AU713804B2 - Pyrazolopyrimidines having CRF antagonist activity - Google Patents

Description

Pyrazolopyrimidines having CRF Antagonist Activity.

This invention relates to pyrazolopyrimidines, pharmaceutical compositions containing them, and methods of administering them to subjects in need of their corticotropin-releasing factor (CRF) antagonist activity.

CRF antagonists are mentioned in U.S. Patents 4,605,642 and 5,063,245 referring to peptides and pyrazolinones, respectively. The importance of CRF antagonists is set out in the literature, e.g. as discussed in U.S. Patent 5,063,245, which is incorporated herein by reference. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), also incorporated herein by reference. Based on the research described in these two and other references, CRF antagonists are effective in the treatment of a wide range of diseases including stress-related illnesses, such as stress-induced depression, anxiety, and headache; abdominal bowel syndrome; inflammatory diseases; immune suppression; human immunodeficiency virus (HIV) infections; Alzheimer's disease; gastrointestinal diseases; anorexia nervosa; haemorrhagic stress; drug and alcohol withdrawal symptoms; drug addiction, and fertility problems.

The present invention relates to a compound of the formula

R

3 R2 .A NN

R

5 N N R4

I

and the acid addition salts thereof, wherein R 5 is hydrogen, C 1

-C

6 alkyl, fluoro, chloro, 20 bromo, hydroxy, amino, O(C 1

-C

6 alkyl), NH(C 1

-C

6 alkyl), N(C 1

-C

6 alkyl)(C 1

-C

6 alkyl), substituted by from 1 to 3 substituents R 6 which is hydroxy, amino, C 1

-C

3 alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(C=O)CH 3 fluoro, chloro, bromo or C 1

-C

3 thioalkyl; :,Poo 25 R 2 is hydrogen, C 1

-C

6 alkyl, hydroxy, amino, O(C 1

-C

6 alkyl), NH(C 1

-C

6 alkyl),

N(C

1

-C

6 alkyl)(C 1

-C

6 alkyl), SH, S(O)n(C 1

-C

6 alkyl) wherein n 0, 1, or 2, cyano, hydroxy, carboxy, or amido, wherein said alkyls may be substituted by one to three of hydroxy, amino, carboxy, amido, NH(C=O)(C 1

-C

6 alkyl), N(C 1

-C

6 alkyl)(C 1

-C

6 alkyl),

(C=O)O(C

1

-C

6 alkyl), C 1

-C

3 alkoxy, C 1

-C

3 thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro;

R

3 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, [N:\LIBH]0117:RRB benizoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrro lyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or 9 to 12 membered bicycloalkyl, optionally containing one to three of 0, S or N-Z wherein Z is hydrogen, C 1

-C

4 alkyl, C 1

-C

4 alkanoyl, phenyl or phenylmethyl, wherei each one of the above groups may be substituted independently by fromn one to three of flUOr-o, chloro, bromo, Cj-C 6 alkyl, C 1

-C

6 alkoxy, or trifluoroinethyl, or one of cyano, nitro, am ino, NH(C I-C 6 alkyl), N(C I-C 4 alkyl)(C I-C 2 alkyl), COO(C I-C 4 alkyl), COW(I -C 4 alkyl),

SO

2 NH(Cj-C 4 alkyl), SO 2

N(C

1

-C

4 alkyl)(C 1

-C

2 alkyl), SO 2

NH

2

NHSO

2

(C

1

-C

4 alkyl),

S(C

1

-C

6 alkyl), S0 2 (Cj-C 6 alkyl), wherein said C 1

-C

4 alkyl and C 1

-C

6 alkyl may be Substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamnino or acetyl; and

R

4 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, m idazo lyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, is oxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, henzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or 3 to 8membered cycloalkyl or 9 to 12-membered bicycloalkyl, optionally containing one to three of 0, S or N-Z wherein Z is hydrogen, C 1

-C

4 alkyl, C 1

-C

4 alkanoyl, phenyl or phenylmethyl, wherein each of the above groups may be substituted independently by from one to three of flUoro, chioro, bromo, trifluoromethyl, C I-C 6 alkyl or C I-C 6 alkoxy, or one of cyano, nitro, amnino, NH(C I-C 6 alkyl), N(C I-C 4 alkyl)(C I-C 2 alkyl), COO(C I-C 4 alkyl), CO(C I-C 4 alkyl),

