WO2007026224A2

WO2007026224A2 - 5-ht1b antagonist composition for depression, anxiety and cognition

Info

Publication number: WO2007026224A2
Application number: PCT/IB2006/002377
Authority: WO
Inventors: Susan Beth Sobolov-Jaynes; Christopher John Helal; Harry Ralph Howard, Jr.
Original assignee: Pfizer Products Inc.
Priority date: 2005-08-31
Filing date: 2006-08-21
Publication date: 2007-03-08
Also published as: TW200744599A; JP2007063278A; AR056480A1; WO2007026224A3

Abstract

The present invention relates to pharmaceutical compositions comprising benzyl(idene)-lactam derivatives of formula (I) wherein R1 is a group of the formula (G1) or (G2) depicted below, and a pharmaceutically acceptable salt or optical isomer thereof and at least one active agent selected from (a) a selective serotonin re-uptake inhibitor (SSRl), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist and optionally a pharmaceutically acceptable carrier.

Description

5-HT₁R ANTAGONIST COMPOSITION FOR DEPRESSION. ANXIETY AND COGNITION

Background of the Invention

The present invention relates to 5-HTi_B antagonist pharmaceutical compositions comprising benzyl(idene)-lactam derivatives in combination with at least one active agent selected from: (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist and optionally a pharmaceutically acceptable carrier, and to their medicinal use in treating or preventing condition such as depression, anxiety, cognitions, ADHD and comorbid indications. The present invention also relates to a method of treating a subject, including a mammal, and particularly a human, suffering from depression, anxiety, attention deficit hyperactivity disorder (ADHD) and comorbid indications, as well as other diseases, disorders and conditions. The method comprises administering to the subject therapeutically effective amounts of a benzyl(idene)-lactam derivative and at least one active agent selected from (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist or a pharmaceutical composition comprising therapeutically effective amounts of a benzyl(idene)-lactam derivative and at least one active agent selected from the aforementioned (a), (b) or (c).

European Patent Publication 434,561 , published on Jun. 26, 1991 , refers to 7-alkyl alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT₁ agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.

European Patent Publication 343,050, published on Nov. 23, 1989, refers to 7- unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)- naphthalenes as useful 5-HT_1A ligand therapeutics. PCT publication WO 94/21619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT₁ agonists and antagonists.

PCT publication WO 96/00720, published Jan. 11 , 1996, refers to naphthyl ethers as useful 5-HTi agonists and antagonists.

PCT publication WO97/36867, published Oct. 9, 1997, and WO 98/14433, published Apr. 9, 1998, refer to related benzyl(idene)-lactam derivatives having utility as psychotherapeutic agents.

European Patent Publication 701 ,819, published Mar. 20, 1996, refers to the use of 5- HT₁ agonists and antagonists in combination with a 5-HT re-uptake inhibitor.

United States Patent US 6,380,186, issued April 30, 2002, refers to aralkyl and aralkylidene heterocyclic lactams and imides.

PCT publication WO 2005/067973, published July 28, 2005, refers to combination of CRF antagonists and 5-HT_1B receptor antagonists. US Patent Application No. 2005-0245521A1 , published November 3, 2005, presents novel benayl(idene)-lactam derivatives.

Glennon et al. refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT-i ligand in their article "5-HT_1D Serotonin Receptors", Clinical Drug Res. Dev., 22, 25-36 (1991 ). Glennon's article "Serotonin Receptors: Clinical Implications", Neuroscience and

Behavioral Reviews, 14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease. PCT publication WO 95/31988, published Nov. 30, 1995, refers to the use of a 5-HT_1D antagonist in combination with a 5-HT_1A antagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive- compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.

G. Maura et al., J. Neurochem, 66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HT_1A receptors or for both 5-HT_1A and 5-HT_1D receptors might represent a great improvement in the treatment of human cerebellar ataxias, a multifaceted syndrome for which no established therapy is available.

Summary of the Invention

The present invention relates to pharmaceutical compositions comprising a 5-HTi_B benzyl(idene)-lactam derivative antagonist of formula I

I wherein R¹ is a group of the formula G¹ or G² depicted below,

G¹ G² a is zero to eight; m is one to three;

R⁶ is selected from the group consisting of hydrogen, (C₁-C₆)BlRyI optionally substituted with (CrC₆)alkoxy or one to three fluorine atoms, or ((Ci-C₄)alkyl)aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH₂)_q-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (Ci-C₆)alkyl, (Ci-C₅)alkoxy, trifluoromethyl, cyano and -SO_t(C_rC₆)alkyI, wherein t is zero, one or two; each R¹³ is, independently, (C₁-C₄)alkyl or a (C-|-C₄)alkylene bridge from one of the ring carbons of the piperazine or piperidine ring of G¹ or G², respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G¹ or G², respectively, having an available bonding site, or to a ring carbon of R⁶, when R⁶ has a ring structure having an available bonding site;

X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (CrC₆)alkyl, hydroxy, (C₁-

C₆)alkoxy, -SO_t(Ci-C₆)alkyl wherein t is zero, one or two, -CO₂R 10 or -CONR >11_D R12. each of R¹⁰, R¹¹ and R¹² is selected, independently, from hydrogen, (Ci-C₄)alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C₁-C₆JaIkVl, (CrC₆)alkoxy, trifluoromethyl, cyano and -SO_t(CrC₆)alkyl wherein t is zero, one or two; or R¹¹ and R¹², together with the nitrogen to which they are attached, form a 5- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;

R³ is vinyl, C(.=O)R, wherein R is C₁-C₈ straight chain or branched alkyl, C₃-C₈ cycloalkyl, or aryl, wherein R is preferably tert-butyl, or

