ES2505665T3 - Procedimiento para bajar el nivel de glucosa en sangre en los mamíferos - Google Patents
Procedimiento para bajar el nivel de glucosa en sangre en los mamíferos Download PDFInfo
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- ES2505665T3 ES2505665T3 ES00119496.8T ES00119496T ES2505665T3 ES 2505665 T3 ES2505665 T3 ES 2505665T3 ES 00119496 T ES00119496 T ES 00119496T ES 2505665 T3 ES2505665 T3 ES 2505665T3
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Classifications
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Abstract
Efector de la actividad enzimática de la dipeptidil-peptidasa IV (DP IV) reductor de la actividad destinado a ser usado para bajar el nivel de azúcar en sangre bajo la concentración de glucosa característica de la hiperglucemia en el suero de un organismo mamífero para mitigar la diabetes mellitus, en donde dicho efector conduce a un reducida descomposición de los péptidos insulinotropicos endógenos GIP1-42 y GLP-17-36 por la DP IV.
Description
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DESCRIPCIÓN
Procedimiento para bajar el nivel de glucosa en sangre en los mamíferos
[0001] La invención se refiere a un sencillo procedimiento para bajar la concentración de azúcar en sangre con ayuda de efectores reductores de la actividad (sustratos, pseudosustratos, inhibidores, proteínas de unión y anticuerpos, entre otros) según la reivindicación 1.
[0002] Además de proteasas, que están incluidas en la proteólisis inespecífica, lo cual produce finalmente la descomposición de proteínas en aminoácidos, se conocen proteasas reguladoras que intervienen en la funcionalización (activación, desactivación, modulación) de principios activos peptídicos endógenos [KIRSCHKE, H., LANGNER, J., RIEMANN, S., WIEDERANDERS, B., ANSORGE, S. und BOHLEY, P., Lysosomal cysteine porteases. Excerpta Medica (Ciba Foundation Symposium 75), 15 (1980); KRÄUSSLICH, H.-G. and WIMMER, E., Viral Proteinases. Ann. Rev. Biochem. 57, 701 (1987)]. En particular en relación con la investigación inmune y la investigación de neuropéptidos se ha descubierto una serie de tales así llamadas convertasas, peptidasas señal o encefalinasas [GOMEZ, S., GLUSCHANKOF, P., LEPAGE, A., MARRAKCHI, N. and COHEN, P., Proc. Natl. Acad. Sci. USA 85, 5468 (1988); ANSORGE, S. and SCHÖNE, E., Histochem. 82, 41 (1987)].
[0003] Debido a la frecuencia de la presencia del aminoácido prolina en una pluralidad de hormonas peptídicas y a las con ello vinculadas propiedades estructurales de estos péptidos se discute para peptidasas específicas de prolina una función análoga a la de las peptidasas señal [YARON, A., The Role of Proline in the Proteolytic Regulation of Biologically Active Peptides, Biopolymers 26, 215 (1987); WALTER, R., SIMMONS, W.H. and YOSHIMOTO, T., Proline Specific Endo-and Exopeptidases. Mol. Cell. Biochem. 30, 111 (1980); VANHOOF, G., GOOSSENS, F., DE MEESTER, I., HENDRIKS, D. and SCHARPE, S., Proline motifs and their biological processing. FASEB Journal 9, 736 (1995)]. Debido a su estructura particular, la prolina determina además en estos péptidos tanto la conformación como la estabilidad de estos péptidos, protegiéndolos contra la descomposición producida por proteasas inespecíficas [KESSLER, H., Konformation und biologische Wirkung von zyklischen Peptiden. Angew. Chem. 94, 509 (1982)]. Las enzimas que por el contrario actúan de manera altamente específica y modificando la estructura en secuencias con contenido de prolina (HIV proteasa y ciclofilina, entre otras) son atractivas dianas de la actual investigación de principios activos. En particular para las peptidasas fragmentadoras post-prolina prolil endopeptidasa (PEP) y dipeptidil peptidasa IV (DP IV) pudieron probabilizarse relaciones entre la modulación de la actividad biológica de sustratos peptídicos naturales y su fragmentación selectiva por medio de estas enzimas. Así, se supone que la PEP desempeña un papel en el aprendizaje y en el proceso de la memoria, y que la DP IV está implicada en la transmisión de señales durante la respuesta inmune [ISHIURA, S., TSUKAHARA, T., TABIRA, T., SHIMIZU, T., ARAHATA K. and SUGITA, H., FEBS-Letters 260, 131 (1990); HEGEN M., NIEDOBI-TEK, G. KLEIN, C.E., STEIN, H. and FLEISCHER, B., J. of Immunology 144, 2908 (1990)].
[0004] Análogamente a la extraordinaria especificidad para prolina de estas enzimas se discute su alta selectividad para el aminoácido alanina dentro de típicas regiones de reconocimiento en sustratos de estas enzimas, según la cual los péptidos con contenido de alanina pueden adoptar conformaciones análogas a las de los péptidos estructuralmente análogos con contenido de prolina. Recientemente se han demostrado mediante mutación puntual (intercambio de prolina por alanina) tales propiedades de las cadenas peptídicas con contenido de alanina [DODGE, R.W. and SCHERAGA, H.A., Folding and unfolding kinetics of the proline-to-alanine mutants of bovine pancreatic ribonuclease A. Biochemistry 35 (5) 1548 (1996)].
[0005] Se da actividad de DP IV y/o actividad análoga a la de DP IV (p. ej. La DP II citosólica posee una especificidad de sustrato casi idéntica a la de la DP IV) en el circuito sanguíneo, donde disocia con alta especificidad dipéptidos del terminal N de péptidos biológicamente activos, cuando la prolina o la alanina representan los residuos contiguos del aminoácido N-terminal en su secuencia. Por consiguiente se parte de que esta enzima interviene en la regulación de polipéptidos in vivo [VANHOOF, G., GOOSSENS, F., DE MEESTER, I., HENDRIKS, D. and SHCARPE, S., Proline motifs and their biological processing, FASEB Journal 9, 736 (1995)].
[0006] Los polipéptidos insulinotrópicos dependientes de glucosa que son el polipéptido inhibidor gástrico 1-42 (GIP1-42) y el péptido amida-1 7-36 análogo al glucagón (GLP-17-36), que son hormonas que estimulan la secreción de insulina del páncreas inducida por glucosa (también llamadas incretinas), son sustratos de la DP IV, puesto que la misma puede disociar in vitro e in situ de las secuencias N-terminales de estos péptidos los dipéptidos tirosinil-alanina e histidil-alanina [MENTLEIN, R., GALLWITZ, B., and SCHMIDT, W.E., Dipeptidyl Peptidase IV hydrolyzes gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidina methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 214, 829 (1993)].
[0007] La reducción de tal actividad enzimática de DP IV y/o análoga a la de DP IV para la fragmentación de tales sustratos in vivo puede servir para suprimir con eficacia la actividad enzimática indeseada en condiciones de laboratorio así como en estados patológicos de organismos mamíferos [DEMUTH, H.-U., Recent developments in the irreversible inhibition of serine and cysteine proteases. J. Enzyme Inhibition 3, 249-278 (1990); DEMUTH, H.-U. and HEINS. J., On
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the catalytic Mechanism of Dipeptidyl Peptidase IV. in Dipeptidyl Peptidase IV (CD 26) in Metabolism and the Immune Response (B. Fleischer, Ed.) R.G. Landes, Biomedical Publishers, Georgetown, 1-35 (1995)]. P. ej. La Diabetes mellitus tipo II (también llamada diabetes del adulto) está basada en una reducida secreción de insulina o en perturbaciones de la función receptora, que se fundamentan, entre otras cosas, en anomalías de concentración de origen proteolítico de las incretinas. [BROWN, J.C., DAHL, M., KWAWK, S., MCINTOSH, C.H.S., OTTE, S.C. and PEDERSON, R.A. Peptides 2, 241 (1981); SCHMIDT, W.E., SIEGEL, E.G., GALLWITZ, B. KUMMEL, H., EBERT, R. and CREUTZFELDT, W., Characterization of the insulinotropic activity of fragments derived from gastric inhibitory polypeptide. Diabetologia 29, 591A (1986); ADELHORST, K., HE-DEGAARD, B.B., KNUDSEN, L.B. and KIRK, O., Structure-activity studies of glucagon-like peptide. J. Biol. Chem. 296, 6275 (1994)].
[0008] La hiperglucemia y las causas y/o consecuencias ligadas a la misma (también llamadas Diabetes mellitus) se tratan según el actual estado de la técnica mediante la administración de insulina (p. ej. de material aislado de páncreas bovino o bien también obtenido mediante técnica genética) a los organismos enfermos en distintas formas posológicas. Todos los procedimientos conocidos hasta la fecha, así como también los más modernos, se distinguen por un alto gasto de material y unos altos costes, y a menudo por decisivos menoscabos de la calidad de vida de los pacientes. El método clásico (inyección i.v. de insulina diaria, habitual desde los años treinta) trata los síntomas agudos de la enfermedad, pero tras una prolongada aplicación conduce, entre otras cosas, a severas modificaciones vasculares (arterioesclerosis) y lesiones nerviosas [LACY, P., Status of Islet Cell Transplantation. Diabetes Care 16 (3) 76 (1993)].
