Traitement en cours

Veuillez attendre...

Paramétrages

Paramétrages

Aller à Demande

1. WO2004099201 - COMPOSES UTILISES COMME ANTAGONISTES DU RECEPTEUR DE TYPE 1 DE LA CORTICOLIBERINE (CRF)

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

CLAIMS
WHAT IS CLAIMED IS:
1. A compound of Formula I,


Formula I
or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein in Formula I,
Ar is selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
V is heteroaryl or phenyl, wherein heterocaryl and phenyl are optionally substituted with 1- 5 of Rt ;
Ra each is independently selected from H, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, and heterocycloalkyl is optionally substituted with 1 to 5 of Rt, -Oalkyl, -S(0)mR,, NRtRt, oxo (=0), thione (=S), phenyl, heteroaryl, or heterocycloalkyl.
Rt each is independently selected from H, halogen, -N02, -NH2, -OH, -SH, -CN, -C(0)NH2, -C(0)-NHalkyl, -C(0)Nalkylalkyl, -Oalkyl, -Ohaloalkyl, NHalkyl, Nalkylalkyl, -S(0)malkyl, S02NH2, S02NhalkyI, S02Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl, heteroaryl, or heterocycloalkyl; and
m is 0,1 or 2;
2. A compound of claim 1 , which is selected from the group consisting of:
5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1 ,3-thiazol-2-yI)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine,
5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-pyridin-2-ylpyrrolidin-3-yi]-3,6-diethylpyrazin-2-amine,
5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-pyridin-3-ylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine,
5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-pyridin-4-ylpyrrolidin-3-yI]-3,6-diethylpyrazin-2-amine,
5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine, N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methyIpyridin-3-yl)pyrazin-2-amine,
N-[(3R,4S)-4-ethoxy-1-pyridin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine,
N-[(3R,4S)-4-ethoxy-1 -(1 ,3-thiazoI-2-yl)pyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine,
5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(3R,4S)-4-ethoxy-1-pyridin-2-ylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine
5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine
5-[6-(dimethyIamino)-4-methylpyridin-3-yl]-N-[(3R,4S)-4-ethoxy-1-(1 ,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine
5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxy-1-(4-methoxypyrimidin-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine
5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxy-1 -(4-methoxypyridin-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine hydrogen chloride
5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine
5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxy-1-pyridin-2-ylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine
5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxy-1-pyridin-3-ylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine
5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxy-1-(1 ,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine
N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine
N-[(3R,4S)-4-ethoxy-1-pyridin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine
N-[(3R,4S)-4-ethoxy-1-(1 ,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine
N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]pyrazin-2-amine
N-[(3R,4S)-4-ethoxy-1-pyridin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]pyrazin-2-amine
N-[(3R,4S)-4-ethoxy-1-(1 ,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethyl-5-[6-methoxy-2- (trifluoromethyl)pyridin-3-yl]pyrazin-2-amine 5-(2,6-dimethoxypyridin-3-yl)-N-[(3R,4S)-4-ethoxy-1-pyridin-2-ylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine hydrogen chloride
5-(2,6-dimethoxypyridin-3-yI)-N-[(3R,4S)-4-ethoxy-1 -(1 ,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazjn-2-amine
5-(2,6-dimethoxypyridin-3-yl)-N-[(3R,4S)-4-ethoxy-1 -pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-afnine
3. A pharmaceutical composition comprising a compound of claim 1 or 2.
4. A method of inhibiting the binding of CRF to the CRFi receptor in vitro, the method comprising contacting, in the presence of CRF, a solution comprising a compound of claim 1 or 2 with cells expressing the CRFi receptor, wherein the compound is present in the solution at a concentration sufficient to reduce levels of CRF binding to the cells in vitro.
5. A method of antagonizing a CRFi receptor in a mammal, comprising administering to the mammal, a therapeutically effective amount of a compound of claim 1 or 2.
6. A method for screening for ligands for CRFi receptors, which method comprises: a) carrying out a competitive binding assay with a CRFi receptor, a compound of claim 1 or 2, which is labeled with a detectable label, and a candidate ligand; and b) determining the ability of said candidate ligand to displace said labeled compound.
7. A method of treating a disorder in a mammal the treatment of which disorder can be effected or facilitated by antagonizing CRF.
8. The method according to claim 7 wherein the disorder manifests hypersecretion of CRF.
9. The method according to claim 8 wherein the mammal is a human and the disorder is selected from anxiety-related disorders; mood disorders; post-traumatic stress disorder; supranuclear palsy; immune suppression; drug or alcohol withdrawal symptoms; inflammatory disorders; pain; asthma; psoriasis and allergies; phobias; sleep disorders induced by stress; fibromyalgia; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer; human immunodeficiency virus infections; neurodegenerative diseases; gastrointestinal diseases; eating disorders; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone; obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; cardiovascular and heart related disorders; immune dysfunctions; muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions; psychosocial dwarfism, hypoglycemia,.and skin disorders; and hair loss.

10. The method according to claim 9 wherein the disorder is selected from anxiety-related disorders; mood disorders; bipolar disorders; post-traumatic stress disorder; inflammatory disorders; chemical dependencies and addictions; gastrointestinal disorders; and skin disorders.
11. The method according to claim 10 wherein the disorder is selected from anxiety-related disorders or mood disorders and wherein the anxiety-related disorder is generalized anxiety and wherein the mood disorder is depression.
12. A method of promoting hair growth in a human, comprising administering to the human in need thereof an effective amount of a compound of claim 1 or 2.
13. A method of promoting smoking cessation in a human, comprising administering to the human in need thereof an effective amount of a compound of claim 1 or 2.
14. A compound of claim 1 or 2 wherein, in a standard in vitro CRF receptor-binding assay, the compound exhibits a Ki value of 1 micromolar or less.
15. A compound of claim 14 wherein the compound exhibits a Ki value of 100 nanomolar or less.