R³ is -(CH₂)_gB, wherein g is zero to three and B is hydrogen, phenyl, naphthyl or a 5- to 6-membered heteroaryl ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms and wherein each of the foregoing phenyl, naphthyl and heteroaryl rings may optionally be substituted with one to three substituents independently selected from (C_rC₈)hydroxyalkyl-, (C_rC₈)alkoxy-(C_rC₈)alkyl-, (C₃-C₈)hydroxycycloalkyl-, (C₃- C₈)cycloalkoxy-, (C₁-C₈)alkoxy-(C₃-C₈)cycloalkyl-, heterocycloalkyl, hydroxyheterocycloalkyl, and (C₁-C₈)alkoxy-heterocycloalkyl, wherein each (C₃-C₈)cycloalkyl or heterocycloalkyl moiety may be independently substituted with from one to three (C_rC₆)alkyl or benzyl groups; when B is a phenyl, naphthyl or heteroaryl ring, each said ring may be optionally substituted with one to three substituents independently selected from phenyl, naphthyl and a 5- to 6-membered heteroaryl ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be substituted with from one to three (Ci-C₈)alkyl or C₃-C₈ cycloalkyl substituents, wherein examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyi, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl; or when B is a phenyl, naphthyl or heteroaryl ring, each said ring may be optionally substituted with one to three substituents independently selected from (a) lactone formed from -(CH₂)_tOH with an ortho -COOH, wherein t is one, two or three; (b) -CONR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ are independently selected from (C^CsJalkyl and benzyl, or R¹⁴ and R¹⁵ together with the nitrogen to which they are attached form a 5- to 7-membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the -CONR¹⁴R¹⁵ group, wherein when any of said heteroatoms is nitrogen it may be optionally substituted with (C_rC₈)alkyl or benzyl, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms; (c) -(CH₂)_VNCOR¹⁶R¹⁷ wherein v is zero, one, two or three and -COR¹⁶ and R¹⁷ taken together with the nitrogen to which they are attached form a 4- to 6-membered lactam ring; and, (d) -(C₁-C₈)NR¹⁸R¹⁹ where each of R¹⁸ and R¹⁹ is selected, independently, from hydrogen and (Ci-C₄)alkyl, or R¹⁸ and R¹⁹, together with the nitrogen to which they are attached, form a A- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; wherein the broken lines indicate optional double bonds; n is one, two, or three; and a pharmaceutically acceptable salt or optical isomer thereof; and at least one active agent selected from (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist and optionally a pharmaceutically acceptable carrier.

Detailed Description of the Invention Unless otherwise indicated, as used herein, the terms "halogen" and "halo" include F,

Cl, Br, and I.

Unless otherwise indicated, as used herein, the term "alkyl" includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethylene (-CFVcyclopropyl) and f-butyl.

Unless otherwise indicated, as used herein, the term "alkenyl" includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

Unless otherwise indicated, as used herein, the term "alkynyl" includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.

Unless otherwise indicated, as used herein, the term "alkoxy", means "alkyl-O-", wherein "alkyl" is as defined above. Examples of "alkoxy" groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy and allyloxy. Unless otherwise indicated, as used herein, the term "alkoxyalkyl" means alkyl-O- alkyl-, wherein alkyl is defined above.

Unless otherwise indicated, as used herein, the term "hydroxyalkyl" means -alkyl-OH, wherein alkyl is defined above.

Unless otherwise indicated, as used herein, the term "alkenoxy", means "alkenyl-O-", wherein "alkenyl" is as defined above.

Unless otherwise indicated, as used herein, the term "alkynoxy", means "alkynyl-O-", wherein "alkynyl" is as defined above.

Unless otherwise indicated, as used herein, the term "cycloalkyl" includes non- aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. "Bicycloalkyl" and "tricycloalkyl" groups include non-aromatic saturated cyclic alkyl moieties consisting of two or three rings respectively, wherein said rings share at least one carbon atom. "Bicycloalkyl" and "tricycloalkyl" groups also include cyclic moieties consisting of two or three rings respectively, wherein one ring is aryl or heteroaryl and wherein said rings share two carbon atoms. For purposes of the present invention, and unless otherwise indicated, bicycloalkyl groups include spiro groups and fused ring groups. Examples of bicycloalkyl groups include, but are not limited to, bicyclo-[3.1.0]-hexyl, bicyclo — [2.2.1]-hept-1-yl, norbornyl, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, spiro[4.2]heptyl, indan, teralene (1 ,2,3,4-tetrahydronaphlene) and 6, 7, 8, θ-tetrahydro-δH-benzocycloheptene. An example of a tricycloalkyl group is adamantanyl. Other cycloalkyl, bicycloalkyl, and tricycloalkyl groups are known in the art, and such groups are encompassed by the definitions "cycloalkyl", "bicycloalkyl" and "tricycloalkyl" herein. "Cycloalkenyl", "bicycloalkenyl", and "tricycloalkenyl" refer to non-aromatic each cycloalkyl, bicycloalkyl, and tricycloalkyl moieties as defined above, except that they each include one or more carbon-carbon double bonds connecting carbon ring members (an "endocyclic" double bond) and/or one or more carbon- carbon double bonds connecting a carbon ring member and an adjacent non-ring carbon (an "exocyclic" double bond). Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclobutenyl, and cyclohexenyl. A non-limiting example of a bicycloalkenyl group is norbornenyl. Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include groups that are substituted with one or more oxo moieties. Examples of such groups with oxo moieties are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl and norcamphoryl. Other cycloalkenyl, bicycloalkenyl, and tricycloalkenyl groups are known in the art, and such groups are included within the definitions "cycloalkenyl", "bicycloalkenyl" and "tricycloalkenyl" herein.

Unless otherwise indicated, as used herein, the term "aryl" includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl (Ph), naphthyl, indenyl, indanyl and fluorenyl. "Aryl" encompasses fused ring groups wherein at least one ring is aromatic.

Unless otherwise indicated, as used herein, the terms "heterocyclic" and "heterocycloalkyl" refer to non-aromatic cyclic groups containing one or more heteroatoms, preferably from one to four heteroatoms, each selected from O, S and N. "Heterobicycloalkyl" groups include non-aromatic two-ringed cyclic groups, wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (O, S, or N). "Heterobicycloalkyl" groups also include two-ringed cyclic groups, wherein said one ring is aryl or heteroaryl ring and wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (O, S, or N). Unless otherwise indicated, for purposes of the present invention, heterobicycloalkyl groups include spiro groups and fused ring groups. In one embodiment, each ring in the heterobicycloalkyl contains up to four heteroatoms (i.e. from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom). The heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3- dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.4]nonyl, 1 ,4- dioxaspiro[4.3]octyl, and 1 ,4-dioxaspiro[4.2]heptyl.

