MXPA97004425A - Certain derivatives of pyrrolopyridine and new specific ligands of c - Google Patents

Abstract

Compounds of the formula are described: (See Fig.) Where AR is optionally substituted aryl or heteroaryl, R1 is hydrogen or alkyl, R7 is hydrogen or alkyl, R2 is hydrogen, halogen, alkyl or alkoxy, or R1 and R2, taken together with the ring sl which are attached form a ring of 5-9 members, saturated or aromatic, having a heteroatom which is selected from oxygen, sulfur or nitrogen, R3 and R4 are independently hydrogen, alkyl, cycloalkyl, aryl or groups heteroaryl; or R3 and R4, together with the nitrogrene atom to which they are attached, form a 5-8 membered ring, and R3 is hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon or alkoxy or thioalkoxy atoms lower, linear or branched chain having 1-6 carbon atoms, compounds which are highly selective partial or antagonist agonists and receptors of human corticotropin-releasing factor 1 (CRF1) and are useful in the diagnosis and treatment to treat stress-related disorders such as post-traumatic pressure disorders (PTSD) as well as depression, headache and anxiety.

Description

CT35RTQS DER-rV? DOS OF PI-MlO OPI IDIN? AND NEW T-JOMronq This invention relates to certain substituted pyrrolopyridine derivatives which selectively bind to corticotropin releasing factor (CRF) receptors. More specifically, it is related to tetrahydro-5H-pyrido [2, 3-b] indole-4-amines, 9H-pyrido [2, 3-b] indole-4-amines and lH-pyrrolo [2, 3 ] pyridin-4-a: .as, and their use as antagonists of the corticotropin releasing factor in the treatment of various disease states.

Corticotropin releasing factor (CRF) antagonists are mentioned in U.S. Patent Nos. 4,605,642 and 5,063,245 and refer to peptides and pyrazoline derivatives, respectively. The importance of CRF antagonists is described in the literature, for example, as described REP: 25005 in U.S. Patent No. 5,063,245 which is incorporated herein by reference in its entirety. CRF antagonists are considered effective in the treatment of a wide range of diseases including stress-related or stress-related diseases, such as depression, anxiety and headache, caused by stress. Other diseases that are considered treatable with CRF antagonists are described in U.S. Pat. Nos. 5, 063, 245 and in Phar. Rev., 43: 425-473 (1991). The international application describes pyrrolo [2, 3-d] pyrimidines having corticotropin releasing factor antagonist activity. J. Het. Chem. 9, 1077 (1972) describes the synthesis of 9-phenyl-pyrrolo [3,2-d] pyrimidines.

BRIEF DBSCRIPTQW DB IA INVENTION This invention provides novel compounds of formula I which interact with CRF receptors. In addition, the invention provides pharmaceutical compositions comprising compounds of Formula I. Additionally, it relates to the use of such compounds to treat disorders or disorders related to stress such as post-traumatic stress disorder (PTSD) as well as depression, headache and anxiety. Accordingly, a broad embodiment of the invention is directed to a compound of Formula I: wherein Ar is optionally substituted aryl or heteroaryl; Rx is hydrogen or alkyl; R7 is hydrogen or alkyl; R2 is hydrogen, halogen, alkyl or alkoxy; or R? and R2 'taken together with the ring to which they are attached form a 5-9 membered, saturated or aromatic ring, having a heteroatom which is selected from oxygen, sulfur or nitrogen; R3 and R4 are independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl groups; or R3 and R together with the nitrogen atom to which they are attached, form a ring of 5-8 members; and R3 is hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms or alsoxi or lower, linear or branched thioalkoxy, having 1-6 carbon atoms. The compounds of the invention are partial agonists or highly selective antagonists of CRF receptors and are useful in the diagnosis and treatment of stress-related disorders such as post-traumatic stress disorder (PTSD) as well as depression and anxiety. Therefore, the invention provides compounds that include pharmaceutically acceptable salts of the compounds of formula I, and pharmaceutical compositions for use in the treatment of disease states associated with corticotropin releasing factor. The invention further provides methods that include animal models relevant to the evaluation of the interaction of the compounds of the invention with CRF receptors. This interaction results in the pharmacological activities of these compounds.

