• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Compounds according to the formula and the pharmaceutically acceptable acid addition salts thereof wherein: n is an integer of 1 to 6; R, is hydrogen or alkyl of 1 to 4 carbon; R2 is hydrogen or R, and R2 are combined to form a carbonyl group; R3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl and its acylates, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or amino acid side chains; R4 is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy lower alkyl; Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; is an amide forming group wherein the nitrogen substituents are: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, -OH, -OCOR5, halo, -NH2, -N(R5)2, -NHCORs, -COOH, or -COO(R5) group wherein Rs is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an -NH2, -N(R5)2, -NHCOR5, -COOH, or -COOR5 group wherein R5 is lower alkyl; morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; pyrrolidinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (±)-decahydroquinolinyl or indolinyl. These compounds are cyclic AMP phosphodiesterase inhibitors useful as antithrombotic agents and the like in mammals. The compounds also have inotropic and anti-metastatic activities.
    公开号:SU1493109A3
    申请号:SU864028265
    申请日:1986-10-08
    公开日:1989-07-07
    发明作者:Генри Джоунс Гордон；Чарльз Венути Майкл；Алварез Роберт；Джозеф Бруно Джон
    申请人:Синтекс /Ю.С.А./ Инк. (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new (2-oxo-1,2,3,5-tetrahydroimidazo 2,1-b quinazolinyl) oxyalkylamides, which have phosphodiesterase inhibiting properties, as well as inotropic and metastasis-inhibiting activities .
    The purpose of the invention is the synthesis of new compounds in their activity superior to that of a structural analogue possessing the same type of activity.
    Example 1. N-Cyclog, exyl-N- -methyl-4- (2-oxo-1,2,3,5-tetrahydropyrimidazo 2,1-L2-hinazolin-7-yl) oxy-6-uthiramide.
     To a solution of 4- (2-oxo-1,2,3,5-tetrahydroimidazo 2,1-bJxinazolin-7-yl) oxanoic acid (3.44 g) and 1-hydroxybenzotriazole (1.5 g) in 25 MP dry add diisopropylcarbodiimide (1.39 g). After holding the solution for 1 hour
    with
     cm
    a solution of N-methylcyclohexylamine (1.56 mp and 1.32 ml of N-methylmorpholine in 10 MP dry) is added at room temperature. The resulting creature is stirred overnight at room temperature and then diluted with water. The resulting precipitate is collected and dried with phosphorus pentoxide to give N-cyclohexyl-β-methyl-A- (2-oxo-1,2,3,5-tetrahydroimidazo 2,1-b quinazolin-7-yl) oxy- butyramide. Similarly, all oxyalkyl acids can be converted to the corresponding amides.
    Example 2. 50 MP of ethylene glycol are pressurized with ammonia gas at 0 ° C, after which ethyl ether (3.2 g) is added. Then, the obtained suspension is heated in a high-pressure steel apparatus for 3 days at 200 s. After cooling, the precipitate is filtered off, washed with ethanol and dried to obtain the unsubstituted (2-OXO-1,2,3,5-tetrahydroimidazo (2, 1-b quinazalin-7-yl) oxybutyramide) with a melting point of 280 -282 p. Under the same conditions using the other primary amines, the corresponding primary amides can be obtained: N-cyclohexyl-4- (2-oxy Q-1,2,3,5-tetrahydroimidazo 2,1-b quinazolin-7 -yl) oxybutyramide, mp 255-256 ° C, N- -methyl - A-2-oxo-1,2,3, 5-tetrahydromimidazo (2, 1-b quinazolin-7-yl) hydroxybutyramide; N-ethyl-4- (2-oco-1,2,3,5-tetrahydroimidazo 2,1-b quinazolin-7-yl) oxybutyramide.
    Example 3. To plant ethyl ester (3.2 g, 10 mmol) obtained in accordance with the method of Preparation 9, and tetra-N-butylammonium bromide (6.44 g 20 mmol) in DMF (100 ml) were added Aqueous KOH (1.5 g in 5 ml) was added and stirred overnight at room temperature. Then molecular sieves (3 A, 25 g) are added, after which the mixture is allowed to stand for 3 days. N-methylcyclohexylamine (2.6 ml, 20 mmol) and bis (o-nitrophenyl) phenylphosphonate (to g, 25 mmol) are then added and stirred for 24 hours. The mixture is then filtered through Celite, and DMF is evaporated under high vacuum. The residue is triturated with 5% aqueous ammonium hydroxide and ethanol (1: 1) to obtain a precipitate, which is collected by filtration, washed with ethanol and you
    five
    0
    five
    0
    dried, thereby obtaining N-cyclohexyl-N-methyl-4- (2-okco-1,2, 3,5-tetrahydroimidazo 2,1-b quinazolin-7-yl) oxybutyramide with mp. 243- 244 S.