Unless otherwise indicated, as used herein, "heteroaryl" refers to aromatic groups containing one or more heteroatoms, preferably from one to four heteroatoms, selected from O, S and N. A multicyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is a "heteroaryl" group. The heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, 1 ,2,3,4-tetrahydroguinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, 1 ,2,4-trizainyl, 1 ,3,5-triazinyl, isoindolyl, 1-oxoisoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl. Unless otherwise indicated, as used herein, the term "cycloalkoxy", means

"cycloalkyl-O-", wherein "cycloalkyl" is as defined above.

Unless otherwise indicated, as used herein, the term "aryloxy", means "aryl-O-", wherein "aryl" is as defined above.

Unless otherwise indicated, as used herein, the term "heterocycloalkoxy", means "heterocycloalkyl-O-", wherein "heterocycloalkyl" is as defined above.

Unless otherwise indicated, as used herein, the term "heteroaryloxy", means "heteroaryl-O-", wherein "heteroaryl" is as defined above.

Unless otherwise indicated, all the foregoing groups derived from hydrocarbons may be optionally substituted by one or more halogen atoms (e.g., -CH₂F, -CHF₂ -CF₃, -PhCI, etc.). Unless otherwise indicated, the term "one or more substituents", as used herein, refers to from one to the maximum number of substituents possible based on the number of available bonding sites.

Unless otherwise indicated, all the foregoing groups derived from hydrocarbons may have up to about 1 to about 20 carbon atoms (e.g. C₁-C₂₀ alkyl, C₂-C_2O alkenyl, C₃-C₂₀ cycloalkyl, 3-20 membered heterocycloalkyl; C₆-C₂₀ aryl, 5-20 membered heteroaryl, etc.) or 1 to about 15 carbon atoms (e.g., C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, C₃-C₁₅ cycloalkyl, 3-15 membered heterocycloalkyl, C₆-C₁₅ aryl, 5-15 membered heteroaryl, etc.) , or 1 to about 12 carbon atoms, or 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms. The foregoing groups, as derived from the compounds listed above, may be C- attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). The terms referring to the groups also encompass all possible tautomers.

The invention also relates to a compound according to formula I wherein R³ is (CH₂)_gB wherein g is zero and B is selected from phenyl, or pyridyl, wherein said (C₃- C₈)cycloalkyl moiety of said (C₃-C₈)hydroxycycloalkyl-, (C₁-C₈)alkoxy-(C₃-C₈)cycloalkyl-, substituents is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The invention also relates to a compound according to formula I wherein R³ is

(CH₂)_gB wherein g is zero and B is selected from phenyl, or pyridyl, wherein said heterocycloalkyl moiety having 4 to 8 atoms, of said 1 to 3 optional substituents, is selected from tetrahydropyranyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, thiomorpholinyl, azepinyl, diazepinyl, oxazepinyl, thiazepinyl, oxetanyl, and tetrahydrofuranyl.

This invention also relates to a compound according to formula I wherein R³ is (CH₂)_gB wherein g is zero and B is selected from phenyl or pyridyl, wherein said alkoxyheterocycloalkyl moiety is selected from tetrahydropyranoxy, tetrahydrofuranoxy, oxetanoxy, azetidinoxy, pyrrolidinoxy, and piperidinoxy.

The invention also relates to a compound according to formula I wherein R³ is

(CH₂)_gB wherein g is zero and B is selected from phenyl, or pyridyl, wherein said 5- to 6- membered heteroaryl ring, of said 1 to 3 optional substituents, is selected from pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

The invention also relates to a compound according to formula I wherein R³ is

(CH₂)_gB wherein g is zero and B is selected from phenyl or pyridyl, wherein said R¹⁴ and said

R¹⁵ groups of said -CONR¹⁴R¹⁵ substituent together with the nitrogen to which they are attached form a 5- to 6-membered heteroalkyl ring selected from piperidine, N-(C₀-C₆)alkylpiperazine and morpholine. The invention also relates to a compound according to formula I wherein R³ is (CH₂)_gB wherein g is zero and B is selected from phenyl or pyridyl, wherein said -COR¹⁶ and R¹⁷ groups of said -(CH₂)_VNCOR¹⁶R¹⁷ substituent together with the nitrogen to which they are attached form a 5- or 6-membered lactam ring, and v is 1. The invention also relates to a compound according to formula I wherein R³ is

(CH₂)_gB wherein g is zero and B is selected from phenyl or pyridyl, wherein a lactone is formed from said -CH₂OH substituent, with said ortho -COOH substituent.

Specific examples of the compounds of formula I comprising the pharmaceutical composition of the present invention are as follows, and include any one individually or any grouped combination of the following compounds:

3-[5-Fluoro-2-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-1 -methyl-ethyl)- phenyl]-pyrrolidin-2-one,

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(6-morpholin-4-yl-pyridin-3-yl)-pyrrolidin-2- one, 1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(4-morpholin-4-yl-phenyl)-pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-pyrrolidin- 2-one, , 1-[4-(1-Hydroxy-cyclohexyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-pyrrolidin-

2-one,

1-[4-(1-Ethyl-1-hydroxy-propyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one,

1-[3-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one,

1-[4-(2-Hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yI)-benzyl]- pyrrolidin-2-one,

1-[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one, 1 -[4-(1 -Methoxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

1-[4-(2-Methoxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrroiidin-2-one,

1-[4-(1-Methoxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-pyrrolidin- 2-one,

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(4-pyridin-4-yl-phenyl)-pyrrolidin-2-one, 1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-(2-piperazin-1-yl-benzyl)-pyrrolidin-2-one,

1-[4-(1-Hydroxy-cyclobutyl)-phenyl]-3-(2-piperazin-1-yl-benzyl)-pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-cyclohexyl)-phenyl]-3-(2-piperazin-1 -yl-benzyl)-pyrrolidin-2-one,

1-[4-(1-Ethyl-1-hydroxy-propyl)-phenyl]-3-(2-piperazin-1-yl-benzyl)-pyrrolidin-2-one, 1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-(2-piperazin-1 -yl-benzyl)-pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzylidene]- pyrrolidin-2-one,

3-[5-Fluoro-2-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-cyclopentyl)-phenyl]- pyrrolidin-2-one, 1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[5-methyl-2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[5-methyl-2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-piperidin- 2-one,

1 -[4-(1 -Hydroxy-1 -methyI-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- piperidin-2-one,

1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[5-methoxy-2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one, 1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[5-methoxy-2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one,