DETAILED DESCRIPTION OF A INVENCTÓM In addition to the novel compounds of the present invention described by general formula I above, the invention encompasses compounds of formula IA: IA wherein Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally disubstituted or trisubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, with the proviso that at least one of the ortho positions of Ar is substituted; Rx is hydrogen or lower alkyl; R7 is hydrogen or alkyl; R 2 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy; or Rx and R2, taken together, represent - (CH2) nA- (CH2) m-, at n is 2, 3 or 4, A is methylene, oxygen, sulfur or NR6, wherein Rs is hydrogen or lower alkyl, and m is 0, 1 or 2; or R? and R2 'taken together, represent -CH = A = CH = CH-; wherein A is CH or N: R3 and R4 are not both hydrogen and independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2- , 4- or 5-pyriminylalkyl, wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n-A- (CH2) m- wherein n is 2, 3 or 4, m is 1, 2 or 3; and G is methylene, 1,2-phenylene, oxygen, sulfur or wherein R6 is lower alkyl, phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-phenyl. -pyrimidinyl, or R6 is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy. Preferred compounds of formula I are those in which Ar is a disubstituted aryl or heteroaryl group having substituents in an ortho position and in the para position. The most preferred compounds of formula I are those in which Ar is a trisubstituted aryl or heteroaryl group having substituents in both ortho and para positions, that is, a 2, 6-trisubstituted aryl group. The most preferred aryl group is phenyl. Preferred aryl substituents are lower alkyl or halogen groups, particularly fluorine. The most preferred aryl substituents are methyl groups. Other preferred compounds of formula I are those in which the group NR3R4 is a disubstituted amino group, for example, dialkylamino. A group NR3R4, particularly preferred is dipropylamino. In compounds of formula I, R5 is preferably lower alkyl and, more preferably, methyl; and R7 is preferably hydrogen.

In further preferred compounds of formula I, Rx and R2, taken together, represent - (CH2) nA- (CH2) m- where n is 2, 3 or 4, A is methylene, oxygen, sulfur or NMe and m is 0, 1 or 2. The invention additionally provides compounds of formula II p Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally disubstituted or trisubstituted with halogen, hydroxy, lower alkyl or alkoxy lower, with the proviso that at least one of the ortho positions of Ar is substituted; R7 is hydrogen or alkyl, - R3 and R4 are not both hydrogen, and independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-4 - or 5-pyrimidinyl, each of which is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n-G- (CH2) m- wherein n is 2 or 3; m is 1, 2 or 3; G is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein Rs is lower alkyl, phenyl, 2-, 3-or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, or R is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy. Preferred compounds of formula II are those in which Ar is a disubstituted aryl or heteroaryl group having substituents in an ortho position and in the para position. The most preferred compounds of formula I are those in which Ar is a trisubstituted aryl or heteroaryl group having substituents in both ortho and para positions, ie, a 2,4,6-substituted-aryl group. The most preferred aryl group is phenyl. Preferred aryl substituents are lower alkyl or halogen groups, particularly fluorine. The most preferred aryl substituents are methyl groups. Other preferred compounds of formula II are those in which the group NR3R4 is a disubstituted amino group, for example, dialkylamino. A group NR3R4, particularly preferred is dipropylamino. In further preferred compounds of formula II, R7 is hydrogen. The invention additionally provides compounds of formula III m wherein Ra, Rb and Rc independently represent halogen, hydroxy, lower alkyl or lower alkoxy; R7 is hydrogen or alkyl; R3 and R4 independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3 - or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2- hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n -G- (CH2) m- wherein n is 2 or 3, - m is 1, 2 or 3; and G is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein R6 is lower alkyl, phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, or R6 is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy. Preferred compounds of formula III are those in which at least Ra, Rb or Rc is present in one of the two ortho positions of the phenyl group to which they are attached. More preferably, the compounds of formula III are those in which at least two of Ra, Rb or Rc are present in the ortho position and in the para position. Further preferred additional compounds of formula III are those in which Ra, Rb or R0 are present in both ortho and para positions, ie, a 2,4,6-trisubstituted phenyl group. Preferred Ra, Rb or Rc groups are lower alkyl or halogen groups, particularly fluorine. The most preferred aryl substituents are methyl groups. Other preferred compounds of formula III are those in which the group NR 3 R 4 is a disubstituted amino group, for example, dialkylamino. A group NR3R4, particularly preferred is dipropylamino. In further preferred compounds of formula III, R7 is hydrogen.

