anhydrous polymorph E of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine claim 5 , characterised in that it melts at 175±3° C.9. ...

NOVEL COMPOUNDS

The present invention relates to therapeutically active xanthine derivative compounds of Formula (I): 2. The method according to claim 1 , wherein said method treats the inflammatory disease or condition of nervous tissue claim 1 , and wherein the disease or condition is multiple sclerosis.3. The method according to claim 1 , wherein said method treats inflammatory sequelae of a viral or bacterial infection.4. The method according to claim 1 , wherein Ris hydrogen claim 1 , Calkyl claim 1 , CHCN or (CH)CF; and Ris Cunsubstituted alkyl claim 1 , (CH)CN claim 1 , Calkyl substituted with one or more fluorine substitutions claim 1 , unbranched Calkenyl claim 1 , or Calkyl substituted with cycloalkyl.5. The method according to claim 1 , wherein Ris hydrogen or methyl.6. The method according to claim 1 , wherein Ris Cunsubstituted n-alkyl claim 1 , (CH)CN claim 1 , Calkyl with one or more fluorine substitutions or Calkenyl.7. The method according to claim 1 , wherein Ris Cunsubstituted n-alkyl.8. The method according to claim 1 , wherein Ris chlorine or bromine.9. The method according to claim 1 , wherein Ris chlorine.10. The method according to claim 1 , wherein the compound of Formula (I) is selected from:(8-chloro-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)acetonitrile;3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione;8-chloro-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione;8-chloro-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione;8-bromo-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione;8-chloro-3-(3,3,3-trifluoropropyl)-3,7-dihydro-1H-purine-2,6-dione;8-chloro-1-propyl-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione;3-butyl-8-chloro-1-methyl-3,7-dihydro-1H-purine-2,6-dione;(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetonitrile;8-chloro-3-(2-cyclopropylethyl)-3,7-dihydro-1H-purine-2,6-dione;8-chloro-1,3-bis(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione;4-(8-chloro-1-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl) ...

8-[3-AMINO-PIPERIDIN-1-YL]-XANTHINES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

The present invention relates to substituted xanthines of general formula 1. 1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine , or an enantiomer , a mixture of enantiomers or a salt thereof.2. 3-Methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine.3. A physiologically acceptable salt of a compound according to with an inorganic or organic acid or base.4. A pharmaceutical composition comprising a compound according to or a physiologically acceptable salt thereof claim 1 , optionally together with one or more inert carriers and/or diluents. The present invention relates to compounds having valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).The present invention relates to new substituted xanthines of general formulathe tautomers, the stereoisomers, the mixtures, the prodrugs thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV), the preparation thereof, the use thereof for the prevention or treatment of diseases or conditions associated with an increased DPP-IV activity or capable of being prevented or alleviated by reducing the DPP-IV activity, particularly type I or type II diabetes mellitus, the pharmaceutical compositions containing a compound of general formula (I) or a physiologically acceptable salt thereof as well as processes for the preparation thereof.In the above formula IRdenotes a methyl group, a methyl group which is substituted by a dimethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, tert.-butylcarbonyl or a cyclohexylcarbonyl-group, a methyl group which is substituted by a naphthyl, methylnaphthyl, methoxynaphthyl, nitronaphthyl or dimethylaminonaphthyl group, ...

COMPOSITIONS AND METHODS FOR THE TREATMENT OF CHRONIC DISEASES AND INFLAMMATORY DISORDERS

The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of chronic diseases and inflammatory disorders may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of intermittent claudication, obstructed arteries in the limbs, vascular dementia, Peyronie's disease, neuropathic injuries, sickle cell disease, nausea and headaches in the mountains (altitude sickness), acute alcoholic and non-alcoholic steatohepatitis, alcoholic liver disease, fibrotic lesions induced by radiation therapy for cancer, cytokine release syndrome, endometriosis, venous disease, inflammation, cancer, stroke, thrombosis, sepsis, gangrene, infection, type 1 diabetes, type 2 diabetes, pancreatic beta cell degeneration, beta cell dysfunction, respiratory diseases, rheumatoid arthritis, arthritis, osteoarthritis and vascular disease. 2. A Pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.3. The pharmaceutical composition of claim 2 , which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration claim 2 , delayed release or sustained release claim 2 , transmucosal claim 2 , syrup claim 2 , topical claim 2 , parenteral administration claim 2 , injection claim 2 , subdermal claim 2 , oral solution claim 2 , rectal administration claim 2 , buccal administration or transdermal administration.4. A method of treating chronic diseases and inflammatory disorders as the underlying etiology claim 3 , the method comprising administering to a patient in need thereof an effective amount of .5. The method of claim 4 , wherein the chronic ...

POLYMORPHS

The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament. 1. A method of preparing polymorph D of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine , characterized in that it melts at 150±3° C. , wherein polymorph D is obtained by heating polymorph C of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine to a temperature of 30-100° C. or by drying at this temperature , wherein Polymorph C is characterized in that it loses water at a temperature of 30-100° C. and exhibits further thermal effects at a temperature of about 150° C. and about 175° C. in a differential scanning calorimetry (DSC) analysis.2. The method according to wherein polymorph C is obtained by a method comprising:(a) refluxing a solution of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in methanol to provide a hot methanolic solution,(b) cooling the hot methanolic solution to a temperature of 40-60° C. to provide a cooled methanolic solution,(c) adding tert-butylmethylether to the cooled methanolic solution to form a suspension,(d) cooling the suspension first to a temperature of 15-25° C. and then to a temperature of 0-5° C. to provide crystals,(e) suction filtering the crystals, and(f) drying the crystals obtained in step (e) in vacuo at a temperature of 70° C. to provide Polymorph C.3. The method according to claim 2 , wherein the X-ray powder diagram of Polymorph C has characteristic reflections at the following d values: 12.90 Å claim 2 , 11.10 Å claim 2 , 6.44 Å claim 2 , 3.93 Å and 3.74 Å.4. The method according to claim 2 , wherein the hot methanolic solution obtained in step (a) is filtered before cooling in step (b). This Application claims priority of EP 06 009 202, which is hereby incorporated by reference in ...

SUBSTITUTED QUINAZOLINES, THE PREPARATION THEREOF AND THE USE THEREOF IN PHARMACEUTICAL COMPOSITIONS

The present invention relates to substituted quinazolines of formula (I) wherein X and Y are defined as in claim , the tautomers, stereoisomers, mixtures and salts thereof, which have valuable pharmacological properties, particularly an inhibitory effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV). 124-. (canceled)26. The method according to claim 25 , further comprising(a) carrying out the dissociation of the compound of formula (IA) in a suitable solvent or mixture of solvents, and(b) isolating the obtained compound of formula (II) from the suitable solvent or mixture of solvents.27. The method according to claim 26 , wherein the solvent or solvent system comprises one or more solvents selected from the group consisting of ketones claim 26 , lactones claim 26 , ethers claim 26 , hydrocarbons claim 26 , chlorinated hydrocarbons claim 26 , low-molecular-weight aliphatic alcohols claim 26 , esters claim 26 , amides or lactames claim 26 , nitriles claim 26 , sulfoxides claim 26 , amines claim 26 , and water; or a mixture thereof.28. The method according to claim 27 , wherein the solvent is a polar solvent or mixture of polar solvents.29. The method according to claim 27 , wherein the solvent or solvent system comprises a low-molecular-weight aliphatic alcohol.30. The method according to claim 27 , wherein the solvent is water or an aqueous medium.31. The method according to claim 26 , wherein the compound of formula (II) or a salt thereof is obtained in crystalline claim 26 , amorphous claim 26 , lyophilized or dried form. The present invention provides substituted quinazolines of formula (I)wherein the groups X and Y are as defined hereinafter, including the tautomers, stereoisomers (e.g. enantiomers, diastereomers), mixtures and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids, which have interesting properties. For example, they have pharmacological properties such as e.g. an inhibitory ...

CAFFEINATED COMPOUNDS AND COMPOSITIONS FOR TREATMENT OF AMYLOID DISEASES AND SYNUCLEINOPATHIES

Compounds and their pharmaceutically acceptable salts for treatment of β-amyloid diseases, such as observed in Alzheimer's disease and synucleinopathies, such as Parkinson's disease. 3. The compound of where Ris substituted with a benzyl group claim 1 , Ror Rare independently substituted with either a methyl or benzyl group and Ris substituted with a hydrogen and wherein the benzyl groups are each substituted with two hydroxyl groups.4. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable excipient.5. A method of treating the formation claim 1 , deposition claim 1 , accumulation claim 1 , or persistence of amyloid or α-synuclein fibrils claim 1 , comprising treating the fibrils with an effective amount of the compound of .6. A method of treating an amyloid disease or a synucleinopathy in a mammal suffering therefrom claim 1 , comprising administration of a therapeutically effective amount of the compound of .7. The method of where the amyloid disease is selected from the group of diseases consisting of Alzheimer's disease claim 5 , type II diabetes claim 5 , systemic AA amyloidosis claim 5 , Down's syndrome claim 5 , hereditary cerebral hemorrhage with amyloidosis of the Dutch type claim 5 , and cerebral β-amyloid angiopathy.8. The method of where the amyloid disease is Alzheimer's disease.9. The method of where the synucleinopathy is selected from the group consisting of Parkinson's disease claim 5 , familial Parkinson's disease claim 5 , Lewy body disease claim 5 , the Lewy body variant of Alzheimer's disease claim 5 , dementia with Lewy bodies claim 5 , multiple system atrophy claim 5 , and the Parkinsonism-dementia complex of Guam.10. The method of where the synucleinopathy is Parkinson's disease.11. The method of claim 5 , where the compound administered is in an amount between 0.1 mg/Kg/day and 1000 mg/Kg/day.12. The method of claim 5 , where the compound is administered in an amount between 1 mg/Kg/day and 100 mg/Kg/day.13 ...

COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATORY DISORDERS

The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for treating or preventing inflammatory disorders may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of intermittent claudication resulting from obstructed arteries in the limbs, and vascular dementia, improves blood flow through peripheral blood vessels and therefore helps with blood circulation in the arms and legs (e.g. intermittent claudication), and the brain (hence its use in vascular dementia), venous disease, Peyronie's disease, neuropathic injuries, strokes, sickle cell disease, nausea and headaches in the mountains (altitude sickness), non-alcoholic steatohepatitis and alcoholic liver disease, fibrotic lesions induced by radiation therapy for breast cancer, cytokine release syndrome, cancer, type 1 diabetes and type 2 diabetes, asthma, bronchodilation, kidney diseases, renal protection, vascular ischemia, neuroprotection, vasodilation, Alzheimer's disease, dementia, stroke, and treatment of endometriosis. 2. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.3. The pharmaceutical composition of claim 2 , wherein said pharmaceutical composition is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration claim 2 , delayed release or sustained release claim 2 , transmucosal claim 2 , syrup claim 2 , topical claim 2 , parenteral administration claim 2 , injection claim 2 , subdermal claim 2 , oral solution claim 2 , rectal administration claim 2 , buccal administration or transdermal administration.4. Compounds and compositions of claim 3 , ...

POLYMORPHS

The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament. 2. The method according to claim 1 , wherein anhydrous polymorph A has an X-ray powder diagram as shown in .3. The method of claim 1 , wherein anhydrous polymorph A is characterized in that the reflection at 11.59 Å in the X-ray powder diagram has a relative intensity of 100% and the X-ray powder diagram exhibits no reflections having a relative intensity of 1% or more at the following d values: 11.3 Å claim 1 , 9.36 Å claim 1 , 7.48 Å claim 1 , and 7.0 Å.5. The method according to wherein anhydrous polymorph B has an X-ray powder diagram as shown in .6. The method of claim 1 , wherein anhydrous polymorph B is characterized in that the reflection at 11.3 Å in the X-ray powder diagram has a relative intensity of 100% and the X-ray powder diagram exhibits no reflections having a relative intensity of 1% or more at the following d values: 11.59 Å claim 1 , 7.60 Å claim 1 , and 7.15 Å.8. A method of preparing a medicament claim 1 , the method comprising{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'i) preparing the anhydrous polymorph A by the method of , and'}ii) combining the anhydrous polymorph A with one or more inert carriers to provide a medicament containing 0.1% to 0.5%, or 0.5% to 1.5%, or 1% to 3% of the anhydrous polymorph A based on the total weight of the polymorph A and the one or more inert carriers.9. A method of preparing anhydrous polymorph A or B claim 1 , or a mixture thereof claim 1 , of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine claim 1 , the method comprising crystallizing polymorph A or B claim 1 , or a mixture thereof claim 1 , from a solution of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in ethanol claim 1 ,wherein anhydrous polymorph A is characterised in ...

COMPOSITIONS AND METHODS FOR THE TREATMENT OF RESPIRATORY DISORDERS

The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of respiratory disorders may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of viscid or excessive mucus, cough, inflammation, redness in sore throat, infection in the throat, sore throat, abnormal mucus secretion, impaired mucus transport, allergic rhinitis, asthma, COPD, respiratory muscular disorders and pain in acute sore throat. 2. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.3. The pharmaceutical composition of claim 2 , wherein said pharmaceutical composition is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration claim 2 , delayed release or sustained release claim 2 , transmucosal claim 2 , syrup claim 2 , topical claim 2 , parenteral administration claim 2 , injection claim 2 , subdermal claim 2 , oral solution claim 2 , rectal administration claim 2 , buccal administration or transdermal administration.4. A method of treating respiratory disorders related diseases as the underlying etiology claim 3 , wherein the method comprises administering to a patient in need thereof an effective amount of .5. The method of claim 4 , wherein the respiratory disorders as the underlying etiology is selected from viscid or excessive mucus claim 4 , cough claim 4 , inflammation claim 4 , redness in sore throat claim 4 , infection in the throat claim 4 , sore throat claim 4 , abnormal mucus secretion claim 4 , impaired mucus transport claim 4 , allergic rhinitis claim 4 , asthma claim 4 , COPD claim 4 , respiratory muscular ...