3-[2-Fluoro-6-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-cyclopentyl)-phenyl]- pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-(3,4,5-trimethyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(3,4,5-trimethyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

1-[4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-(3,4,5-trimethyl-piperazin-1-yl)- benzyl]-pyrrolidin-2-one, 1-[4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- piperidin-2-one,

1-[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(3,4,5-trimethyl-piperazin-1-yl)-benzyl]- piperidin-2-one,

^^-(i-Hydroxy-cyclopentylVphenylj-S-p-CS^.S-trimethyl-piperazin-i-yO-benzyl]- piperidin-2-one, 3-[5-Fluoro-2-(3,4,5-trimethyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-1 -methyl-ethyl)- phenyl]-piperidin-2-one,

3-[5-Fluoro-2-(3,4,5-trimethyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-cyclopentyl)- phenyl]-piperidin-2-one, 3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-1 -[4-(2-oxo-pyrrolidin-1 -ylmethyl)-phenyl]- piperidin-2-one,

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1 -(3-0X0-1 ,3-dihyd ro-isobenzofuran-5-yl)- piperidin-2-one,

3-[5-Fluoro-2-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-cyclobutyl)-phenyl]- piperidin-2-one,

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(3-[1 ,3,4]oxadiazol-2-yl-phenyl)-pyrroIidin-2- one,

6"-(1 -Hydroxy-1 -methyl-ethyl)-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-3,4,5,6- tetrahydro-[1 ,3']bipyridinyl-2-one, 3-[5-Fluoro-2-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[6-(1 -hydroxy-1 -methyl-ethyl,)- pyridin-3-yl]-pyrrolidin-2-one,

3-[2-Fluoro-6-(4-methyl-piperazin-1-yl)-benzyl]-1-[6-(1 -hydroxy-1 -methyl-ethyl )- pyridin-3-yl]-pyrrolidin-2-one,

1-[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-[2-(3,4,5-trimethyl-piperazin-1-yl)- benzyl]-pyrrolidin-2-one,

6"-(1 -Hydroxy-1 -methyl-ethyl)-3-[2-(3,4,5-trimethyl-piperazin-1 -yl)-benzyl]-3,4,5,6- tetrahydro-[1 ,3']bi-pyridinyl-2-one,

3-[5-Fluoro-2-(3,4,5-trimethyl-piperazin-1-yl)-benzyl]-6'-(1 -hydroxy-1 -methyl-ethyl)- 3,4,5,6-tetrahydro-[1 ,3']bipyridinyl-2-one, 3-[5-Fluoro-2-(4-methyl-piperazin-1 -yl)-benzyl]-6'-(1 -hydroxy-1 -methyl-ethyl)-3,4,5,6- tetrahydro-[1 ,3']bipyridinyl-2-one,

1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-[1 ,4]diazepan-1 -yl)-benzyl]- pyrrolidin-2-one,

1-[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-[1 ,4]diazepan-1-yl)-benzyl]- pyrrolidin-2-one,

3-[2-(4-Ethyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-1 -methyl-ethyl)-phenyl]- pyrrolidin-2-one,

3-[2-(2,5-Dimethyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-cyclopentyl)-phenyl]- pyrrolidin-2-one, 1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one, 3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]- pyrrolidin-2-one,

1 -[6-(1 -Hydroxy-cyclopentyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one, 1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-pyrrolidin-2- one,

1 -[5-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-2-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

1 -[5-(1 -Hydroxy-cyclopentyl)-pyridin-2-yi]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(4-oxazol-4-yl-phenyl)-piperidin-2-one,

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(4-pyrazol-1-yl-phenyl)-piperidin-2-one,

1-[4-(2-Methyl-oxazol-4-yi)-phenyl]-3-[2-(4-methyI-piperazin-1-yl)-benzyl]-piperidin-2- one, 3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-1 -(4-oxazol-5-yl-phenyl)-piperidin-2-one, .

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-[4-(morpholine-4-carbonyl)-phenyl]-pyrrolidin- 2-one,

1 -[4-(4-Methyl-piperazine-1 -carbonyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one, 3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-[4-(piperidine-1-carbonyl)-phenyl]-pyrrolidin-

2-one,

1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2r(1 -methyl-piperidin-4-yl)-benzyl]-pyrrolidin-2- one,

1 -[4-(1 -Hydroxy-cyclohexyl)-phenyl]-3-[2-(1 -methyl-piperidin-4-yl)-benzyl]-pyrrolidin-2- one,

1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(1 -methyl-piperidin-4-yl)-benzyl]- pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-(1 -methyl-piperidin-4-yl)-benzyl]-pyrrolidin- 2-one,and pharmaceutically acceptable salts and optical isomers thereof. Specific optical isomers of the compounds of formula I comprising the pharmaceutical composition of the present invention include any one of the following individually or in any combination of grouped compounds:

1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one, 1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one, 1-[4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl- piperazin-1-yl)-benzyl]-pyrrolidin-2-one,

1-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-[2-((3R,5S)-3,4,5-trimethyl-pipera2in-1- yl)-benzyl]-pyrrolidin-2-one, (R)-3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-1 -(6-morpholin-4-yl-pyridin-3-yl)-pyrrolidin-

2-one,

(R)-1-[4-(1-Hydroxy-1-methyI-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one,

(R)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(4-morphoIin-4-yl-phenyl)-pyrrolidin-2- one,

(R)-1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(R)-1-[4-(2-Hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one, (R)-1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-t2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one,

(R)-1 -[4-(1 -Methoxy-1 -methyI-ethyi)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(R)-1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- piperidin-2-one,

(R)-3-[2-Fluoro-6-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-cyclopentyl)- phenyl]-pyrrolidin-2-one,

(R)-1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one, (R)-1-[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1- yl)-benzyl]-pyrrolidin-2-one,

(R)-1-[4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl- piperazin-1 -yl)-benzyl]-pyrrolidin-2-one, '

(R)-6'-(1 -Hydroxy-1 -methyl-ethyl)-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-3,4,5,6- tetrahydro-[1 ,3']bipyridinyl-2-one,

(R)-3-[2-Fluoro-6-(4-methyl-piperazin-1-yl)-benzyl]-1-[6-(1 -hydroxy-1 -methyl-ethyl)- pyridin-3-yl]-pyrrolidin-2-one,