The invention additionally provides compounds of formula IV IV wherein E represents CH2 or NRS, wherein R6 is hydrogen or lower alkyl; R7 is hydrogen or alkyl; Ra, Rb and Rc independently represent halogen, hydroxy, lower alkyl or lower alkoxy; R3 and R4 independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n-G- (CH2) m- wherein n is 2 or 3; m is 1, 2 or 3; and G is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein R6 is lower alkyl, phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, or R6 is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl; and Rs is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy. Preferred compounds of formula IV are those in which at least one of Ra, Rb or Rc is present in one of the two ortho positions of the phenyl group to which they are attached. More preferably, the compounds of formula III are those in which at least two of Ra, Rb or Rc are present in the ortho position and in the para position. Additional preferred compounds of formula IV are those in which Ra, Rb or Rc are present in both ortho and para positions, ie, a 2,4,6-trisubstituted phenyl group. Preferred Ra, Rb or Rc groups are lower alkyl or halogen groups, particularly fluorine. The most preferred aryl substituents are methyl groups. Other preferred compounds of formula IV are those in which the group NR3R4 is a disubstituted amino group, for example, dialkylamino. A group NR3R4, particularly preferred is dipropylamino. In the preferred compounds of formula IV, E represents carbon. In other compounds of formula IV, R7 is hydrogen. The invention additionally provides compounds of formula V wherein E represents CH2 or NR6, wherein R6 is hydrogen or lower alkyl; R7 is hydrogen or alkyl; Ar is phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally disubstituted or trisubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, with the proviso that at least one of the ortho positions of Ar is substituted; R3 and R4 independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2 -, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n -G- (CH2) m- - li in which n is 2 or 3; m is 1, 2 or 3; and G is methylene, 1,2-phenylene, oxygen, sulfur or NR 6, wherein R 6 is lower alkyl, phenyl, 2-, 3-or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, or R6 is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy. Preferred compounds of formula V are those in which Ar is a disubstituted aryl or heteroaryl group having substituents in an ortho position and in the para position. The most preferred compounds of formula V are those in which Ar is a trisubstituted aryl or heteroaryl group having substituents at both ortho and para positions, that is, a 2,4,6-trisubstituted aryl group. The most preferred aryl group is phenyl. Preferred aryl substituents are lower alkyl or halogen groups, particularly fluorine. The most preferred aryl substituents are methyl groups. Other preferred compounds of formula V are those in which the group NR3R4 is a disubstituted amino group, for example, dialkylamino. A group NR3R4, particularly preferred is dipropylamino. In the preferred compounds of formula IV, E represents carbon. Further preferred compounds of formula V are those in which R7 is hydrogen. The invention additionally provides compounds of formula VI wherein E represents CH2 or NR6, wherein Rs is hydrogen or lower alkyl; R7 is hydrogen or alkyl; Ra, Rb and Rc independently represent halogen, hydroxy, lower alkyl or lower alkoxy; R3 and R4 independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n -G- (CH2) m- wherein n is 2 or 3, - m is 1, 2 or 3; and G is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein R6 is lower alkyl, phenyl, 2-, 3-or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, or R6 is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyridinidinylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy. Preferred compounds of formula VI are those in which at least one of Ra, Rb or Rc is present in one of the two ortho positions of the phenyl group to which they are attached. More preferably, the compounds of formula VI are those in which at least two of Ra; Rb or Rc are present in the ortho position and in the para position. Additional preferred compounds of formula VI are those in which Ra, Rb or Rc are present in both ortho and para positions, that is, a 2,4,6-trisubstituted phenyl group. Preferred Ra, Rb or Rc groups are lower alkyl or halogen groups, particularly fluorine. The most preferred aryl substituents are methyl groups. Other preferred compounds of formula VI are those in which the group NR3R4 is a disubstituted amino group, for example, dialkylamino. A group NR3R4, particularly preferred is dipropylamino. In the preferred compounds of formula IV, E represents carbon. In other compounds of formula VI, R7 is hydrogen. The invention additionally provides compounds of formula VII vp wherein E represents CH2 or NR6, wherein R6 is hydrogen or lower alkyl; Ar is phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally disubstituted or trisubstituted with halogen, hydroxy, lower alkyl or lower alkoxy , with - the proviso that at least one of the ortho positions of Ar is substituted; R7 is hydrogen or alkyl; R3 and R4 are not both hydrogen and independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n -G- (CH2) m- wherein n is 2 or 3, - m is 1, 2 or 3; and G is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein R6 is lower alkyl, phenyl, 2-, 3-or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, or R6 is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy. Preferred compounds of formula VII are those in which Ar is a disubstituted aryl or heteroaryl group having substituents in an ortho position and in the para position. The most preferred compounds of formula VII are those in which Ar is a trisubstituted aryl or heteroaryl group having substituents in both ortho and para positions, that is, a 2,4,6-trisubstituted aryl group. The most preferred aryl group is phenyl. Preferred aryl substituents are lower alkyl or halogen groups, particularly fluorine. The most preferred aryl substituents are methyl groups.

