WO2009151862A1

WO2009151862A1 - Method of treatment

Info

Publication number: WO2009151862A1
Application number: PCT/US2009/043883
Authority: WO
Inventors: Connie L. Erickson-Miller
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 2008-05-15
Filing date: 2009-05-14
Publication date: 2009-12-17
Anticipated expiration: 2010-11-15

Abstract

Invented is a method of treating a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in a human in need thereof which comprises the administration of a therapeutically effective amount of a non-peptide TPO receptor agonist to such mammal.

Description

METHOD OF TREATMENT

FIELD OF THE INVENTION This invention relates to a method of treating a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in a human by administration of a non-peptide thrombopoietin (TPO) receptor agonists and pharmaceutical compositions containing the same. Suitably, the method relates to methods of treating a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac by the administration of 3'-[(2Z)-[1 -(3,4-dimethylphenyl)-1 ,5-dihydro-3-methyl-5-oxo- 4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1 ,1 '-biphenyl]-3-carboxylic acid or a pharmaceutically acceptable salt thereof, suitably the bis-(monoethanolamine) salt, (hereinafter the bis-(monoethanolamine) salt is Compound A and the corresponding salt free compound is Compound B).

BACKGROUND OF THE INVENTION Thrombopoietin (TPO) has been shown to be the main humoral regulator in situations involving thrombocytopenia. See, e.g., Metcalf Nature 369:519-520 (1994). TPO has been shown in several studies to increase platelet counts, increase platelet size, and increase isotope incorporation into platelets of recipient animals. Because platelets (thrombocytes) are necessary for blood clotting and when their numbers are very low a patient is at risk of death from catastrophic hemorrhage, TPO is considered to have potential useful applications in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects. In addition, studies have provided a basis for the projection of efficacy of TPO therapy in the treatment of thrombocytopenia, and particularly thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transplantation as treatment for cancer or lymphoma. See e.g., McDonald (1992) Am. J. Ped. Hematoloqv/Oncoloqy 14: 8- 21 (1992).

The slow recovery of platelet levels in patients suffering from thrombocytopenia is a serious problem, and has lead to the search for small molecule non-peptide TPO receptor agonists that are able to accelerate platelet regeneration, (e.g. see, International Application Number PCT/US01/16863, having International Filing Date May 24, 2001 , which specifically discloses Compound B, in Example 3, and the use of non-peptide TPO receptor agonists in combination with further active ingredients). Compound A is disclosed in International Application No. PCT/US03/16255, having an International filing date of May 21 , 2003; International Publication Number WO 03/098002 and an International Publication date of December 4, 2003.

Non-peptide TPO receptor agonists, including Compound A, are disclosed for the treatment of degenerative diseases/injuries in International Application No. PCT/US04/013468, having an International filing date of April 29, 2004;

International Publication Number WO 04/096154 and an International Publication date of November 11 , 2004.

The present invention concerns novel therapeutic uses of a known class of compounds, non-peptide TPO receptor agonists.

SUMMARY OF THE INVENTION

This invention relates to a method of treating a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in a human, in need thereof which comprises administering to such human a therapeutically effective amount of a non-peptide TPO receptor agonists.

Included among the non-peptide TPO receptor agonists of the invention are compounds of Formula (I):

wherein:

R, R1 , R2 and R^ are each independently selected from hydrogen, C-μ galkyl, -(CH2)_pOR⁴, -C(O)OR⁴, formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(O)_nR⁴, cycloalkyl, -NR⁵R⁶, protected -OH, -CONR5R6, phosphonic acid, sulfonic acid, phosphinic acid, - SC>2NR5R6, and a heterocyclic methylene substituent as represented by Formula (III),

where, p is 0-6, n is 0-2,

V, W, X and Z are each independently selected from O, S and NR¹6, where R¹^ is selected from: hydrogen, alkyl, cycloalkyl, C"|-C-|2^aryl_> substituted alkyl, substituted cycloalkyl and substituted C-i-C^ary'. R⁴ is selected from: hydrogen, alkyl, cycloalkyl, C-i-C^ary'. substituted alkyl, substituted cycloalkyl and substituted C-|-C-|2aryl, and R^ and R6 are each independently selected from hydrogen, alkyl, substituted alkyl, C3_gcycloalkyl, and aryl, or R5 and R^ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;