    Example 4: Conversion of free base to salt. A two-fold HbDi stoichiometric excess of 3% hydrogen chloride in methanol is added to a solution of 1.0 g of N-cyclohexyl-N-methyl-4- (2-oxo-1,2,3,5-tetrahydroimidazo 2,1-L-quinazylin-7-yl) oxybutyramide in 20 mp of methanol. Diethyl ether is then added until precipitation is complete. The resulting product is filtered, washed with ether, dried with air and recrystallized to obtain K-cyclohexyl-N-methyl-4- (2-oxo-1,2,3,5-tetrahydroimide-, 1-bZhinazolin-7-yl) oxybutyr hydrochloride - midi with so pl. 232-234 s.
    In a similar way, all compounds of formula (1) as a free base can be converted to the corresponding salt with an acid by treatment with hydrogen chloride or another of the listed acids to form (their pharmacologically acceptable salts.
    Example 5. The transformation of salt in the free base. 1.0 g of K-cyclohexyl-M-methyl-4-c - (2-OXO-1,2,3,5-tetrahydroimidazo 2,1-b quinazolin-7-yl) oxybutyramide hydrochloride, suspended in 50 ml of ether, mix with a stoichiometric twofold excess of a dilute aqueous potassium carbonate solution until the salt is completely dissolved. Then, the resulting organic layer is separated, washed twice with water, dried with magnesium sulfate and triturated to obtain M-cyclohexyl-L-methyl-4- (2-oxo-1,2, 3,5-tetrahydroimidazo 2,1-b quinazo- lin-7-yl) oxybutyramide as a free base.
    Example 6. Direct interchange of salts with acids, 1.0 g of N, N-dibenzyl-4- (2-oxo-1,2,3,5-tetrahydroimidazo 2, 1-b quinazolin-7-yl) oxybutyramide acetate is dissolved in 50 ml of water containing a stoichiometric equivalent of sulfuric acid and the resulting solution is evaporated to dryness. Then the resulting product is weighed in ethanol and filtered, dried with air and recrystallized from
    0
    five
    0
    five
    methanol (acetone) to obtain N, N- -dibenzyl-4- (2-oxo-1,2,3,5-tetrahydroimidazo 2,1-bj quinazolin-7-yl) oxybutyramide sulfate.
    Example. The proposed compounds — free bases or pharmacologically compatible salts with an acid — can be administered orally in the form of tablets. Although the amount of the compound of formula (I) or its components are well mixed and filled into gelatin capsules with a hard shell.
    Example 9. For the purpose of oral administration, the proposed compounds can still be formulated as suspensions. To prepare such suspensions, you can use any
    The venous proportion of the active principle may in any case be 5-90% of the preparation; it should preferably be administered to the body of 20-100 mg of the active principle per tablet. The following is a typical formulation of tablets, in which the active principle is N-cyclohexyl-M methyl-4- (2-oxo-1,2,3,5-tetrahydroimidazo 2,1-b-quinazolin-7-yl ) -oxybutiramide. However, it can also be used to form tablets from any other compound represented by formula (I).
    15
    20
    25
    in free form or in the form of a salt with acid.
    The suspension for oral administration has, for example, the following composition: Components
    Active principle O, 1 g Fumaric acid 0.5 g Sodium chloride 2.0 g
    Methyl para-aminobenzoic acid, 1 g
    Granulated sugar25.5 g Sorbitol (70% solution) 12.85 g Whigam K / VeegumK / (f-We Vanderbilt Ka./Va./Vanderbilt Co. /) 1.0 g Aromatic
    Components
    Active principle
    Corn starch
    Spray-dried Lactose Magnesium Stearate
    Number per pill mg
    25 20
    153 2
    thirty
    Granulated sugar25, 5 g Sorbitol (70% solution) 12.85 Vigam K / VeegumK / (f-We Vanderbilt Ka./Va./Vanderbilt Co.) 1.0 g Aromatic
    substance0.035
    KrasiteliO, 5 m
    Distilled water up to 100 m. Example 10. Acute and delayed toxic effects of the S-cycloyl-N-methyl 4- (2-oxo-1,2,3,5-tetra
    These components are well mixed - hydroimidazo 2,1-.L quinazolin-7-yl)
    The compound of formula (I) or its components are well mixed and filled into hard gelatin capsules.