[0009] Últimamente se propone la instalación de implantes de depósito subcutáneos (la liberación de insulina es dosificada, y se prescinde de las inyecciones diarias), así como la implantación (el trasplante) de células de Langerhans intactas en la glándula pancreática u otros órganos y tejidos funcionalmente perturbados. Tales trasplantes son técnicamente costosos. Además representan una intervención quirúrgica arriesgada en el organismo receptor y exigen también en los trasplantes celulares métodos para la supresión del sistema inmune o para eludirlo [LACY, P., Treating Diabetes with Transplanted Cells. Sci. Americ. 273 (1)40-46 (1995)].
[0010] La aplicación en lo posible oral de inhibidores enzimáticos de bajo peso molecular por el contrario es una alternativa más rentable p. ej. a las técnicas quirúrgicas invasivas en el tratamiento de fenómenos patológicos. Inhibidores enzimáticos de este tipo encuentran entre tanto aplicación terapéutica como inmunosupresores, antitrombóticos y virostáticos para el SIDA. Mediante diseño químico de propiedades de estabilidad, transporte y eliminación su forma de actuación puede ser modificada y adaptada a propiedades individuales [SANDLER, M. and SMITH, H.J., Hrsg., Design of Enzyme Inhibitors as Drugs. Oxford University Press, Oxford (1989); MUNRÖ, J.E., SHEPHERD, T.A., JUNGHEIM, L.N., HORNBACK, W.J., HATCH, S.D., MÜSING, M.A., WISKERCHEN, M.A., SU, K.S., CAMPANALE, K.M., BAXTER, A.J., and COLACINO, J.M., Potent, orally bioavailable HIV-1 protease inhibitors containing noncoded D-amino acids. Bioorg. Medicinal Chem. Letters 5 (23) 2897 (1995)].
[0011] La finalidad de la invención es un procedimiento sencillo y novedoso para bajar el nivel de glucosa en sangre, que según la invención puede lograrse gracias al hecho de que mediante la administración de efectores reductores de la actividad a un organismo mamífero, como consecuencia causal los péptidos insulinotrópicos endógenos (o administrados además exógenamente) GIP1-42 y GLP-17-36 son menos descompuestos por la DP IV y con ello se reduce
o se retarda la disminución de la concentración de estas hormonas peptídicas, en el tratamiento de diabetes mellitus.
[0012] La invención se basa en el sorprendente descubrimiento de que una reducción de la actividad de DP IV que actúa en el circuito sanguíneo conduce causalmente a que se vea influenciado el nivel de azúcar en sangre. Se descubrió que
- 1.
- la reducción de actividad de DP IV tiene como consecuencia un relativo incremento de la estabilidad de las incretinas estimuladas por glucosa o aportadas externamente, es decir que mediante la aplicación de efectores de la DP IV reductores de la actividad puede controlarse la descomposición de las incretinas en la sangre;
- 2.
- una incrementada estabilidad a la descomposición biológica de las incretinas tiene como consecuencia una modificación del efecto de la insulina endógena;
- 3.
- el incremento de la estabilidad de las incretinas que se logra en la sangre gracias a la reducción de la actividad de DP IV redunda en una consecutiva modificación del efecto de la insulina inducida por glucosa y con ello conduce a una modulación controlable mediante efectores de la DP IV reductores de la actividad del nivel de glucosa en sangre.
[0013] La invención se refiere con ello a efectores de la actividad enzimática de la dipeptidil peptidasa IV (DP IV) reductores de la actividad destinados a ser usados para bajar el nivel de azúcar en sangre bajo la concentración de glucosa característica de la hiperglucemia en el suero de un organismo mamífero para la mitigación de la diabetes mellitus.
[0014] Los efectores de la DP IV reductores de la actividad que se aplican según la invención pueden llegar a ser usados en complejos de formulación aplicables farmacéuticamente como inhibidores, sustratos, pseudosustratos, inhibidores de la expresión de DP IV, proteínas de unión o anticuerpos de estas proteínas enzimáticas o combinaciones de estas distintas sustancias, que reducen la concentración de la proteína DP IV en el organismo mamífero. Son efectores reductores de la actividad según la invención p. ej. inhibidores de DP IV como los derivados dipeptídicos o
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miméticos dipeptídicos alanil-pirrolidida e isoleucil-tiazolidida, así como el pseudosustrato N-valil-prolil, Obenzoilhidroxilamina. Compuestos de este tipo son conocidos por la literatura [DEMUTH, H.-U., Recent developments in the irreversible inhibition of serine and cysteine porteases. J. Enzyme Inhibition 3, 249 (1990)] o bien son producibles en analogía a los métodos descritos en la literatura.
[0015] El procedimiento que se hace público representa un novedoso enfoque para la disminución de la concentración incrementada de glucosa en sangre en el suero de mamíferos. Es sencillo, explotable comercialmente y adecuado para ser usado en la terapia en particular de enfermedades que se basan en valores de glucosa en sangre superiores a los medios, en la medicina humana.
[0016] Los efectores reductores de la actividad se administran en forma de preparados farmacéuticos que contienen el principio activo en combinación con habituales materiales de soporte conocidos por el estado de la técnica. Por ejemplo se aplican por vía parenteral (p. ej. i.v. en solución de sal común fisiológica) o bien por vía enteral (p. ej. oral, combinados con habituales materiales de soporte, como p. ej. glucosa).
[0017] En dependencia de su estabilidad endógena y de su biodisponibilidad, deben administrarse dosis únicas o bien también dosis múltiples de los efectores reductores de la actividad, para lograr la deseada normalización de los valores de glucosa en sangre. P. ej. en el caso de las aminoacil-tiazolididas una gama de dosis de este tipo puede estar situada entre 1,0 mg y 10,0 mg de sustancia efectora.
Figuras:
[0018]
Fig. 1: Análisis MALDI-TOF de la hidrólisis de GIP1-42 (b) y GLP-17-36 catalizada por DP IV y su inhibición mediante isoleucil-tiazolidida (a). Fig. 2: Análisis por HPLC de la presencia en suero de metabolitos de GLP-1 en presencia y en ausencia del inhibidor de DP IV isoleucil-tiazolidida in vivo. Fig. 3: Influencia del inhibidor de la DP IV isoleucil-tiazolidida en distintos parámetros hemáticos de la rata estimulada con glucosa i.d.
Ejemplos de realización
Ejemplo 1: Inhibición de la hidrólisis de las incretinas GIP1-42 y GLP-17-36 catalizada por DP IV in situ
[0019] Tanto in vitro con enzima purificada como también in situ, p. ej. en suero humano combinado, puede demostrarse
o suprimirse con ayuda de inhibidores la hidrólisis de las incretinas ocasionada por la actividad de DP IV (Fig. 1).
[0020] Según la invención, en la incubación de GIP1-42 30µM y de GLP-17-36 30µM e isoleucil-tiazolidida 20µM (1a), un inhibidor de DP IV reversible, se logra in situ en suero al 20% a un pH de 7,6 y a 30ºC la completa supresión de la hidrólisis catalizada enzimáticamente de ambas hormonas peptídicas dentro de un periodo de tiempo de 24 horas (sendos espectros superiores 1b y 1c). Se incubaron con suero humano (al 20%) en tampón de TRICINA 0,1mM a un pH de 7,6 y a 30ºC y por espacio de 24 horas GIP1-42 (5µM) sintético y GLP-17-36 (15µM) sintético. Se tomaron tras distintos periodos de tiempo muestras de las preparaciones de incubación (para el GIP1-42 2,5 pmoles y en el caso del GLP-17-36 7,5 pmoles). Las muestras fueron cocristalizadas con 2’,6’-dihidroxiacetofenona como matriz y se analizaron mediante MALDI-TOF-espectrometría de masas. Los espectros (Fig. 1) representan acumulaciones de 250 disparos láser individuales. (1b) Las señales en la zona de m/z 4980,1 ± 5,3 corresponden al GIP1-42 (M 4975,6) y en la zona de m/z 4745,2 ± 5,5 corresponden al producto de hidrólisis con DP IV GIP3-42 (M 4740,4). (1c) Las señales en m/z 3325,0 ± 1,2 corresponden al GLP-17-36 (M 3297,7) y en m/z 3116,7 ± 1,3 corresponden al producto de hidrólisis con DP IV GLP-19-36 (M 3089,6).
[0021] En las preparaciones de ensayo sin inhibidor las incretinas fueron descompuestas casi por completo en este periodo de tiempo (Figs. 1b y 1c, sendos espectros inferiores).
Ejemplo 2: Inhibición de la descomposición de GLP-17-36 mediante el inhibidor de la DP IV isoleucil-tiazolidida in vivo.