m is 0-6; and

AR is a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, -C(O)OR⁴, -C(O)NR¹⁰R^{1 1} , -S(O)₂NR^{1 0}R^{1 1} , -S(O)_nR⁴ and protected -OH, where n is 0-2, R⁴ is hydrogen, alkyl, cycloalkyl, C-|-C-|2^ary'' substituted alkyl, substituted cycloalkyl and substituted C-i-C^ary'. ^and R-IO and R-11 are independently hydrogen, cycloalkyl, C-i-C^ary'. substituted cycloalkyl, substituted C-|-C-|2^ary'' alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR⁴, - S(O)_nR⁴, -C(O)NR⁴R⁴, -S(O)₂NR⁴R⁴, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected -OH, or R1 O and R^ 1 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where R⁴ is as described above and n is 0-2; or a pharmaceutically acceptable salt thereof;

provided that at least one of R, R-I , R^ and R^ is a substituted aryl group or a heterocyclic methylene substituent as represented in Formula (III).

This invention relates to a method of treating a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in a human, in need thereof which comprises administering to such human a therapeutically effective amount of a non-peptide TPO receptor agonist of Formula (I)-

Included in the present invention are pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention.

Also included in the present invention are methods of co-administering non- peptide TPO receptor agonists with further active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to methods of treating a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in a human, in need thereof which comprises administering to such human a therapeutically effective amount of a non-peptide TPO receptor agonist, including compounds of Formula (I) as described above.

Suitably, the invention relates to a method of treating depression in a human in need thereof. The term depression, as used herein, includes: depression, anxiety, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome, premenstrual dysphoric disorder (PMDD), adolescent depression, trichotillomania and dysthymia. The term depression, as used herein, also includes depression subtypes including: bipolar, elderly, major, minor, moderate, recurrent, refractory, severe unipolar, dysthymia, post natal, double depression, post psychotic, post viral, bereavement, primary, secondary, post traumatic stress disorder. The term depression, as used herein, also includes depression associated with withdrawal from substances of abuse including: alcohol, nicotine, cocaine, heroin and benzodiazepines. As such, the method of this invention suitably relates to assisting a human, in need thereof, in the cessation from abuse and/or dependence from substances of abuse including: cocaine, heroin, benzodiazepines, alcohol and nicotine (including the chewing and/or smoking of tobacco).

Suitably, the invention relates to a method of treating fatigue in a human in need thereof. The term fatigue, as used herein, includes: Chronic Fatigue Syndrome (CFS) and the fatigue of cancer.

Suitably, the invention relates to a method of treating autism in a human in need thereof. The term autism, as used herein, includes: classic autism, Asperger's Syndrome, childhood disintegrative disorder, Rett Syndrome and pervasive developmental disorder not otherwise specified. Suitably, the invention relates to a method of treating psoriasis in a human in need thereof. The term psoriasis, as used herein, includes the Plaque, Guttate, Inverse, Pustular and Erythrodermic types.

Suitably, the invention relates to a method of treating digestive disorders in a human in need thereof. The term digestive disorders, as used herein, includes: celiac.

Included among compounds of Formula (I) that are useful in the current invention are those having Formula (Vl):

wherein:

R, R-I , R2 and R^ are each independently selected from hydrogen, C-μ galkyl, C-μ_βalkoxy, -(CH2)_pOR⁴, -C(O)OR⁴, formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(O)_nR⁴, cycloalkyl, -NR⁵R⁶, protected -OH, -CONR⁵Re₁ phosphonic acid, sulfonic acid, phosphinic acid and -Sθ2NR⁵R⁶, where p is 0-6, n is 0-2,

R⁴ is hydrogen, alkyl, cycloalkyl, C-|-C-|2^ary'' substituted alkyl, substituted cycloalkyl and substituted C-i-C^aryl. and

R⁵ and R^ are each independently selected from hydrogen, alkyl, substituted alkyl, C3_gcycloalkyl, and aryl, or R⁵ and R^ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;

R^⁵ is selected from the group consisting of alkyl, C-i-C^aryl. hydroxy, alkoxy, substituted alkyl, substituted C-|-C-i2^ary' ^and halogen;

m is 0-6; and

Y is selected from alkyl, substituted alkyl and a cyclic or polycyclic aromatic ring containing from 3 to 14 carbon atoms and optionally containing from one to three heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, C-i-C^aryl. substituted cycloalkyl, substituted C-i-C^ary'. hydroxy, aryloxy, alkoxy, cycloalkyl, nitro, cyano, halogen and protected -OH;

or a pharmaceutically acceptable salt thereof;

provided that at least one of R, R^ , R^ and R^ is a substituted aryl group.