COMPOSITIONS AND METHODS FOR THE TREATMENT OF PERIODONTITIS AND RHEUMATOID ARTHRITIS

The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of periodontitis and rheumatoid arthritis may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. 2. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.3. The pharmaceutical composition of claim 2 , wherein said pharmaceutical composition is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration claim 2 , delayed release or sustained release claim 2 , transmucosal claim 2 , syrup claim 2 , topical claim 2 , parenteral administration claim 2 , injection claim 2 , subdermal claim 2 , oral solution claim 2 , rectal administration claim 2 , buccal administration or transdermal administration.4. A method of treating periodontitis and rheumatoid arthritis as the underlying etiology claim 3 , wherein the method comprises administering to a patient in need thereof an effective amount of .5. The pharmaceutical composition of claim 2 , further comprising a molecular conjugate of leflunomide and carboxylic acid compounds selected from a group consisting of R-Lipoic acid claim 2 , eicosapentaenoic acid claim 2 , docosahexaenoic acid claim 2 , fumaric acid claim 2 , arginine claim 2 , salsalate and nicotinic acid.6. The molecular conjugate of claim 5 , wherein the carboxylic acid compound is R-Lipoic acid.7. The molecular conjugate of claim 5 , wherein the carboxylic acid compound is eicosapentaenoic acid.8. The molecular conjugate of claim 5 , wherein the carboxylic acid compound is docosahexaenoic acid.9. The molecular conjugate of claim 5 , wherein the carboxylic acid compound is fumaric ...

PHOSPHODIESTERASE 1-TARGETING TRACERS AND METHODS

Tracers targeting phosphodiesterase for use in gamma radiation detection-based diagnostic techniques, particularly gamma-emitter labeled tracers for SPECT and positron emitter-labeled compositions for PET are disclosed. Radio-labeled multiple novel scaffolds as PDE1 inhibitors such as substituted pyrazolo-pyrimidin-4-one derivatives, biomarkers for phosphodiesterase 1 [PDE1) in vivo, methods for developing novel therapies for PDE1-implicated conditions such as pulmonary arterial hypertension (PAH), Central Nervous System (CNS) and Cardiovascular (CV) disorders, and methods of detection and treatment are also disclosed. 1. A radiolabeled PDE1 inhibitor.2. A radiotracer composition for use in gamma radiation-based diagnostic imaging comprising:a) a phosphodiesterase 1-selective ligand in free, salt or prodrug form selected from:i)7,8-dihydro-[1H or 2H]-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one;ii)7,8,9-trihydro-[1H or 2H]-pyrimido [1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one;iii) 3-(optionally hetero)arylamino-[2H]-pyrazolo[3,4-d] pyrimidine-4,6(5H, 7H)-dione; andiv)(6aR*,9aS*)-3-(phenylamino)-5-6a,7,8,9,9a-hexahydro-5-methylcyclopent [4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(1H or 2H)-one;{'sub': 3', '9, 'wherein each of (i), (ii), (iii) and (iv) are substituted at the 1- or 2-position with C2-9 alkyl, C-cycloalkyl, heteroarylalkyl, or substituted arylalkyl; and'}b) a radionuclide chemically bound to said ligand.3. The composition of claim 2 , wherein the radionuclide is selected from Carbon-11 claim 2 , Fluorine-18 claim 2 , Technetium-99m claim 2 , Indium-111 and Iodine-123.4. A method of selective reversible binding and mapping of functional phosphodiesterase 1 activity in vivo in tissue and/or organ of interest using positron emission tomography which comprises:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(a) administering an effective amount of a compound of to the subject, and then'}(b) allowing a period of time sufficient for the radiotracer to ...

ADENOSINE RECEPTOR ANTAGONISTS AND USES THEREOF

Disclosed herein are compounds, compositions, formulations, and methods for modulating the Aadenosine receptor. 2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein:{'sup': 1', '2, 'sub': 1', '6, 'Rand Rare each independently selected from substituted or unsubstituted C-Calkyl;'}{'sup': '3', 'Ris selected from substituted or unsubstituted phenyl.'}3. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein:{'sup': 1', '2, 'Rand Rare each independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.'}4. The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof claim 3 , wherein:{'sup': '1', 'Ris ethyl;'}{'sup': '2', 'Ris n-propyl; and'}{'sup': '3', 'Ris 3-(trifluoromethyl)phenyl.'}6. The compound of claim 5 , or a pharmaceutically acceptable salt or solvate thereof claim 5 , wherein:{'sup': 5', '7, 'Ris R;'}{'sup': 7', '10', '11', '11', '10', '11, 'sub': 1', '6', '1', '6', '3', '8', '5', '10', '2', '8', '5', '10', '2', '2', '2', '2', '8', '2', '2', 'n', '2', 'p, 'Ris C-Calkyl, substituted or unsubstituted C-Cheteroalkyl, substituted or unsubstituted monocyclic C-Ccycloalkyl, substituted or unsubstituted bicyclic C-Ccycloalkyl, substituted or unsubstituted monocyclic C-Cheterocycloalkyl, substituted or unsubstituted bicyclic C-Cheterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, —CH-(substituted or unsubstituted phenyl), —CH-(substituted or unsubstituted heteroaryl), —CH-(substituted or unsubstituted C-Cheterocycloalkyl), —CH(R)O—R, —(CHCHO)—R, or —(C(R))—OR;'}{'sup': '10', 'each Ris independently selected from hydrogen and methyl;'}{'sup': 11', '12', '12', '12', '8', '12', '9, 'sub': 1', '6', '1', '6', '2', '10', '2, 'Ris ...

PROCESS FOR THE PREPARATION OF A XANTHINE-BASED COMPOUND

This invention relates to a method for preparation of a xanthine-based compound, as well as to intermediates useful in such preparation. 4. The method according to claim 1 , wherein the suitable base is NaCO claim 1 , KCO claim 1 , NaHCOor KHCO.5. The method according to claim 1 , wherein the suitable solvent comprises NMP claim 1 , DMSO claim 1 , DMAc or DMF.6. The method according to claim 1 , wherein X is Cl.7. The method according to claim 1 , wherein X is Cl claim 1 , the suitable base is NaHCOand the suitable solvent is NMP.8. The method according to claim 1 , wherein X is I.9. The method according to claim 1 , wherein X is I claim 1 , the suitable base is NaHCOand the suitable solvent is DMSO.10. The method according to claim 1 , wherein the reaction is conducted at elevated reaction temperature of from 20° C. to 120° C. claim 1 , or from 40° C. to 110° C. This invention relates to a method for preparation of a xanthine-based pharmaceutically active ingredient, namely Linagliptin, as well as to intermediates useful in such preparation.1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, whose international nonproprietary name is Linagliptin, has the following structure as shown below:Up to now, several synthetic routes to synthesize the molecule have been described by several references.For example, a process for the preparation of Linagliptin is disclosed in the references WO 2004/018468 and WO 2006/048427.The reference WO 2014/059938 describes a further process for preparation of Linagliptin involving a phase transfer catalyst and using protected (R)-piperidine-3-amine derivatives. The process of WO 2014/059938 requires an amine protecting group, such as tert-butyloxy carbonyl (Boc) protection and de-protection of the intermediates used in the late stage of the synthesis process.The reference WO 2013/098775 describes a further process for preparation of Linagliptin: (R)-piperidine-3-amine (or its ...

8-[3-AMINO-PIPERIDIN-1-YL]-XANTHINES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

The present invention relates to substituted xanthines of general formula 2. The compound of claim 1 , wherein{'sup': '1', 'Rdenotes a [2-(methylcarbonylamino)-phenyl]-carbonylmethyl group,'}a [2-(ethylcarbonylamino)-phenyl]-carbonylmethyl group ora [2-(isopropylcarbonylamino)-phenyl]-carbonylmethyl group,or a pharmaceutically acceptable salt thereof.3. The compound of claim 1 , wherein{'sup': '1', 'Rdenotes a [2-(aminocarbonylmethoxy)-phenyl]-carbonylmethyl group,'}[2-(methylaminocarbonylmethoxy)-phenyl]-carbonylmethyl group,a [2-(ethylaminocarbonylmethoxy)-phenyl]-carbonylmethyl group ora [2-(isopropylaminocarbonylmethoxy)-phenyl]-carbonylmethyl group,or a pharmaceutically acceptable salt thereof.4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , selected from the group consisting of:(14) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(15) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(16) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(17) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine, and(18) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine.5. A physiologically acceptable salt of a compound according to claim 1 , with inorganic or organic acids or bases.6. A pharmaceutical composition comprising a pharmaceutically acceptable amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , optionally together with one or more inert carriers and/or diluents. The present invention relates to compounds having valuable pharmacological properties, particularly an inhibiting effect on the activity of ...

COMPOUNDS AND COMPOSITIONS FOR TREATING CHEMICAL WARFARE AGENT-INDUCED INJURIES

Compounds and compositions for treating injuries caused by exposure to chemical warfare agents are described herein. This application is a continuation of U.S. application Ser. No. 15/922,402, filed Mar. 15, 2018, which is a continuation of U.S. application Ser. No. 13/661,812, filed Oct. 26, 2012, which is a continuation of U.S. application Ser. No. 12/466,195, filed May 14, 2009, which claims priority to U.S. Ser. No. 61/127,722, filed May 14, 2008, and U.S. Ser. No. 61/082,809, filed Jul. 22, 2008, each of which is incorporated herein by reference in its entirety.The invention relates to compounds and compositions useful for treating injuries caused by chemical warfare and similar agents.A variety of ion channel proteins exist to mediate ion flux across cellular membranes. The proper expression and function of ion channel proteins is essential for the maintenance of cell function and intracellular communication. Numerous diseases and disorders are the result of misregulation of membrane potential or aberrant calcium handling. Given the central importance of ion channels in modulating membrane potential and ion flux in cells, identification of agents that can promote or inhibit particular ion channels are of great interest, both as research tools and as therapeutic agents.The present invention provides compounds and compositions for treating or preventing injuries resulting from chemical warfare agents by modulating the activity of the TRPA1 channel.In one aspect, the invention features methods for treating injuries caused by exposure to a chemical warfare agent, or a similar agent, by administering a compound of formula (I) or a salt thereof,Wherein each of Rand Ris, independently, H, C-Calkyl, C-Calkenyl, or C-Calkynyl, each of which is optionally substituted with 1-4 R; L is NRSO, SONR, C(O)NR, NRC(O), OC(O)NR, NRC(O)O, NRC(O)NR, S, S(O), S(O), NR, CH, O, C(O)NS(O), S(O)NC(O), heteroaryl, or cyclyl; Ris C-Ccyclyl, heterocyclyl, aryl, or heteroaryl, each of ...

INTERMEDIATES AND PROCESSES FOR THE PREPARATION OF LINAGLIPTIN AND ITS SALTS

Disclosed are new intermediates for the synthesis of Linagliptin and of its salts and a process for its preparation involving said intermediates. 2. The compounds according to wherein R and Rare selected from hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , isopropyl claim 1 , butyl claim 1 , isobutyl claim 1 , sec-butyl claim 1 , tert-butyl claim 1 , phenyl claim 1 , benzyl claim 1 ,p-tolyl, p-methoxyphenyl, m-methoxyphenyl, p-nitrophenyl, p-chlorophenyl,{'sub': '1', '3,4-dimethoxyphenyl, 2-thiophenyl, 2-furanyl, cyclopentyl, cyclohexyl, —CH═CH-Ph, R and Rare linked together to form a cyclohexane or a 3-methyl or 4-methyl substituted cyclohexane.'}3. The compounds according to wherein R is hydrogen and Ris phenyl.5. The process according to wherein in step (a) the bases are selected from alkali and alkaline-earth metal hydroxides claim 4 , carbonates claim 4 , bicarbonates and phosphates claim 4 , or mixtures thereof; solvents are aprotic apolar or polar claim 4 , aromatic claim 4 , aliphatic claim 4 , ether claim 4 , ester claim 4 , keto solvents or mixtures thereof having a water content ranging from 0% to 6% (v/v); the optional phase transfer agent is selected from tetrasubstituted ammonium or phosphonium salts and the molar ratio of compound of formula (II) to compound of formula (VI) ranges from 1/1 to 1/1 claim 4 ,5; optional isolation in step (b) is effected by precipitation or crystallization in the presence of a straight or branched C1-C4 alcohol or of an ester or ether or mixtures thereof in the presence of aprotic apolar or polar claim 4 , aromatic claim 4 , aliphatic solvents or mixtures thereof and the deprotection is effected under mildly acid or basic conditions.6. The process according to wherein in step (a) the bases are selected from sodium carbonate claim 5 , potassium carbonate claim 5 , cesium carbonate claim 5 , sodium phosphate claim 5 , potassium phosphate; solvents are selected from acetonitrile claim 5 , ...