[0022] Si se sigue el metabolismo de las incretinas nativas (aquí GLP-17-36) en el suero de la rata en dependencia y en presencia del inhibidor de la DP IV isoleucil-tiazolidida (inyección i.v. de una solución de inhibidor 1,5µM en solución de sal común al 0,9%) frente a un control, para una concentración del inhibidor isoleucil-tiazolidida de aprox. 0,1 mg/kg de rata de laboratorio no se observa en los animales de ensayo tratados con inhibidor (n = 5) a lo largo del espacio de tiempo de ensayo descomposición alguna de la hormona peptídica insulinotrópica GLP-17-36 (Fig. 2).
[0023] Para la detección de los metabolitos en presencia y en ausencia del inhibidor de la DP IV (20 minutos después de la previa administración i.v. de la dosis de inhibidor y de solución de sal común) los animales de ensayo y de control
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recibieron por vía i.v.125I-GLP-17-36 50 – 100pM (actividad específica aprox. 1 µMCi/pM). Se tomaron muestras de sangre tras 2 – 5 min. y el plasma se sometió a extracción mediante acetonitrilo al 20%. A continuación fue separado el extracto peptídico mediante RP-HPLC y la radiactividad de las fracciones fue analizada en un contador γ. La actividad hallada está indicada en cpm (cuentas por minuto) con respecto al máximo.
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Ejemplo 3: Modulación del efecto de la insulina y descenso del nivel de glucosa en sangre tras la aplicación i.v. del inhibidor de la DP IV isoleucil-tiazolidida in vivo.
[0024] En la rata estimulada por glucosa mediante inyección intraduodenal (i.d.), mediante dosis i.v. de distintos
10 efectores de la DP IV, p. ej. de 0,1 mg de isoleucil-tiazolidida por kg de rata, puede observarse un descenso del nivel de glucosa que es debido a la acción inhibidora y se produce con retardo en el tiempo. Este efecto es dosis-dependiente y reversible tras ser suspendida la infusión de 0,05 mg/min. del inhibidor de la DP IV isoleucil-tiazolidida por kg de rata. La aplicación i.v. de la misma cantidad de glucosa de animales tratados con inhibidor y de control no muestra contrariamente a los animales de ensayo estimulados por glucosa i.d. efecto equiparable alguno.
15 [0025] La Figura 3 aclara estas relaciones con las modificaciones inhibidor-dependientes de los parámetros plasmáticos: A – actividad de DP IV, B – nivel de insulina en plasma, C – nivel de glucosa en sangre.
[0026] Los animales de ensayo (n = 5, ratas Wistar macho, de 200 – 225 g) recibieron como dosis inicial isoleucil
20 tiazolidida 1,5µM en solución de sal común al 0,9% (A) o iguales volúmenes de solución de sal común al 0,9% sin inhibidor (■) (grupo de control, n = 5). El grupo de ensayo recibió además una infusión del inhibidor de 0,75 SM/min. a lo largo de un tiempo de ensayo de 30 min. (*). Al grupo de control le fue en el mismo espacio de tiempo infundida una solución de sal común al 0,9% exenta de inhibidor. En el punto en el tiempo t = 0 los animales recibieron por vía i.d. una dosis de glucosa de 1 g/kg de solución de dextrosa al 40% (en peso/volumen).
25 [0027] A todos los animales de ensayo les fueron tomadas muestras de sangre a intervalos de tiempo de diez minutos.
[0028] Las mediciones de glucosa se hicieron en la sangre total (Lifescan One Touch II analyzer), mientras que la actividad de DP IV y las concentraciones de insulina se determinaron en el plasma.
30 [0029] La prueba de insulina aquí usada es sensible entre 10 y 160 mU/ml [PEDERSON, R.A., BUCHAN, A.M.J., ZAHEDI-ASH, S., CHEN, C.B. and BROWN, J.C. Reg. Peptides. 3, 53-63 (1982)]. La actividad de DP IV fue determinada mediante análisis espectral fotométrico [DEMUTH, H.-U-and HEINS, J., On the catalytic Mechanism of Dipeptidyl Peptidase IV, in Dipeptidyl Peptidase IV (CD 26) in Metabolism and the Immune Response (B. Fleischer, Ed.)
35 R.G. Landes, Biomedical Publishers, Georgetown, 1-35 (1995)]. Todos los valores de medición están indicados como valores medios con la desviación estándar.
Claims (3)
- EP 1084705E0011949623-09-2014REIVINDICACIONES1. Efector de la actividad enzimática de la dipeptidil-peptidasa IV (DP IV) reductor de la actividad destinado a ser usado para bajar el nivel de azúcar en sangre bajo la concentración de glucosa característica de la5 hiperglucemia en el suero de un organismo mamífero para mitigar la diabetes mellitus, en donde dicho efector conduce a un reducida descomposición de los péptidos insulinotropicos endógenos GIP1-42 y GLP-17-36 por la DPIV.
- 2. Efector reductor de la actividad destinado a ser usado según la reivindicación 1, en donde dicho efector es un 10 inhibidor de la DP IV.
- 3. Efector reductor de la actividad destinado a ser usado según la reivindicación 1 o 2, en donde dicho efector es aplicado por vía parenteral o enteral.15 4. Efector reductor de la actividad destinado a ser usado según la reivindicación 3, en donde dicho efector es aplicado por vía oral con materiales de soporte habituales.6
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DE19616486 | 1996-04-25 | ||
DE19616486.9A DE19616486C5 (de) | 1996-04-25 | 1996-04-25 | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
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ES00119496.8T Expired - Lifetime ES2505665T3 (es) | 1996-04-25 | 1997-04-24 | Procedimiento para bajar el nivel de glucosa en sangre en los mamíferos |
ES97924866T Expired - Lifetime ES2158562T3 (es) | 1996-04-25 | 1997-04-24 | Utilizacion de inhibidores de dipeptidil peptidasa iv para reducir el nivel de glucosa en la sangre en mamiferos. |
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EP (3) | EP0896538B1 (es) |
JP (3) | JP2001510442A (es) |
KR (5) | KR20120014064A (es) |
CN (2) | CN1132578C (es) |
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AU (1) | AU721477C (es) |
CA (1) | CA2252576C (es) |
DE (5) | DE19616486C5 (es) |
DK (2) | DK1084705T3 (es) |
ES (2) | ES2505665T3 (es) |
FR (1) | FR14C0089I1 (es) |
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HK (2) | HK1019204A1 (es) |
LT (3) | LTPA2014045I1 (es) |
LU (7) | LU91334I2 (es) |
NL (2) | NL300280I2 (es) |
NZ (1) | NZ332707A (es) |
PT (2) | PT1084705E (es) |
RU (1) | RU2189233C2 (es) |
SI (1) | SI1084705T1 (es) |
WO (1) | WO1997040832A1 (es) |
Families Citing this family (291)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19616486C5 (de) | 1996-04-25 | 2016-06-30 | Royalty Pharma Collection Trust | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
US20020006899A1 (en) * | 1998-10-06 | 2002-01-17 | Pospisilik Andrew J. | Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals |
ATE357509T1 (de) * | 1997-09-29 | 2007-04-15 | Point Therapeutics Inc | Stimulierung von hämatopoietischen zellen im vitro |
DE69839279T2 (de) * | 1997-11-18 | 2009-05-28 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Neue physiologisch aktive substanz sulphostin, herstellung und verwendung derselben |
EP2433623A1 (en) * | 1998-02-02 | 2012-03-28 | Trustees Of Tufts College | Use of dipeptidylpeptidase inhibitors to regulate glucose metabolism |
AU2007202745B2 (en) * | 1998-02-02 | 2010-11-18 | 1149336 Ontario, Inc. | Method of regulating glucose metabolism, and reagents related thereto |
US6255772B1 (en) | 1998-02-27 | 2001-07-03 | Micron Technology, Inc. | Large-area FED apparatus and method for making same |
DE19823831A1 (de) * | 1998-05-28 | 1999-12-02 | Probiodrug Ges Fuer Arzneim | Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen |
DE19828114A1 (de) * | 1998-06-24 | 2000-01-27 | Probiodrug Ges Fuer Arzneim | Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV |
DE19828113A1 (de) | 1998-06-24 | 2000-01-05 | Probiodrug Ges Fuer Arzneim | Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV |
DE19834591A1 (de) | 1998-07-31 | 2000-02-03 | Probiodrug Ges Fuer Arzneim | Verfahren zur Steigerung des Blutglukosespiegels in Säugern |
US6979697B1 (en) | 1998-08-21 | 2005-12-27 | Point Therapeutics, Inc. | Regulation of substrate activity |
US20030176357A1 (en) * | 1998-10-06 | 2003-09-18 | Pospisilik Andrew J. | Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels |
PT1171465E (pt) | 1999-03-29 | 2004-12-31 | Uutech Ltd | Analogos de petido inibidor gastrico e sua utilizacao para o tratamento de diabetes |
US20050272652A1 (en) | 1999-03-29 | 2005-12-08 | Gault Victor A | Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity |
US6890904B1 (en) * | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
DE19926233C1 (de) | 1999-06-10 | 2000-10-19 | Probiodrug Ges Fuer Arzneim | Verfahren zur Herstellung von Thiazolidin |
DE19940130A1 (de) | 1999-08-24 | 2001-03-01 | Probiodrug Ges Fuer Arzneim | Neue Effektoren der Dipeptidyl Peptidase IV zur topischen Anwendung |
AU1916401A (en) * | 1999-11-12 | 2001-06-06 | Guilford Pharmaceuticals Inc. | Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors |
GB9928330D0 (en) | 1999-11-30 | 2000-01-26 | Ferring Bv | Novel antidiabetic agents |
NZ519231A (en) * | 1999-12-23 | 2004-05-28 | Novartis Ag | Use of nateglinide as an insulin secretion enhancer for treating impaired glucose metabolism |
US6380398B2 (en) | 2000-01-04 | 2002-04-30 | Novo Nordisk A/S | Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
PT1248604E (pt) | 2000-01-21 | 2007-01-31 | Novartis Ag | Associações compreendendo inibidor de dipeptidilpeptidase-iv |
WO2001055105A1 (en) * | 2000-01-24 | 2001-08-02 | Novo Nordisk A/S | N-substituted 2-cyanopyroles and -pyrrolines which are inhibitors of the enzyme dpp-iv |
WO2001062266A2 (en) * | 2000-02-25 | 2001-08-30 | Novo Nordisk A/S | Use of dpp-iv inhibitors for the treatment of diabetes |
US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
US6500804B2 (en) | 2000-03-31 | 2002-12-31 | Probiodrug Ag | Method for the improvement of islet signaling in diabetes mellitus and for its prevention |
AR033390A1 (es) | 2000-08-22 | 2003-12-17 | Novartis Ag | Una composicion farmaceutica que comprende un antagonista del receptor at1 y un potenciador de la secrecion de insulina, el uso de dicha composicion para la fabricacion de un medicamento y un kit de partes |
US7132104B1 (en) | 2000-10-27 | 2006-11-07 | Probiodrug Ag | Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders |
EP1328270A2 (en) * | 2000-10-27 | 2003-07-23 | Probiodrug AG | Method for the treatment of neurological and neuropsychological disorders |
EP1891948A1 (en) | 2000-10-27 | 2008-02-27 | Probiodrug AG | Treatment of neurological and neuropsychological disorders |
DE60139087D1 (de) * | 2000-12-14 | 2009-08-06 | Ortho Mcneil Janssen Pharm | Verfahren zu Herstellung von Zubereitungen enthaltend einen Steroidhormon und ein Stabilisierungsmittel in nicht-kristallinen Form |
EP1354882A1 (en) * | 2000-12-27 | 2003-10-22 | Kyowa Hakko Kogyo Co., Ltd. | Dipeptidyl peptidase iv inhibitor |
DE10100053A1 (de) * | 2001-01-02 | 2002-08-22 | Keyneurotek Ag I G | Verwendung von Enzyminhibitoren der Dipeptidylpeptidase IV sowie der Aminopeptidase N und pharmazeutischen Zubereitungen daraus zur Prävention und/oder Therapie Ischämie-bedingter akuter und chronischer neurodegenerativer Prozesse und Erkrankungen |
BRPI0207767B8 (pt) * | 2001-02-24 | 2021-05-25 | Boehringer Ingelheim Pharma | derivados de xantina, seu uso, composições farmacêuticas, seus processos de preparação, e sais fisiologicamente aceitáveis |
EP1385508B1 (en) | 2001-03-27 | 2008-05-21 | Merck & Co., Inc. | Dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
US6890905B2 (en) | 2001-04-02 | 2005-05-10 | Prosidion Limited | Methods for improving islet signaling in diabetes mellitus and for its prevention |
GB0109146D0 (en) * | 2001-04-11 | 2001-05-30 | Ferring Bv | Treatment of type 2 diabetes |
US20030060494A1 (en) * | 2001-05-18 | 2003-03-27 | Nobuyuki Yasuda | Pharmaceutical use of N-carbamoylazole derivatives |
FR2826003B1 (fr) * | 2001-06-18 | 2003-08-15 | Servier Lab | Nouveaux derives cycliques d'alpha-amino-gamma-hydroxy- amides, leur procede de preparation et les compositions pharmaceutiques que les contiennent |
DE60209348T2 (de) | 2001-06-20 | 2006-10-12 | Merck & Co., Inc. | Dipeptidylpeptidase-hemmer zur behandlung von diabetes |
AU2002344820B2 (en) | 2001-06-20 | 2006-12-14 | Merck & Co., Inc. | Dipeptidyl peptidase inhibitors for the treatment of diabetes |
US7368421B2 (en) | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis |
DE10150203A1 (de) | 2001-10-12 | 2003-04-17 | Probiodrug Ag | Peptidylketone als Inhibitoren der DPIV |
AU2002322344C1 (en) | 2001-06-27 | 2006-02-16 | Smithkline Beecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
US20030130199A1 (en) | 2001-06-27 | 2003-07-10 | Von Hoersten Stephan | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
UA74912C2 (en) | 2001-07-06 | 2006-02-15 | Merck & Co Inc | Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes |
WO2003015768A2 (en) * | 2001-08-16 | 2003-02-27 | Probiodrug Ag | Use of inhibitors of proline endopeptidase to modulate inositol (1,4,5) triphosphate concentration dependent on intracellular signal cascades |
US6844316B2 (en) | 2001-09-06 | 2005-01-18 | Probiodrug Ag | Inhibitors of dipeptidyl peptidase I |
US6861440B2 (en) | 2001-10-26 | 2005-03-01 | Hoffmann-La Roche Inc. | DPP IV inhibitors |
KR20040058324A (ko) * | 2001-11-26 | 2004-07-03 | 다이이찌 산토리 파마 가부시키가이샤 | 경비흡수용 의약 조성물 |
EP1487471A4 (en) | 2001-11-26 | 2010-03-10 | Tufts College | METHOD FOR TREATING AUTOIMMUNE DISEASES AND ASSOCIATED REAGENTS |
JP4771661B2 (ja) | 2001-11-26 | 2011-09-14 | トラスティーズ オブ タフツ カレッジ | Post−プロリン開裂酵素の擬ペプチド性阻害剤 |
MXPA04007743A (es) | 2002-02-13 | 2004-10-15 | Hoffmann La Roche | Nuevos derivados de piridina y quinolina. |
BR0307665A (pt) | 2002-02-13 | 2005-01-04 | Hoffmann La Roche | Compostos, processo para a sua manufatura, composições farmacêuticas que compreendem os mesmos, método para o tratamento e/ou profilaxia de enfermidades associadas com dpp iv e utilização dos compostos |
DE60304911D1 (de) * | 2002-02-25 | 2006-06-08 | Eisai Co Ltd | Xanthin-Derivate als DPP-IV-Inhibitoren |
PL372316A1 (en) | 2002-02-28 | 2005-07-11 | Prosidion Limited | Glutaminyl based dpiv inhibitors |
GB0205693D0 (en) * | 2002-03-09 | 2002-04-24 | Astrazeneca Ab | Chemical compounds |
DE10211555A1 (de) * | 2002-03-15 | 2003-10-02 | Imtm Inst Fuer Medizintechnolo | Verwendung der Inhibitoren von Enzymen mit Aktivitäten der Aminopeptidase N und/oder der Dipeptidylpeptidase IV und pharmazeutischen Zubereitungen daraus zur Therapie und Prävention dermatologischer Erkrankungen mit sebozytärer Hyperproliferation und veränderten Differenzierungszuständen |
US7307164B2 (en) * | 2002-03-25 | 2007-12-11 | Merck & Co., Inc. | β-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
US20030232761A1 (en) * | 2002-03-28 | 2003-12-18 | Hinke Simon A. | Novel analogues of glucose-dependent insulinotropic polypeptide |
PT1513519E (pt) * | 2002-06-03 | 2009-05-06 | Novartis Ag | Uso de cianopirrolidinas substituídas e preparações de combinações que as contêm para tratar hiperlipidemia e doenças associadas |
US6710040B1 (en) * | 2002-06-04 | 2004-03-23 | Pfizer Inc. | Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors |
WO2004007468A1 (en) * | 2002-07-15 | 2004-01-22 | Merck & Co., Inc. | Piperidino pyrimidine dipeptidyl peptidase inhibitors for the treatment of diabetes |