Other preferred compounds of formula VII are those in which the group NR3R4 is a disubstituted amino group, for example, dialkylamino. A group NR3R4, particularly preferred is dipropylamino. In the preferred compounds of formula VII, E represents carbon. Further preferred compounds of formula VII are those in which R7 is hydrogen. The invention additionally provides compounds of formula VIII: vra wherein Rj is hydrogen or lower alkyl; R 2 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy; or Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally disubstituted or trisubstituted with halogen, hydroxy, alkyl lower or lower alkoxy, with the proviso that at least one of the ortho positions of Ar is substituted, - R7 is hydrogen or alkyl, - R3 and R4 are not both hydrogen and independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyriminylalkyl, wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n-G- (CH2) m- wherein n is 2, or 3, m is 1, 2 or 3; and G is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein R6 is lower alkyl, phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, or Rs is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy. Preferred compounds of formula VIII are those in which Ar is a disubstituted aryl or heteroaryl group having substituents in an ortho position and in the para position. The most preferred compounds of formula VIII are those in which Ar is a trisubstituted aryl or heteroaryl group having substituents in both ortho and para positions, that is, a 2, 4, 6-trisubstituted aryl group. The most preferred aryl group is phenyl. Preferred aryl substituents are lower alkyl or halogen groups, particularly fluorine. The most preferred aryl substituents are methyl groups. Other preferred compounds of formula VIII are those in which the group NR 3 R 4 is a disubstituted amino group, for example, dialkylamino. A particularly preferred NR3R4 group is dipropylamino. In further preferred compounds of formula VIII, Rx and R2 are independently alkyl groups.

In more preferred compounds of formula VIII, R1 and R2 are both methyl. In the compounds of the invention, preferred NR3R4 groups include the following: Representative compounds of the present invention, which are included by the formula I, include, but are not limited to the compounds of Figure 1 and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulfonic, and iohydride, acetic and the like. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable non-toxic addition salts. The present invention also encompasses the acylated prodrugs or prodrugs of the compounds of formula I. Those skilled in the art will recognize various synthetic methodologies which can be used to prepare the pharmaceutically acceptable non-toxic addition salts and the acylated prodrugs of the encompassed compounds. by the formula I. By aryl or "Ar" is meant an aromatic carbocyclic group having a single ring (for example phenyl), multiple rings (for example biphenyl) or multiple condensed rings in which at least one is aromatic ( for example 1, 2, 3, 4-tetrahydronaphthyl, naphthyl, anthryl or phenanthryl), which is optionally monosubstituted, disubstituted or trisubstituted for example with halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxy. By "aryl" or "Ar" is meant also heteroaryl groups in which heteroaryl is defined as 5, 6 or 7-membered aromatic ring systems having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur . Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl and thienyl, which is optionally substituted with, for example, halogen, lower alkyl, lower alkoxy, lower alkyl , trifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxy. By alkyl and lower alkyl is meant straight or branched chain alkyl groups having 1-6 carbon atoms. Specific non-limiting examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl and n-pentyl. By "lower alkoxy" and "alkoxy" are meant straight or branched chain alkyl groups having 1-6 carbon atoms. By "thioalkoxy" or "alkylthio" is meant a group of the formula -S-alkyl, wherein alkyl is straight or branched chain alkyl having 1-6 carbon atoms. By halogen it is meant fluorine, chlorine, bromine and iodine. The pharmaceutical utility of the compounds of this invention is indicated by the following assay for CRF receptor activity.