(R)-1-[6-(1 -Hydroxy-1 -methyi-ethyl)-pyridin-3-yl]-3-[2-((3R,5S)-3,4,5-trimethyl- piperazin-1-yl)-benzyl]-pyrrolidin-2-one, (R)-3-[2-(4-Ethyl-piperazin-1-yl)-benzyl]-1-[4-(1 -hydroxy-1 -methyl-ethyO-phenyl]- pyrrolidin-2-one, (R)-1-[6-(1-Ethyl-1-hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one,

(R)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]- pyrrolidin-2-one, (R)-1-[6-(1-Hydroxy-cyclopentyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one,

(R)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyi-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(R)-1 -[5-(1 -Hydroxy-cyclopentyl)-pyridin-2-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(R)-1-[4-(2-Methyl-oxazol-4-yl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- piperidin-2-one,

(R)-3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-1 -[4-(piperidine-1 -carbonyl)-phenyl]- pyrrolidin-2-one, (S)-3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-1 -(6-morpholin-4-yl-pyridin-3-yl)-pyrrolidin-

2-one,

(S)-1-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one,

(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(4-morpholin-4-yl-phenyl)-pyrrolidin-2- one,

(S)-1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(S)-1-[4-(2-Hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one, (S)-1-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1-yl)- benzyl]-pyrrolidin-2-one,

(S)-1 -[4-(1 -Methoxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(S)-1-[4-(1-Hydroxy-1-methy!-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- piperidin-2-one,

(S)-3-[2-Fluoro-6-(4-methyl-piperazin-1-yl)-benzyl]-1-[4-(1-hydroxy-cyclopentyl)- phenyl]-pyrrolidin-2-one,

(S)-1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one, (S)-1-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1- yl)-benzyl]-pyrrolidin-2-one, (S)-1-[4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-((3R,5S)-3,4,5-trinnethyl- piperazin-1-yl)-benzyl]-pyrrolidin-2-one,

(S)-6'-(1 -Hydroxy-1 -methyl-ethyl)-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-3,4,5,6- tetrahydro-[1 ,3']bipyridinyl-2-one, (S)-3-[2-Fluoro-6-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[6-(1 -hydroxy-1 -methyl-ethyl)- pyridin-3-yl]-pyrrolidin-2-one,

(S)-1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-[2-((3R,5S)-3,4,5-trimethyl- piperazin-1-yl)-benzyl]-pyrrolidin-2-one,

(S)-3-[2-(4-Ethyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-1 -methyl-ethyl )-pheny!]- pyrrolidin-2-one,

(S)-1 -[6-(1 -EthyI-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]- pyrrolidin-2-one, (S)-1 -[6-(1 -Hydroxy-cyclopentyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(S)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(S)-1 -[5-(1 -Hydroxy-cyclopentyl)-pyridin-2-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(S)-1-[4-(2-Methyl-oxazol-4-yl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- piperidin-2-one,

(S)-3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-1 -[4-(piperidine-1 -carbonyl)-phenyl]- pyrrolidin-2-one, and pharmaceutically acceptable salts thereof. Compounds of formula I may be produced, for example, by the procedure outlined in

U.S. Application Serial No. 11/083,188, filed March 17, 2005, published as US 2005- 0245521 A1 on November 3, 2005, herein incorporated by reference in its entirety. An assay to determine the activity of the aforementioned compounds and other 5-HT_1B antagonists may be found in U.S. Patent No. 6,380,186. The compounds of formula I may have chiral centers and therefore may occur in different enantiomeric configurations. The invention includes all enantiomers, diastereomers, and other stereoisomers, as well as any possible tautomers of such compounds of formula I, as well as racemic and other mixtures thereof.

The present invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal, including a human, selected from depression, anxiety, depression with concomitant anxiety, dysthymia, post traumatic stress disorder, panic phobias, obsessive compulsive disorder (OCD), OCD with comorbid Tourette's Syndrome, borderline personality disorder, sleep disorder, psychosis, seizures, dyskinesis, symptoms of Huntington's or Parkinson's diseases, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, faintness attacks, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, premenstrual syndrome (PMS) associated mood and appetite disorder, inflammatory bowel disease, modification of feeding behavior, blocking carbohydrate cravings, late luteal phase dysphoric disorder, tobacco withdrawal- associated symptoms, panic disorder, bipolar disorder, sleep disorders, jet lag, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions selected from dependencies on, or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine; pathological gambling; trichotilomania; headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and at least one active agent selected from (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist and optionally a pharmaceutically acceptable carrier. The present invention also relates to a method of treating a disorder or condition referred to hereinabove in a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and an amount of at least one active agent selected from (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist that in combination are effective in treating such disorder or condition.

The present invention also relates to a pharmaceutical composition for use in treating a disorder or condition referred to hereinabove in a mammal, comprising an amount of a compound according of the formula I that is an effective antagonist of 5-HT_1B receptors and at least one active agent selected from (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist and optionally a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating a disorder or condition referred to hereinabove in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I that is an effective antagonist of 5-HT-|_B receptors and an amount of at least one active agent selected from (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist that in combination are effective in treating such disorder or condition.

Selective serotonin reuptake inhibitors (SSRIs) function by inhibiting the reuptake of serotonin by afferent neurons. SSRI's, which are well known in the art include, but are not limited to sertraline (Zoloft^®), fluoxetine (Prozac^®), fluvoxamine (Luvox^®), paroxetine

(Seroxat^®, Paxil^®), citalopram (Celexa^®), d,l-fenfluramine (Redux^®), femoxetine, trazodone, cericlamine, ifoxetine, cyanodothiepin, litoxetine, indalpine, indeloxazine, milnacipran, sibutramine zimeldine norfluoxetine, escitalopram (Lexapro™) dapoxetine, nefazodone

(Serxone®), trazodone (Desyrel®), and analogs, derivatives, prodrugs and pharmaceutically acceptable salts of any of the aforementioned SSRI's. Preferred SSRI's are fluoxetine, sertraline or sibutramine.