    Example 9 For the purpose of oral administration, the compounds of the invention can still be formulated as suspensions. To prepare such suspensions, you can use any
    compound of formula (I) either in its
    free-form, or in the form of a salt with an acid.
    The suspension for oral administration has, for example, the following composition: Components
    Active principle O, 1 g Fumaric acid 0.5 g Sodium chloride 2.0 g
    Methyl para-aminobenzoic acid, 1 g
    Granulated sugar25.5 g Sorbitol (70% solution) 12.85 g Whigam K / VeegumK / (f-We Vanderbilt Ka./Va./Vanderbilt Co. /) 1.0 g Aromatic
    substance0.035 ml
    Dye, 5 mg
    Distilled water up to 100 ml. Example 10. Acute and delayed toxic effect of N-cyclohex-sil-N-methyl 4- (2-oxo-1,2,3,5-tetrahydroimidazo 2, 1-.b quinazolin-7-yl)
    vayut and pressed into pills with a notch.
    Example 8. Another type of preparation for oral administration is hard gelatin capsules that are filled with a powder containing the active principle in the desired amount. Using the active principle of example 6, salts with acids or another compound according to formula (I) using the following ingredients, you can get hard shell gelatin capsules


    Number per pill mg
    100
    148 2
    oxybutyramide.
    For the toxicity study, three groups were used, consisting of each of three mice - males (Sim (1SK) Rvy) weighing 20-24 g.
    N-cyclohexyl-K-methyl-4- (2-oxo-1,2,3,5-tetrahydroimidazo 2, 1-b quinazsm1in-7-yl) oxybutyramide was administered intraperitoneally in the form of an aqueous suspension (in polysorbate 80), Determine the acute and delayed lethal effect of the compound on mice.
    Dose, mg / kg Mortality 1 3000/3
    1 0000/3
    5000/3
    The results show that LD jg N-cyclohexyl-N-methyl-4- - (2-oxo-1,2,3,5-tetrahydroimidazo 2,1-b} quinazolin-7-yl) oxybutyramide when administered intraperitoneally 71300 mg / kg. When orally administered a test compound, in the form
    water suspension (in polysorbate 80) the following results were obtained: Dose, mg / kg
    1. 500.0 / 3
    1 0000/3
    5000/3
    The LD50 (orally) K-cyclohexyl-L- -methyl-4- (2-oxo-1,2,3,5-tetrahydropyrimidazo 2,1-b quinazolin-7-yl) oxybutyramide is also 1500 mg (Example 11, Cyclic phosphodiesterase activity) and inhibition of platelet agglutination were determined as follows. A test for inhibiting cyclic AMP phosphodiesterase activity, Inhibiting cyclic AMP phosphodiesterase activity by the compounds proposed was determined by the method of Filburn and Kapha (Filburn and Karn, Analyt, Biochem, 52: 505-516, 1973 using 1 µm cyclic AMP in as a substrate. 1 osfodisterase cyclic AMP of human platelets was obtained
    .7
    7 7
    7 7
    7 7 7 7
    from human donors. The obtained platelets were isolated and washed by centrifugation, and the membranes were ruptured by freezing, followed by thawing and hypotonic liis, after which the soluble enzyme was isolated by high-speed centrifugal NIN. Finally, the labyrinum was stored in certain portions at a temperature.
    Platelet agglutination. Blood was collected into evacuated tubes containing sodium citrate (ZOmmole),
    2 After centrifugation, platelet rich plasma was collected. After agglutination, a known nephelometric method was carried out.
    The results of the test for inhibition of cyclic AMP phosphodiesterase (relative to theophylline) are given in Table 1, which summarizes the ICjQ values for human platelet phosphodiesterase and the IC value.
    5 for rat heart phosphodiesterase,
    Table 1
    0



    260
    70
    350
    240 60
    6Q
    16. 7000 1500 1700
    160
    21600 21600 10400
    10400 29300
    18,000
    186000 169 1040 794
    27,000
    1493109
    10 Continuation of table 1
    Optical out
    N-Cyclohexyl N-Methyl 3-1-hydroxymethyl
    N-Cyclohexyl
    K-Methyl-3-B-hydroxymethyl
    N-Cyclohexyl
    L-methyl-3-D-methyl
    Notes e. The potency in terms of theophylline, the effect of which on the phosphodiesterase of human platelets is assumed to be 1.
    at
    The position of the oxyalkylamide side chain on the ring, formula (1), where Y, R, Rj. Rj R 4 means hydrogen formula (1), where Y, R ,, R means hydrogen.