SO

2 NH(Cj-C 4 alkyl), SO 2

N(C

1

-C

4 alkyl)(Cj-C 2 alkyl), SO 2

NH

2

NH

2

SO

2

(C

1

-C

4 alkyl),

S(C

1

-C

6 alkyl), S0 2

(C

1

-C

6 alkyl), wherein said CI-C 4 alkyl and CI-C 6 alkyl may be sO. Substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, diinethylamino or provided that R 4 is not unsubstituted phenyl; or a compound 4-(2-chlorophenyl)-6-(4- 25etlhoxycarbonylpiperizinyl)-3-methylthio- I -(2,4,6-trichlorophenyl)pyrazolo[3 ,4-d]pyrimidine; provided that the compound of formula I is not 4-(lH-benzim-idazol-l-yl)-l-(2-pyridinyl)pyrazolo[3,4,d]-pyrimidine.

More specific compounds of the formula I include those wherein R 3 is phenyl substituted i ndependently with one or two of fluoro, chioro, bromo, methyl, trifluoromethyl, nitro, C 1

I-C

6 Cj-C 6 alkyloxy, SO 2

NH

2

SO

2

NH(C

1

-C

6 alkyl), SO 2

N(C

1

-C

6 alkyl) 2 or R 3 is S* primary, secondary or tertiary alkyl of from 4-9 carbon atomns wherein said C 4

-C

9 alkyl may contain from one to two double or triple bonds and may be substituted by from I to 3 substituents R 6 which are independently selected from hydroxy, amino, Cj-C 3 alkoxy, dirnethylamino, diethylamino, methylamino, ethylamino, NH(C=0)CH 3 fluoro, chloro, bromo, or C I-C 3 thioalkyl.

More specific compounds of the formula I are those wherein R 2 is ethyl or methylthio and those wherein R 4 is 2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl, 2,6-dichloro-4trifluoromethyiphenyl or 4-bromo-2,6-dimethylphenyl.

More specific compounds of formula I further include those wherein R 3 is phenyl which may be substituted at positions 2 or 5 with one or two of mnethyl, C 2

-C

6 IN:\LIBHJOO1 1 7:KBM straight-chain or branched alkyl, trifluoromethyl, fluoro, chloro, bromo or nitro, those wherein R 5 is substituted at the 6 position; and those wherein R 3 is phenyl substituted independently with one or two of fluoro, chloro, bromo, methyl, trifluoromethyl, nitro,

C

1

-C

6 alkyl, C 1

-C

6 alkyloxy, SO 2

NH

2

SO

2

NH(C

1

-C

6 alkyl), or S02N(C 1

-C

6 alkyl) 2

R

4 is 2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl, and R 2 is methylthio, methyl or ethyl.

The invention also relates to a composition for the treatment of illness induced or facilitated by corticotropin releasing factor which comprises a compound of the formula I, in an amount effective in the treatment of said illnesses, and a pharmaceutically acceptable carrier, and to a composition for the treatment of inflammatory disorders, stress and anxiety related disorders including stress-induced depression and headache, abdominal bowel syndrome, immune suppression, HIV infections, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems, which comprises a compound of the formula I, as defined above, in an amount effective in the treatment of said disorders, and a pharmaceutically acceptable carrier.

The invention further includes a method for the treatment of illnesses induced or facilitated by corticotropin releasing factor which comprises administering to a subject in need of such treatment a compound of formula I, as defined above, and a method for the treatment of stress and anxiety related disorders, including stress-induced depression and headache, abdominal bowel syndrome, inflammatory disorders, immune suppression, HIV infections, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems, particularly depression, which comprises administering to a subject in need of such 25 treatment a compound of formula I as defined above.

Whenever reference is made herein to C 1

-C

6 alkyl, a straight or branched chain alkyl of one to six carbon atoms is meant, such as methyl, ethyl, isopropyl or hexyl.

Whenever reference is made herein to C 1

-C

6 alkyl, in the definition of R 5 this includes unsaturated C 2

-C

6 alkyl, such as C 2

-C

6 alkyl having one double or triple bond,

C

3

-C

6 alkyl having two double bonds, and C 4

-C

6 alkyl having two triple bonds.