US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US7569574B2 (en) | 2002-08-22 | 2009-08-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Purine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US7495005B2 (en) * | 2002-08-22 | 2009-02-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, their preparation and their use in pharmaceutical compositions |
US20040058876A1 (en) * | 2002-09-18 | 2004-03-25 | Torsten Hoffmann | Secondary binding site of dipeptidyl peptidase IV (DP IV) |
DE60331747D1 (de) * | 2002-09-18 | 2010-04-29 | Prosidion Ltd | Sekundäre bindungsstelle von dipeptidylpeptidase iv (dp iv) |
US7262207B2 (en) | 2002-09-19 | 2007-08-28 | Abbott Laboratories | Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV) |
EP1554280B1 (en) | 2002-10-07 | 2007-08-15 | Merck & Co., Inc. | Antidiabetic beta-amino heterocyclic dipeptidyl peptidase inhibitors |
AU2003298596B2 (en) * | 2002-10-18 | 2008-12-18 | Merck Sharp & Dohme Corp. | Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
MXPA05004890A (es) | 2002-11-07 | 2005-07-22 | Merck & Co Inc | Derivados de fenilalanina como inhibidores de dipeptidilpeptidasa para el tratamiento o prevencion de diabetes. |
US7482337B2 (en) * | 2002-11-08 | 2009-01-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
DE10254304A1 (de) * | 2002-11-21 | 2004-06-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
CA2508487A1 (en) * | 2002-12-04 | 2004-06-17 | Merck & Co., Inc. | Phenylalanine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
EP1583534A4 (en) * | 2002-12-20 | 2007-08-29 | Merck & Co Inc | 3-AMINO-4-PHENYLBUTANIC ACID DERIVATIVES AS DIPEPTIDYL-PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES |
CN102558155A (zh) | 2003-01-14 | 2012-07-11 | 阿伦纳药品公司 | 作为代谢调节剂的芳基和杂芳基衍生物及其所涉及的疾病如糖尿病和高血糖症的预防和治疗 |
JP4564952B2 (ja) | 2003-01-17 | 2010-10-20 | メルク・シャープ・エンド・ドーム・コーポレイション | 糖尿病の治療および予防のためのジペプチジルペプチダーゼ阻害薬としての3−アミノ−4−フェニルブタン酸誘導体 |
PT1595866T (pt) * | 2003-01-31 | 2016-09-14 | Sanwa Kagaku Kenkyusho Co | Cianopirrolidinas úteis para o tratamento entre outras de síndrome metabólica |
CA2513684A1 (en) | 2003-01-31 | 2004-08-19 | Merck & Co., Inc. | 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
CN1894234A (zh) | 2003-03-25 | 2007-01-10 | 武田药品工业株式会社 | 二肽基肽酶抑制剂 |
NZ572274A (en) | 2003-05-05 | 2009-06-26 | Probiodrug Ag | Use of effectors of glutaminyl and glutamate cyclases |
DE602004026289D1 (de) | 2003-05-05 | 2010-05-12 | Probiodrug Ag | Glutaminylcyclase-hemmer |
ATE464889T1 (de) | 2003-05-05 | 2010-05-15 | Probiodrug Ag | Medizinische verwendung von hemmern von glutaminyl und glutamatcyclasen |
ATE447574T1 (de) | 2003-05-14 | 2009-11-15 | Merck & Co Inc | 3-amino-4-phenylbutansäurederivate als dipeptidylpeptidase-hemmer zur behandlung oder vorbeugung von diabetes |
JP2007511467A (ja) | 2003-05-14 | 2007-05-10 | タケダ サン ディエゴ インコーポレイテッド | ジペプチジルペプチダーゼインヒビター |
AU2004247068A1 (en) * | 2003-06-06 | 2004-12-23 | Merck & Co., Inc. | Fused indoles as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
US7456204B2 (en) * | 2003-06-17 | 2008-11-25 | Merck & Co., Inc. | Cyclohexylglycine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
US7566707B2 (en) | 2003-06-18 | 2009-07-28 | Boehringer Ingelheim International Gmbh | Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions |
PT1638970E (pt) | 2003-06-20 | 2010-12-13 | Hoffmann La Roche | Derivados de pirid(2,1-a)isoquinolina como inibidores de dpp-iv |
CN101090901B (zh) | 2003-06-20 | 2010-12-15 | 霍夫曼-拉罗奇有限公司 | 作为dpp-iv抑制剂的六氢吡啶并异喹啉类 |
SI1648933T1 (sl) * | 2003-07-25 | 2010-01-29 | Conjuchem Biotechnologies Inc | Dolgo delujoäś inzulinski derivat in metoda zanj |
CN1882551A (zh) | 2003-07-31 | 2006-12-20 | 麦克公司 | 用作用于治疗或预防糖尿病的二肽基肽酶-iv酶抑制剂的六氢二氮杂吖庚因酮 |
US7678909B1 (en) | 2003-08-13 | 2010-03-16 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7169926B1 (en) | 2003-08-13 | 2007-01-30 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
KR20060041309A (ko) | 2003-08-13 | 2006-05-11 | 다케다 야쿠힌 고교 가부시키가이샤 | 4-피리미돈 유도체 및 펩티딜 펩티다제 저해제로서의 그의용도 |
JP2007505121A (ja) | 2003-09-08 | 2007-03-08 | 武田薬品工業株式会社 | ジペプチジルぺプチダーゼ阻害剤 |
EA010108B1 (ru) * | 2003-10-15 | 2008-06-30 | Пробиодруг Аг | Применение эффекторов глутаминил- и глутаматциклаз |
KR20060109923A (ko) * | 2003-10-31 | 2006-10-23 | 알자 코포레이션 | 철분의 개선된 흡수를 위한 조성물 및 제형 |
US20100099721A1 (en) * | 2003-11-03 | 2010-04-22 | Probiodrug Ag | Novel compounds for the treatment of neurological disorders |
US20050171112A1 (en) * | 2003-11-03 | 2005-08-04 | Probiodrug Ag | Combinations useful for the treatment of neuronal disorders |
EP1680120A2 (en) | 2003-11-03 | 2006-07-19 | Probiodrug AG | Combinations useful for the treatment of neuronal disorders |
WO2005044195A2 (en) * | 2003-11-04 | 2005-05-19 | Merck & Co., Inc. | Fused phenylalanine derivatives as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
US7317109B2 (en) | 2003-11-12 | 2008-01-08 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
US7576121B2 (en) | 2003-11-12 | 2009-08-18 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
US7767828B2 (en) | 2003-11-12 | 2010-08-03 | Phenomix Corporation | Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
SI1689757T1 (sl) | 2003-11-12 | 2015-01-30 | Sino-Med International Alliance, Inc. | Heterociklične spojine boronske kisline |
KR20060109911A (ko) | 2003-11-17 | 2006-10-23 | 노파르티스 아게 | 디펩티딜 펩티다제 ⅳ 억제제의 용도 |
DE10355304A1 (de) * | 2003-11-27 | 2005-06-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 8-(Piperazin-1-yl)-und 8-([1,4]Diazepan-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
ES2332920T3 (es) | 2004-01-20 | 2010-02-15 | Novartis Ag | Proceso y formulacion de compresion directa. |
US7230002B2 (en) | 2004-02-03 | 2007-06-12 | Glenmark Pharmaceuticals Ltd. | Dipeptidyl peptidase IV inhibitors; processes for their preparation and compositions thereof |
US7304086B2 (en) | 2004-02-05 | 2007-12-04 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
CN101684089A (zh) * | 2004-02-05 | 2010-03-31 | 杏林制药株式会社 | 双环酯类衍生物 |
US7501426B2 (en) * | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
DE102004009039A1 (de) * | 2004-02-23 | 2005-09-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und Verwendung als Arzneimittel |
EP1593671A1 (en) * | 2004-03-05 | 2005-11-09 | Graffinity Pharmaceuticals AG | DPP-IV inhibitors |
US7732446B1 (en) | 2004-03-11 | 2010-06-08 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7393847B2 (en) | 2004-03-13 | 2008-07-01 | Boehringer Ingleheim International Gmbh | Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions |
AU2004318013B8 (en) | 2004-03-15 | 2011-10-06 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7179809B2 (en) * | 2004-04-10 | 2007-02-20 | Boehringer Ingelheim International Gmbh | 2-Amino-imidazo[4,5-d]pyridazin-4-ones, their preparation and their use as pharmaceutical compositions |
AU2005241056A1 (en) * | 2004-05-04 | 2005-11-17 | Merck & Co., Inc. | 1,2,4-oxadiazole derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
US7439370B2 (en) * | 2004-05-10 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides |
CN1960990A (zh) * | 2004-05-18 | 2007-05-09 | 默克公司 | 作为用于治疗或预防糖尿病的二肽基肽酶-ⅳ抑制剂的环己基丙氨酸衍生物 |
EP1598341A1 (en) * | 2004-05-21 | 2005-11-23 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | DPP-IV inhibitors |
WO2005118555A1 (en) | 2004-06-04 | 2005-12-15 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
EP1604989A1 (en) * | 2004-06-08 | 2005-12-14 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | DPP-IV inhibitors |
EP1604980A1 (en) * | 2004-06-08 | 2005-12-14 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | DPP-IV inhibitors |
DE102004030502A1 (de) | 2004-06-24 | 2006-01-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Imidazole und Triazole, deren Herstellung und Verwendung als Arzneimittel |