SALT FORMS OF ORGANIC COMPOUND

The present invention relates to novel salt forms of a certain DPP-4 inhibitor and their use in pharmaceutical compositions useful in the treatment of type 2 diabetes, as well as their production. 1. (canceled)2. An acid addition salt of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine with an acid selected from nitric acid , acetic acid , 2 ,2-dichloroacetic acid , adipic acid , D-ascorbic acid , L-ascorbic acid , D-aspartic acid , L-aspartic acid , benzenesulfonic acid , benzoic acid , 4-acetamido-benzoic acid , (+)-camphoric acid , (−)-camphoric acid , (+)-camphor-10-sulfonic , (−)-camphor-10-sulfonic , capric acid (decanoic acid) , caproic acid (hexanoic acid) , caprylic acid (octanoic acid) , carbonic acid , cinnamic acid , cyclamic acid , dodecylsulfuric acid , ethane-1 ,2-disulfonic acid , ethanesulfonic acid , 2-hydroxy-ethanesulfonic acid , formic acid , galactaric acid , gentisic acid , D-glucoheptonic acid , L-glucoheptonic acid , D-gluconic acid , L-gluconic acid; D-glucuronic acid , L-glucuronic acid , glutamic acid , glutaric acid , 2-oxo-glutaric acid , glycerophosphoric acid , glycolic acid , hippuric acid , isobutyric acid , D-lactic acid , L-lactic acid , lactobionic acid , lauric acid , maleic acid , D-malic acid , L-malic acid , malonic acid , D-mandelic acid , L-mandelic acid naphthalene-1 ,5-disulfonic acid , naphthalene-2-sulfonic acid , 1-hydroxy-2-naphthoic acid , nicotinic acid , oleic acid , orotic acid , oxalic acid , palmitic acid , pamoic acid (embonic acid) , propionic acid , D-pyroglutamic acid , L-pyroglutamic acid , salicyclic acid , 4-aminosalicyclic acid , sebacic acid , stearic acid , thiocyanic acid , p-toluenesulfonic acid and undecylenic acid.3. The salt according to claim 2 , which is selected from the group consisting of a besylate salt claim 2 , a benzoate salt claim 2 , an esylate salt claim 2 , a fumarate salt claim 2 , a mesylate salt claim 2 , a salicylate salt claim ...

SUBSTITUTED XANTHINES AND METHODS OF USE THEREOF

Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5. 2. The method of claim 1 , wherein the TRPC5 mediated disorder is selected from the group consisting of: a neuropsychiatric disorder claim 1 , a neurodegenerative disorder claim 1 , nephropathy claim 1 , and seizure disorder.3. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris C-Calkyl.4. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris C-Calkyl and Ris independently C-Caryl or heteroaryl.5. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris C-Caryl claim 1 , C-Caryloxy or heteroaryloxy.6. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris C-Caryloxy.7. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris C-Calkoxy.8. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris C-Calkyl.9. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris or C-Cakylamino.10. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris —S(O)— or —S(O)—.11. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris C-Calkyl claim 1 , C-Chydroxyalkyl claim 1 , or C-Calkoxy.12. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris hydroxypropyl.13. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris C-Calkyl.14. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris independently C-Caryl claim 1 , heteroaryl claim 1 , C-Ccycloalkyl claim 1 , or heterocycloalkyl.15. The method of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris phenyl claim 1 , pyridyl claim 1 , thiazolyl claim 1 , pyrimidinyl ...

POLYMORPHS

The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament. 1. A method of preparing polymorph D of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine , characterized in that it melts at 150±3° C. , wherein polymorph D is obtained by heating polymorph C of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine to a temperature of 30-100° C. or by drying at this temperature , wherein Polymorph C is characterized in that it loses water at a temperature of 30-100° C. and exhibits further thermal effects at a temperature of about 150° C. and about 175° C. in a differential scanning calorimetry (DSC) analysis.2. The method according to wherein polymorph C is obtained by a method comprising:(a) refluxing a solution of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in methanol to provide a hot methanolic solution,(b) cooling the hot methanolic solution to a temperature of 40-60° C. to provide a cooled methanolic solution,(c) adding tert-butylmethylether to the cooled methanolic solution to form a suspension,(d) cooling the suspension first to a temperature of 15-25° C. and then to a temperature of 0-5° C. to provide crystals,(e) suction filtering the crystals, and(f) drying the crystals obtained in step (e) in vacuo at a temperature of 70° C. to provide Polymorph C.3. The method according to claim 2 , wherein the X-ray powder diagram of Polymorph C has characteristic reflections at the following d values: 12.90 Å claim 2 , 11.10 Å claim 2 , 6.44 Å claim 2 , 3.93 Å and 3.74 Å.4. The method according to claim 2 , wherein the hot methanolic solution obtained in step (a) is filtered before cooling in step (b). This Application claims priority of EP 06 009 202, which is hereby incorporated by reference in ...

METHOD FOR PREPARING AN IMPORTANT INTERMEDIATE OF LINAGLIPTIN

The present invention discloses an improved process for preparing an important intermediate of linagliptin. In particular, disclosed are a process for preparing a compound V which is an important intermediate of linagliptin and has the structure V, and an industrial process of preparing linagliptin having excellent chemical and optical purities, which is an inhibitor of dipeptidyl peptidase-4 (DPP-IV), from the compound V. The process employs a phase-transfer catalyst, is high in yield, easy and simple to handle, environmentally friendly, suitable for industrial mass production, and can be implemented by a “one-pot process”. 2. The process according to claim 1 , wherein claim 1 ,{'sub': 1', '2', '3', '1', '2', '3, 'X, Xand Xare each independently selected from the group consisting of a halogen, such as fluorine, chlorine or bromine; and a sulfonate group, such as methylsulfonyloxy, phenylsulfonyloxy, p-toluenesulfonyloxy, p-chlorophenylsulfonyloxy, benzylsulfonate, 2-(4-nitrophenylethyl)sulfonate or trifluoromethylsulfonyloxy, Xis preferably bromine, Xis preferably chlorine, Xis preferably bromine or chlorine;'}{'sub': 5', '6, 'Rand Rare each independently H, C1-C16 alkoxycarbonyl, C6-C18 aryl C1-C16 alkoxycarbonyl, benzyl, p-methoxybenzyl, p-methylbenzyl, p-chlorobenzyl, p-bromobenzyl, p-nitrobenzyl, diphenylmethyl, 2,4-dimethoxybenzyl, 2-hydroxybenzyl, bis(4-methoxyphenyl)methyl, triphenylmethyl, (4-methoxyphenyl)diphenylmethyl, 9-phenylfluorenyl, formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, phenylpropionyl, benzoyl, p-phenylbenzoyl, phthaloyl, 4-nitrophthaloyl, dithiosuccinoyl, tetrachlorophthaloyl, p-toluenesulfonyl, benzenesulfonyl, methanesulfonyl, 2,4,6-trimethoxybenzenesulfonyl, pentamethylbenzenesulfonyl, 4-methoxybenzenesulfonyl, 2,4,6-trimethylbenzenesulfonyl, 2,6-dimethoxy-4-methyl-benzenesulfonyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl, pyridine-2-sulfonyl, 2-(trisilyl)ethylsulfonyl, 9- ...

POLYMORPHS

The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament. 113-. (canceled)14. A method of preparing an anhydrous polymorph A of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine , the method comprising:(a) dissolving 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in absolute ethanol to provide a solution;(b) refluxing the solution to provide a hot solution and, optionally filtering the hot solution to provide a hot filtrate,(c) cooling the hot solution or the hot filtrate until crystallisation sets in,(d) diluting the cooled solution or the cooled filtrate with a solvent to provide a solvent mixture,(e) suction filtering the solvent mixture, and said anhydrous polymorph A melts at 206±3° C., and', 'said anhydrous polymorph A exhibits an X-ray powder diagram having characteristic reflections at the following d values: 11.59 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Åand 3.47 Å., '(f) drying the solids collected by filtration at 45° C. in vacuo to provide said anhydrous polymorph A; wherein'}15. The method of claim 14 , wherein the solvent used for diluting the hot solution or hot filtrate in Step (d) is tert.-butylmethylether.16. The method according to claim 14 , wherein anhydrous polymorph A has an X-ray powder diagram as shown in .17. The method of claim 14 , further characterized in that the reflection at 11.59 Å in the X-ray powder diagram has a relative intensity of 100% and further characterized in that the X-ray powder diagram exhibits no reflections having a relative intensity of 1% or more at the following d values: 11.25 Å claim 14 , 9.32 Å claim 14 , 7.46 Å claim 14 , and 6.98 Å.20. The method of claim 19 , wherein the solvent used for diluting the hot solution or hot filtration in Step (d) is tert.-butylmethylether.21. The method according to ...

COMPOUNDS AND COMPOSITIONS FOR TREATING CHEMICAL WARFARE AGENT-INDUCED INJURIES

Compounds and compositions for treating injuries caused by exposure to chemical warfare agents are described herein. 3. The method of claim 1 , wherein the compound is administered orally claim 1 , via intramuscular injection claim 1 , or topically.4. The method of claim 1 , wherein the chemical warfare agent is tear gas.5. The method of claim 1 , wherein the chemical warfare agent is chlorine.6. The method of claim 1 , wherein the chemical warfare agent is mustard gas.7. The method of claim 1 , wherein the subject is a human.8. The method of claim 2 , wherein the compound is administered orally claim 2 , via intramuscular injection claim 2 , or topically.9. The method of claim 2 , wherein the chemical warfare agent is tear gas.10. The method of claim 2 , wherein the chemical warfare agent is chlorine.11. The method of claim 2 , wherein the chemical warfare agent is mustard gas.12. The method of claim 2 , wherein the subject is a human. This application is a continuation of U.S. application Ser. No. 13/661,812, filed Oct. 26, 2012, which is a continuation of U.S. application Ser. No. 12/466,195, filed May 14, 2009, which claims priority to U.S. Ser. No. 61/127,722, filed May 14, 2008, and U.S. Ser. No. 61/082,809, filed Jul. 22, 2008, each of which is incorporated herein by reference in its entirety.The invention relates to compounds and compositions useful for treating injuries caused by chemical warfare and similar agents.A variety of ion channel proteins exist to mediate ion flux across cellular membranes. The proper expression and function of ion channel proteins is essential for the maintenance of cell function and intracellular communication. Numerous diseases and disorders are the result of misregulation of membrane potential or aberrant calcium handling. Given the central importance of ion channels in modulating membrane potential and ion flux in cells, identification of agents that can promote or inhibit particular ion channels are of great interest, both ...

AN IMPROVED PROCESS FOR THE PREPARATION OF LINAGLIPTIN

The present invention relates to a process for preparing Linagliptin by purifying the intermediate compounds converting the purified intermediates into Linagliptin. The present invention also relates to the preparation of an amorphous Linagliptin. 2. The process according to the claim 1 , wherein the solvent is dichloromethane.3. The process according to the claim 1 , wherein the suitable acid is trifluoro acetic acid.4. The process according to the claim 1 , wherein protecting group P is di t-Butyl dicarbamate (Boc)6. The process according to the claim 5 , wherein bromination of a xanthine compound of formula A is carried out with liquid bromine in presence of a metal acetate such as sodium acetate and a suitable solvent.7. The process according to the claim 5 , wherein reaction of the bromoxanthine compound of formula B with a butynyl compound of formula H is carried out in presence of a base and solvent.8. The process according to the claim 5 , wherein the condensation of the butyl xanthine compound of formula C claim 5 , with a quinazoline compound of formula D is carried put in the presence of a base claim 5 , suitable solvent and optionally in presence of a phase transfer catalyst.9. The process according to the claim 5 , wherein the reaction of the compound of formula E with a protected piperidine compound of formula F is carried out in presence of a base claim 5 , solvent and optionally in presence of a metal halide.10. The process according to the claim 5 , wherein the deprotection is carried out by treating the protected compound of formula G with an acid.12. The use of compound of claim 11 , in the preparation of Linagliptin. This application claims priority to this Indian patent application number 5242/CHE/2012 dated on Dec. 17, 2012.The present invention relates to an improved process for the preparation of Linagliptin and further relates to process for the preparation of amorphous Linagliptin.Linagliptin is chemically described as 8-[(3R)-3- ...