Whenever R 3 is a heterocyclic group, the attachment to the pyrimidine ring is through one of the carbons in the heterocyclic group. Similarly, when R 4 is a heterocyclic group, the attachment to the nitrogen in the pyrazole ring is through one of the carbons in the heterocyclic group.

Whenever reference is made herein to 3- to 8-membered cycloalkyl or 9- to 12membered bicycloalkyl containing one to three of O, S or N-Z, it is understood that the oxygen and sulfur ring atoms are not adjacent to each other.

[N:\LIBHIOO117:RRB The compounds of formula I 3 R 2

I

R4

I

wherein R 2

R

3

R

4 and R 5 are as defined above. These compounds may be prepared by cyclization of a compound of the formula II R3 A

R

2 I I R, N R4 Swherein A is C=O and R 1 is amino with a compound of the formula III 0

II

O

R5-C-NH2 wherein R 5 is as defined with reference to formula I. This reaction is generally carried out at 100 to 250°C, and conveniently at the reflux temperature of the compound III.

10 The acid addition salts are prepared in a conventional manner by treating a solution or suspension of the free base of formula I with one chemical equivalent of a S. pharmaceutically acceptable acid. Conventional concentration or crystallization techniques are employed in isolating the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toluenesulfonic, and related acids.

The compound of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and [N:\LIBH001 17:RRB various organic solvents. The pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.

Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.

Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration, solutions of the novel compound of formula I in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

25 Additionally, it is possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes and ointments, in accordance with standard pharmaceutical practice.

The effective dosage for the compound of formula I depends on the intended route 30 of administration and other factors such as age and weight of the patient, as generally known to a physician. The dosage also depends on the illness to be treated, although in general the daily dosage will range from about 0.1 to 50 mg/kg of the body weight of the patient. More specifically, the daily dosage for stress-induced illnesses will generally range from about 0.1 to 50 mg/kg of the body weight of the patient to be treated, for treatment of inflammatory diseases about 0.1 to about 100 mg/kg will be needed, for Alzheimer's disease, about 0.1 to about 50 mg/kg, as well as for gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, and drug and alcohol withdrawal symptoms.

The methods for testing the compounds of formula I for their CRF antagonist activity are according to the procedures of Endocrinology, 116, 1653-1659 (1985) and Peptides, 10, 179-188 (1985) which determine the binding activity of a test compound to [N:\LIBH10O0117:RRB a CRF receptor. The binding activity for the compounds of formula I generally ranges from about 0.2 nanomolar to about 10 micromolar.

The following abbreviations are used in the Examples: Ph=phenyl; iPr=isopropyl; HRMS= high resolution mass spectrum.

Example 1 4-(2-Chlorophenyl)-1-(2.

6 -dichloro-4-trifluoromethvlnhenvl)3 methvlthionvraiolor3l 4-dllnvrimidfin L r A suspension of 669 mg (1.39 mmol) of 5-amino-l-(2,6-dichloro-4trifluoromethylphenyl)-4-(2-chlorobenzoyl)-3-methylthiopyrazole in 5 mL of formamide was heated at 150 0 C overnight. A pale yellow solid precipitated upon cooling of the reaction mixture. A total of 50 mL of water was added to the stirred suspension to complete the precipitation of the product which was filtered off and washed with water.

An inseparable trace of starting material was observed in the product by thin layer chromatography (TLC) and so the above procedure was repeated on the mixture giving a brown solid containing no trace of starting material. Trituration of this solid with methylene chloride gave a pale yellow solution which was concentrated to give the desired product as a white crystalline solid, m.p. 156-158 0

C.