WO2006019965A2 (en) | 2004-07-16 | 2006-02-23 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
ATE553077T1 (de) * | 2004-07-23 | 2012-04-15 | Nuada Llc | Peptidaseinhibitoren |
EP1623983A1 (en) * | 2004-08-05 | 2006-02-08 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | Heterocyclic compounds useful as DPP-IV inhibitors |
DE102004043944A1 (de) * | 2004-09-11 | 2006-03-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 8-(3-Amino-piperidin-1-yl)-7-(but-2-inyl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
DE102004044221A1 (de) * | 2004-09-14 | 2006-03-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 3-Methyl-7-butinyl-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
US20060063719A1 (en) * | 2004-09-21 | 2006-03-23 | Point Therapeutics, Inc. | Methods for treating diabetes |
AU2005293266B2 (en) | 2004-10-12 | 2011-09-29 | Glenmark Pharmaceuticals S.A. | Novel dipeptidyl peptidase IV inhibitors, pharmaceutical compositions containing them, and process for their preparation |
DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
CN101107247B (zh) * | 2004-11-30 | 2011-10-19 | 霍夫曼-拉罗奇有限公司 | 作为用于治疗糖尿病的dpp-iv抑制剂的取代的苯并喹嗪衍生物 |
US7411093B2 (en) | 2004-12-20 | 2008-08-12 | Hoffman-La Roche Inc. | Aminocycloalkanes as DPP-IV inhibitors |
RU2396257C2 (ru) | 2004-12-20 | 2010-08-10 | Ф.Хоффманн-Ля Рош Аг | Производные 4-аминопиперидина |
EP1828192B1 (en) | 2004-12-21 | 2014-12-03 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
DOP2006000008A (es) | 2005-01-10 | 2006-08-31 | Arena Pharm Inc | Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1 |
US8263545B2 (en) | 2005-02-11 | 2012-09-11 | Amylin Pharmaceuticals, Inc. | GIP analog and hybrid polypeptides with selectable properties |
KR20070115947A (ko) | 2005-02-11 | 2007-12-06 | 아밀린 파마슈티칼스, 인크. | 선택가능한 특성들을 가지는 gip 유사체 및 하이브리드폴리펩타이드 |
WO2006088129A1 (ja) | 2005-02-18 | 2006-08-24 | Mitsubishi Pharma Corporation | プロリン誘導体の塩、またはその溶媒和物、及びその製造方法 |
BRPI0608469A2 (pt) | 2005-04-22 | 2010-01-05 | Alantos Pharmaceuticals Holding Inc | inibidores de dipeptidil peptidase-iv |
JP5100375B2 (ja) * | 2005-04-26 | 2012-12-19 | 田辺三菱製薬株式会社 | 糖・脂質代謝異常の予防及び/又は治療薬 |
US7521557B2 (en) * | 2005-05-20 | 2009-04-21 | Bristol-Myers Squibb Company | Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods |
US7825139B2 (en) * | 2005-05-25 | 2010-11-02 | Forest Laboratories Holdings Limited (BM) | Compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
EP2356997A1 (en) | 2005-06-06 | 2011-08-17 | Georgetown University | Compositions and methods for lipo modeling |
DE102005035891A1 (de) * | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
GT200600381A (es) | 2005-08-25 | 2007-03-28 | Compuestos organicos | |
WO2007028633A2 (en) * | 2005-09-08 | 2007-03-15 | Uutech Limited | Treatment of diabetes related obesity |
WO2007028632A2 (en) * | 2005-09-08 | 2007-03-15 | Uutech Limited | Analogs of gastric inhibitory polypeptide as a treatment for age related decreased pancreatic beta cell function |
CA2622472C (en) | 2005-09-14 | 2013-11-19 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors for treating diabetes |
US8222411B2 (en) | 2005-09-16 | 2012-07-17 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
EP1971614A1 (en) * | 2005-11-14 | 2008-09-24 | Probiodrug AG | Cyclopropyl-fused pyrrolidine derivatives as dipeptidyl peptidase iv inhibitors |
DE102005054994B4 (de) * | 2005-11-18 | 2015-02-12 | Bader Gmbh & Co. Kg | Verkleidungsanordnung, insbesondere Maschinenverkleidung, mit einer Schiebetür und Führungsanordnung hierfür |
GB0526291D0 (en) | 2005-12-23 | 2006-02-01 | Prosidion Ltd | Therapeutic method |
CA2645154C (en) | 2006-03-08 | 2011-11-29 | Kyorin Pharmaceutical Co., Ltd. | Method for producing aminoacetylpyrrolidinecarbonitrile derivative and production intermediate thereof |
WO2007112347A1 (en) | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
PE20071221A1 (es) | 2006-04-11 | 2007-12-14 | Arena Pharm Inc | Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas |
RS51745B (en) | 2006-04-11 | 2011-10-31 | Arena Pharmaceuticals Inc. | PROCEDURE FOR USING GPR119 RECEPTORS FOR INDENTIFICATION OF UNITS USEFUL FOR BONE WEIGHT INCREASE |
BRPI0709984A2 (pt) | 2006-04-12 | 2011-08-02 | Probiodrug Ag | inibidores de enzima |
PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
EP1852108A1 (en) * | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
BRPI0711558A2 (pt) | 2006-05-04 | 2011-11-08 | Boeringer Ingelheim Internat Gmbh | polimorfos |
WO2008017670A1 (en) * | 2006-08-08 | 2008-02-14 | Boehringer Ingelheim International Gmbh | Pyrrolo [3, 2 -d] pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus |
US8497240B2 (en) | 2006-08-17 | 2013-07-30 | Amylin Pharmaceuticals, Llc | DPP-IV resistant GIP hybrid polypeptides with selectable properties |
KR20090088854A (ko) * | 2006-09-13 | 2009-08-20 | 다케다 야쿠힌 고교 가부시키가이샤 | 2-6-(3-아미노-피페리딘-엘-일)-3-메틸-2,4-디옥소-3,4-디하이드로-2h-피리미딘-1-일메틸-4-플루오로-벤조니트릴의 용도 |
US8324383B2 (en) | 2006-09-13 | 2012-12-04 | Takeda Pharmaceutical Company Limited | Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile |
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
US8217025B2 (en) * | 2006-11-17 | 2012-07-10 | Harbor Therapeutics, Inc. | Drug screening and treatment methods |
TW200838536A (en) | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
ATE554085T1 (de) | 2006-11-30 | 2012-05-15 | Probiodrug Ag | Neue inhibitoren von glutaminylcyclase |
US8093236B2 (en) | 2007-03-13 | 2012-01-10 | Takeda Pharmaceuticals Company Limited | Weekly administration of dipeptidyl peptidase inhibitors |
US20070172525A1 (en) * | 2007-03-15 | 2007-07-26 | Ramesh Sesha | Anti-diabetic combinations |
US20080064701A1 (en) * | 2007-04-24 | 2008-03-13 | Ramesh Sesha | Anti-diabetic combinations |
EP2123636B1 (en) | 2007-03-22 | 2012-03-21 | Kyorin Pharmaceutical Co., Ltd. | Method for producing aminoacetylpyrrolidinecarbonitrile derivative |
EP2143443B1 (en) | 2007-04-03 | 2014-11-19 | Mitsubishi Tanabe Pharma Corporation | A combination of dipeptidyl peptidase iv inhibitor and sweetener for use in the treatment of obesity |
EP2865670B1 (en) | 2007-04-18 | 2017-01-11 | Probiodrug AG | Thiourea derivatives as glutaminyl cyclase inhibitors |
US7820666B2 (en) | 2007-05-08 | 2010-10-26 | Concert Pharmaceuticals, Inc. | Tetrahydrotriazolopyrazine derivatives and uses thereof |
EP2025674A1 (de) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
CL2008002427A1 (es) * | 2007-08-16 | 2009-09-11 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende 1-cloro-4-(b-d-glucopiranos-1-il)-2-[4-((s)-tetrahidrofurano-3-iloxi)bencil]-benceno combinado con 1-[(4-metilquinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(r)-aminopiperidin-1-il)xantina; y su uso para tratar diabetes mellitus tipo 2. |
EP2190434B1 (en) * | 2007-08-17 | 2019-04-17 | Boehringer Ingelheim International GmbH | Purin derivatives for use in the treatment of fap-related diseases |
US20090076013A1 (en) * | 2007-09-17 | 2009-03-19 | Protia, Llc | Deuterium-enriched sitagliptin |
CL2008003653A1 (es) | 2008-01-17 | 2010-03-05 | Mitsubishi Tanabe Pharma Corp | Uso de un inhibidor de sglt derivado de glucopiranosilo y un inhibidor de dppiv seleccionado para tratar la diabetes; y composicion farmaceutica. |
US8551524B2 (en) * | 2008-03-14 | 2013-10-08 | Iycus, Llc | Anti-diabetic combinations |
PE20091730A1 (es) | 2008-04-03 | 2009-12-10 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
EP2146210A1 (en) | 2008-04-07 | 2010-01-20 | Arena Pharmaceuticals, Inc. | Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
PE20100156A1 (es) * | 2008-06-03 | 2010-02-23 | Boehringer Ingelheim Int | Tratamiento de nafld |
