Certain pyrazole derivatives as corticotropin-releasing factor CRF1 ligands

Disclosed are compounds that are highly selective partial agonists or antagonists at human CRF1 receptors that are useful in the diagnosis and treatment of treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety. The compounds have the formula or the pharmaceutically acceptable salts thereof wherein Ar, R1, R2, A, and Z are various organic and inorganic substituents.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain pyrazole derivatives which selectively bind to corticotropin-releasing factor (CRF) receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.

2. Description of the Related Art

A variety of pyrazoles have been described in the prior art. International Patent Application Publication No. WO96/01254 (Jan. 18, 1996) discloses certain pyrazole derivatives as herbicides. International Patent Application Publication No. WO94/13643 (Jun. 23, 1994 ) discloses certain pyrazoles and pyrazolopyrimidines as CRF antagonists. International Patent Application Publication No. WO94/13644 (Jun. 23, 1994) and International Patent Application Publication No. WO94/13661 (Jun. 23, 1994) also disclose certain substituted pyrazoles which have CRF antagonistic activities. German Patent DD210265 (Jun. 06, 1984) discloses certain pyrazoles as xanthine oxidase inhibitors.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact with CRF receptors.

The invention provides pharmaceutical compositions comprising compounds of Formula 1. It further relates to the use of such compounds in treating stress related disorders 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 phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3- thienyl 4 or 5-pyrimidinyl, mono, disubstituted, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy with the proviso that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted,

A is CH 2 or C O;

Z is a group of the formula

where

m is 0, 1 or 2;

n is 0, 1 or 2; and

E is a group of the formula

where

the B ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or a saturated 5- or 6- membered ring or a partially unsaturated ring having one or two double bonds; or

Z is NR 6 R 7

where R 6 and R 7 are the same or different and represent

These compounds are highly selective partial agonists or antagonists at 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.

DETAILED DESCRIPTION OF THE INVENTION

In addition to the compounds of Formula I above, the invention provides compounds encompassed by Formula IIA:

wherein

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3- thienyl, 4- or 5- pyrimidinyl, mono, disubstituted, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy with the proviso that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;

Z is a group of the formula

where

m is 0, 1 or 2;

n is 0, 1 or 2;and

E is a group of the formula

where

the B ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or a saturated 5- or 6- membered ring or a partially unsaturated ring having one or two double bonds; or

Z is NR 6 R 7 ,

where R 6 and R 7 are the same or different and represent

Preferred compounds of formula IIA are those where Z is 1,2,3,4-tetrahydroisoquinoline, 3-hydroxymethyl-1,2,3,4tetrahydroisoquinoline or 3-methoxymethyl-1,2,3,4-tetrahydroisoquinoline.

The invention also provides compounds of formula IIB:

wherein

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;

Z is a group of the formula

where

n is 0, 1 or 2; and

E is a group of the formula

where

the B ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, or a saturated 5- or 6-membered ring or a partially unsaturated ring having one or two double bonds; or

Z is NR 6 R 7

where R 6 and R 7 are the same or different and represent

Preferred compounds of formula IIB are those where Z is 1,2,3,4 tetrahydroisoquinoline, 3-hydroxyinethyl-1,2,3,4tetrahydroisoquinoline or 3-methoxymethyl-1,2,3,4tetrahydroisoquinoline.

The invention provides compounds of formula III

wherein

A is methylene or carbonyl;

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4pyridinyl, 4 or 5-pyriridinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;

m is 0, 1 or 2;

n is 0, 1 or 2; and

E is a group of the formula

where

the B ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, or a saturated 5- or 6-membered ring or a partially unsaturated ring having one or two double bonds.

Preferred compounds of formula III are those where Ar is phenyl that is mono-, di-, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the pyrazole ring is substituted. More preferred compounds of Formula III are those where R 1 and R 2 are independently hydrogen or lower alkyl, most preferably hydrogen or C 1 -C 3 alkyl; and Ar is phenyl that is trisubstituted with C 1 -C 6 alkyl, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the pyrazole ring is substituted. Most preferred compounds of Formula III are those where R 1 and R 2 are independently C 1 -C 3 alkyl; and Ar is phenyl that is trisubstituted in the 1, 3, and 5 positions (para and both ortho positions relative to the point of attachment to the pyrazole ring) with C 1 -C 3 alkyl, most preferably methyl.