XANTHINE-SUBSTITUTED ALKYNYL CARBAMATES/REVERSE CARBAMATES AS A2B ANTAGONISTS

The present invention provides xanthine-substituted alkynyl carbamates/reverse carbamates and derivatives thereof and pharmaceutical compositions containing the same that are selective antagonists of Aadenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents. 2. A compound of claim 1 , wherein the compound is of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof.3. A compound of claim 2 , wherein:{'sup': '1', 'sub': 1-3', '3-6, 'Ris selected from: Calkyl and Ccycloalkyl;'}{'sup': '2', 'sub': 1-3', '3-6, 'Ris selected from: Calkyl and Ccycloalkyl;'}{'sup': '3', 'sub': 1-6', '1-3', '3-6, 'Ris selected from: Calkyl and —Calkylene-Ccycloalkyl;'}{'sup': '4', 'Ris selected from: phenyl and 5-6 membered heteroaryl;'}{'sup': 4', 'a', 'a', 'a', 'b', 'a', 'a', 'a', 'b', 'a', 'a', 'a', 'b', 'b', 'a', 'b', 'a', 'b', 'a', 'b', 'a', 'b, 'sub': 1-4', '3-6', '1-3', '3-6', '3', '3', '2', '2', '2', 'p, 'the phenyl and heteroaryl groups of Rare optionally substituted with 1-2 groups independently selected from: Calkyl, Ccycloalkyl, —Calkylene-Ccycloalkyl, F, Cl, Br, I, —CN, OR, SR, NRR, CF, OCF, COR, COR, C(O)NRR, OC(O)R, OCOR, OC(O)NRR, NRCOR, NRCOR, NRC(O)NRR, and S(O)NRR;'}{'sup': 'a', 'sub': 1-4', '3-6, 'claim-text': {'sub': 1-3', '3-6, 'and —Calkylene-Ccycloalkyl;'}, 'each Ris independently selected from: H, Calkyl, Ccycloalkyl,'}{'sup': 'b', 'sub': 1-4', '3-6, 'claim-text': {'sub': 1-3', '3-6, 'and —Calkylene-Ccycloalkyl; and,'}, 'each Ris independently selected from: H, Calkyl, Ccycloalkyl,'}p is independently selected from: 0, 1, and 2.4. A compound of claim 3 , wherein:{'sup': '4', 'ring Ris selected from phenyl, pyridyl, thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidyl, and pyridazinyl.'}5. A compound of claim 4 , wherein:{'sup': '4', 'ring Ris selected from phenyl and pyridyl.'}6. A compound of claim 5 , wherein:{'sup': '1', 'Ris selected from: methyl, ethyl, and cyclopropyl;'}{' ...

8-[3-AMINO-PIPERIDIN-1-YL]-XANTHINES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

The present invention relates to substituted xanthines of general formula 2. The method according to claim 1 , wherein the amino group of the 3-aminopiperidine claim 1 , an enantiomer thereof or a salt thereof claim 1 , is protected during the reaction by a protecting group which is cleaved after the reaction.3. The method according to claim 2 , wherein the protecting group is tert-butoxycarbonyl.4. The method of claim 1 , wherein Zis chlorine claim 1 , bromine claim 1 , methanesulphonyl or methanesulphonyloxy.6. The compound of claim 4 , wherein Zis chlorine claim 4 , bromine claim 4 , methanesulphonyl or methanesulphonyloxy. The present invention relates to compounds having valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).The present invention relates to new substituted xanthines of general formulathe tautomers, the stereoisomers, the mixtures, the prodrugs thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV), the preparation thereof, the use thereof for the prevention or treatment of diseases or conditions associated with an increased DPP-IV activity or capable of being prevented or alleviated by reducing the DPP-IV activity, particularly type I or type II diabetes mellitus, the pharmaceutical compositions containing a compound of general formula (I) or a physiologically acceptable salt thereof as well as processes for the preparation thereof.In the above formula IRdenotes a methyl group, a methyl group which is substituted by a dimethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, tert.-butylcarbonyl or a cyclohexylcarbonyl-group, a methyl group which is substituted by a naphthyl, methylnaphthyl, methoxynaphthyl, nitronaphthyl or ...

An improved process for preparing Linagliptin and its key Intermediates

The present invention relates to a process for the preparation of Linagliptin or a pharmaceutically acceptable slat thereof. Further aspects of the present invention relates to process for the preparation of Linagliptin key intermediate, having purity more than 98.0%. 124-. (canceled)26. The process according to claim 25 , wherein the suitable solvent is selected from the group comprising one or more dimethyl acetamide claim 25 , dimethyl formamide and dimethyl sulfoxide or mixture thereof.27. The process according to claim 26 , wherein the suitable solvent used in step (b) and (c) is combination of dimethyl acetamide claim 26 , dimethyl formamide claim 26 , dimethyl sulfoxide and water.28. The process according to claim 25 , wherein suitable base used in step a) and c) comprising one or more of inorganic bases or organic bases or mixture thereof.29. The process according to claim 25 , wherein the substantially pure 8-bromo xanthine has the purity more than 99% by HPLC.30. The process according to claim 25 , wherein the substantially pure Boc-Linagliptin has the purity more than 98% by HPLC.33. The according to claim 32 , wherein the organic base is selected from the group of triethyl amine (Et3N) claim 32 , trimethyl amine (Me3N) claim 32 , pyridine claim 32 , tributylamine and diisopropyl ethyl amine (DIPEA).34. The process according to claim 32 , wherein suitable solvent is selected from dimethyl formamide claim 32 , dimethylacetamide claim 32 , dimethyl sulfoxide and water or mixtures thereof.35. The process according to claim 32 , wherein the substantially pure Boc-Linagliptin has the purity more than 95% by HPLC.36. The process according to claim 32 , wherein the 3-(R)-Bocaminopiperidine or its salt is 1 to 1.5 molar equivalents for the equivalent of 8-bromo xanthine of Formula II or its salt.37. The process according to claim 32 , wherein the base is 1 to 4 molar equivalents per the equivalent of the compound of Formula II or its salt.38. The process ...

XANTHINE DERIVATIVE INHIBITORS OF BET PROTEINS

This invention relates to xanthine derivative compounds that are inhibitors of BET bromodomains proteins, the method of preparation thereof and applications thereof. 3. The inhibitor according to claim 1 , wherein:X represents an oxygen atom;{'sub': 'o', 'claim-text': {'sub': o', 'p', 'p', '1', '4, 'wherein Rrepresents —C(O)ORwherein Rrepresents a C-Calkyl;'}, 'Y represents an oxygen atom, an amino group, NHR, or a linker-ligand for the E3 ubiquitin ligase;'}{'sub': '1', 'Rrepresents a hydrogen atom or a lone pair;'}{'sub': 3', '1', '6', '1', '4', '5', '12', '1', '6, 'claim-text': a halogen atom, or', {'sub': 1', '4, 'a C-Calkyl;'}], 'Rrepresents a C-Calkyl, preferably a C-Calkyl, a linker-ligand for the E3 ubiquitin ligase, or a (C-C)aryl-(C-C)alkyl, optionally substituted by{'sub': 7', '1', '6', '1', '4, 'Rrepresents a C-Calkyl, preferably a C-Calkyl and even more preferably a methyl or ethyl group;'}{'sub': 8', 'q', '2', 'q', '2', 'q, 'Rrepresents a hydrogen atom, —SH, —SR—, —CH—O—Ror —CH—S—R;'}{'sub': 'q', 'claim-text': [{'sub': 1', '6', '1', '4, 'C-Calkyl, preferably a C-Calkyl,'}, 'amino groups,', 'halogen atoms,', {'sub': 1', '4, '(C-C)alkanoic acid,'}, {'sub': 2', '1', '4, '—S(O)—(C-C)alkyl,'}, {'sub': '2', '—S(O)-piperidine,'}, {'sub': '2', '—S(O)—(N,N)dimethylamine,'}, {'sub': '2', '—S(O)-morpholine,'}, 'nitro groups,', {'sub': 1', '4, '—C(═O)—O—(C-C)alkyl,'}, {'sub': 2', '1', '4, '—S(O)—N(H)—(C-C)alkyl,'}, {'sub': 1', '4, 'oxo-pyrazole optionally substituted by one or more (C-C)alkanoic acid,'}, 'ketone groups,', {'sub': 1', '4', '1', '4, 'pyrazole optionally substituted by one or more (C-C)alkanoic acid or (C-C)alkyl,'}, {'sub': 1', '4, 'pyrrolidine optionally substituted by one or more (C-C)alkanoic acid,'}, 'phenyl,', 'benzyl,', 'oxy-phenyl,', 'oxy-benzyl,', {'sub': 1', '4, 'thiazolidin optionally substituted by one or more (C-C)alkanoic acid,'}, '—C(═O)—N(H)-benzyl,', '—N(H)-quinazolinone,', '—OH,', {'sub': 1', '4, 'thiophenyl optionally substituted ...

CRYSTAL FORM OF 4H-PYRAZOLO[1,5-alpha]BENZOIMIDAZOLE COMPOUND, PREPARATION METHOD THEREOF AND INTERMEDIATE THEREOF

The invention discloses a crystal form A of a compound (I) and a preparation method thereof, and further discloses an application of the crystal form A as a PDE2 or TNF-α inhibitor. 3. A crystal form A of compound (I) according claim 1 , wherein the XRPD pattern of the crystal form A is as shown in .4. A crystal form A of compound (I) according claim 1 , wherein the DSC diagram of the crystal form A is as shown in .5. A crystal form A of compound (I) according claim 1 , wherein the TGA diagram of the crystal form A is as shown in .6. A preparation method of the crystal form A according to claim 1 , comprising dissolving any form of the compound (I) in ester solvent claim 1 , alcoholic solvent claim 1 , acetonitrile claim 1 , acetone or a mixed solvent of the alcoholic solvent with water while heating claim 1 , and then cooling crystallization.7. A preparation method of the crystal form A according to claim 6 , further comprising a step of concentrating the solvent to 1/30-½ of its original volume claim 6 , after the step of dissolving while heating claim 6 , preferably 1/20-⅕.8. A preparation method of the crystal form A according to claim 6 , wherein the weight ratio of the compound (I) to the solvent is selected from 10:1 to 1:1 claim 6 , preferably selected from 6:1 to 3:1 claim 6 , and more preferably selected from 5:1 to 4:1.9. A preparation method of the crystal form A according to claim 6 , wherein the heating temperature is selected from 40° C. to refluxing temperature claim 6 , and preferably selected from 50° C. to 60° C.10. The preparation method of the crystal form A according to claim 6 , wherein the cooling crystallization temperature is selected from 0° C. to 30° C. claim 6 , and preferably selected from 20° C. to 30° C.11. The preparation method of the crystal form A according to claim 6 , wherein the ester solvent is selected from the group consisting of ethyl acetate claim 6 , isopropyl acetate and propyl acetate claim 6 , and preferably selected ...

PREVENTION OR TREATMENT OF URIC ACID OR GOUT DISEASE

The present invention relates to the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutical composition containing the same in reducing uric acid level, preventing or reducing inflammations, and preventing or treating uratic or gouty diseases. In particular, the present invention relates to the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutical composition containing the same in the manufacture of a medicament for the treatment or prevention of hyperuricemia, gout, gouty inflammations, pain and uric acid nephropathy. 114.-. (canceled)16. The compound according to claim 15 , or a pharmaceutically acceptable salt thereof or a solvate thereof claim 15 , wherein{'sub': '1', 'Rrepresents hydrogen or methyl,'}{'sub': '2', 'Rrepresents ethyl, cyclopropylethyl, cyclopropylmethyl, propyl, 2-methylpropyl, butyl, 3-methylbutyl or pentyl, and'}{'sub': '3', 'Rrepresents fluorine or chlorine.'}17. The compound according to claim 15 , or a pharmaceutically acceptable salt thereof or a solvate thereof claim 15 , wherein the compound is selected from the group consisting of:8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-dione,8-chloro-1-methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,8-chloro-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,8-chloro-3-(3-methylbutyl) -3,7-dihydro-1H-purine-2,6-dione,8-chloro-3-(2-cyclopropylethyl)-3,7-dihydro-1H-purine-2,6-dione,8-chloro-3-(2-methylpropyl)-3,7-dihydro-1H-purine-2,6-dione,8-chloro-3-(cyclopropylmethyl)-3,7-dihydro-1H-purine-2,6-dione,8-chloro-1-methyl-3-(3-methylbutyl)-3,7-dihydro-1H-purine-2,6-dione, and8-chloro-1-methyl-3-(2-cyclopropylethyl)-3,7-dihydro-1H-purine-2,6-dione.18. The compound according to claim 15 , or a pharmacologically acceptable salt or a solvate thereof claim 15 , which is a hydrate.19. The compound according to claim 16 , or a ...

SUBSTITUTED XANTHINES AND METHODS OF USE THEREOF

Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5. 2. The method of claim 1 , wherein the TRPC5 mediated disorder is selected from the group consisting of: a neuropsychiatric disorder claim 1 , a neurodegenerative disorder claim 1 , nephropathy claim 1 , and seizure disorder.322-. (canceled)2426-. (canceled)2832-. (canceled) This application is a Continuation of, and claims priority to, U.S. patent application Ser. No. 15/968,941, filed May 2, 2018 (allowed), which is a Continuation of, and claims priority to, U.S. patent application Ser. No. 15/622,838, filed Jun. 14, 2017 (U.S. Pat. No. 9,969,736); which is a Continuation of, and claims priority to, U.S. patent application Ser. No. 15/137,327, filed Apr. 25, 2016 (abandoned); which is a Continuation of, and claims priority to, U.S. patent application Ser. No. 14/210,781, filed Mar. 14, 2014, (U.S. Pat. No. 9,359,359); which claims priority to U.S. Provisional Application No. 61/789,724, filed Mar. 15, 2013 (expired), the contents of which are incorporated herein by reference in its entirety.A variety of ion channel proteins exist to mediate ion flux across cellular membranes. The proper expression and function of ion channel proteins is essential for the maintenance of cell function, intracellular communication, and the like. Numerous diseases are the result of misregulation of membrane potential or aberrant calcium handling. Given the central importance of ion channels in modulating membrane potential and ion flux in cells, identification of agents that can promote or inhibit particular ion channels are of great interest as research tools and as possible therapeutic agents.The present invention provides methods of treating a TRPC5 mediated disorder in a subject, comprising administering to the subject a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein constituent members are provided herein.The present invention ...