Test to determine the activity of the rae union «pfcr > r The test is performed to determine the binding of the CRF receptor using a modified version of the assay described by Grigoriadis and De Souza (Biochemical, Pharmacological, and Autoradiographic Methods to Study Corticotropin-Releasing Factor Receptors, Methods in. Neurosciences, Vol. 5, 1991 ). Membrane pellets containing CRF receptors are resuspended in 50 mM Tris buffer, pH 7.7, containing 10 mM MgCl 2 and 2 mM EGTA, and centrifuged for 10 minutes at 48,000 g. The membranes are again washed and brought to a final concentration of 1,500 μg / ml in binding buffer (anterior Tris buffer with 0.1% BSA, 0.15 mM bacitracin and 0.01 Mg / ml aprotinin). For the binding assay, 100 μl of membrane preparation is added to 96-well microtube plates containing 100 μl 12S1-CRF (SA 2200 Ci / mmol, final concentration of 100 pM) and 50 μl of drug. The binding is carried out at room temperature for 2 hours. Subsequently, the plates are collected in a Brandel 96-well cell harvester and the filters are counted for gamma emissions in a liquid scintillation counter allac 1205 Betaplate. The non-specific binding is defined by 1 μM of cold CRF. The IC50 values are calculated with the RS / 1 non-linear curve fitting program (BBN Software Products Corp., Cambridge, MA). The IC50 for the joint 1 of this invention is 0.11 μM. The compounds of general formula I can be administered orally, topically, parenterally or by inhalation or spray or rectally in unit dosage formulations containing pharmaceutically acceptable, non-toxic and conventional carriers, adjuvants and vehicles. The term parenteral, as used herein, includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier is provided. One or more compounds of general formula I may be present in association with one or more pharmaceutically acceptable, non-toxic carriers and / or diluents and / or adjuvants and, if desired, with other active ingredients. The pharmaceutical compositions containing the compounds of the general formula I may be in a form suitable for oral use, for example, as tablets, troches, dragees, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions designed for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents that are selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a material for time delay such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are agents that improve the suspension, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents which may be naturally occurring phosphatides, for example lecithin or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxyethane or condensation products of ethylene oxides with partial esters derived from fatty acids and a hexitol such as polyexyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above and flavoring agents may be added to provide palatable oral preparations. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, an agent that improves the suspension and one or more preservatives. The dispersing or wetting agents and agents that improve the suspension are exemplified by those mentioned above. Additional excipients may also be present, for example, sweetening, flavoring and coloring agents.The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally occurring gums, for example acacia gum or tragacanth gum, naturally occurring phosphatides, for example soybeans, lecithin and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a condom and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known technique using those suitable dispersing or wetting agents and suspension improving agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution of 1,3-butanediol. Among the vehicles and acceptable solvents that can be used is water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspension medium. For this purpose, any fixed mixture oil which includes monoglycerides or synthetic diglycerides can be used. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of general formula I can also be administered in the form of suppositories for rectal administration of the medicament. These compositions can be prepared by mixing the drug or drug with a suitable non-irritating excipient which is solid at the usual temperature, but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The compounds of general formula I can be administered parenterally in a sterile medium. Based on the vehicle and the concentration used, the medication may be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. Dosage levels of the order from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the conditions indicated above (approximately 0.5 mg to approximately 7 g per patient, per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary based on the host treated and the particular mode of administration. The unit dosage forms will generally contain between about 1 mg and about 500 mg of an active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration and speed of excretion, combination with other medications and the severity of the particular disease that is under therapy. A representative illustration of the methods suitable for the preparation of compounds of the present invention is shown in Schemes I and II. Those skilled in the art will recognize that the starting materials may vary and that additional steps may be used to produce compounds included by the present invention.

Scheme 1 1) RßCOCHa 2) Base wherein Ar, Rx, R2, R3, R4 and R5 are as defined above for formula E. In the case where a desired compound of the invention that can be prepared according to scheme I, include R7 as alkyl, the intermediate 2-amino-1-aryl-3-cyanopyrrole is reacted with a base and a compound of the formula R5COCH2R7, wherein R7 is alkyl.

