Traitement en cours

Veuillez attendre...

Paramétrages

Paramétrages

Aller à Demande

1. WO2004099148 - DERIVES PYRIMIDIQUES SUBSTITUES

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
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, or a pharmaceutically acceptable salt of a prodrug thereof, wherein:
X is selected from -NR3R4, -OR3, -CR3R5R5, -C(0)R3, -S(0)mR3, -NR3C(0)R4, or -NR3S(0)mR4;
m is 0,1 or 2;
G is selected from N or C(R2);
Ri and R2 are independently selected from -H, -NH(alkyl), -N(alkyl)2, -NH(substituted alkyl), -N(substituted alkyl)2, -O(alkyl), -0(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, -CR5R5Ar, -OAr, -S(0)mAr, -NR5Ar, -S(0)malkyl, -S(0)msubstituted alkyl, -CN, -N02, -OH, -NH2, -SH, -C(0)NR4R5 and -C(S)NR4R5;
R3 and j are independently selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R3 and R4 are present one of the R3 or R4 is selected from a group previded herein above and the other R3 or R is selected from -H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl.
Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
R5 each is independently selected from -H, alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted with 1-3 substituents selected from halogen , -O(alkyl), -NH(alkyl), -N(alkyl)2, -C(0)NH(alkyl), -C(0)N(alkyl)2, -NHC(0)alkyl, -N(aIkyl)C(0)alkyl, and -S(0)malkyl, heterocycloalkyl, substituted heterocycloalkyl and Ar.
2. A pharmaceutical composition comprising a compound of claim 1 or 2.
3. A pharmaceutical composition according to claim 2 further comprising a pharmaceutically acceptable carrier.
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.