EP2650296A1 (en) | 2008-07-03 | 2013-10-16 | Ratiopharm GmbH | Crystalline salts of sitagliptin |
KR20190016601A (ko) | 2008-08-06 | 2019-02-18 | 베링거 인겔하임 인터내셔날 게엠베하 | 메트포르민 요법이 부적합한 환자에서의 당뇨병 치료 |
UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
JP5476305B2 (ja) * | 2008-08-07 | 2014-04-23 | 杏林製薬株式会社 | ビシクロ[2.2.2]オクチルアミン誘導体の製造方法 |
US20110152342A1 (en) * | 2008-08-14 | 2011-06-23 | Hiroshi Uchida | Stabilized pharmaceutical composition |
EP2326326B1 (en) * | 2008-08-15 | 2019-10-09 | Boehringer Ingelheim International GmbH | Dpp-4 inhibitors for use for the treatment of wound healing in diabetic patients |
RU2011113823A (ru) | 2008-09-10 | 2012-10-20 | БЕРИНГЕР ИНГЕЛЬХАЙМ ИНТЕРНАЦИОНАЛЬ ГмбХ (DE) | Комбинированная терапия, предназначенная для лечения диабета и связанных с ним состояний |
US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
JO2870B1 (en) | 2008-11-13 | 2015-03-15 | ميرك شارب اند دوهم كورب | Amino Tetra Hydro Pirans as Inhibitors of Peptide Dipeptide IV for the Treatment or Prevention of Diabetes |
WO2010062861A2 (en) | 2008-11-26 | 2010-06-03 | Satiogen Pharmaceuticals, Inc. | Bile acid recycling inhibitors for treatment of obesity and diabetes |
CN102316889B (zh) | 2008-11-26 | 2014-11-26 | 萨蒂奥根制药公司 | 组合物及使用方法 |
KR20110103968A (ko) | 2008-12-23 | 2011-09-21 | 베링거 인겔하임 인터내셔날 게엠베하 | 유기 화합물의 염 형태 |
US8404727B2 (en) | 2009-01-07 | 2013-03-26 | Glenmark Pharmaceuticals S.A. | Pharmaceutical composition that includes a dipeptidyl peptidase-IV inhibitor |
TW201036975A (en) | 2009-01-07 | 2010-10-16 | Boehringer Ingelheim Int | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy |
AP2011005794A0 (en) | 2009-02-13 | 2011-08-31 | Boehringer Ingelheim Int | Pharmaceutical composition comprising a SGLT2 inhibitor, a DPP-IV inhibitor and optionally a furtherantidiabetic agent and uses thereof. |
EA201101621A1 (ru) | 2009-05-15 | 2012-05-30 | Новартис Аг | Производные бензоксазолона в качестве ингибиторов альдостеронсинтазы |
EP2429995B1 (en) | 2009-05-15 | 2014-01-22 | Novartis AG | Aryl pyridine as aldosterone synthase inhibitors |
ES2523734T3 (es) | 2009-05-28 | 2014-12-01 | Novartis Ag | Derivados aminopropiónicos sustituidos como inhibidores de neprilisina |
CA2763565A1 (en) | 2009-05-28 | 2010-12-02 | Novartis Ag | Substituted aminobutyric derivatives as neprilysin inhibitors |
AR077642A1 (es) | 2009-07-09 | 2011-09-14 | Arena Pharm Inc | Moduladores del metabolismo y el tratamiento de trastornos relacionados con el mismo |
CN102595897A (zh) | 2009-09-02 | 2012-07-18 | 默沙东公司 | 作为用于糖尿病的治疗或预防的二肽基肽酶-iv抑制剂的氨基四氢吡喃 |
EP2475428B1 (en) | 2009-09-11 | 2015-07-01 | Probiodrug AG | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
US20110160159A1 (en) | 2009-09-15 | 2011-06-30 | John Ryan | Treatment of cancer |
JP5654608B2 (ja) | 2009-11-17 | 2015-01-14 | ノバルティス アーゲー | アルドステロンシンターゼ阻害剤としてのアリール−ピリジン誘導体 |
JO2967B1 (en) | 2009-11-20 | 2016-03-15 | نوفارتس ايه جي | Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors |
EA201200617A1 (ru) | 2009-11-23 | 2012-11-30 | Серулин Фарма Инк. | Полимеры на основе циклодекстрина для доставки лекарственных средств |
MX364651B (es) | 2009-11-27 | 2019-05-03 | Boehringer Ingelheim Int Gmbh Star | Inhibidores de dpp-iv, tales como la linagliptina, y composiciones farmacéuticas o combinaciones que comprenden los mismos, para usarse en el tratamiento de pacientes diabéticos tipificados genéticamente. |
CN102666535B (zh) | 2009-11-30 | 2015-02-25 | 诺华股份有限公司 | 作为醛固酮合酶抑制剂的咪唑衍生物 |
WO2011090940A1 (en) | 2010-01-19 | 2011-07-28 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutic delivery |
US8853212B2 (en) | 2010-02-22 | 2014-10-07 | Merck Sharp & Dohme Corp | Substituted aminotetrahydrothiopyrans and derivatives thereof as dipeptidyl peptidase-IV inhibitors for the treatment of diabetes |
ES2586231T3 (es) | 2010-03-03 | 2016-10-13 | Probiodrug Ag | Inhibidores de glutaminil ciclasa |
CN102791704B (zh) | 2010-03-10 | 2015-11-25 | 前体生物药物股份公司 | 谷氨酰胺酰环化酶(qc, ec 2.3.2.5)的杂环抑制剂 |
WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
EP2560953B1 (en) | 2010-04-21 | 2016-01-06 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
EP2566469B1 (en) | 2010-05-05 | 2022-12-21 | Boehringer Ingelheim International GmbH | Combination therapy |
US8980929B2 (en) | 2010-05-21 | 2015-03-17 | Merck Sharp & Dohme Corp. | Substituted seven-membered heterocyclic compounds as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes |
EP2575821B1 (en) | 2010-05-26 | 2015-08-12 | Satiogen Pharmaceuticals, Inc. | Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions |
WO2011157827A1 (de) | 2010-06-18 | 2011-12-22 | Sanofi | Azolopyridin-3-on-derivate als inhibitoren von lipasen und phospholipasen |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
EP2585101A1 (en) | 2010-06-24 | 2013-05-01 | Boehringer Ingelheim International GmbH | Diabetes therapy |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
US10894787B2 (en) | 2010-09-22 | 2021-01-19 | Arena Pharmaceuticals, Inc. | Modulators of the GPR119 receptor and the treatment of disorders related thereto |
WO2012049566A1 (en) | 2010-10-14 | 2012-04-19 | Japan Tobacco Inc. | Combination therapy for use in treating diabetes |
US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
US8877815B2 (en) | 2010-11-16 | 2014-11-04 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP |
US8673974B2 (en) | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
AR085689A1 (es) | 2011-03-07 | 2013-10-23 | Boehringer Ingelheim Int | Composiciones farmaceuticas de metformina, linagliptina y un inhibidor de sglt-2 |
US8530670B2 (en) | 2011-03-16 | 2013-09-10 | Probiodrug Ag | Inhibitors |
WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145361A1 (en) | 2011-04-19 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145603A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
US20140051714A1 (en) | 2011-04-22 | 2014-02-20 | Arena Pharmaceuticals, Inc. | Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013006526A2 (en) | 2011-07-05 | 2013-01-10 | Merck Sharp & Dohme Corp. | Tricyclic heterocycles useful as dipeptidyl peptidase-iv inhibitors |
MX366629B (es) | 2011-07-15 | 2019-07-17 | Boehringer Ingelheim Int | Quinazolinas sustituidas, su preparación y su uso en composiciones farmacéuticas. |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
CA2853285C (en) | 2011-10-28 | 2020-05-05 | Lumena Pharmaceuticals, Inc. | Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases |
US9115082B2 (en) | 2012-01-18 | 2015-08-25 | Catherine Yang | Dipeptidyl-peptidase-IV inhibitors for treatment of type 2 diabetes complex with hypertension |
WO2013122920A1 (en) | 2012-02-17 | 2013-08-22 | Merck Sharp & Dohme Corp. | Dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
EP3685839A1 (en) | 2012-05-14 | 2020-07-29 | Boehringer Ingelheim International GmbH | Linagliptin for use in the treatment of albuminuria and kidney related diseases |
WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
EP2874622A4 (en) | 2012-07-23 | 2015-12-30 | Merck Sharp & Dohme | TREATMENT OF DIABETES WITH DIPEPTIDYLPEPTIDASE IV INHIBITORS |
TWI500613B (zh) | 2012-10-17 | 2015-09-21 | Cadila Healthcare Ltd | 新穎之雜環化合物 |
IN2015DN03795A (es) | 2012-10-24 | 2015-10-02 | Inserm Inst Nat De La Santé Et De La Rech Médicale | |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
UY35144A (es) | 2012-11-20 | 2014-06-30 | Novartis Ag | Miméticos lineales sintéticos de apelina para el tratamiento de insuficiencia cardiaca |
LT2956464T (lt) | 2013-02-14 | 2018-07-10 | Novartis Ag | Pakeisti bisfenilbutanoinės fosfonrūgšties dariniai, kaip nep (neutralios endopeptidazės) inhibitoriai |