SUBSTITUTED XANTHINE DERIVATIVES

This invention relates to novel compounds that are substituted xanthine derivatives and pharmaceutically acceptable salts thereof. For example, this invention relates to novel substituted xanthine derivatives that are derivatives of pentoxifylline. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions for which pentoxifylline and related compounds are beneficial. 2. (canceled)3. The method of claim 1 , wherein Ris —CH.4. The method of claim 1 , wherein Ris —CD.5. The method of claim 1 , wherein Ris —CH.6. The method of claim 1 , wherein Ris —CD.7. (canceled)8. The method of claim 1 , wherein Yis deuterium.9. The method of claim 1 , wherein Yis hydrogen.12. (canceled)13. The method of claim 11 , wherein Ris —CH.14. The method of claim 11 , wherein Ris —CD.15. The method of claim 11 , wherein Ris —CH.16. The method of claim 11 , wherein Ris —CD.17. (canceled)18. The method of claim 11 , wherein Yis deuterium.19. The method of claim 11 , wherein Yis hydrogen.21. The method of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance claim 1 , and the isotopic enrichment factor for each designated deuterium atom is at least 6000.22. The method of claim 11 , wherein any atom not designated as deuterium is present at its natural isotopic abundance claim 11 , and the isotopic enrichment factor for each designated deuterium atom is at least 6000.2329-. (canceled)30. The method of claim 21 , wherein the isotopic enrichment factor for each designated deuterium atom is at least 6333.3.31. The method of claim 22 , wherein the isotopic enrichment factor for each designated deuterium atom is at least 6333.3.3243-. (canceled) This application is a continuation of U.S. patent application Ser. No. 15/291,764, filed Oct. 12, 2016, which is a continuation of U.S. patent application Ser. No. ...

CRYSTALLINE LINAGLIPTIN INTERMEDIATE AND PROCESS FOR PREPARATION OF LINAGLIPTIN

The present invention provides novel crystalline forms B1 & B2 of linagliptin intermediate of structural formula V and methods for production of novel crystalline form of linagliptin intermediate represented by the following structural formula V. 2. The crystalline form B1 of Linagliptin intermediate of formula V claim 1 , of having prominent peaks at 3.14±0.2 claim 1 , 6.31±0.2 claim 1 , 8.34±0.2 claim 1 , 10.93±0.2 claim 1 , 13.75±0.2 & 14.46±0.2 degrees 2θ.3. The crystalline form B1 of Linagliptin intermediate of formula V claim 1 , of having DSC endotherms at 53.87 & 162.97° C.4. The process for preparation of crystalline form B1 of Linagliptin intermediate of formula V claim 1 , of comprising following steps of:a. Heating crude linagliptin intermediate of formula V in a solvent.b. Adding a suitable anti-solvent to the reaction mass of above step at elevated temperature.c. Heating the reaction mass to an elevated temperature.d. Reaction mass was cooled and isolated the crystalline form of Linagliptin intermediate of formula V.5. The process for preparation of claim 4 , wherein solvent is acetonitrile.6. The process for preparation of claim 4 , wherein anti-solvent is water.8. The crystalline form B2 of Linagliptin intermediate of formula V claim 7 , of having prominent peaks at 3.43±0.2 claim 7 , 8.10±0.2 claim 7 , 9.96±0.2 & 17.02±0.2 degrees 2θ.9. The crystalline form B2 of Linagliptin intermediate of formula V claim 7 , of having DSC endotherms at 168.69° C.10. The process for preparation of crystalline form B2 of Linagliptin intermediate of formula V claim 7 , of comprising following steps of:a. Treating crude linagliptin intermediate of formula V with preheated solvent.b. Adding an anti-solvent to the reaction mass of above step.c. Heating the reaction mass to an elevated temperature.d. Reaction mass was cooled and isolated the crystalline form of Linagliptin intermediate of formula V. This application is a continuation of International Application No. PCT/ ...

XANTHINE DERIVATIVES AND USES THEREOF AS INHIBITORS OF BROMODOMAINS OF BET PROTEINS

The present invention relates to a compound having the following formula (I): (I) wherein: —R is a (C-C)alkyl group; —R″ is preferably H; —Ar is a (C-C)arylene radical; —Xis —C(═O)— or —SO—; and —R′ is chosen from the group consisting of possibly substituted (C-C)alkyl, heteroaryl, (C-C)aryl, and (hetero)cycloalkyl groups, or a pharmaceutically acceptable salt and/or tautomeric form thereof, or its racemates, diastereomers or enantiomers 4. The compound of claim 1 , wherein Ar is a phenylene (—CH—) radical.5. The compound of claim 1 , wherein R″ is H.6. The compound of claim 1 , wherein R is methyl or ethyl claim 1 , preferably ethyl.9. The compound of claim 1 , for use as a medicament.10. A pharmaceutical composition claim 1 , comprising a compound according to claim 1 , and also at least one pharmaceutically acceptable excipient.11. The compound of claim 1 , for use in the treatment of cancer claim 1 , inflammatory disease claim 1 , sepsis claim 1 , autoimmune disease claim 1 , neurodegenerative disease claim 1 , cardiovascular disorder claim 1 , renal disorder claim 1 , viral infection claim 1 , or obesity. The present invention concerns xanthine derivatives, their preparation process as well as their uses as inhibitors of bromodomains of BET proteins.Bromodomains (BRD) are protein domains called protein interaction modules that preferentially bind ε-N-acetylated lysine residues through structurally well-defined pockets BRDs are found in 8 protein families which include a total of 46 nuclear or cytoplasmic proteins in human with diverse structures and functions, including chromatin-modifying enzymes, helicases, chromatin remodelers, transcriptional co-activators and mediators, and the bromodomain and extra-terminal domain (BET) family of proteins BET proteins (BRD2, BRD3, BRD4, and the testis-specific BRDT) have a conserved modular architecture including two N-terminal tandem BRDs (BD1 and BD2) The BETs play a central role in chromatin biology by acting as tissue ...

Toll-like receptor 7 (TLR7) agonists having a tricyclic moiety, conjugates thereof, and methods and uses therefor

Compounds having a structure according to formula (I), (II), or (III) where R 1 , R 2 , R 3 , R 5 X 1 , X 2 , and X 3 are as defined herein, are agonists for the Toll-like receptor 7 (TLR7) and can be used as adjuvants for stimulating the immune system. Some such compounds can be used in conjugates for targeted delivery to the organ or tissue of intended action.

Toll-like receptor 7 (tlr7) agonists having a tricyclic moiety, conjugates thereof, and methods and uses therefor

Compounds having a structure according to formula (I), (II), or (III) where R1, R2, R3, R5 X1, X2, and X3 are as defined herein, are agonists for the Toll-like receptor 7 (TLR7) and can be used as adjuvants for stimulating the immune system. Some such compounds can be used in conjugates for targeted delivery to the organ or tissue of intended action.

1-Arylpyrimidine derivatives and their pharmaceutical use

Xanthine derivative

FIELD: chemistry.SUBSTANCE: invention relates to a xanthine derivative of formula (I),formula (I),where R is selected from;Ris selected from methoxycarbonyl; Ris selected from hydrogen and halogen atoms; each of X and Y is independently selected from C or N; n equals 0, 1, 2, 3 or 4, for treating diseases associated with dipeptidyl peptidase IV.EFFECT: disclosed is a xanthine derivative.8 cl, 6 dwg, 7 tbl РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2 709 348 C2 (51) МПК C07D 473/06 (2006.01) A61K 31/522 (2006.01) A61P 3/10 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (52) СПК C07D 473/06 (2019.05); A61K 31/522 (2019.05); A61P 3/10 (2019.05) (21)(22) Заявка: 2017145919, 26.05.2016 (24) Дата начала отсчета срока действия патента: R U 26.05.2016 (72) Автор(ы): ГАО Юйчже (CN), ВАН Гочэн (CN) (73) Патентообладатель(и): ЦЗЯНСУ ТАСЛИ ДИИ ФАРМАСЬЮТИКАЛ КО., ЛТД. (CN) Дата регистрации: 18.12.2019 29.05.2015 CN 201510290336.0 (43) Дата публикации заявки: 02.07.2019 Бюл. № 19 (56) Список документов, цитированных в отчете о поиске: DE 102004008112 A1, 01.09.2005. WO 2010043688 A1, 22.04.2010. EP 2540724 А1, 02.01.2013. WO 2005085246 A1, 15.09.2005. US 7501426 B2, 10.03.2009. EA 13411 B1, 30.04.2010. (45) Опубликовано: 18.12.2019 Бюл. № 35 (85) Дата начала рассмотрения заявки PCT на национальной фазе: 29.12.2017 2 7 0 9 3 4 8 Приоритет(ы): (30) Конвенционный приоритет: CN 2016/083406 (26.05.2016) C 2 C 2 (86) Заявка PCT: (87) Публикация заявки PCT: Адрес для переписки: 123242, Москва, пл. Кудринская, д. 1, а/я 35, "Михайлюк, Сороколат и партнеры патентные поверенные" (54) ПРОИЗВОДНОЕ КСАНТИНА (57) Реферат: Изобретение относится к производному ксантина, представленному формулой (I), R выбран из R U 2 7 0 9 3 4 8 WO 2016/192559 (08.12.2016) ; R1 выбран из метоксикарбонила; R2 выбран из водорода и атомов галогена; каждый из X и Y независимо выбран из C или N; n равняется 0, 1, формула (I), где Стр.: 1 2, 3 или 4, для лечения ...

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ВУ” 2017145919” АЗ Дата публикации: 09.08.2019 Форма № 18 ИЗ,ПМ-2011 Федеральная служба по интеллектуальной собственности Федеральное государственное бюджетное учреждение ж 5 «Федеральный институт промышленной собственности» (ФИПС) ОТЧЕТ О ПОИСКЕ 1. . ИДЕНТИФИКАЦИЯ ЗАЯВКИ Регистрационный номер Дата подачи 2017145919/04(078570) 26.05.2016 РСТ/СМ№2016/083406 26.05.2016 Приоритет установлен по дате: [ ] подачи заявки [ ] поступления дополнительных материалов от к ранее поданной заявке № [ ] приоритета по первоначальной заявке № из которой данная заявка выделена [ ] подачи первоначальной заявки № из которой данная заявка выделена [ ] подачи ранее поданной заявки № [Х] подачи первой(ых) заявки(ок) в государстве-участнике Парижской конвенции (31) Номер первой(ых) заявки(ок) (32) Дата подачи первой(ых) заявки(ок) (33) Код страны 1. 201510290336.0 29.05.2015 СМ Название изобретения (полезной модели): [Х] - как заявлено; [ ] - уточненное (см. Примечания) ПРОИЗВОДНОЕ КСАНТИНА Заявитель: ЦЗЯНСУ ТАСЛИ ДИИ ФАРМАСЬЮТИКАЛ КО., ЛТД., СМ 2. ЕДИНСТВО ИЗОБРЕТЕНИЯ [Х] соблюдено [ ] не соблюдено. Пояснения: см. Примечания 3. ФОРМУЛА ИЗОБРЕТЕНИЯ: [Х] приняты во внимание все пункты (см. п см. Примечания [ ] приняты во внимание следующие пункты: р [ ] принята во внимание измененная формула изобретения (см. Примечания) 4. КЛАССИФИКАЦИЯ ОБЪЕКТА ИЗОБРЕТЕНИЯ (ПОЛЕЗНОЙ МОДЕЛИ) (Указываются индексы МПК и индикатор текущей версии) (070 473/06 (2006.01) 5. ОБЛАСТЬ ПОИСКА 5.1 Проверенный минимум документации РСТ (указывается индексами МПК) С07р 473/06, Аб1КЗ1/522, Аб1РЗ/10 5.2 Другая проверенная документация в той мере, в какой она включена в поисковые подборки: 5.3 Электронные базы данных, использованные при поиске (название базы, и если, возможно, поисковые термины): РУ\УР1, ЕАРАТТУ, Езрасепе, боозе, РАТЕМТСОРЕ, РаеагсВ, РиБСвет, эСОРОЪ, Уапаех 6. ДОКУМЕНТЫ, ОТНОСЯЩИЕСЯ К ПРЕДМЕТУ ПОИСКА Кате- Наименование документа с указанием (где необходимо) частей, Относится к гория* относящихся к предмету ...