Included among the compounds useful in the present invention are those having Formula (Vl) in which, either:

R is a substituted aryl; and R^ is hydrogen; or:

R is hydrogen; and R^ is a substituted aryl; and in either case: R^ and R^ are each independently selected from hydrogen, C-|.galkyl, C-|_ galkoxy, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, cycloalkyl, phosphonic acid, phosphinic acid and sulfonic acid; R15 is selected from the group consisting of alkyl, substituted alkyl, C-|- Ci2^ary'> alkoxy and halogen; m is 0-4; and

Y is selected from, phenyl, pyridinyl and pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl are optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C-|-C-|2aryl, substituted C-|-C-|2aryl, alkoxy and halogen; or a pharmaceutically acceptable salt thereof.

Included among the compounds useful in the present invention are those having Formula (Vl) in which, R is a substituted C-|-C-|2aryl; and

R-I is hydrogen; R^ and R^ are each independently selected from hydrogen, C-|.galkyl, C-|_ galkoxy, nitro, cyano, halogen, substituted alkyl and cycloalkyl; R15 is selected from the group consisting of alkyl, substituted alkyl, C-|-

C-|2aryl, alkoxy and halogen; m is 0-2; and Y is selected from, phenyl, pyridinyl and pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl are optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C-i-C^ary'. substituted C-i-C^ary'. alkoxy and halogen; or a pharmaceutically acceptable salt thereof.

Included among the compounds useful in the present invention are those having Formula (Vl) in which, R is a substituted phenyl or pyridinyl ring; and

R1 is hydrogen; R2 and R^ are each independently selected from hydrogen, C-|.galkyl, substituted alkyl and halogen;

R15 is selected from the group consisting of C-|_4alkyl, C-|.4alkoxy, C-|- C-|2aryl and halogen; m is 0; and

Y is selected from, phenyl, pyridinyl and pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl is optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C-|-C-|2aryl, substituted C-|-C-|2aryl, alkoxy and halogen; or a pharmaceutically acceptable salt thereof.

Included among the compounds useful in the present invention are: 3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1 ,5-dihydropyrazol-4- ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid;

3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1 ,5-dihydropyrazol-4- ylidene]hydrazino}-2-hydroxy-3'-(tetrazol-5-yl)biphenyl;

1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2- ylJcarbamoylJpyridine^-yOpiperidine^-carboxylic acid;

3'-{Λ/-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1 ,2-dihydro-indol-3-ylidene]- hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; and

2'-hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1 ,2-dihydro-indol-3-ylidene]-hydrazino}- biphenyl-4-carboxylic acid; or a pharmaceutically acceptable salt thereof. Included among the non-peptide TPO receptor agonists of the invention are the non-peptide compounds described in: WO 02/59099; WO 02/59100; EP 1 207 155;

EP 1 253 142A1 ; WO 01/92211 A1 ; WO 01/53267-A1 ; WO 03/62233 WO 02/62775

EP 1 104 674- A1 ; and WO 01/07423-A1.

Included among the compounds of the above listed applications that are useful in the present invention are:

N-[4-(5-bromo-2-thienyl)-1 ,3-thiazol-2-yl]-4-[(Z)-(2,4-dioxo-1 ,3-thiazolidin-5- ylidene)methyl]benzamide;

N-[4-(3,4-dimethylphenyl)-1 ,3-thiazol-2-yl]-4-[(Z)-(2,4-dioxo-1 ,3-thiazolidin-5- ylidene)methyl]benzamide; N-{4-[4-(1 ,1-dimethylethyl)phenyl]-1 ,3-thiazol-2-yl}-4-[(Z)-(2,4-dioxo-1 ,3- thiazolidin-5-ylidene)methyl]benzamide;

N-[4-(3,4-dichlorophenyl)-1 ,3-thiazol-2-yl]-4-[(Z)-(2,4-dioxo-1 ,3-thiazolidin-5- ylidene)methyl]benzamide; and

(2E)-3-[4-({[4-(3,4-dichlorophenyl)-1 ,3-thiazol-2-yl]amino}carbonyl)phenyl]-2- methyl-2-propenoic acid; or a pharmaceutically acceptable salt thereof.