    Example 12. Isotropic activity of the proposed compounds. Hybrid dogs are anesthetized by intravenous administration of 35 mg / kg sodium pentobarbital with the addition, if necessary, of the necessary substances. Blood pressure is measured using a Statham pressure transducer (Statham using a cannula inserted through the femoral artery into the abdominal aorta. - The number of heartbeats is measured using a cardiotachometer electrocardiography using lead-1 electrodes. 1. Reducing force the right ventricle is measured using a Solton-Brodie strain gauge (WAlton-Brodie) Stitched to the right ventricle followed by opening the chest with an incision along the sternum line. Harvard respirator is used to ventilate dogs with air through the endotracheal tube. (Harvard Respirator). Dogs are bilaterally Continued tab. 1
    27.5
    90
    9800
    18.5
    72
    14600
    5.4
    27
    50,000
    0
    five
    0
    five
    reconcile. After a midline laparotomy, the cannula is sutured into the duodenum to inject the test compound into it, and a cannula is injected into the femoral vein to inject isroprotenol. All data is recorded with a Beckman R611 Dynograph.
    The response of each dog is determined, and isoproterenol is administered intravenously at doses in the half-log range of 0.007 to 2.1 or 6.67 µg / kg. The test compound is administered to the duodenum, usually first at a low dose (2 mg / kg) and then at higher doses, i.e. at 6.32 and / or 20 mg / kg (if necessary). In certain cases, some compounds are administered to the duodenum in doses of 0.316-3.16 mg / kg.
    The test results are summarized in table. 2
    -1,2,3,5-tetrahydro imidae 2,1-bJ quinazolin-7-yl) oxybutyramide
    N-UHKnoreKCHH-N- -methyl-4- (2-oxo-3-b-methyl-1,2,3,5-tetrahydroimidazo 2,1-b quinazolin-7-yl) oxybutyramide
    N-Cyclohexyl-N- -methyl-4- (2-oxo- -3-B-methyl-1,2,3,5-tetrahydroimide 3o 2,1-b quinazoline-7- -yl) oxybutyramide


    Example 13. Activity, an inhibitor of metastases of lung cancer, Lewis (spontaneous metastases).
    The 1 & 1 female females of the C57B1 / 6 strain weighing 16-18 g infect subcutaneously between the inguinal and axillary regions of 0.2 ml with freshly prepared gruel of tumor cells. Mice were orally administered with either a control liquid (0.5% carboxymethylcellulose (CMC), or the test compound in suspension in

    Primary tumor weight (r1)
    Control fluid
    N-Cycpohexyl-N- -methyl-4- (2-oxo--1,2,3,5-tetrahydropyrimidazo 2,1-bJxHH-azolin-7-yl) oxybutyramide (5 mg (kg)
    p iO, 05.
    23 69 55 32
    11 44 58 55
    17 54
    94 97
    18
    50 53 43
    18 48 72 73
    13 49 82 82
    five
    0
    0.5% CMC. They begin to process mice one day after they are infected with tumor cells and continue to process them every two days throughout the entire experiment. After 20-21 days after infection, the mice are killed, the weight of the primary tumor and the number of metastae in the lung are determined by counting them under a dissecting microscope.
    The results of the experiment are given in table. 3
    Table 3
    Pulmonary metastases on average
    28
    10.5
    15
    Example 14. Activity against metastasis of B-16 melinomas.
    Female C57B1 / 6 mice weighing 16-18 g were intravenously injected with 7.5 x 10 viable melanoma cells of the strains in B16-B16 or B16-F1Q between the indicated body areas. Next, oral control liquid or test compound was administered from the first days after the introduction of tumor cells and continuing to enter every two days until killing 20-21 days after the introduction of the tumor cells. Then, the number of lung metals is determined in the manner described.
    The results are shown in Table. 4 (B16-BL6) and 5 (B16-F10).
    Table 4


    Pulmonary metastases (on average)
    ten
    3
    “P 0.02.