The invention provides compounds of formula IV

wherein

A is carbonyl or methylene;

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl 4 or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C 1 -C 6 , alkyl, or C 1 -C 6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;

Preferred compounds of formula IV are those where Ar is phenyl that is mono-, di-, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the pyrazole ring is substituted. More preferred compounds of Formula IV are those where R 1 and R 2 are independently hydrogen or lower alkyl, most preferably hydrogen or C 1 -C 3 alkyl; and Ar is phenyl that is trisubstituted with C 1 -C 6 alkyl, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the pyrazole ring is substituted. Most preferred compounds of Formula IV are those where R is represents hydrogen, methoxymethyl, or hydroxymethyl, R 1 and R 2 are independently C 1 -C 3 alkyl; and Ar is phenyl that is trisubstituted in the 1, 3, and 5 positions (i.e., the para and both ortho positions relative to the point of attachment to the pyrazole ring) with C 1 -C 3 alkyl, most preferably methyl.

Other preferred hydroxy alkyl or alkoxy alkyl groups at R in Formula IV are hydroxymethyl and methoxymethyl. Preferred compounds of formula IV are those where Z is 1,2,3,4tetrahydroisoquinoline, 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline or 3-methoxymethyl- 1,2,3,4-tetrahydroiso-quinoline.

The invention further provides compounds of formula V

wherein

A is methylene or carbonyl;

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;

G is CH or N; and

R represents C 1 -C 6 alkyl or a phenyl group optionally substituted with C 1 -C 6 alkyl,

Preferred compounds of formula V are those where G is nitrogen, Ar is phenyl that is mono-, di-, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the pyrazole ring is substituted. More preferred compounds of Formula V are those where G is nitrogen, R 1 and R 2 are independently hydrogen or lower alkyl, most preferably hydrogen or C 1 -C 3 alkyl; and Ar is phenyl that is trisubstituted with C 1 -C 6 alkyl, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the pyrazole ring is substituted. Most preferred compounds of Formula V are those where G is nitrogen, R is methyl or phenyl, R 1 and R 2 are independently C 1 -C 3 alkyl; and Ar is phenyl that is trisubstituted in the 1, 3, and 5 positions (para and both ortho positions relative to the point of attachment to the pyrazole ring) with C 1 -C 3 , alkyl, most preferably methyl. Other most preferred compounds of Formula V are those where A is methylene and G is nitrogen, R is methyl or phenyl, R 1 and R 2 are independently C 1 -C 3 alkyl; and Ar is phenyl that is trisubstituted in the 1, 3, and 5 positions (para and both ortho positions relative to the point of attachment to the pyrazole ring) with C 1 -C 3 alkyl, most preferably methyl.

The invention provides compounds of formula VI

wherein

A is methylene or carbonyl;

Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 4 or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;

R a represents hydrogen or C 1 -C 6 alkyl; and

Preferred compounds of formula VI are those where Ar is phenyl that is mono-, di-, or trisubstituted with halogen, hydroxy, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the pyrazole ring is substituted. More preferred compounds of Formula VI are those where R 1 and R 2 are independently hydrogen or lower alkyl, most preferably hydrogen or C 1 -C 3 alkyl; and Ar is phenyl that is trisubstituted with C 1 -C 6 alkyl, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the pyrazole ring is substituted. Most preferred compounds of Formula V are those where R a is hydrogen or lower alkyl, most preferably methyl, R b is optionally substituted phenyl, R 1 and R 2 are independently C 1 -C 3 alkyl; and Ar is phenyl that is trisubstituted in the 1, 3, and 5 positions (para and both ortho positions relative to the point of attachment to the pyrazole ring) with C 1 -C 3 alkyl, most preferably methyl.

Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC (CH 2 ) n COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

When a compound of formula I is obtained as a mixture of enantiomers these may be separated by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral HPLC column.

By the terms (C 1 -C 6 )alkyl and lower alkyl is meant straight and branched chain alkyl groups having from 1-6 carbon atoms as well as cyclic alkyl groups such as, for example, cyclopropyl, cyclobutyl, or cyclohexyl. Specific examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl and n-pentyl. Preferred C 1 -C 6 alkyl groups are methyl, ethyl, propyl, butyl or cyclopropylmethyl.

By the terms (C 1 -C 6 )alkoxy and lower alkoxy is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms.

By hydroxy C 1 -C 6 alkyl is meant a C 1 -C 6 alkyl group carrying a terminal hydroxy moiety.

By C 1 -C 6 alkoxy C 1 -C 6 alkyl is meant a group of the formula (CH 2 ) x O(CH 2 ) y CH 3 , where x and y independently represent integers of from 1-6.

By the term C 1 -C 6 alkenyl is meant straight or branched chain hydrocarbon groups having from 1-6 carbon atoms and at least one double bond.

By halogen, halo, or halide is meant fluorine, chlorine, bromine and iodine substituents.

By aryl(C 1 -C 6 )alkyl is meant aryl groups attached to the parent group by a straight or branched chain alkyl group having 1-6 carbon atoms. The aryl groups include phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5- pyrimidinyl and are optionally substituted with up to two groups selected from halogen, hydroxy, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy.