Example 2 The following compounds were prepared in accordance with Example 1.

g o o a..

a a a a R3 R5 R7 m.p.(oC) or HRMS 2-Cl-Ph H Cl 193-195 3-Cl-Ph H Cl 171-173 2-Cl-Ph H

CF

3 156-158 2-Cl-Ph OH Cl 313-316 2-Cl-Ph Cl Cl 193-195 2-Cl-Ph 4-ethoxycarbonyl-piperizinyl Cl 222-225 1-napthyl H CF 3 171-173 2-Cl-Ph

CH

3 Cl 210-212 [N:\LIBH00117:RRB R3 R5 R7m.p.( 0 C) or HRMS 2-CH 3 -5-iPrPh CH 3 Cl 141-142 2,6-(C11 3 2 -Ph CH 3 Cl HRMS: Calcd. 462.0239 Found: 462.0369 2

H

5 )-Ph CH 3 Cl 189.192 2

H

5

CH

3 Cl HRMS: Calcd. 528.0345 naphthyl Found: 528.0226 3 -Ph CH 3 Cl 214-216 2-CH 2

H

5 -Ph CH 3 Cl HRMS: Caled. 462.0239 Found: 462.0219 Ph CH 3

CF

3 114-116 3 2 -Ph CH 3

CF

3 HRMS: Calcd. 497.0579 497.0602 2-CF 3 -Ph CH 3 Cl HRMS: Caled. 501.9800 Found: 501.9778

S

5.55 S S *5

S

S

*5*5

S

*S S S [N:\LIBH]OO1 1 7:RRB

Claims (9)

1. A compound of the formula R 5 N N I wherein R 5 is hydrogen, C 1 -C 6 alkyl, fluoro, chioro, bromo, hydroxy, amino, O(Cl-C 6 alkyl), NH(CI-C 6 alkyl), N(Cl-C 6 alkyl)(C 1 -C 6 alkyl), SH, S(O)n(Cl-C 6 alkyl) wherein n 1 or 2, wherein said Cl-C 6 alkyl may contain from one to two double or triple bonds and may be substituted by from 1 to 3 substituents R 6 which are independently selected from hydroxy, amino, Cl-C 3 alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NLI(C O)C11 3 fluoro, chloro, bromo or C 1 -C 3 thioalkyl. R 2 is hydrogen, C 1 -C 6 alkyl, hydroxy, amino, O(C 1 -C 6 alkyl), NH(CI-C 6 alkyl), N(CI-C 6 alkyl)(Cl-C 6 alkyl), SH, S(O)n(Cl-C 6 alkyl) wherein n 0, 1 or 2, cyano, hydroxy, carboxy, or amido, wherein said alkyls may be substituted by one to three of hydroxy, amino, carboxy, amido, NH(C=O)(Cl-C 6 alkyl), N(CI-C 6 alkyl)(Cl-C 6 alkyl), (C =O)O(C-Caky)C- 3 alo, Cl-C 3 thioalkyl, fluoro, bromo, chioro, iodo, cyano or nitro; 3 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazoly, or 3 to 8-membered cycloalkyl or 9 to 12 membered bicycloalkyl, optionally containing one to three of 0, S or N-Z wherein Z is hydrogen, C 1 -C 4 alkyl, Cl-C 4 alkanoyl, phenyl or phenylmethyl, wherein each one of the above groups may be substituted independently by from one to three of fluoro, chioro, bromo, trifluoromethyl, Cl-C 6 alkyl or C 1 -C 6 alkoxy, or one of cyano, nitro, amino, NH(C 1 -C 6 alkyl), N(Cl-C 4 alkyl)(Cl-C 2 alkyl), COO(Cl-C 4 alkyl), CO(Cl-C 4 alkyl), -C4 aly) 4NC-4akl( C ly) 0N C ly) .:SO 2 NIJ(C 1 4 aly) SN( 1 -C ayl( 1 -C aly) N 2 NHSO 2 (C 1 4 aly) S(CI-C 6 alkyl), S0 2 (Cl-C 6 alkyl), wherein said C 1 -C 4 alkyl and C 1 -C 6 alkyl may be substituted by one or two of fluoro, chioro, hydroxy, amino, methylamino, dimethylamino or acetyl; and R 4 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, [N:\LIBH]OO1 1 7:RRB 9 pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or 9 to 12-membered bicycloalkyl, optionally containing one to three of O, S or N-Z wherein Z is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkanoyl, phenyl or phenylmethyl, wherein each of the above groups may be substituted independently by from one to three of fluoro, chloro, bromo, trifluoromethyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, or one of cyano, nitro, amino, NH(Ci-C 6 alkyl), N(C 1 -C 4 alkyl)(C 1 -C 2 alkyl), COO(C 1 -C 4 alkyl), CO(Ci-C 4 alkyl), SO 2 NH(Ci-C 4 alkyl), SO 2 N(C 1 -C 4 alkyl)(C 1 -C 2 alkyl), SO 2 NH 2 NH 2 SO 2 (CI-C 4 alkyl), S(Ci-C 6 alkyl), SO 2 (C 1 -C 6 alkyl), wherein said C 1 -C 4 alkyl and CI-C 6 alkyl may be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl; provided that R 4 is not unsubstituted phenyl; or a compound 4-(2-chlorophenyl)-6-(4-ethoxycarbonylpiperizinyl)-3 -methylthio- 1 trichlorophenyl)pyrazolo[3,4-d]-pyrimidine; provided that the compound of formula I is not 4-(1H-benzimidazol-l-yl)-l-(2-pyridinyl)- pyrazolo[3,4,d]-pyrimidine. 15 2. A compound according to claim 1 wherein R 3 is phenyl substituted independently with one or two of fluoro, chloro, bromo, methyl, trifluoromethyl, nitro, C 1 C 6 alkyl, CI-C 6 alkyloxy, SO 2 NH 2 SO 2 NH(Ci-C 6 alkyl), SO 2 N(Ci-C 6 alkyl) 2 or R 3 is primary, secondary or tertiary alkyl of from 4-9 carbon atoms wherein said C 4 -C 9 alkyl may contain from one to two double or triple bonds and may be substituted by from 1 to 3 substituents R 6 which are independently selected from hydroxy, amino, C 1 -C 3 alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(C=O)CH 3 fluoro, chloro, bromo, or CI-C 3 thioalkyl.