利格列汀新晶型及其制备方法

本发明涉及利格列汀的一种新晶型，也涉及制备该新晶型的方法。本发明的利格列汀新晶型通过常规手段制备，具有良好的结晶纯度及物理化学稳定性，生产操作简单，易于商业化。

Xanthine derivatives as selective hm74a agonists

本发明涉及为黄嘌呤衍生物的式(I)化合物，制备所述衍生物的方法，含有所述化合物的药物制剂以及所述化合物在治疗、例如在治疗由HM74A受体激活不足所引起的疾病或者受益于激活HM74A受体的疾病中的用途。

TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS HAVING A TRICYCLIC GROUP, CONJUGATES THEREOF, AND METHODS AND USES THEREOF

Substituted with sulfamides xantine derivatives for application as phosphoenolpyruvatcarboxykinase (pepck) inhibitors

Настоящее изобретение относится к замещенным сульфамидами производным ксантина формулы I или к их фармацевтически приемлемым солям, где R 1 , R 2 и R 3 являются такими, как приведено в описании изобретения. Соединения формулы (I) и их фармацевтически приемлемые соли проявляют активность в качестве модуляторов глюконеогенеза и могут использоваться для получения фармацевтических композиций, которые могут быть полезны для лечения диабета типа 2. 2 н. и 33 з.п. ф-лы, 1 табл. ÐÎÑÑÈÉÑÊÀß ÔÅÄÅÐÀÖÈß (19) RU (11) 2 340 613 (13) C2 (51) ÌÏÊ C07D 473/04 (2006.01) A61K 31/52 (2006.01) A61P 3/10 (2006.01) C07D 473/06 (2006.01) ÔÅÄÅÐÀËÜÍÀß ÑËÓÆÁÀ ÏÎ ÈÍÒÅËËÅÊÒÓÀËÜÍÎÉ ÑÎÁÑÒÂÅÍÍÎÑÒÈ, ÏÀÒÅÍÒÀÌ È ÒÎÂÀÐÍÛÌ ÇÍÀÊÀÌ (12) ÎÏÈÑÀÍÈÅ ÈÇÎÁÐÅÒÅÍÈß Ê ÏÀÒÅÍÒÓ (21), (22) Çà âêà: 2005128833/04, 12.02.2004 (24) Äàòà íà÷àëà îòñ÷åòà ñðîêà äåéñòâè ïàòåíòà: 12.02.2004 (30) Êîíâåíöèîííûé ïðèîðèòåò: 19.02.2003 US 60/448,562 (73) Ïàòåíòîîáëàäàòåëü(è): Ô.ÕÎÔÔÌÀÍÍ-Ëß ÐÎØ Àà (CH) (43) Äàòà ïóáëèêàöèè çà âêè: 27.07.2006 R U (72) Àâòîð(û): ÔÎÓËÈ Ëóèñà Õåëåí (US), ÕÜÞÁÈ Íèêîëàñ Äæîí Ñèëâåñòåð (US), ÏÈÒÐÀÍÈÊÎ-ÊÎÓË Øåððè Ëèíí (US), ÞÍÜ Âý (US), ÄÀÍÒÅÍ Ïèò Óèëëü ì (US) (45) Îïóáëèêîâàíî: 10.12.2008 Áþë. ¹ 34 2 3 4 0 6 1 3 (56) Ñïèñîê äîêóìåíòîâ, öèòèðîâàííûõ â îò÷åòå î ïîèñêå: RU 95109100 A1, 10.03.1995. WO 01/77110 A1, 18.10.2001. EP 0956855 A1, 24.04.1998. (85) Äàòà ïåðåâîäà çà âêè PCT íà íàöèîíàëüíóþ ôàçó: 19.09.2005 2 3 4 0 6 1 3 R U (87) Ïóáëèêàöè PCT: WO 2004/074288 (02.09.2004) C 2 C 2 (86) Çà âêà PCT: EP 2004/001289 (12.02.2004) Àäðåñ äë ïåðåïèñêè: 101000, Ìîñêâà, Ì.Çëàòîóñòèíñêèé ïåð., 10, êâ.15, "ÅÂÐÎÌÀÐÊÏÀÒ", ïàò.ïîâ. È.À.Âåñåëèöêîé, ðåã. ¹ 11 (54) ÇÀÌÅÙÅÍÍÛÅ ÑÓËÜÔÀÌÈÄÀÌÈ ÏÐÎÈÇÂÎÄÍÛÅ ÊÑÀÍÒÈÍÀ ÄËß ÏÐÈÌÅÍÅÍÈß Â ÊÀ×ÅÑÒÂÅ ÈÍÃÈÁÈÒÎÐΠÔÎÑÔÎÅÍÎËÏÈÐÓÂÀÒÊÀÐÁÎÊÑÈÊÈÍÀÇÛ (ÐÅÐÑÊ) (57) Ðåôåðàò: Íàñòî ùåå èçîáðåòåíèå îòíîñèòñ ê çàìåùåííûì ñóëüôàìèäàìè ïðîèçâîäíûì êñàíòèíà ôîðìóëû I èëè ê èõ ôàðìàöåâòè÷åñêè ïðèåìëåìûì ñîë ì, ãäå R 1, R 2 è R 3 âë þòñ òàêèìè, êàê ïðèâåäåíî â îïèñàíèè èçîáðåòåíè . Ñîåäèíåíè ôîðìóëû (I) è ...

DERIVATIVE XANTHINE

РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2017 145 919 A (51) МПК C07D 473/06 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ЗАЯВКА НА ИЗОБРЕТЕНИЕ (21)(22) Заявка: 2017145919, 26.05.2016 (71) Заявитель(и): ЦЗЯНСУ ТАСЛИ ДИИ ФАРМАСЬЮТИКАЛ КО., ЛТД. (CN) Приоритет(ы): (30) Конвенционный приоритет: 29.05.2015 CN 201510290336.0 (85) Дата начала рассмотрения заявки PCT на национальной фазе: 29.12.2017 R U (43) Дата публикации заявки: 02.07.2019 Бюл. № 19 (72) Автор(ы): ГАО Юйчже (CN), ВАН Гочэн (CN) (86) Заявка PCT: (87) Публикация заявки PCT: WO 2016/192559 (08.12.2016) A Адрес для переписки: 123242, Москва, пл. Кудринская, д. 1, а/я 35, "Михайлюк, Сороколат и партнеры патентные поверенные" (57) Формула изобретения 1. Производное ксантина, представленное формулой I, и его сольваты или их фармацевтически приемлемые соли, A формула I, где R U 2 0 1 7 1 4 5 9 1 9 (54) ПРОИЗВОДНОЕ КСАНТИНА 2 0 1 7 1 4 5 9 1 9 CN 2016/083406 (26.05.2016) R выбран из ; Стр.: 1 R1 выбран из циано или метоксикарбонила; R2 выбран из водорода, атомов галогена, линейной или разветвленной C1-6алкильной группы, которая является замещенной или незамещенной 1-5 атомами галогена, линейной или разветвленной C1-6алкоксигруппы, которая является замещенной или незамещенной 1-5 атомами галогена; каждый из X и Y независимо выбран из C или N; n равняется 0, 1, 2, 3 или 4. 2. Производные ксантина и их сольваты или их фармацевтически приемлемые соли по п. 1, где R2 выбран из водорода, атомов галогена, метила, этила, изопропила, метоки, этокси, трифторметила или трифторметокси; n равняется 0, 1 или 2. 3. Производные ксантина и их сольваты или их фармацевтически приемлемые соли по п. 2, где R2 выбран из водорода, атома хлора, атома фтора, атома брома, метила или метокси. 4. Производные ксантина и их сольваты или их фармацевтически приемлемые соли 2 0 1 7 1 4 5 9 1 9 A I-1, или I-2, или A 2 0 1 7 1 4 5 9 1 9 R U по п. 3, где R2 выбран из водорода или атома фтора. 5. Производные ксантина и их ...

Crystalline form of linagliptin and preparation method thereof

본 발명은 리나글립틴 결정형 및 이의 제조방법에 관한 것으로서, 본 발명에 따른 리나글립틴 결정형은 열안정성이 우수하고 단일 결정형으로 재현성 있게 제조할 수 있을 뿐만 아니라 이로 인하여 일정한 품질로 대량 생산이 가능하므로 당뇨병 치료용 약학 조성물로 유용하게 사용할 수 있다. The present invention relates to a linagliptin crystalline form and a method for producing the same, and the linagliptin crystalline form according to the present invention has excellent thermal stability and can be reproducibly prepared as a single crystalline form, and thus can be mass-produced with a constant quality. It can be usefully used as a pharmaceutical composition for the treatment of diabetes.

Synthesis method of linagliptin intermediate

本发明公开了一种利格列汀中间体的合成方法，包括以下步骤：将1‑[(4‑甲基喹唑啉‑2‑基)甲基]‑3‑甲基‑7‑(2‑丁炔‑1‑基)‑8‑溴黄嘌呤(e)、(R)‑3‑Boc‑氨基哌啶(f)、碳酸钾和乙腈加入反应器内并混合均匀，在加热回流的状态下进行反应，反应温度80～85℃，反应24～48h，1‑[(4‑甲基喹唑啉‑2‑基)甲基]‑3‑甲基‑7‑(2‑丁炔‑1‑基)‑8‑溴黄嘌呤(e)、(R)‑3‑Boc‑氨基哌啶(f)、碳酸钾的摩尔比为1:(1.2～1.6):(3～7)，1‑[(4‑甲基喹唑啉‑2‑基)甲基]‑3‑甲基‑7‑(2‑丁炔‑1‑基)‑8‑溴黄嘌呤(e)与和乙腈的比例为100:(400～1000)g/ml。本发明的中间体(g)的合成方法，切实避免了脱溴杂质(i)的产生，而且在后处理步骤中简单易行，解决了该中间体在溶剂中因不易析出而纯化分离困难的问题。

Xanthic derivative

FIELD: pharmacology. SUBSTANCE: invention relates to the mixtures represented by the general formula or to its pharmaceutically acceptable salts that are able to find an application in treatment of the diseases related to dipeptidyl peptidase IV. In the formula I R1 is selected from the hydrogen atom, the fluorine atom, the chlorine atom, the bromine atom, the iodine atom or the cyano group. The invention also relates to the mentioned mixtures production process and to its application in obtaining the therapeutic agent for the connected to dipeptidyl peptidase IV diseases treatment. EFFECT: compound application efficiency upgrading. 12 cl, 4 tbl, 8 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2 635 109 C2 (51) МПК C07D 473/04 (2006.01) C07D 473/06 (2006.01) A61K 31/522 (2006.01) A61P 3/10 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (21)(22) Заявка: 2015101339, 15.05.2013 (24) Дата начала отсчета срока действия патента: 15.05.2013 Дата регистрации: Приоритет(ы): (30) Конвенционный приоритет: 20.06.2012 CN 201210205678.4 (85) Дата начала рассмотрения заявки PCT на национальной фазе: 20.01.2015 (56) Список документов, цитированных в отчете о поиске: WO 02/068420 A1, 06.09.2002. WO (43) Дата публикации заявки: 10.08.2016 Бюл. № 22 2004/018468 A2, 04.03.2004. US 2007/0197563 A1, 23.08.2007. RU 2003103103 A, 20.08.2004. (86) Заявка PCT: CN 2013/075627 (15.05.2013) (87) Публикация заявки PCT: 2 6 3 5 1 0 9 (45) Опубликовано: 09.11.2017 Бюл. № 31 (73) Патентообладатель(и): ЧЭНДУ ИСТОН БИОФАРМАСЬЮТИКАЛС КО., ЛТД. (CN) R U 09.11.2017 (72) Автор(ы): ВАН Ин (CN), СЯН Юнчжэ (CN), ЦЭНЬ Годун (CN), ХУАН Лун (CN), ЛЮ Цзян (CN), ЧЖОУ Нин (CN), ЧЖАН Цзибин (CN) 2 6 3 5 1 0 9 R U C 2 C 2 WO 2013/189219 (27.12.2013) Адрес для переписки: 123242, Москва, Кудринская площадь, 1, а/я 35, "Михайлюк, Сороколат и партнеры-патентные поверенные" (54) КСАНТИНОВОЕ ПРОИЗВОДНОЕ (57) Реферат: Изобретение относится к соединениям, представленным общей ...

Method for producing amorphous linagliptin

The present invention relates to a process for the preparation of a pharmaceutical composition comprising the steps of: A) dissolving crystalline lignagliptin or polymorphinagliptin in an organic solvent selected from tetrahydrofuran, chloroform and dichloromethane; B) cooling the solution to 50-70 < 0 > C, slowly dropping the purified water while maintaining the temperature; C) slowly cooling the solution to 0-10 < 0 > C and aging; D) filtering the solution, washing it with purified water, and drying the solution, thereby providing a method for producing amorphous linagliptin. The present invention also relates to a method for preparing a pharmaceutical composition comprising the steps of: A) dissolving crystalline lignagliptin or polymorphinagliptin in purified water together with citric acid hydrate; B) cooling the solution to 5-15 [deg.] C and slowly dropwise adding aqueous sodium hydroxide solution; C) aging the solution at 0-15 [deg.] C; D) filtering the solution, washing it with purified water, and drying the solution, thereby providing a method for producing amorphous linagliptin.