Some of the above SRRI's may be prepared by the procedures described below: femoxetine, which may be prepared as described in U.S. Pat. No. 3,912,743; fluoxetine, which may be prepared as described in U.S. Pat. No. 4,314,081; fluvoxamine, which may be prepared as described in U.S. Pat. No. 4,085,225; indalpine, which may be prepared as described in U.S. Pat. No. 4,064,255; indeloxazine, which may be prepared as described in U.S. Pat. No. 4,109,088; milnacipran, which may be prepared as described in U.S. Pat. No. 4,478,836; paroxetine, which may be prepared as described in U.S. Pat. No. 3,912,743 or U.S. Pat. No. 4,007,196; sertraline, which may be prepared as described in U.S. Pat. No. 4,536,518; sibutramine, which may be prepared as described in U.S. Pat. No. 4,929,629; and zimeldine, which may be prepared as described in U.S. Pat. No. 3,928,369. The disclosures thereof are incorporated herein by reference.

An alpha-2-delta receptor ligand (A2D ligands) is any molecule which binds to any sub-type of the human calcium channel alpha-2-delta sub-unit. The calcium channel alpha-2- delta sub-unit comprises a number of receptor sub-types which have been described in the literature: e.g. N. S. Gee, J. P. Brown, V. U. Dissanayake, J. Offord, R. Thurlow, and G. N. Woodruff, J-Biol-Chem 271 (10):5768-76, 1996, (type 1); Gong, J. Hang, W. Kohler, Z. Li, and T-Z. Su, J. Membr. Biol. 184 (1):35-43, 2001 , (types 2 and 3); E. Marais, N. Klugbauer, and F. Hofmann, MoI. Pharmacol. 59 (5): 1243-1248, 2001. (types Z and 3); and N. Qin, S. Yagel, M. L. Momplaisir, E. E. Codd, and M. R. D'Andrea. MoI. Pharmacol. 62 (3):485-496, 2002, (type 4). They may also be known as GABA analogs. A2D ligands that are useful for the present invention include but are not limited to gabapentin (Neurontin®), pregabalin, vigabatrin and baclofen. GABA agonists well known in the art include muscimol, progabide, riluzole, valproic acid, tiagabine (Gabitril®), lamotrigine (Lamictal®), phenytoin (Dilantin®), carbamazepine (Tegretol®), topiramate (Topamax®) and analogs, derivatives, prodrugs and pharmaceutically acceptable salts of any of the aforementioned A2D ligands. Still other examples of A2D ligands for use with the present invention are those compounds generally or specifically disclosed in U.S. Pat. No. 4,024,175, particularly gabapentin, EP641330, particularly pregabalin, U.S. Pat. No. 5,563,175, WO9733858, WO9733859, WO9931057, WO9931074, WO9729101 , WO02085839, particularly [(1 R,5R,6S)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl]acetic acid, WO9931075, particularly 3-(1- Aminomethyl-cyclohexylmethyl)-4H-[1 ,2,4]oxadiazol-5-one and C-[1-(1 H-Tetrazol-5-ylmethyl)- cycloheptylj-methylamine, WO9921824, particularly (3S,4S)-(1-Aminomethyl-3,4-dimethyl- cyclopentyl)-acetic acid, WO190052, WO0128978, particularly (1α,3σ,5σ)(3-amino-methyl- bicyclo[3.2.0]hept-3-yl)-acetic acid, EP0641330, WO9817627, WO0076958, particularly (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, PCT/IB03/00976, particularly (3S,5R)-3- amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid and (3S,5R)-3- Amino-5-methyl-octanoic acid, EP1178034, EP1201240, WO9931074, WO03000642, WO0222568, WO0230871 , WO0230881 WO02100392, WO02100347, WO0242414, WO0232736 and W00228881 and analogs, derivatives, prodrugs and pharmaceutically acceptable salts of any of the aforementioned A2D ligands.

Preferred A2D ligands of the present invention include: gabapentin, pregabalin, [(1 R,5R,6S)-6-(Aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-Aminomethyl- cyclohexylmethyl)-4H-[1 ,2,4]oxadiazol-5-one, C-[1 -(1 H-Tetrazol-5-ylmethyl)-cycloheptyl]- methylamine, (3S,4S)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (1σ,3σ,5σ)(3- amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (SS.δR^S-Aminomethyl-δ-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid and (3S,5R)-3-Amino-5-methyl-octanoic acid, or pharmaceutically acceptable salts thereof.

Corticotropin Releasing Factor (CRF) antagonists refers to a compound having the ability to inhibit or reverse the deleterious effects of the presence of CRF. It is well known that CRF profoundly stimulates the pituitary-adrenalcortical axis and, in dysfunctional states, initiates behavioral, physiological and endocrine responses that are essentially identical to those observed when animals, including humans and companion animals, are subjected to a stressful environment. Therefore, CRF antagonists are known to have utility, inter alia, in the amelioration of certain stress-induced conditions including memory loss, mood alteration, depression, hypertension and the like.

Any CRF antagonist may be used in the present invention. Examples include, but are not limited to, those that are described in U.S. Pat. Nos. 4,605,642 and 5,063,245; International patent publications WO 95/33750; WO 95/34563; WO 94/13661; WO 94/13644; WO 94/13643; WO 94/13676; WO94/13677; WO 95/33727; WO 98/05661 ; WO 98/08847; and WO 98/08846; and European patent publications EP 778277; and EP 773023. They also include those of the following patent publications: EP 576350; EP 659747; EP 812831 ; WO 95/10506; WO 96/35689; WO 96/39400; WO 97/00868; WO 97/14684; WO 97/29109; WO 97/29110; WO 97/35539; WO 97/35580; WO 97/35846; WO 97/44038; WO 97/45421 ; WO 98/03510; WO 98/08821 ; WO 98/11075; WO 98/15543; WO 98/21200; WO 98/27066; WO 98/29397; WO 98/29413; WO 98/42699; WO 98/35967; WO 98/42706; WO 98/45295; WO 98/47874; WO 98/47903; WO 98/51312; WO 99/01454; WO99/01439; WO99/10350; WO99/12908; WO99/00373; WO 99/38868; WO 99/51597; WO 99/51599; WO 99/40089; WO 99/51598; and WO 99/51600. They are also disclosed in U.S. Pat. Nos. 5,109,111 ; 5,132,111 ; 5,245,009; 5,464,847; 5,493,006; 5,510,458; 5,644,057; 5,663,292; 5,668,145; 5,705,646; 5,712,303; and 5,723,608. Additional information relating to preparing certain of these compounds is provided in WO 96/39388, which describes the production of certain intermediates. The texts of all of these publications are incorporated by reference herein in their entireties.