Scheme II wherein A is NH or CH2 and Ar, R3, R4 and R5 are as defined above for formula I. As mentioned above, when a desired compound of the invention to be prepared according to scheme II includes R7 as alkyl, the 2-amino-l-aryl-3-cyanopyrrole intermediate is reacted with a base and a compound of the formula R5COCH2R7, wherein R7 is alkyl. The description in this application of all articles and references, including patents, are incorporated herein by reference. One skilled in the art will recognize that modifications can be made to the present invention without deviating from the spirit or scope of the invention. The invention is further illustrated by the following examples which are not considered as limiting the invention or the scope of the specific methods or compositions described herein. the One refluxes. mixture of 2,4,6-trimethylaniline (10.5 g, 78 mmol), dimer of 2-hydroxycyclohexanone (8.9 g, 39 mmol) and pTsOH (44 mg) in 100 ml of toluene. The water is removed using a Dean-Stark apparatus. After 2 hours the solution is cooled and malononitrile (5.2 g) dissolved in 20 ml of toluene is added. The mixture is refluxed for another 8 hours and then the solvent is removed under reduced pressure. The crude product is triturated with ether and part of ethanol and collected by filtration as a tan solid to provide the aminonitrile ia.

Example IB The aminonitrile (1.1 g, 4.0 mmol) prepared above is stirred with anhydrous acetone (1.5 ml), pTsOH (10 mg) and 4A molecular sieves (1 g) in 10 ml of benzene at 60 ° C for 10 hours. Subsequently, the mixture is filtered through Celite pretreated with triethylamine. The volatile solvents are removed under reduced pressure. The residual material is dissolved in 20 ml of THF and treated with lithium diisopropylamide (2.0 M, 4 ml) under cooling with ice. After 1 hour, the mixture is poured into water and extracted with ethyl acetate. The organic layer is subsequently extracted with 5% hydrochloric acid. The aqueous layer is made alkaline with 10 N sodium hydroxide and extracted with dichloromethane. The extract is washed with water and then dried over sodium sulfate and concentrated to give 2-methyl-6,7,8,9-tetrahydro- (2,4,6-trimethylphenyl) -5H-pyrido [2, 3-b] indole-4-amine Ib as a white solid.

Kjflmplo T £ ' lfi The compound 2-methyl-6,7,8,9-tetrahydro-9- (2,4,6-trimethylphenyl) -5H-pyrido [2,3-b] indol-4-amine (Ua) (470 mg ) is dissolved in 10 ml of dichloroethane and refluxed for 3 hours with propionyl chloride (0.5 ml). The residual reactants are evaporated under reduced pressure. The crude product is divided between an aqueous solution of sodium carbonate and dichloromethane. The organic extract is dried over sodium sulfate and concentrated. The solid diacylated product is triturated with hexanes and collected by filtration to provide N, N-dipropionyl-2-methyl-6,7,8,9-tetrahydro-9- (2,4,6-trimethylphenyl) -5H-pyrido [2,3-b] -indol-4-amine him. as a white solid.

Example U? Compound 1 N, N-dipropionyl-2-methyl-9- (2,4,6-trimethylphenyl) -5H-pyrido [2,3-b] -indol--amine is refluxed. (312 mg) in 8 ml of THF with a complex of borane-methyl sulfide (10 M, 1.2 ml) for 10 hours. After cooling, the solution is carefully suspended with 5 ml of methanol. The resulting solution is refluxed for another 2 hours and then concentrated. The dialkylamine product is purified on silica gel using 20% ethyl acetate in hexanes as eluent to give N, N-dipropyl-2-methyl-6,7,8,9-tetrahydro-9- (2,4,6 -trimethylphenyl) -5H-pyrido [2,3-b] -indol-4 -amine (Compound 1) as a white solid, mp 117-118 ° C.

Example II The following compounds are prepared essentially according to the procedure described in examples IA-D: a) N-propyl-N-cyclopropylmethyl-2-methyl-6,7,8,8-tetrahydro-9- (2,, 6-trimethylphenyl) -5H-pyrido [2, 3-b] indole-4-amino '(Compound 2). b) N-propyl-N-cyclopropylmethyl-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrido [2,3-b] indol-4-amine (Compound 3). c) N-butyl-N-ethyl-2-methyl-6,7,8,9-tetrahydro-9 - (2,4,6-trimethylphenyl) -5H-pyrido [2,3-b] indole-4- amine (Compound 4). d) N, N-dipropyl-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrido [2, 3-b] indol-4-amine (Compound 5). e) N-butyl-N-ethyl-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrido [2, 3-b] indol-4-amine (Compound 6), f) N, N-dipropyl-1- (2,4,6-trimethylphenyl) -2,3,6-trimethyl-lH-pyrrolo [2, 3-b] pyridin-4-amine (Compound 7). g) N-cyclopropylmet i 1-N-propyl-1- (2,4,6-trimethylphenyl) -2,3,6-trimethyl-lH-pyrrolo [2,3-b] pyridin-amine (Compound 8) . (h) N-Butyl-N-ethyl-1- (2,4,6-trimethylphenyl) -2,3,6-trimethyl-lH-pyrrolo [2,3-pyridin-4-amine (Compound 9) . The invention, and the manner and process to elaborate and use it have been described in a complete, clear, concise and in exact terms so that any person skilled in the art to which it belongs, acquires the ability to develop and use the same. It should be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made thereto without departing from the spirit or scope of the present invention, as set forth in the claims. To particularly emphasize and differentiate the claim of the subject matter considered as an invention, the following claims conclude this specification. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (21)