TN2016000031A1 (en) | 2013-07-25 | 2017-07-05 | Novartis Ag | Cyclic polypeptides for the treatment of heart failure |
MX2016001021A (es) | 2013-07-25 | 2016-08-03 | Novartis Ag | Bioconjugados de polipeptidos de apelina sinteticos. |
US9902751B2 (en) | 2013-12-30 | 2018-02-27 | Mylan Laboratories Limited | Process for the preparation of empagliflozin |
EP3110449B1 (en) | 2014-02-28 | 2023-06-28 | Boehringer Ingelheim International GmbH | Medical use of a dpp-4 inhibitor |
GB201415598D0 (en) | 2014-09-03 | 2014-10-15 | Univ Birmingham | Elavated Itercranial Pressure Treatment |
DE102014018663A1 (de) | 2014-12-13 | 2015-03-05 | Heinz Kiefer | Nachweis von vermehrungsfähigen Zellen zur Überprüfung von Arzneimittel-Wirkstoffangaben bei Zulassungsverfahren |
KR20230151072A (ko) | 2015-01-06 | 2023-10-31 | 아레나 파마슈티칼스, 인크. | S1p1 수용체와 관련된 상태의 치료 방법 |
AU2016209968B2 (en) | 2015-01-23 | 2018-11-29 | Novartis Ag | Synthetic apelin fatty acid conjugates with improved half-life |
KR20220070057A (ko) | 2015-03-09 | 2022-05-27 | 인테크린 테라퓨틱스, 아이엔씨. | 비알코올성 지방간 질환 및/또는 지방이영양증의 치료 방법 |
EP3273981B1 (en) | 2015-03-24 | 2020-04-29 | INSERM - Institut National de la Santé et de la Recherche Médicale | Method and pharmaceutical composition for use in the treatment of diabetes |
HUE060476T2 (hu) | 2015-06-22 | 2023-03-28 | Arena Pharm Inc | (R)-2-(7-(4-ciklopentil-3-(trifluormetil)benziloxi)-1,2,3,4- tetrahidrociklopenta[B]indol-3-il)ecetsav kristályos L-arginin-sója S1P1 receptorral kapcsolatos rendellenességek esetén való alkalmazásra |
BR112018013195A2 (pt) | 2015-12-28 | 2018-12-11 | Wockhardt Ltd | composição farmacêutica osmótica oral de vildagliptina |
US11013738B2 (en) * | 2016-04-29 | 2021-05-25 | Fundació Hospital Universitari Vall D'hebron—Institut De Recerca | Dipeptidyl peptidase-4 inhibitors for topical eye treatment of retinal neurodegenerative diseases |
WO2017211979A1 (en) | 2016-06-10 | 2017-12-14 | Boehringer Ingelheim International Gmbh | Combinations of linagliptin and metformin |
JOP20190086A1 (ar) | 2016-10-21 | 2019-04-18 | Novartis Ag | مشتقات نافثيريدينون جديدة واستخدامها في معالجة عدم انتظام ضربات القلب |
WO2018162722A1 (en) | 2017-03-09 | 2018-09-13 | Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke | Dpp-4 inhibitors for use in treating bone fractures |
AU2018249822A1 (en) | 2017-04-03 | 2019-10-31 | Coherus Biosciences Inc. | PPArgamma agonist for treatment of progressive supranuclear palsy |
EP3424927B1 (en) | 2017-07-04 | 2019-04-17 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Efficient process for the preparation of sitagliptin through a very effective preparation of the intermediate 2,4,5-trifluorophenylacetic acid |
AR112480A1 (es) | 2017-08-24 | 2019-10-30 | Novo Nordisk As | Composiciones de glp-1 y sus usos |
PL3461819T3 (pl) | 2017-09-29 | 2020-11-30 | Probiodrug Ag | Inhibitory cyklazy glutaminylowej |
UY38072A (es) | 2018-02-07 | 2019-10-01 | Novartis Ag | Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos |
EP3524605B1 (en) | 2018-02-13 | 2019-11-27 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | New efficient process for the preparation of sitagliptin |
WO2020110011A1 (en) | 2018-11-27 | 2020-06-04 | Novartis Ag | Cyclic peptides as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders |
WO2020110008A1 (en) | 2018-11-27 | 2020-06-04 | Novartis Ag | Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder |
UY38485A (es) | 2018-11-27 | 2020-06-30 | Novartis Ag | Compuestos tetrámeros cíclicos como inhibidores de proproteína convertasa subtilisina/kexina tipo 9 (pcsk9), método de tratamiento, uso y su preparación |
MX2022001647A (es) | 2019-09-17 | 2022-03-11 | Novartis Ag | Terapia de combinacion con vildagliptina y metformina. |
US20230082544A1 (en) | 2020-02-18 | 2023-03-16 | Novo Nordisk A/S | Pharmaceutical formulations |
EP4192509A1 (en) | 2020-08-05 | 2023-06-14 | Ellipses Pharma Ltd | Treatment of cancer using a cyclodextrin-containing polymer-topoisomerase inhibitor conjugate and a parp inhibitor |
WO2023084449A1 (en) | 2021-11-12 | 2023-05-19 | Novartis Ag | Diaminocyclopentylpyridine derivatives for the treatment of a disease or disorder |
AR127698A1 (es) | 2021-11-23 | 2024-02-21 | Novartis Ag | Derivados de naftiridinona para el tratamiento de una enfermedad o un trastorno |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE296075C (es) | ||||
US2961377A (en) | 1957-08-05 | 1960-11-22 | Us Vitamin Pharm Corp | Oral anti-diabetic compositions and methods |
DE2009743A1 (de) | 1970-03-03 | 1971-09-16 | Farbenfabriken Bayer Ag, 5090 Leverkusen | Substituierte Biguanide mit antihyperglykämischer Wirkung |
US3960949A (en) | 1971-04-02 | 1976-06-01 | Schering Aktiengesellschaft | 1,2-Biguanides |
CH602612A5 (es) | 1974-10-11 | 1978-07-31 | Hoffmann La Roche | |
US4935493A (en) | 1987-10-06 | 1990-06-19 | E. I. Du Pont De Nemours And Company | Protease inhibitors |
US5433955A (en) | 1989-01-23 | 1995-07-18 | Akzo N.V. | Site specific in vivo activation of therapeutic drugs |
DD296075A5 (de) * | 1989-08-07 | 1991-11-21 | Martin-Luther-Universitaet Halle-Wittenberg,De | Verfahren zur herstellung neuer inhibitoren der dipeptidyl peptidase iv |
EP0512042B1 (en) * | 1990-01-24 | 1998-04-08 | BUCKLEY, Douglas I. | Glp-1 analogs useful for diabetes treatment |
US5462928A (en) * | 1990-04-14 | 1995-10-31 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type IV |
WO1991017767A1 (en) * | 1990-05-21 | 1991-11-28 | New England Medical Center Hospitals, Inc. | Method of treating inhibition of dipeptidyl aminopeptidase type iv |
JPH04334357A (ja) | 1991-05-02 | 1992-11-20 | Fujirebio Inc | 酵素阻害作用を有するアシル誘導体 |
JPH07504158A (ja) | 1991-10-22 | 1995-05-11 | ニュー イングランド メディカル センター ホスピタルズ インク | ジペプチジル−アミノペプチダーゼiv型のインヒビタ |
IL106998A0 (en) | 1992-09-17 | 1993-12-28 | Univ Florida | Brain-enhanced delivery of neuroactive peptides by sequential metabolism |
FR2696740B1 (fr) | 1992-10-13 | 1994-12-30 | Dospharma Sa | Dérivés prodrogués de la diméthylbiguanide et applications comme médicaments. |
WO1995011689A1 (en) | 1993-10-29 | 1995-05-04 | Trustees Of Tufts College | Use of inhibitors of dipeptidyl-aminopeptidase to block entry of hiv into cells |
IL111785A0 (en) | 1993-12-03 | 1995-01-24 | Ferring Bv | Dp-iv inhibitors and pharmaceutical compositions containing them |
EP0658568A1 (en) | 1993-12-09 | 1995-06-21 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
JPH07228529A (ja) * | 1994-02-17 | 1995-08-29 | Zeria Pharmaceut Co Ltd | コリンエステラーゼ賦活剤 |
US5543396A (en) * | 1994-04-28 | 1996-08-06 | Georgia Tech Research Corp. | Proline phosphonate derivatives |
US5512549A (en) | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
US5614379A (en) | 1995-04-26 | 1997-03-25 | Eli Lilly And Company | Process for preparing anti-obesity protein |
DE19616486C5 (de) | 1996-04-25 | 2016-06-30 | Royalty Pharma Collection Trust | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
AU3224997A (en) | 1996-05-29 | 1998-01-05 | Prototek, Inc | Prodrugs of thalidomide and methods for using same as modulators of t-cell function |
US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
AR016751A1 (es) | 1996-11-22 | 2001-08-01 | Athena Neurosciences Inc | Metodo para inhibir la liberacion del peptido beta-amiloide en una celula, composicion farmaceutica y compuestos utiles en dicho metodo |
WO2000053171A1 (en) | 1999-03-05 | 2000-09-14 | Molteni L. E C. Dei Fratelli Alitti Societa' Di Esercizio S.P.A. | Use of metformin in the preparation of pharmaceutical compositions capable of inhibiting the enzyme dipeptidyl peptidase iv |
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1996
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