Included among the non-peptide TPO receptor agonists of the invention are the non-peptide compounds described in: WO 99/1 1262.

Included among the non-peptide TPO receptor agonists of the invention are the non-peptide compounds described in:

International Application No. PCT/US05/018924, having an International filing date of May 27, 2005; International Publication Number WO 05/118551 and an International Publication date of December 15, 2005, International Application No. PCT/US05/038055, having an International filing date of October 21 , 2005; International Publication Number WO 06/047344 and an International Publication date of May 4, 2006,

International Application No. PCT/US06/045129, having an International filing date of November 21 , 2006; International Publication Number WO 07/062078 and an International Publication date of May 31 , 2007, and

International Application No. PCT/US07/006547, having an International filing date of March 14, 2007; International Publication Number WO 07/106564 and an International Publication date of September 20, 2007. The compounds that are final products in WO 05/1 18551 , WO 06/047344,

WO 07/062078 and WO 07/106564 are useful in the present invention, these compounds are included herein by reference.

The compound that is the product of Example 4 in WO 07/106564, 3'-{Λ/-[1- (3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1 ,2-dihydro-indol-3-ylidene]- hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid, as the salt free compound or in the form of a pharmaceutically acceptable salt, hydrate, solvate or ester, is a compound useful in the present invention.

The compound that is the product of Example 6 in WO 07/106564, 2'- hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1 ,2-dihydro-indol-3-ylidene]-hydrazino}- biphenyl-4-carboxylic acid, as the salt free compound or in the form of a pharmaceutically acceptable salt, hydrate, solvate or ester, is a compound useful in the present invention.

Included among the non-peptide TPO receptor agonists of the invention is the non-peptide compound described in:

International Application No. PCT/JP03/012419, having an International filing date of September 29, 2003; International Publication Number WO 04/029049 and an International Publication date of April 8, 2004, 2005.

The compound that is the final product in WO 04/029049, both the salt and non-salt forms, is useful in the present invention, these compounds are included herein by reference.

Suitably, the compound that is the final product in WO 04/029049 is 1-(3- chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2- ylJcarbamoylJpyridine^-yOpiperidine^-carboxylic acid, as the salt free compound (hereinafter Compound E), or in the form of a pharmaceutically acceptable salt hydrate solvate or ester thereof. Suitably, the salt is a maleic acid salt (hereinafter Compound F). The structure of Compound F is indicated below.

Non-peptide TPO receptor agonists are included in the pharmaceutical compositions of the invention and used in the methods of the invention.

By the term "protected hydroxy" or "protected -OH" as used herein, is meant the alcoholic or carboxylic-OH groups which can be protected by conventional blocking groups in the art such as described in "Protective Groups In Organic Synthesis" by Theodora W. Greene, Wiley-lnterscience, 1981 , New York. Compounds containing protected hydroxy groups may also be useful as intermediates in the preparation of the pharmaceutically active compounds of the invention.

By the term "aryl" as used herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic ring containing from 1 to 14 carbon atoms and optionally containing from one to five heteroatoms, provided that when the number of carbon atoms is 1 the aromatic ring contains at least four heteroatoms, when the number of carbon atoms is 2 the aromatic ring contains at least three heteroatoms, when the number of carbons is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom.

By the term "C-|-C-|2^aryl" ^as used herein, unless otherwise defined, is meant phenyl, naphthalene, 3,4-methylenedioxyphenyl, pyridine, biphenyl, quinoline, pyrimidine, quinazoline, thiophene, furan, pyrrole, pyrazole, imidazole and tetrazole.

When referring to compounds of Formula (I) and (II), the term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: -CO₂R²⁰, aryl, -C(O)NHS(O)₂R²⁰, -NHS(O)₂R²⁰, hydroxyalkyl, alkoxy, -C(O)NR²¹ R²², acyloxy, alkyl, amino, N-acylamino, hydroxy, -(CH₂)_gC(O)OR⁸, -S(O)_nR⁸, nitro, tetrazole, cyano, oxo, halogen, trifluoromethyl, protected -OH and a heterocyclic methylene substituent as represented by Formula (III),

, where g is 0-6; R⁸ is hydrogen or alkyl; R²⁰ is selected form hydrogen, C-_|- C4alkyl, aryl and trifluoromethyl; R^2"! and R²² are independently selected form hydrogen, C-_|-C4alkyl, aryl and trifluoromethyl; V, W, X and Z are each independently selected from O, S, and NR^₁ where R¹6 is selected from: hydrogen, alkyl, cycloalkyl, C-_|-C-_{| 2}aryl, substituted alkyl, substituted cycloalkyl and substituted C-|-C-|₂aryl; and n is 0-2.