1. R-Bi- Y -U-WICACT ES 1 . A compound of the formula or the pharmaceutically acceptable salts thereof, characterized in that Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally disubstituted or trisubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, with the proviso that at least one of the ortho positions of Ar is substituted; j is hydrogen or lower alkyl; R7 is hydrogen or alkyl; R 2 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy; or Rx and R2, taken together, represent - (CH2) nA- (CH2) m-, at n is 2, 3 or 4, A is methylene, oxygen, sulfur or NR6, wherein R6 is hydrogen or lower alkyl, and m is 0, 1 or 2; or Rj and R2, taken together, represent -CH = A = CH = CH-, -wherein A is CH or N; R3 and R4 are not both hydrogen and independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyriminylalkyl, in wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n-A- (CH2) ra- wherein n is 2 or 3; m is 1, 2 or 3, - and G is methylene, 1,2-phenylene, oxygen, sulfur or NR 6, wherein R 6 is lower alkyl, phenyl, 2-, 3-or 4-pyridyl, 2- or 3 -thienyl, or 2-, 4- or 5-pyrimidinyl, or R6 is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy.
2. 2. The compound according to claim 1, characterized in that Rx and R2, taken together, represent - (CH2) nA- (CH2) m- wherein n is 2, 3 or 4, A is methylene, oxygen, sulfur or NMe and m is 0, 1 or 23.
3. The compound according to claim 2, characterized in that Ar is wherein Ra, Rb and Rc independently represent halogen, hydroxy, lower alkyl or lower alkoxy.
4. 4. The compound according to claim 1, characterized in that Ar is wherein Ra, Rb and Rc independently represent halogen, hydroxy, lower alkyl or lower alkoxy.
5. 5. A compound of the formula: or the pharmaceutically acceptable salts thereof, characterized in that E represents CH2 or NRg, wherein R6 is hydrogen or lower alkyl; Ar is phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally disubstituted or trisubstituted with halogen, hydroxy, lower alkyl or lower alkoxy , with the proviso that at least one of the ortho positions of Ar is substituted; R3 and R4 are not both hydrogen and independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which it is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, in which each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n-G- (CH2) m- wherein n is 2 or 3; m is 1, 2 or 3; and G is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein Rs is lower alkyl, phenyl, 2-, 3-or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, or R6 is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy.
6. 6. The compound according to claim 5, characterized in that Ar is wherein Ra, Rb and Rc independently represent halogen, hydroxy, lower alkyl or lower alkoxy.
7. 7. The compound according to claim 2, characterized in that Ar is wherein Ra, Rb and Rc independently represent halogen, hydroxy, lower alkyl or lower alkoxy.
8. 8. A compound of the formula: or the pharmaceutically acceptable salts thereof, characterized in that E represents CH2 or NR6, wherein R6 is hydrogen or lower alkyl; Ar is phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally disubstituted or trisubstituted with halogen, hydroxy, lower alkyl or lower alkoxy , with the proviso that at least one of the ortho positions of Ar is replaced; R3 and R4 are not both hydrogen and independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which it is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n -G- (CH2) ra- wherein n is 2 or 3; m is 1, 2 or 3; and G is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein Rs is lower alkyl, phenyl, 2-, 3-or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, or Rs is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy.
9. 9. The compound according to claim 8, characterized in that Ar is wherein Ra, Rb and Rc independently represent halogen, hydroxy, lower alkyl or lower alkoxy.
10. 10. The compound according to claim 8, characterized in that Ar is wherein Ra, Rb and Rc independently represent halogen, hydroxy, lower alkyl or lower alkoxy.