In one aspect, the CRF antagonist is a compound of formula II,

YγNγR₂1

R₂o^N^Ar

Formula Il or a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof, wherein

Y is selected from -NR22R23, -OR₂₂, -CR22R24R24, -C(O)R₂₂, -S(O)_mR₂₂, -NR₂₂C(O)R₂₃, or -NR₂₂S(OXR₂₃; r is 0,1 or 2;

Ar is selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R₂₀, R₂₁, and each R₂₄ are independently selected from halogen, -NO_2, -CN, -R_a,

-OR₃, -S(OJ_rR_a, -NR_aR_a, -C(O)NR₃R₃, -C(S)NR₃R₃ -S(O)_nNR₃R₃, -NR_aS(O)_rR_a, -NR₃C(O)OR₃, -OC(O)NR₃R₃, -NR₃C(O)NR₃R₃, -NR₃C(S)NR₃R₃, -C(O)OR₃, -C(S)OR₃, or -OC(O)OR₃;

R₂₂ and R₂₃ are independently selected from R_a, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, substituted aryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl provided at least one of R₂₂ or R₂₃ are heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl; each R_a is independently selected from H, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substituted with 1 to 5 of R_t, -0R_t, -S(O)_rR_t, NR_tR_t, oxo (=0), thione (=S), phenyl, heteroaryl, or heterocycloalkyl where phenyl, heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5 independently taken from R_t; each R_t is independently selected from H, halogen, -NO₂, -NH₂, -OH, -SH, -CN, - C(O)NH₂, -C(O)-NHalkyl, -C(O)Nalkylalkyl, -Oalkyl, NHalkyl, Nalkylalkyl, -S(O)_ralkyl, SO₂NH₂, SO₂NHalkyl and SO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl, heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryl and heterocycloalkyl may be optionally r substituted with alkyl or halogen; and

Aryl is either phenyl or naphthyl.

A preferred compound of formula Il is represented by formula Na:

or a pharmaceutically acceptable salt thereof, wherein

R₂₅ is C₁-C₆ alkyl, C₁-C₆ alkenyl, C_rC₆ alkynyl, C(O)Ci-C₆ alkyl, C(O)C₁-C₆ alkenyl or C(O)C₁-C₆ alkynyi; R₂₆ is Ci-C₆ alkyl, C₁-C₆ alkenyl, or C₁-C₆ alkynyl;

R₂₇ is C₁-C₆ aikyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, halogen, OC_rC₆ alkyl, OC₁-C₆ alkenyl, or OCi-C₆ alkynyl;

R₂₈ is C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, halogen, OC₁-C₆ alkyl, OC₁-C₆ alkenyl, OC₁-C₆ alkynyl or NR₃₀R₃i; R₂₉ is C₁-C₆ alkyl, C₁-C₆ alkenyl, or C₁-C₆ alkynyl;

R₃₀ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, or C₁-C₆ alkynyl; and

R₃₁ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, or C₁-C₆ alkynyl.

The compounds of formula Il may have chiral centers and therefore may occur in different enantiomeric configurations. The invention includes all enantiomers, diastereomers, and other stereoisomers, as well as any possible tautomers of such compounds of formula II, as well as racemic and other mixtures thereof. Other active agents, in addition to those specified above, which may be used in combination with the compounds of formula I include 5-HT_2A antagonists, alpha2 antagonists and 5-HT_2C agonists/antagonists.

Any 5-HT_2A may be used in combination with the compounds of formula I. Examples include, but are not limited to those described in US20050119253, such as Pipamperone®,

Fananserin®, ORG 5222, mirtazepine (Remeron®), Zotepine®, Olanzepine®, Clozapine®,

S16924, S18327, Amperozide®, Sertindole®, MDL 100.907, Tiospirone®, Fluspirilene®,

Ocaperidone, Risperidone® and Ziprasidone®.

Any alpha2 antagonist may be used in combination with the compounds of formula I. Examples include, but are not limited to those described in US 20050074772, such as yohimbine, prazosin, Arc 239, rauwolscine, idazoxan, mirtazepine (Remeron®), tolazoline, and phentolamine.

Any 5HT₂c agonist/antagonist may be used in combination with the compounds of formula I. Examples include, but are not limited to those described in US 20030032636, such as ketanserin, SB 242084, SB 206553, SB 243213, SB 228356, ritanserin, deramcjclane, mirtazepine, mianserine, sertindole, YM 35 992, Ro 60-0795, Org 38457, Org 12962, EGIS 8465 and RS 102221.

The present invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal, including a human, selected from depression, anxiety, depression with concomitant anxiety, dysthymia, post traumatic stress disorder, panic phobias, obsessive compulsive disorder (OCD), OCD with comorbid Tourette's Syndrome, borderline personality disorder, sleep disorder, psychosis, seizures, dyskinesis, symptoms of Huntington's or Parkinson's diseases, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, faintness attacks, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, premenstrual syndrome (PMS) associated mood and appetite disorder, inflammatory bowel disease, modification of feeding behavior, blocking carbohydrate cravings, late luteal phase dysphoric disorder, tobacco withdrawal- associated symptoms, panic disorder, bipolar disorder, sleep disorders, jet lag, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions selected from dependencies on, or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine; pathological gambling; trichotilomania; headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, with at least one active agent selected from: (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist and optionally a pharmaceutically acceptable carrier.

The present invention also relates to a method of, treating a disorder or condition referred to hereinabove in a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of a compound of the formula Ia, or a pharmaceutically acceptable salt thereof, and an amount of at least one active agent selected from: and optionally a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition for use in treating a disorder or condition referred to hereinabove in a mammal, comprising an amount of a compound according to formula I that is an effective antagonist of 5-HT_1B receptors and at least one active agent selected from: (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist and optionally a pharmaceutically acceptable carrier The present invention also relates to a method of treating a disorder or condition referred to hereinabove in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I that is an effective antagonist of 5-HT_1B receptors and an amount of at least one active agent selected from: (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist and optionally a pharmaceutically acceptable carrier that in combination are effective in treating such disorder or condition.

As used herein, the term "depression" includes depressive disorders, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias, seasonal affective disorder, or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar Il disorder and cyclothymic disorder.

Other mood disorders encompassed within the term "depression" include dysthymic disorder with early or late onset and with or without atypical features; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood, disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood. As used herein, the term "anxiety" includes anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders.