3. A compound according to claim 1 or 2 wherein R 4 is 2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6- 25 dimethylphenyl.

4. A compound according to any one of claims 1 to 3 wherein R 2 is methylthio or S ethyl.

5. A compound according to any one of claims 1 to 4 wherein R 5 is substituted at S, the 6 position. S 30 6. A pharmaceutical composition comprising a compound of the formula I or an acid addition salt thereof, according to any one of claims 1 to 5, together with a pharmaceutically acceptable diluent or carrier.

7. A method of manufacturing a medicament-comprising mixing a compound of formula I or an acid addition salt thereof, according to any one of claims 1 to 5 with a pharmaceutically acceptable diluent or carrier.

8. A pyrazolopyrimidine having CRF antagonist activity, substantially as hereinbefore described with reference to any one of the Examples.

9. A method for the treatment of illnesses induced by corticotropin releasing factor or stress-induced or anxiety-related illnesses including stress-induced depression S 40 and headache, abdominal bowel syndrome, inflammatory disorders, immune suppression, IN:\LIBH]00117:KBM and headache, abdominal bowel syndrome, inflammatory disorders, immune suppression, HIV infections, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems, particularly depression, which comprises administering to a subject in need of such treatment a compound of formula I as defined in any one of claims 1 to 5 or 8, or a composition as defined in claim 6. A compound of formula I as defined in any one of claims 1 to 5 or 8, or a composition as defined in claim 6, when used for the treatment of illnesses induced by corticotropin releasing factor or stress-induced or anxiety-related illnesses including stress-induced depression and headache, abdominal bowel syndrome, inflammatory disorders, immune supression, HIV infections, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems, particularly depression, in a subject in need of such S• treatment.

11. A compound of formula I as defined in any one of claims 1 to 5 or 8, or a r composition as defined in claim 6, for the treatment of(a) illnesses induced by corticotropin releasing factor or stress-induced or anxiety-related illnesses including stress-induced depression and headache, abdominal bowel syndrome, inflammatory disorders, immune o supression, HIV infections, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems, particularly depression, in a subject in need of such treatment.

12. The use of a compound of formula I as defined in any one of claims 1 to 5 or 8, for the manufacture of a medicament for the treatment of illnesses induced by corticotropin releasing factor or stress-induced or anxiety-related illnesses including stress-induced depression and headache, abdominal bowel syndrome, inflammatory disorders, immune supression, HIV infections, Alzheimer's disease, gastrointestinal S diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, r drug addiction, and fertility problems, particularly depression, in a subject in need of such treatment. Dated 23 August, 1999 Pfizer Inc Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [N:\LIBH]0011 7:mcc