When referring to compounds of Formula (V) and (Vl), the term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: -CO₂R²⁰, aryl, -C(O)NHS(O)₂R²⁰, -NHS(O)₂R²⁰, hydroxyalkyl, alkoxy, -C(O)NR^2"! R²², _aCy|_Oχy, alkyl, amino, N-acylamino, hydroxy, -(CH₂)_gC(O)OR⁸, -S(O)_nR⁸, nitro, tetrazole, cyano, oxo, halogen, trifluoromethyl and protected -OH, where g is 0-6, R⁸ is hydrogen or alkyl, R²⁰ is selected form hydrogen, C-_|-C4alkyl, aryl and trifluoromethyl, and R²¹ and R²² are independently selected form hydrogen, C-_|- C4alkyl, aryl and trifluoromethyl, and n is 0-2.

By the term "alkoxy" as used herein is meant -Oalkyl where alkyl is as described herein including -OCH3 and -OC(CH3)₂CH3.

The term "cycloalkyl" as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C-|₂

Examples of cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4- methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl, cyclopropyl and cyclopentyl. By the term "acyloxy" as used herein is meant -OC(O)alkyl where alkyl is as described herein. Examples of acyloxy substituents as used herein include: - OC(O)CH₃, -OC(O)CH(CH₃)₂ and -OC(O)(CH₂)3CH₃.

By the term "N-acylamino" as used herein is meant -N(H)C(O)alkyl, where alkyl is as described herein. Examples of N-acylamino substituents as used herein include: -N(H)C(O)CH₃, -N(H)C(O)CH(CH₃)₂ and -N(H)C(O)(CH₂)₃CH₃.

By the term "aryloxy" as used herein is meant -Oaryl where aryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionally substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy, trifuloromethyl, acyloxy, amino, N-acylamino, hydroxy, -(CH₂)gC(O)OR8, - S(O)_nR^, nitro, cyano, halogen and protected -OH, where g is 0-6, R^ is hydrogen or alkyl, and n is 0-2. Examples of aryloxy substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.

By the term "heteroatom" as used herein is meant oxygen, nitrogen or sulfur.

By the term "halogen" as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.

By the term "alkyl" and derivatives thereof and in all carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain, and unless otherwise defined, the carbon chain will contain from 1 to 12 carbon atoms. Examples of alkyl substituents as used herein include: -CH₃, -CH₂-CH₃, -CH₂-CH₂-CH₃, -CH(CH₃)₂, -C(CH₃)₃, -(CH₂)₃-CH₃, -CH₂-CH(CH₃)₂, -CH(CH₃)- CH₂-CH₃, -CH=CH₂, and -C=C-CH₃.

By the term "treating" and derivatives thereof as used herein, is meant prophylactic and therapeutic therapy. Prophylactic therapy is appropriate, for example, when a subject is attempting cessation from abuse and/or dependence from substances of abuse and withdrawal symptoms are anticipated. Also, prophylactic therapy is appropriate, for example, when a human is diagnosed with a cancer and, after treatment, the fatigue of cancer is anticipated.

By the phrases "to a therapeutic extent", "treating" and "therapeutically effective amount" and derivatives thereof as used herein, unless otherwise defined, is meant that amount of non-peptide TPO receptor agonist that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term

"therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, lessening in severity or amelioration of: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac.

The disease states of: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac are known to have many causative factors. This invention relates to the treatment of such disease states regardless of the factor or factors causing the condition. The pharmaceutically active compounds of this invention are also useful in treating such disease states when the causative factor or factors of the condition are unknown or have yet to be identified.

A skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of, for example, Chronic Fatigue Syndrome, for administration by methods of the present invention.

By the phrase "non-peptide" as used herein is meant a chemical compound, or a protein or peptide not comprised primarily of natural amino acids. Suitably, the "non-peptide" is a small molecule chemical compound having a molecular weight under 1 ,500 daltons, suitably under 1 ,000 daltons.

By the term "primarily" as used above is meant about 60% by weight of naturally occurring amino acid residue.

Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also, it is understood that all tautomers and mixtures of tautomers are included within the scope of the compounds of the invention.