Representative examples of-pyrazoles according to the invention are shown in Table I below.

TABLE 1 Compound No. 1 2 3 11 12 15 16 The pharmaceutical utility of compounds of this invention are indicated by the following assay for CRF receptor activity.

Assay for CRF Receptor Binding Activity

CRF receptor binding was performed 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 were resuspended in 50 mM Tris buffer pH 7.7 containing 10 mM MgCl 2 and 2 mM EDTA and centrifuged for 10 minutes at 48000 g. Membranes were washed again and brought to a final concentration of 1500 mg/ml in binding buffer (Tris buffer above with 0.1% BSA, 15 mM bacitracin and 0.01 mg/ml aprotinin.). For the binding assay, 100 ml of the membrane preparation was added to 96 well microtube plates containing 100 ml of 1251-CRF (SA 2200 Ci/mmol, final concentration of 100 pM) and 50 ml of drug. Binding was carried out at room temperature for 2 hours. Plates were then harvested on a Brandel 96 well cell harvester and filters were counted for gamma emissions on a Wallac 1205 Betaplate liquid scintillation counter. Non specific binding was defined by 1 mM cold CRF. IC 50 values were calculated with the non-linear curve fitting program RS/1 (BBN Software Products Corp., Cambridge, Mass.). The binding affinity for the compounds of formula I expressed as IC50 value, generally range from about 0.5 nanomolar (nM) to about 10 micromolar ( M).

The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compounds of general formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either 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 of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.

A representative illustration of methods suitable for the preparation of compounds of the present invention is shown in Scheme I. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention.

wherein

Ar, R 1 , R 2 , and Z are as defined as above for Formula I; and

X is a leaving group, such as, for example, chloride or bromide.

The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.

Sodium (1.0 g, 42.1 mmol, spheres) was cautiously added to 25 mL of absolute EtOH with stirring. After the sodium had dissolved, diethyl oxalate (6.0 g, 42.1 mmol) was added dropwise to the resulting solution at 0 C., followed by addition of a solution of 2 , 4 , 6 -trimethylbutyrophenone (8 g, 42.1 mmol) in 5 mL of absolute EtOH. The reaction mixture was slowly warmed to 50 C. and stirred overnight. The solvent was then evaporated. The resulting residue was washed with hexane, diluted with water, acidified with 1 N HCl, and then extracted with ether. The extacts were washed with brine, dried over Na 2 SO 4 and concentrated to give 6.5 g of an oil which was used in the next reaction without further purification.

A mixture of ethyl 3-ethyl-2,4-dioxo4(2,4,6trimethylphenyl)butanoate (6.0 g, 20.7 mmol) and hydrazine dihydrochloride (2.17 g, 20.7 mmoL) in 100 mL of EtOH was stirred at 80 C. for 6 hours. The solvent was then removed from the mixture. 200 mL of water was added to the residue and mixture was neutralized by the addition of solid NaHCO 3 . The product was extracted into ether. The ether extract was dried over Na 2 SO 4 and evaporated to give 5.8 g as an oil which was used in the next reaction without further purification.

To a red mixture of the product of step B (1.0 g, 3.5 mmol) and powdered KOH (2.0 g) in 50 mL of DMSO was added bromoethane (2.0 mL) at 60 C. The reaction mixture was stirred for I hour then poured into ice-water. The resulting mixture was extracted with ether. The ether extract was washed with brine, dried over Na2SO 4 , and concentrated to provide an oil which was comprised of the isomeric pair ethyl 1,4-diethyl-3-2,4,6-trimethylphenyl)-pyrazole-5-carboxylate and ethyl 1,4-diethyl-5-(2,4,6-trimethylphenyl)-pyrazole-3- carboxylate in a 1:1 mixture. The isomers were separated by column chromatography over silica gel using CH 2 Cl 2 as eluent. The faster moving fraction, comprising the titled compound, was collected. Evaporation of the solvent gave about 400 mg of the desired compound as an oil. 1 H NMR (CDCl 3 ): 0.95 (t, 3H), 1.42 (mn, 6H) 2.00 (s, 6H), 2.30 (s, 3H), 2.42 (q, 2H), 4.40 (q, 2H), 4.59 (q, 2H), 6.90 (s, 2H) ppm.

To a solution of the product of step C (320 mg, 1 mmol) in 10 mL of anhydrous THF was added dropwise a solution of LiAiH4 (3 mL, 1 M in THF) at 0 C. After stirring for 2 hours, water was cautiously added. The mixture was then extracted repeatedly with ether. The combined extracts were washed with brine, dried and concentrated. The residue was dissolved in 1 mL of SOCl 2 , stirred at 60 C. for 2 hours and evaporated to provide the title compound which was used in the next reaction without further purification.

The following compounds are prepared essentially according to procedures set forth above in Example 1.