AMIDO SUBSTITUTED Xanthine derivatives possessing modulatory activity in relation to glucose biosynthesis from non-carbohydrate substrates

ÐÎÑÑÈÉÑÊÀß ÔÅÄÅÐÀÖÈß (19) RU (51) ÌÏÊ 7 (11) 2005 100 761 (13) A C 07 D 473/02, A 61 K 31/52 ÔÅÄÅÐÀËÜÍÀß ÑËÓÆÁÀ ÏÎ ÈÍÒÅËËÅÊÒÓÀËÜÍÎÉ ÑÎÁÑÒÂÅÍÍÎÑÒÈ, ÏÀÒÅÍÒÀÌ È ÒÎÂÀÐÍÛÌ ÇÍÀÊÀÌ (12) ÇÀßÂÊÀ ÍÀ ÈÇÎÁÐÅÒÅÍÈÅ (21), (22) Çà âêà: 2005100761/04, 05.06.2003 (71) Çà âèòåëü(è): Ô.ÕÎÔÔÌÀÍÍ-Ëß ÐÎØ Àà (CH) (30) Ïðèîðèòåò: 12.06.2002 US 60/388,164 (43) Äàòà ïóáëèêàöèè çà âêè: 10.09.2005 Áþë. ¹ 25 (86) Çà âêà PCT: EP 03/05922 (05.06.2003) (87) Ïóáëèêàöè PCT: WO 03/106459 (24.12.2003) Àäðåñ äë ïåðåïèñêè: 101000, Ìîñêâà, Ì.Çëàòîóñòèíñêèé ïåð., ä.10, êâ.15, "ÅÂÐÎÌÀÐÊÏÀÒ", È.À.Âåñåëèöêîé A (54) ÀÌÈÄÇÀÌÅÙÅÍÍÛÅ ÏÐÎÈÇÂÎÄÍÛÅ ÊÑÀÍÒÈÍÀ, ÎÁËÀÄÀÞÙÈÅ ÌÎÄÓËßÒÎÐÍÎÉ ÀÊÒÈÂÍÎÑÒÜÞ Â ÎÒÍÎØÅÍÈÈ ÁÈÎÑÈÍÒÅÇÀ ÃËÞÊÎÇÛ ÈÇ ÍÅÓÃËÅÂÎÄÍÛÕ ÑÓÁÑÒÐÀÒΠÔîðìóëà èçîáðåòåíè R U A 2 0 0 5 1 0 0 7 6 1 1. Ñîåäèíåíèå ôîðìóëû â êîòîðîì R 1 âûáðàí èç ãðóïïû, ñîäåðæàùåé (íèçø.)àëêåíèë, (íèçø.)àëêèíèë, (íèçø.)àëêåíèë, çàìåùåííûé ãàëîãåíîì, ôåíèë è ôåíèë, çàìåùåííûé îäíèì èëè äâóì çàìåñòèòåë ìè, íåçàâèñèìî âûáðàííûìè èç ãðóïïû, ñîäåðæàùåé ãàëîãåí, ãèäðîêñè, (íèçø.)àëêîêñèãðóïïó, íèòðîãðóïïó, àìèíîãðóïïó è 5- èëè 6-÷ëåííîå àðîìàòè÷åñêîå ãåòåðîöèêëè÷åñêîå êîëüöî, èìåþùåå 1, 2, 3 èëè 4 àòîìà àçîòà, ïðèñîåäèíåííîå ê ôåíèëó ïîñðåäñòâîì àòîìà óãëåðîäà êîëüöà; R 2 âûáðàí èç ãðóïïû, ñîäåðæàùåé íåçàìåùåííûé (íèçø.)àëêèë, (íèçø.)àëêèë, çàìåùåííûé (íèçø.)àëêîêñèãðóïïîé èëè ãèäðîêñè, (íèçø.)àëêåíèë, Ñòðàíèöà: 1 RU 2 0 0 5 1 0 0 7 6 1 (74) Ïàòåíòíûé ïîâåðåííûé: Âåñåëèöêà Èðèíà Àëåêñàíäðîâíà R U (85) Äàòà ïåðåâîäà çà âêè PCT íà íàöèîíàëüíóþ ôàçó: 12.01.2005 (72) Àâòîð(û): Ïèò Óèëëü ì ÄÀÍÒÅÍ (US), Ëóèñà Õåëåí ÔÎÓËÈ (US), Íèêîëàñ Äæîí Ñèëâåñòåð ÕÜÞÁÈ (US), Øåððè Ëèíí ÏÈÒÐÀÍÈÊÎ-ÊÎÓË (US), Âåé ÞÍÜ (US) ôåíèë, -(ÑÍ2)n- íåçàìåùåííûé (íèçø.)öèêëîàëêèë è -(ÑÍ2)n- (íèçø.)öèêëîàëêèë, çàìåùåííûé ïî ìåíüøåé ìåðå îäíèì çàìåñòèòåëåì, âûáðàííûì èç ãðóïïû, ñîäåðæàùåé êàðáîêñèãðóïïó, (íèçø.)àëêèë, êàðáîêñè-(íèçø.)àëêèë è (íèçø.)àëêèë, çàìåùåííûé ãèäðîêñè, -(CH2)n-C(O)R 6, ãäå R 6 âûáðàí èç ãðóïïû, ñîäåðæàùåé ãèäðîêñèë, (íèçø.)àëêîêñèãðóïïó, -NHR ñ, è ãäå R ñ ...

Sulfonamide substituted xanthine derivatives for use as pepck inhibitors

본 발명은 하기 화학식 I의 설폰아마이드 치환된 크산틴 유도체 또는 이들의 약학적으로 허용가능한 염 또는 전구체에 관한 것이다: 화학식 I 상기 식에서, R 1 , R 2 및 R 3 은 본원의 명세서에 정의되어 있다. 화학식 I의 화합물 및 이들의 약학적으로 허용가능한 염 또는 전구체는 글루코즈 신합성의 조절자로서 활성을 나타낸다.

Method of synthesis of 3,7-dialkylxanthines

FIELD: organic chemistry. SUBSTANCE: 3,7-dialkylxanthines are synthesized by alkylation of the corresponding 3-alkylxanthines in two-phase mixture in the presence of quaternary, ammonium and/or phosphonic base and linear simple polyester. Synthesized compounds are used in medicine as intermedium substances for synthesis of drugs. EFFECT: high yields and purity of compounds. 8 cl, 6 ex ДУЗУЬЕГС ПЧ Го РОССИЙСКОЕ АГЕНТСТВО ПО ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ (19) ВИ” 2114 847‘ 13) СЛ ОМК © 070 473/10, 473/06 12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ РОССИЙСКОЙ ФЕДЕРАЦИИ (21), (22) Заявка: 93050206/04, 09.11.1993 (30) Приоритет: 10.11.1992 ОЕ Р 42 37 814.1 (46) Дата публикации: 10.07.1998 (56) Ссылки: СЗ, патент 267796, кл. С 07 О 473/06, 1990. (71) Заявитель: Хехст АГ (0Е) (72) Изобретатель: Герхард Корб (0Е), Ханс-Вольфрам Флемминг (0Е) (73) Патентообладатель: Хехст АГ (0Е) (54) СПОСОБ ПОЛУЧЕНИЯ 3,7-ДИАЛКИЛКСАНТИНОВ (57) Реферат: Использование: в медицине в качестве промежуточных продуктов для получения лекарственных средств. Сущность: получение 3,/-диалкилксантинов алкилированием соответствующих 3-алкилксантинов В двухфазной смеси в присутствии основания, четвертичного аммониевого и/или фосфониевого соединения и линейного простого полиэфира. Целевые соединения получают с очень высокими выходами с высокой степенью чистоты. 8 з.п. ф-лы. 2114847 С1 КО ДУЗУЬЕГС ПЧ Го КУЗЗАМ АСЕМСУ ГОК РАТЕМТ$ АМО ТКАОЕМАКК$ (19) КО 2 114 847” С1 (51) 1. СИ. с 07 р 473/10, 473/06 12) АВЗТКАСТ ОЕ 1МУЕМТОМ (21), (22) АррИсаНоп: 93050206/04, 09.11.1993 (71) АррисапЕ (30) РПошу: 10.11.1992 ОЕ Р 42 37 814.1 (46) Рае о! рибИсаНоп: 10.07.1998 Кпекиз{ АС (ОЕ) (72) пуетог. — Сегквага КогЬ (ОЕ), КПап5-МоЧтат Неттта (ОЕ) (73) Ргорпеюг: Кпекл${ Ас (ОЕ) (54) МЕТНОО ОЕ ЗУМТНЕ$!$ ОР 3,7-СЛАЕКУЕХАМТНМЕЗ$ (57) АБзГасЕ: НЕГО: огдапс спептгу. ЗОВЗТАМСЕ: 3, /-Чакухаттез$ аге зупПезгхеа Бу а!куаНоп ог {фе согезропЯта 3-аКухатптез$ ш &мо-рпазе пихшге шт Ше ргезепсе ог дицаегагу, аттопшит апа/ог рпозрпопс Базе апа Шпеаг ...

Riagliptin intermediate compound IV

本发明属于医药化工领域，本发明公开了利格列汀中间体Ⅳ ，及利用利格列汀中间体Ⅳ合成利格列汀重要中间体的新路线

1-arylpyrimidine derivatives and pharmaceutical use thereof

The present invention relates to 1-arylpyrimidine derivatives represented by general formula (I): ##STR1## wherein R 1 is H, alkyl or aralkyl; Ar is 1-naphthyl, or a substituted or unsubstituted phenyl group; R 4 is a substituted phenyl, a substituted styryl, 1-methylcyclohexyl, 4-methylcyclohexyl, 4-oxo-4H-pyran-2-yl or 2-oxo-2H-pyran-5-yl group; R 5 and R 6 are each independently H or alkyl; R 3 is H, and R 7 and R 8 are combined together to be oxo, or else R 3 and R 7 are combined together to be another direct bond, and R 5 and R 8 are combined together to be a direct bond, or pharmaceutically acceptable salts thereof; and methods for treating allergic diseases with such compounds.

Preparation method of linagliptin intermediate

本发明提出了一种利格列汀中间体的制备方法，包括如下步骤：(1)将2‑溴‑4‑甲基咪唑、N‑甲基脲与氧化剂反应得到化合物Ⅱ；(2)在碱存在下，化合物Ⅱ与溴源反应得到化合物Ⅲ；(3)在碱存在下，化合物Ⅲ与1‑溴‑2‑丁炔反应得到化合物Ⅳ，即利格列汀关键中间体。本发明方法具有起始原料便宜易得、步骤简化、原子利用率高、反应条件温和、产率高和适合工业化生产等优点。

NOVEL XANTHINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Adenosine receptor prodrugs

A functionalized congener approach to drugs acting at A1 and A2 adenosine receptor types is applicable to prodrug design. The prodrugs affect a more efficient delivery of the drug at the particular site of the body affected and take advantage of selective biochemical cleavages and alteration in distribution characteristics. In particular, kidney functions and lipid functions are stressed in the invention.

Purine derivatives and their use as anti-coagulants

This invention is directed to purine derivatives of the following formulae: ##STR1## wherein Z 1 is --O--, --N(R 10 )-- or --CH 2 O--; Z 2 is --O--, --N(R 10 )-- or --OCH 2 --; R 1 and R 4 are each independently hydrogen, halo, alkyl, --OR 10 , --C(O)OR 10 , --C(O)N(R 10 )R 11 , --N(R 10 )R 11 , --N(R 10 )C(O)R 10 , or --N(H)S(O) 2 R 13 ; R 2 is --C(NH)NH 2 , --C(NH)N(H)OR 10 , --C(NH)N(H)C(O)OR 13 , --C(NH)N(H)C(O)R 10 , --C(NH)N(H)S(O) 2 R 13 , or --C(NH)N(H)C(O)N(H)R 10 ; R 3 is halo, alkyl, haloalkyl, haloalkoxy, ureido, cyano, guanidino, --OR 10 , --C(NH)NH 2 , --C(NH)N(H)OR 10 , --C(O)N(R 10 )R 11 , --R 12 --C(O)N(R 10 )R 11 , --CH(OH)C(O)N(R 10 )R 11 , --N(R 10 )R 11 , --R 12 --N(R 10 )R 11 , --C(O)OR 10 , --R 12 --C(O)OR 10 , --N(R 10 )C(O)R 10 , (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl); R 5 is hydrogen, halo, alkyl, cycloalkyl, haloakyl, aryl, aralkyl, alkylthio, hydroxy, mercapto, alkoxy, or --N(R 10 )R 11 ; and R 6 is defined herein. These compounds are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.

New 8-(3-amino-piperidin-1-yl)-xanthine derivatives are dipeptidylpeptidase-IV inhibitors useful for, e.g. treating diabetes mellitus, arthritis or obesity

8-(3-amino-piperidin-1-yl)-xanthine derivatives (I) are new. 8-(3-amino-piperidin-1-yl)-xanthine derivatives of formula (I) and their tautomers, enantiomers, diastereomers (or mixtures), prodrugs and salts are new. R1 = CH2Q1, CH2CH2OMe, CH2CH2OPh, CH2CH2CN, CH2COPh or CHMeCOPh, phenylcarbonylmethyl mono-substituted in the ring by Q2 or phenylcarbonylmethyl substituted in the ring by two OMe groups or on two adjacent C-atoms by OCH2O, OCH2CH2O or N(Me)COO; Q1 = CONMe2, heterocycle or heteroaryl (optionally substituted); Q2 = NH2, NHCH2CN, NHCOMe, NHCOEt, NHCOCHMe2, NHCOOMe, NHCONHCOOEt, 2-oxo-imidazolin-1-yl, COOH, COMe, COOEt, CONH2, CONHMe, CONMe2, morpholinocarbonyl, SMe, SOMe, SO2Me, OCH2COOH, OCH2COOEt, OCH2COOCHMe2, OCH2CONH2, OCH2CONHMe, OCH2CONHEt, OCH2CONHCHMe2, OCH2CONMe2, pyrrolidinocarbonyl-methoxy, morpholinocarbonyl-methoxy, OCHMeCOOEt, OCHMeCONH2 or OCH2SOMe; R2 = Me, CHMe2 or Ph, and R3 = CH2C(Me)=CH2, CH2C(Cl)=CH2, CH2CH=CHBr, CH2CH=CHMe, CH2C(Me)=CMe2, CH2CCMe, 1-cyclopenten-1-ylmethyl or 2-furanylmethyl. An Independent claim is included for the preparation of (I).