Certain compounds described herein may form a solvate which is understood to be a complex of variable stoichiometry formed by a solute (for example, a compound of Formula I of a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Suitably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Suitably, the solvent used is water. The compounds of the invention are included in the pharmaceutical compositions of the invention and used in the methods of the invention. Where a - COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics, for use as sustained release or prodrug formulations.

Salt forms, including pharmaceutically acceptable salts, of the compounds of the invention are readily prepared by those of skill in the art.

The compounds of Formula I are disclosed and claimed, along with pharmaceutically acceptable salts, hydrates, solvates and esters thereof, as being useful as an agonist of the TPO receptor, particularly in enhancing platelet production and particularly in the treatment of thrombocytopenia, in International Application No. PCT/US01/16863, having an International filing date of May 24, 2001 ; International Publication Number WO 01/89457 and an International Publication date of November 29, 2001 , the entire disclosure of which is hereby incorporated by reference. Compounds of Formulas I and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, are prepared as described in International Application No. PCT/US01/16863. The bis-(monoethanolamine) salt of a compound described in International Application No. PCT/US01/16863, is described in International Application No. PCT/US03/16255, having an International filing date of May 21 , 2003; International Publication Number WO 03/098992 and an International Publication date of December 4, 2003.

The treatment of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac, as described herein, is accomplished by the administration of a non-peptide TPO receptor agonist and is not limited to any particular mechanism of action.

When referring to the treatment of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac, the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a non-peptide TPO receptor agonist, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of the corresponding disease state. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for the corresponding disease state. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

The current invention relates to the use of non-peptide TPO receptor agonists in the treatment of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in a human.

One skilled in the art can readily determine by known methods if a compound is a non-peptide TPO receptor agonist and thus included within the scope of the current invention. By way of example, the following assays can be employed:

Luciferase Assay

Compounds are tested for potency as agonists of the TPO receptor in a Luciferase assay such as described in Lamb, et al., Nucleic Acids Research 23:

3283-3289 (1995) and Seidel, et al., Proc. Natl. Acad. ScL USA 92: 3041-3045

(1995) by substituting a TPO-responsive BaF3 cell line (Vigon et al. Proc. Natl.

Acad. Sci. USA 1992, 89, 5640-5644) for the HepG2 cells utilized therein. The murine BaF3 cells express TPO receptors and closely match the pattern of STAT (signal transducers and activators of transcription) activation observed in primary murine and human bone marrow cells.

Proliferation Assay

Compounds are tested in an in vitro proliferation assay using the human

UT7TPO cell line. UT7TPO cells are a human megakaryoblastic cell line that express Tpo-R, whose survival and growth is dependent on the presence of TPO

(Komatsu et al. Blood 1996, 87,4552).

Differentiation Assay

Compounds are tested for their ability in stimulating the maturation of megakaryocytes from human bone marrow cells. In this assay, purified human CD34+ progenitor cells are incubated in liquid culture with test compounds for 10 days and the number of cells expressing the transmembrane glycoprotein CD41 (gpllb), a megakaryocyte marker, is then measured by flow cytometry (see Cwirla, S. E. et al Science, 1997, 276, 1696).

The pharmaceutically active compounds within the scope of this invention are useful as non-peptide TPO receptor agonists in humans, in need thereof.

The TPO receptor agonists of the present invention lead to the increased production of platelets. Platelets are considered to act as peripheral reservoirs of serotonin and the serotonin precursor L-tryptophan, among others. Increasing the platelet population is also considered to increase the number of serotonin transporters. Because 1 ) TPO receptor agonists increase the population of platelets, 2) platelets are reservoirs of serotonin and the serotonin precursor L- tryptophan, among others and 3) increasing the population of platelets increases the numbers of serotonin transporters; the administration of a TPO receptor agonist will increase the availability of serotonin and numbers of serotonin transporters, thereby increasing serotonin activity and treat disease states wherein increased serotonin activity is implicated or suspected of being useful. Specifically: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac.

Serotonin levels have been found to be low in Down's syndrome patients. Am. J. Hum. Genet. 1975 March; 27(2): 257 - 258. E. E. McCoy, et al. Journal of Intellectual Disability Research volume 12, Issue 1 , pages 18 -21 , 1968.