    Table 5
    Introduced agent or compound
    Fluid control
    K-Cyclohexyl-H- -methyl-4- (2-oxo--1,2,3,5-tetra
    1493109
    1 6 Continuation of table. five
    hydroimidazo.2, 1-b} quinazolin-7-yl) oxybutyramide (5 mg / kg)
      0.01.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining (2-oxo-1,2,3,5-tetrahydroimidazo C 2,1-b quinazolinyl) oxyalkylamides of the general formula
    AosSnLo,
    , n
    d./
    N N (I) I
    where n 1-6,
    A is a group where RT is hydrogen or C2 Ca; Cycloalkl and hydrogen or Cd-C-alkyl, or their pharmaceutically acceptable salts with acids, characterized in that the compound is in the form (CH,) riO or
    ) irJ V V
    (
    H N -N
    N N
    (Ii)
    where n has the specified value;
    R-- hydrogen or alkyl, is reacted with an amine of the general formula
    HNR, R, (III)
    where R is hydrogen or C d-KZ "-cycloalkyl;
    RI is hydrogen or C, -C-alkyl, with the desired product being isolated as a free base or as a pharmaceutically acceptable salt.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3932407A|1973-11-19|1976-01-13|Bristol-Myers Company|Optionally substituted 1,2,3,5-tetrahydroimidezo-quinazolin-2-ones and 6-1,2,3,4-tetrahydropyimidoquinazolin-2-ones|
    FI59246C|1974-06-24|1981-07-10|Otsuka Pharma Co Ltd|FOERFARANDE FOER FRAMSTAELLNING AV BENSCYKLOAMIDDERIVAT ANVAENDBARA VID TROMBOS- OCH EMBOLITERAPIN|
    US4313947A|1974-06-24|1982-02-02|Otsuka Pharmaceutical Co., Ltd.|Platelet aggregation inhibiting 2-oxyindoles, their compositions and method of use|
    NZ187452A|1977-06-10|1980-05-27|Otsuka Pharma Co Ltd|N- substituted-aminocarbonylpropoxy-carbostyrils and their preparation|
    NL7807507A|1977-07-25|1979-01-29|Hoffmann La Roche|TRICYCLICAL CONNECTIONS.|
    FR2512674B1|1981-09-16|1986-01-10|Sandoz Sa|NOVEL TRICYCLIC DERIVATIVES OF QUINAZOLINONE, THEIR PREPARATION AND MEDICAMENTS CONTAINING THESE DERIVATIVES|
    NZ211117A|1984-02-15|1987-10-30|Syntex Inc|Fused tetrahydroimidazo-quinazoline derivatives and pharmaceutical compositions|US4593029A|1984-02-15|1986-06-03|SyntexInc.|Novel ω-alkyl ethers of 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-ones|
    NZ211117A|1984-02-15|1987-10-30|Syntex Inc|Fused tetrahydroimidazo-quinazoline derivatives and pharmaceutical compositions|
    GB8514207D0|1985-06-05|1985-07-10|Pfizer Ltd|Cardiac stimulants|
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    US4670434A|1985-11-14|1987-06-02|SyntexInc.|oxyalkylamides useful as cyclic AMP phosphodiesterase inhibitors|
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    NZ234186A|1989-07-07|1991-10-25|Janssen Pharmaceutica Nv|Imidazo quinazolin-one derivatives and pharmaceutical compositions|
    US4943573A|1989-11-01|1990-07-24|Bristol-Myers Squibb Company|Imidazo[4,5-b]quinolinyloxyalkanoic acid amides with enhanced water solubility|
    WO1993000903A1|1991-07-05|1993-01-21|Byk Gulden Lomberg Chemische Fabrik Gmbh|Use of substituted pyridazines against dermatosis|
    US5196428A|1992-04-03|1993-03-23|Bristol-Myers Squibb Company|Imidazo[4,5-b]qinolinyl oxy alkyl ureas|
    US5348960A|1992-04-03|1994-09-20|Bristol-Myers Squibb Company|Imidazo[4,5-b]quinolinyl oxy alkyl tetrazolyl piperidine derivatives|
    US5208237A|1992-04-03|1993-05-04|Bristol-Meyers Squibb Company|7-oxypropylsulfonamido-imidazo[4,5-b]quinolin-2-ones|
    US5158958A|1992-04-03|1992-10-27|Bristol-Myers Squibb Company|Imidazo[4,5-b]quinolinyl oxy alkyl sulfonyl piperidine derivatives|
    EP1216037A2|1999-09-21|2002-06-26|Emory University|Methods and compositions for treating platelet-related disorders using mpl pathway inhibitory agents|