Hemisuccinate salts of heterocyclic dpp-iv inhibitors

The method for transformation of a kind of dimer

本发明涉及一种利格列汀的二聚体转化为利格列汀的方法，通过将二聚体在pH不低于8的碱性条件下，在碱作用下，可转化为产物利格列汀，除去了杂质，提高了收率，工艺简单，降低了生产成本，有利于工业化生产。

A kind of Li Gelieting preparation method

本发明属于原料药制备技术领域，具体涉及利格列汀的制备方法改进。本发明提供了一种利格列汀的制备方法，在利格列汀两步缩合反应中将用到的缚酸剂无水碳酸钠控制粒径为微米级，反应无需使用碘化物催化剂，同样使反应温度降低，反应时间缩短，并且将两步反应改为“一锅法”制备得到纯度高、产率高的关键中间体E化合物。本发明的制备方法适合利格列汀的工业化大生产，并且最终得到高纯度、高得率的利格列汀。

Xanthine Derivative

1. Формула изобретенияСоединение, представленное общей формулой I, или его фармацевтически приемлемая соль,,где Rвыбран из атома водорода, атома фтора, атома хлора, атома брома, атома йода или цианогруппы.2. Соединение или его фармацевтически приемлемая соль по п. 1, где Rпредставляет собой заместитель в положении 5 (1,3-бензотиазол-2-ил)метила.3. Соединение или его фармацевтически приемлемая соль по п. 1 или п. 2, где Rвыбран из атома водорода, атома фтора или атома хлора.4. Соединение или его фармацевтически приемлемая соль по п. 1, где соединение выбрано из.5. Соединение или его фармацевтически приемлемая соль по п. 1, где соединение выбрано из.6. Соединение или его фармацевтически приемлемая соль по п. 1, где соединение выбрано из.7. Соединение или его фармацевтически приемлемая соль по п. 1, где фармацевтически приемлемая соль образована соединением и кислотой, выбранной из соляной кислоты, п-толуолсульфоновой кислоты, винной кислоты, малеиновой кислоты, молочной кислоты, метансульфоновой кислоты, серной кислоты, фосфорной кислоты, лимонной кислоты, уксусной кислоты или трифторуксусной кислоты.8. Соединение или его фармацевтически приемлемая соль по п. 7, где кислота представляет собой п-толуолсульфоновую кислоту, соляную кислоту, винную кислоту или трифторуксусную кислоту.9. Соединение или его фармацевтически приемлемая соль по п. 1, где соединение или его фармацевтически приемлемые соли представляют собой:1-[(5-фтор-1,3-бензотиазол-2-ил)метил]-3-метил-7-(2-бутин-1-ил)-8-[(R)-3-амино-пиперидин-1-ил]-ксантин;1-[(1,3-бензотиазол-2-ил)метил]-3-метил-7-(2-бутин-1-ил)-8-[(R)-3- РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (51) МПК C07D 473/04 (13) 2015 101 339 A (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ЗАЯВКА НА ИЗОБРЕТЕНИЕ (21)(22) Заявка: 2015101339, 15.05.2013 (71) Заявитель(и): ЧЭНДУ ИСТОН ФАРМАСЬЮТИКАЛ КО., ЛТД. (CN) Приоритет(ы): (30) Конвенционный приоритет: 20.06.2012 CN 201210205678.4 (85) Дата начала рассмотрения заявки PCT на национальной ...

Preparation method of important intermediate of linagliptin

本发明公开了一种利拉列汀重要中间体的改进制备方法。具体地，公开了具有如下结构的化合物V(利拉列汀重要中间体)的制备方法，进而由化合物V工业化制备具有极佳的化学和光学纯度的二肽基肽酶-4(DPP-IV)抑制剂利拉列汀。所述方法中采用相转移催化剂，产率高、操作简便、环境友好、适用于工业化大规模生产，并可采用“一锅法”实施。

Xanthine derivative

The present invention discloses a xanthine derivative having the structure of the following general formula (I) or a pharmaceutically acceptable salt thereof; further discloses a preparation method for the xanthine derivative or a pharmaceutically acceptable salt thereof; and further discloses the use of the xanthine derivative or a pharmaceutically acceptable salt thereof. Through experiments of DPP-IV activity inhibition experiments in vitro, impact on glucose tolerance in normal mice and impact on blood glucose in spontaneous diabetic mice, it proves that the compounds and pharmaceutically acceptable salts thereof show good DPP-IV inhibition activity, can be applied to prepare medicines for treating dipeptidyl peptidase IV-related diseases, and more particularly, can be applied to the use of medicines for treating type II diabetes or diseases of abnormal glucose tolerance.

NOVEL XANTHIN DERIVATIVES, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAME

NOUVEAUX DERIVES DE LA XANTHINE UTILISABLES COMME MEDICAMENTS, ET REPONDANT A LA FORMULE: (CF DESSIN DANS BOPI) DANS LAQUELLE: R EST HYDROGENE OU ALCOYLE DE C A C; R EST HYDROGENE OU ALCOYLE DE C A C COMPORTANT EVENTUELLEMENT UNE DOUBLE LIAISON, OU BENZYLE; R EST HYDROGENE OU METHYLE; A EST -(CH)- (N ETANT UN NOMBRE ENTIER DE 1 A 4) EVENTUELLEMENT SUBSTITUE, LORSQUE N EST SUPERIEUR A 1, POUR UN HYDROXYLE; X EST UN NEW XANTHINE DERIVATIVES FOR USE AS MEDICINAL PRODUCTS, AND RESPONDING TO THE FORMULA: (CF DRAWING IN BOPI) IN WHICH: R IS HYDROGEN OR ALCOHOL OF C TO C; R IS HYDROGEN OR ALCOYL OF C A C POSSIBLE A DOUBLE BOND, OR BENZYL; R IS HYDROGEN OR METHYL; A IS - (CH) - (N BEING AN INTEGER FROM 1 TO 4) POSSIBLY SUBSTITUTED, WHEN N IS GREATER THAN 1, FOR A HYDROXYL; X IS A

Improvements in processes for manufacturing oxyalkylxanthines

Acylacetylaminobenzene compounds containing sulfonic groups and process for their preparation

Patent FR2081573B2

Process for preparing xanthine

Improvements in diuretic acting xanthine derivatives

The invention comprises substituted xanthines of the general formula <FORM:0759174/IV(a)/1> wherein X represents oxygen or sulphur, Alk -OH represents a hydroxyalkyl radical containing 2 to 4 carbon atoms and R1 and R11 represent the same or different lower alkyl or alkenyl radicals which together contain at least 3 carbon atoms, and the preparation thereof by reacting a 1,3-dialkyl-xanthine or -thioxanthine of the general formula <FORM:0759174/IV(a)/2> wherein X, R1 and R11 have the above significance, or an alkali metal salt thereof, with a halogen hydrin of or an inner ether of an alkane diol having 2 to 4 carbon atoms, if necessary with the addition of acid binding agents, or by reacting a 1,3-dialkyl-xanthine or -thioxanthine of the above general formula, or an alkali metal salt thereof, with an ester of a halogen hydrin derived from an alkane diol having 2 to 4 carbon atoms and hydrolyzing the 7-acyloxyalkylxanthine- or -thioxanthine thus obtained to form the 7-hydroxyalkyl radical, or by reducing a 7-oxoalkyl-xanthine or -thioxanthine of the general formula <FORM:0759174/IV(a)/3> wherein m is 1, 2 or 3 and n is 0, 1 or 2 (the sum of m and n being at the most 3) and R1, R11 and X have the above significance, or a 7-carboxyalkyl-xanthine- or -thioxanthine of the general formula <FORM:0759174/IV(a)/4> wherein R represents a hydrocarbon radical, m is 1, 2 or 3 and R1, R11 and X have the above significance, the reducing agent in each case being lithium aluminium hydride or sodium borohydride or, in the case of a xanthine of the above general formula in which X is oxygen, by treating the corresponding compound in which X is sulphur with an inorganic desulphurizing agent, e.g. by heating with a heavy metal oxide such as mercuric oxide or lead oxide. Suitable halogen hydrins for use in the processes referred to above are ethylene-chlorohydrin and -bromohydrin, 2-chloro-1-propanol, 1-chloro- 2 - propanol, 3 - chloro - 1 - propanol, 1 - chloro- ...

XANTHINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE INTERMEDIATES THEREOF, THEIR APPLICATION AS A MEDICAMENT AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The invention concerns xanthine derivatives of formula (I) and their salts wherein: R1 represents a monocyclic or polycyclic system containing 0, 1, 2, 3 or 4 substituted or unsubstituted heteroatoms; R2 = H, R4, -(CH2)n-R4 or (CH2)m-O-R4, with R4 = R1 or substituted or unsubstituted alkyl; R3 = H; n and m = 1, 2 or 3. The invention also concerns the method for preparing said derivatives and intermediates of said method, their use as medicine and pharmaceutical compositions containing them.

Dimethyl xanthine derivatives and their preparation

Process for the preparation of purine derivatives

Process for the production of hypoxanthine derivatives

8-pyridyl purines

8-PYRIDLY PURINES CAN BE SYNTHESIZED BY CONDENSATION OF 4,5-DIAMINOPYRIMIDINES WITH AMIDINOPYRIDINES. PROTONATION OF THE PYRIDINE NITROGEN CAUSES A MARKED BATHOCHROMIC SHIFT OF $MAX IN THE 2- AND 4-PYRIDYL DERIVATIVES, BUT NOT IN THE 3-PYRIDYL ISOMERS. A SIMILAR EFFECT IS PRODUCED BY QUATERNISATION OF THE 4-, BUT NOT OF THE 3-PRIDYL SUBSTITUENT. THE 8-(N-METHYLPYRIDINIUM) GROUP ALSO FACILITATES GREATLY ANION FORMATION IN THE PRUINE RING. THE NEW COMPOUNDS SHOWED A VARIETY OF BIOLOGICAL ACTIVITIES, SUCH AS PROLONGED HYPOTENSION WHEN INJECTED INTO CATS WHICH WERE ANESTHETIZED WITH NEMBUTAL.

New derivative of theophylline and its preparation

Intermediates and processes for the preparation of linagliptin and its salts

The present invention relates to new intermediates for the synthesis of Linagliptin and of its salts and a process for its preparation involving said intermediates.

New substituted purines and purine derivatives

1,201,997. Purines and purine derivatives. YISSUM RESEARCH DEVELOPMENT CO. OF THE HEBREW UNIVERSITY OF JERUSALEM. 25 July, 1968 [4 Aug., 1967], No. 35513/68. Heading C2C. Novel 8-pyridyl- and 8-N-methylpyridiniumsubstituted purines and purine derivatives are prepared by direct condensation of the appropriate 4,5-diaminopyrimidines with an amidine. In forming the 6-mercaptopurine compounds it is preferred to sulphurate the corresponding hypoxanthine. 1 - Methyl - 3 - amidinopyridinium iodide hydriodide is prepared by keeping a solution of 3-amidinopyridine hydrochloride in dimethylformamide and methyl iodide at room temperature for 24 hours. 6-mercapto-8-phenylpurine is prepared by refluxing a mixture of 8-phenylhypoxanthine, phosphorus pentasulphide and dry pyridine 8-phenyl-6-thioxan. thine is prepared by sulphurating 8-phenylxanthine as described above. Pharmaceutical compositions comprising of 8 - pyridyl - and 8 - N - methyl-pyridinium-substituted purines and purine derivatives and having anti-tumor and hypotensive activity. Reference is made to Specifications 1,073,039, 1,073,040 and 1,077,689.

Xanthinderivate

Process for producing xanthine derivative

A process for converting a xanthine derivative represented by general formula (I) [compound (I)], (wherein R?1 and R2¿ are the same or different from each other and each represents hydrogen or hydroxy-, oxo- or unsubstituted lower alkyl) into another xanthine derivative represented by general formula (II) [compound (II)], (wherein R?3 and R4¿ are the same or different from each other and each represents hydrogen or hydroxy-, oxo- or unsubstituted lower alkyl; R?5 and R6¿ are the same or different from each other and each represents hydrogen, hydroxy or oxo, provided when both of R?5 and R6¿ are hydrogen, at least one of R?3 and R4¿ is hydroxy- or oxo-substituted lower alkyl; and X and Y represent both hydrogen or they are combined together to represent a single bond) in the presence of an enzyme source which catalyzes the hydroxylation or carbonylation of compound (I) into compound (II).

Process for the production of new xanthine bases and their salts

1-arylpyrimidine derivatives and pharmaceutical use thereof

The present invention relates to 1-arylpyrimidine derivatives represented by general formula (I): (I) wherein R1 is H, alkyl or aralkyl; Ar is 1-naphthyl, or a substituted or unsubstituted phenyl group; R4 is a substituted phenyl, a substituted styryl, 1-methylcyclohexyl, 4-methylcyclohexyl, 4-oxo-4H-pyran-2-yl or 2-oxo-2H-pyran-5-yl group; R5 and R6 are each independently H or alkyl; R3 is H, and R7 and R8 are combined together to be oxo, or else R3 and R7 are combined together to be another direct bond, and R5 and R8 are combined together to be a direct bond, or pharmaceutically acceptable salts thereof; and uses of such compounds as agents for treating allergic diseases.

Amide substituted xanthine derivatives with gluconeogenesis modulating activity

The present invention is a 1,3,8 substituted xanthine derivative of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2 and R3 are as defined in the specification. Compounds of formula (I) and pharmaceutical ly acceptable salts or prodrugs thereof show activity as modulators of gluconeogenesis.