Many current treatments for the disease states of: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac may be considered toxic to the patient and/or are known to trigger adverse events which require the patient to stop the treatment periodically in order to recover from the toxic effects and/or to allow the adverse events to subside. This recovery period also provides the disease state the opportunity to re-establish. One advantage of the compounds of the invention, non-peptide TPO receptor agonists, suitably a compound selected from the following: 3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1 ,5-dihydropyrazol-4- ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1 ,5-dihydropyrazol-4- ylidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl;

1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1- yOthiazol^-yllcarbamoylJpyridine^-yOpiperidine^-carboxylic acid; 3'-{Λ/ -[1 -(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1 ,2-dihydro-indol-3- ylidene]-hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; and

2'-hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1 ,2-dihydro-indol-3-ylidene]- hydrazino}-biphenyl-4-carboxylic acid; or a salt thereof, is that the compounds may be less toxic than standard therapies for such disease states and are capable of being administered on a daily basis over a long period of time, suitably for over three months, suitably for over six months, suitably for over nine months, suitably for over a year, thereby providing continuous treatment of the disease state. This advantage in the treatment of said disease states can be realized whether non-peptide TPO receptor agonist is being administered alone or co-administered with another agent known to treat the corresponding disease state. Even when the co-administered agent is periodically stopped, the non-peptide TPO receptor agonist can continue to be administered in order to provide sustained treatment of the disease state.

The present invention therefore provides a method of treating a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac which comprises the administration an effective amount of a non-peptide TPO receptor agonist to a human in need thereof.

The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, topically, transdermally, subcutaneous, intradermal, and parenteral.

The non-peptide TPO receptor agonists of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products. Doses of the pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.002 - 50 mg/kg. When treating a human patient in need of a non-peptide TPO receptor agonist, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermal^, by injection and continuously by infusion. Oral dosage units for human administration suitably contain from 0.05 to 3500 mg, suitably from 0.1 to 3000 mg, suitably from 10 to 200 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular non-peptide TPO receptor agonist in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.

The method of this invention of treating disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in humans comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically active compound of the present invention.

The present invention relates to the use of non-peptide TPO receptor agonist compounds in the treatment of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism;

Down's syndrome; psoriasis; and digestive disorders, including celiac in a human. The present invention relates to the in vivo administration of a non-peptide TPO receptor agonist in the treatment of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in a human.

The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in the treatmet of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in a human.

The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in therapy.

The invention also provides for a pharmaceutical composition for use in the treatment of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.

The invention also provides for the use of a compound of Formula (Vl) in the manufacture of a medicament for use in the treatmet of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac.

The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in therapy. The invention also provides for a pharmaceutical composition for use in the treatment of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac which comprises a compound of Formula (Vl) and a pharmaceutically acceptable carrier.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; or digestive disorders, including celiac.

Contemplated Equivalents - It will be appreciated by the person of ordinary skill in the art that the compounds of Formulas I and Vl may also exist in tautomeric forms. For example, in Formula I, the double bond that is drawn between the two nitrogen atoms exists between the lower nitrogen atom and the AR substituent. Tautomeric forms of the compounds of Formulas I and Vl are exemplified by the following Formula (X):

where the 'R' groups are as defined above. All such compounds are included in the scope of the invention and inherently included in the definition of the compounds of Formulas I and Vl.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Experimental Details

Example 1- Capsule Composition

An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.

Table

INGREDIENTS AMOUNTS

3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1 ,5- 25 mg dihydropyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3- carboxylic acid

Mannitol 55 mg

Talc 16 mg

Magnesium Stearate 4 mg Example 2 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by stirring 1.5% by weight of 3-{N'-[1 -(3,4-dimethylphenyl)-3-methyl-5-oxo-1 ,5- dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3'-(tetrazol-5-yl)biphenyl, in 10% by volume propylene glycol in water.

Example 3 - Tablet Composition

The sucrose, microcrystalline cellulose and a non-peptide TPO agonist, as shown in Table Il below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.

Table Il

INGREDIENTS AMOUNTS

3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1 ,5- 20 mg dihydropyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl- 3-carboxylic acid

Microcrystalline cellulose 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:

1. A method of treating a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in a human in need thereof which comprises the administration of a therapeutically effective amount of a non-peptide TPO receptor agonist to such mammal.