11. 11. The compound according to claim 2, characterized in that Rj and R2, taken together, represent -CH = A-CH = C- wherein A is CH or N.
12. 12. The compound according to claim 1, characterized in that it is N, N-dipropyl-2-methyl-6,7,8,9-tetrahydro-9- (2,4,6-trimethylphenyl) -5H-pyrido [2, 3-b] indole-4-amine.
13. 13. The compound according to claim 1, characterized in that it is N-propyl-N-cyclopropylmethyl-2-methyl-6,7,8,9-tetrahydro-9- (2,4,6-trimethylphenyl) -5H-pyrido [ 2, 3-b] indole-4-amine.
14. 14. The compound according to claim 1, characterized in that it is N-propyl-N-cyclopropylmethyl-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrido [2,3-b] indole-4 -amine.
15. 15. The compound according to claim 1, characterized in that it is N-butyl-N-ethyl-2-methyl-6,7,8,9-tetrahydro-9- (2,4,6-trimethylphenyl) -5H-pyrido [ 2, 3-b] indole-4-amine.
16. 16. The compound according to claim 1, characterized in that it is N, N-dipropyl-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrido [2,3-b] indol-4-amine.
17. 17. The compound according to claim 1, characterized in that it is N-butyl-N-ethyl-2-methyl-9- (2,4,6-trimethylphenyl) -9H-pyrido [2,3-b] indole-4- amine.
18. 18. The compound according to claim 1, characterized in that it is N, N-dipropyl-1- (2,4,6-trimethylphenyl) -2,3,6-trimethyl-lH-pyrrolo [2,3-b] pyridine- 4-amine.
19. 19. The compound according to claim 1, characterized in that it is N-cyclopropylmethyl-N-propyl-1- (2,4,6-trimethylphenyl) -2,3,6-trimethyl-lH-pyrrolo [2, 3- b] pyridin-4-amine.
20. 20. The compound according to claim 1, characterized in that it is N-butyl-N-ethyl-1- (2,4,6-trimethylphenyl) -2,3,6-trimethyl-lH-pyrrolo [2, 3-b] pyridin-4 -amine.
21. 21. The compound of the formula: or the pharmaceutically acceptable salts thereof, characterized in that Rj is hydrogen or lower alkyl, - R7 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy; Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally disubstituted or trisubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, with the proviso that at least one of the ortho positions of Ar is substituted; R7 is hydrogen or alkyl; R3 and R4 are not both hydrogen and independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally monosubstituted or disubstituted with halogen, hydroxy, lower alkyl or lower alkoxy, phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyriminylalkyl, in wherein each alkyl is lower alkyl, cycloalkyl having 3-8 carbon atoms, cycloalkyl-lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or R3 and R4, taken together, represent - (CH2) n-G- (CH2) m- wherein n is 2 or 3; is 1, 2 or 3; and G is methylene, 1,2-phenylene, oxygen, sulfur or NR 6, wherein R 6 is lower alkyl, phenyl, 2-, 3-or 4-pyridyl, 2- or 3-thienyl, or 2-, 4- or 5-pyrimidinyl, or R6 is phenylalkyl, 2-, 3- or 4-pyridylalkyl, 2-or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, wherein each alkyl is lower alkyl; and R5 is hydrogen, halogen, lower alkyl, lower alkoxy or thioalkoxy. Compounds of the formula are described: RVRl Ar wherein Ar is aryl or optionally substituted heteroaryl; Rj is hydrogen or alkyl; R7 is hydrogen or alkyl; R2 is hydrogen, halogen, alkyl or alkoxy; or Rj and R2, taken together with the ring to which they are attached form a 5-9 membered, saturated or aromatic ring, having a heteroatom which is selected from oxygen, sulfur or nitrogen; R3 and R4 are independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl groups; or R3 and R together with the nitrogen atom to which they are attached, form a ring of 5-8 members; and, R3 is hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms or lower alkoxy or thioalkoxy, straight or branched chain having 1-6 carbon atoms, compounds which are partial agonists or highly selective antagonists and receptors of human corticotropin-releasing factor 1 (CRF1) and are useful in diagnosis and treatment to treat stress-related disorders such as post-traumatic pressure disorders (PTSD) as well as depression, headache and anxiety.