    AU2003297562A1|2002-11-27|2004-06-23|Artesian Therapeutics, Inc.|COMPOUNDS WITH MIXED PDE-INHIBITORY AND Beta-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITY FOR TREATMENT OF HEART FAILURE|
    US7772188B2|2003-01-28|2010-08-10|Ironwood Pharmaceuticals, Inc.|Methods and compositions for the treatment of gastrointestinal disorders|
    WO2007025177A2|2005-08-26|2007-03-01|Braincells, Inc.|Neurogenesis by muscarinic receptor modulation|
    EP2258357A3|2005-08-26|2011-04-06|Braincells, Inc.|Neurogenesis with acetylcholinesterase inhibitor|
    CA2625153A1|2005-10-21|2007-04-26|Braincells, Inc.|Modulation of neurogenesis by pde inhibition|
    WO2007134136A2|2006-05-09|2007-11-22|Braincells, Inc.|Neurogenesis by modulating angiotensin|
    EP1942879A1|2005-10-31|2008-07-16|Braincells, Inc.|Gaba receptor mediated modulation of neurogenesis|
    US20100216734A1|2006-03-08|2010-08-26|Braincells, Inc.|Modulation of neurogenesis by nootropic agents|
    EP2026813A2|2006-05-09|2009-02-25|Braincells, Inc.|5 ht receptor mediated neurogenesis|
    US7998971B2|2006-09-08|2011-08-16|Braincells Inc.|Combinations containing a 4-acylaminopyridine derivative|
    US20100184806A1|2006-09-19|2010-07-22|Braincells, Inc.|Modulation of neurogenesis by ppar agents|
    FR2910001B1|2006-12-18|2009-03-20|Sod Conseils Rech Applic|IMIDAZO, PYRIMIDO AND DIAZEPINE PYRIMIDINE-DIONE DERIVATIVES AND THEIR USE AS A MEDICINAL PRODUCT|
    EA020466B1|2007-06-04|2014-11-28|Синерджи Фармасьютикалз Инк.|Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders|
    US8969514B2|2007-06-04|2015-03-03|Synergy Pharmaceuticals, Inc.|Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases|
    GB0808944D0|2008-05-16|2008-06-25|Shire Llc|Substituted quinazolines|
    GB0808950D0|2008-05-16|2008-06-25|Shire Llc|Substituted quinazolines|
    GB0808953D0|2008-05-16|2008-06-25|Shire Llc|substituted quinazolines|
    JP2011522828A|2008-06-04|2011-08-04|シナジーファーマシューティカルズインコーポレイテッド|Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer, and other disorders|
    CA2730603C|2008-07-16|2019-09-24|Synergy Pharmaceuticals Inc.|Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders|
    US20100216805A1|2009-02-25|2010-08-26|Braincells, Inc.|Modulation of neurogenesis using d-cycloserine combinations|
    WO2010099323A1|2009-02-26|2010-09-02|Thar Pharmaceuticals, Inc.|Crystalization of pharmaceutical compounds|
    US9616097B2|2010-09-15|2017-04-11|Synergy Pharmaceuticals, Inc.|Formulations of guanylate cyclase C agonists and methods of use|
    ES2664873T3|2011-03-01|2018-04-23|Synergy Pharmaceuticals Inc.|Preparation process for guanylate cyclase C agonists|
    US20150119399A1|2012-01-10|2015-04-30|President And Fellows Of Harvard College|Beta-cell replication promoting compounds and methods of their use|
    EP2958577A2|2013-02-25|2015-12-30|Synergy Pharmaceuticals Inc.|Guanylate cyclase receptor agonists for use in colonic cleansing|
    EP2968439A2|2013-03-15|2016-01-20|Synergy Pharmaceuticals Inc.|Compositions useful for the treatment of gastrointestinal disorders|
    EP2970384A1|2013-03-15|2016-01-20|Synergy Pharmaceuticals Inc.|Agonists of guanylate cyclase and their uses|
    EA201592263A1|2013-06-05|2016-05-31|Синерджи Фармасьютикалз, Инк.|ULTRASCULAR AGONISTS OF GUANYLACYCLASE C, METHOD OF THEIR RECEIVING AND USING|
    KR20160042039A|2013-08-09|2016-04-18|알데릭스, 인코포레이티드|Compounds and methods for inhibiting phosphate transport|
    US20200368223A1|2019-05-21|2020-11-26|Ardelyx, Inc.|Methods for inhibiting phosphate transport|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/467,125|US4490371A|1983-02-16|1983-02-16|N,N-Disubstituted-oxyalkylamides|
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