2. The method of claim 1 wherein the TPO receptor agonist is a compound having the following Formula:

wherein:

R, R-I , R2 and R^ are each independently selected from hydrogen, C-μ 6alkyl,

-(CH2)pOR⁴, -C(O)OR⁴, formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(O)_nR⁴, cycloalkyl, -NR⁵R⁶, protected -OH, - CONR5R6, phosphonic acid, sulfonic acid, phosphinic acid, -SO2NR5R6, and a heterocyclic methylene substituent as represented by Formula (III),

(III) where, p is 0-6, n is 0-2,

V, W, X and Z are each independently selected from O, S and NR^ 6, where R^⁶ is selected from: hydrogen, alkyl, cycloalkyl, C"|-C-|2^aryl_> substituted alkyl, substituted cycloalkyl and substituted C-i-C^aryl. R⁴ is selected from: hydrogen, alkyl, cycloalkyl, C-|-C-|₂aryl, substituted alkyl, substituted cycloalkyl and substituted C-|-C-|₂aryl, ^and R5 and R^ are each independently selected from hydrogen, alkyl, substituted alkyl, C3_gcycloalkyl, and aryl, or R5 and R^ taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;

m is 0-6; and

AR is a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and containing one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, - C(O)OR⁴, -C(O)NR¹⁰R^{1 1} , -S(O)₂NR^{1 0}R^{1 1} , -S(O)_nR⁴ and protected -

OH, where n is 0-2,

R⁴ is hydrogen, alkyl, cycloalkyl, C-|-C-|2^ary'' substituted alkyl, substituted cycloalkyl and substituted C-|-C-|2^ary'' ^and R¹⁰ and R^{1 1} are independently hydrogen, cycloalkyl, C-|-C-|2aryl, substituted cycloalkyl, substituted C-|-C-|2^ary'' alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR⁴, - S(O)_nR⁴, -C(O)NR⁴R⁴, -S(O)₂NR⁴R⁴, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected -OH, or R¹ ° and R^{1 1} taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where R⁴ is as described above and n is 0-2; or a pharmaceutically acceptable salt thereof; provided that at least one of R, R^ , R^ and R^ is a substituted aryl group or a heterocyclic methylene substituent as represented in Formula (III).

3. The method of claim 1 wherein the compound is selected from:

3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1 ,5-dihydropyrazol-4- ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid;

3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1 ,5-dihydropyrazol-4- ylidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl;

1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1- y^thiazol^-yljcarbamoyljpyridine^-y^piperidine^-carboxylic acid;

3'-{Λ/-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1 ,2-dihydro-indol-3- ylidene]-hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; and

2'-hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1 ,2-dihydro-indol-3-ylidene]- hydrazino}-biphenyl-4-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 wherein the disease state is depression which includes: depression, anxiety, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome, premenstrual dysphoric disorder (PMDD), adolescent depression, trichotillomania, dysthymia; depression subtypes including: bipolar, elderly, major, minor, moderate, recurrent, refractory, severe unipolar, dysthymia, post natal, double depression, post psychotic, post viral, bereavement, primary, secondary, post traumatic stress disorder; depression associated with withdrawal from substances of abuse including: alcohol, nicotine, cocaine, heroin and benzodiazepines.

5. The method of claim 3 wherein the disease state is fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer.

6. The method of claim 3 wherein the disease state is autism which includes: classic autism, Asperger's Syndrome, childhood disintegrative disorder, Rett Syndrome and pervasive developmental disorder not otherwise specified.

7. The method of claim 3 wherein the disease state is psoriasis which includes the Plaque, Guttate, Inverse, Pustular and Erythrodermic types.

8. The method of claim 3 wherein the disease state is digestive disorders, including celiac.

9. The method of claim 3 wherein the compound is administered orally.

10. The method of claim 3 wherein the compound is administered parenterally.

11. A method of treating a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in a human in need thereof, which comprises: administering to such mammal a therapeutically effective amount of a) a compound as disclosed in claim 3 or a pharmaceutically acceptable salt thereof; and b) at least one further active ingredient.

12. A pharmaceutical combination as claimed in claim 1 1 for use in therapy.

13. Use of a non-peptide TPO receptor agonist in the manufacture of a medicament for use in the treatment of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac.

14. A pharmaceutical composition for use in the treatment of a disease state selected from: depression; fatigue, including Chronic Fatigue Syndrome (CFS) and the fatigue of cancer; autism; Down's syndrome; psoriasis; and digestive disorders, including celiac in humans comprising a non-peptide TPO receptor agonist.

15. The method of claim 3 wherein the disease state is Down's syndrome.