"Generalized anxiety" is typically defined as an extended period (e.g. at least six months) of excessive anxiety or worry with symptoms on most days of that period. The anxiety and worry are difficult to control and may be accompanied by restlessness, being easily fatigued, difficulty concentrating, irritability, muscle tension, and disturbed sleep. "Panic disorder" is defined as the presence of recurrent panic attacks followed by at least one month of persistent concern about having another panic attack. A "panic attack" is a discrete, period in which there is a sudden onset of intense apprehension, fearfulness or terror. During a panic attack, the individual may experience a variety of symptoms including palpitations, sweating, trembling, shortness of breath, chest pain, nausea and dizziness. Panic disorder may occur with or without agoraphobia.

"Phobias" include agoraphobia, specific phobias and social phobias. "Agoraphobia" is characterized by an anxiety about being in places or situations from which escape might be difficult or embarrassing or in which help may not be available in the event of a panic attack. Agoraphobia may occur without history of a panic attack. A "specific phobia" is characterized by clinically significant anxiety provoked by feared object or situation. Specific phobias include the following subtypes: animal type, cued by animals or insects; natural environment type, cued by objects in the natural environment, for example storms, heights or water; blood- injection-injury type, cued by the sight of blood or an injury or by seeing or receiving an injection or other invasive medical procedure; situational type, cued by a specific situation such as public transportation, tunnels, bridges, elevators, flying, driving or enclosed spaces; and other type where fear is cued by other stimuli. Specific phobias may also be referred to as simple phobias. A "social phobia" is characterized by clinically significant anxiety provoked by exposure to certain types of social or performance circumstances. Social phobia may also be referred to as social anxiety disorder. Other anxiety disorders encompassed within the term "anxiety" include anxiety disorders induced by alcohol, amphetamines, caffeine, cannabis, cocaine, hallucinogens, inhalants, phencychdine, sedatives, hypnotics, anxiolytics ^' and other substances, and adjustment disorders with anxiety or with mixed anxiety and depression.

The compounds of the formula I and the active agents (SSRI, A2D, CRF) may be administered via either the oral, transdermal (e.g., through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred. In general, when the active agent is a SSRI, preferably sertraline, it is normally administered in dosages ranging from about 0.01 to about 100 mg per kg (of body weight) per day, and preferably from about 0.1 about 10 mg per kg per day. When the active agent is a CRF₁ it is administered from about 0.1 to about 500 mg per kg per day. When the active agent is an A2D, it is administered from about 5 to about 2000 mg per kg per day. In combination with at least one active agent, a compound of formula I is also administered, either in the same or different composition, from about 0.001 to about 100 mg per kg per day, preferably from about 0.01 to about 30 mg per kg per day, more preferably from about 0.01 to about 10 mg per kg per day. Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.

The compounds of the formula I and the active agents can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated. More particularly, the compounds of the formula I and the active agents can be administered in a wide variety of different dosage forms, e.g., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the compounds of formula I and the active agents are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tableting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar] as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration the active ingredient may be combined with various sweetening or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, a solution of the compounds of formula I and the active agents in either sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

It is also possible to administer the compounds of formula I and the active agents topically and this can be done by way of creams, a patch, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

In connection with the use of the compounds of formula I with the active agents for the treatment of subjects possessing any of the above conditions, it is to be noted that these compounds can be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the, active combination can be administered in a wide variety of different dosage forms, i.e., they can be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and an active agent is present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.

A proposed daily dose of the compound of formula I for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.

A proposed daily dose of the active agent in the composition for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the active agent per unit dose which could be administered, for example, 1 to 4 times per day.

A proposed dose ratio of active agent to the compound of formula I in the composition for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.

Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains from about 0.01 μg to about 2000 mg of the compound of formula I and the active agent, preferably from about 1 μg to about 200 mg of such compounds. Administration can be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.

Claims

1. A pharmaceutical composition comprising a compound of formula I

I

wherein R¹ is a group of the formula G¹ or G² depicted below,

G¹ G² a is zero to eight; m is one to three;

R⁶ is selected from the group consisting of hydrogen, (C-rCβJalkyl optionally substituted with (Ci-C₆)alkoxy or one to three fluorine atoms, or ((CrC₄)alkyl)aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH₂)_q-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C_rC₆)alkyl, (C₁-C₆)^kOXy, trifluoromethyl, cyano and -SO_t(Ci-C₆)alkyl, wherein t is zero, one or two; each R¹³ is, independently, (C_rC₄)alkyl or a (CrC₄)alkylene bridge from one of the ring carbons of the piperazine or piperidine ring of G¹ or G², respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G¹ or G², respectively, having an available bonding site, or to a ring carbon of R⁶, when R⁶ has a ring structure having an available bonding site;

X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (Ci-C₆)alkyl, hydroxy, (CrC₆)alkoxy, -SO_t(Ci-C₆)alkyl wherein t is zero, one or two, -CO₂R¹⁰ or -CONR¹¹R¹²; each of R¹⁰, R¹¹ and R¹² is selected, independently, from hydrogen, (C_rC₄)alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C_rC₆)alkyl, (C₁- C_B)alkoxy, trifluoromethyl, cyano and -SO_t(C₁-C₆)BlKyI wherein t is zero, one or two; or R¹¹ and R¹², together with the nitrogen to which they are attached, form a 5- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; R³ is -(CH₂)_gB, wherein g is zero to three and B is hydrogen, phenyl, naphthyl or a 5- to

6-membered heteroaryl ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms and wherein each of the foregoing phenyl, naphthyl and heteroaryl rings may optionally be substituted with one to three substituents independently selected from (C_rC₈)hydroxyalkyl-, (C₁-C₈)alkoxy-(C₁-C₈)alkyl-, (C₃-C₈)hydroxycycloalkyl-, (C₃- C₈)cycloalkoxy-, (C₁-C₈)BIkOXy-(C₃-C₈)CyClOaIkVl-, heterocycloalkyl, hydroxyheterocycloalkyl, and (C_rC₈)aIkoxy-heterocycloalkyl, wherein each (C₃-C₈)cycloalkyl or heterocycloalkyl moiety may be independently substituted with from one to three (CrC^alkyl or benzyl groups; when B is a phenyl, naphthyl or heteroaryl ring, each said ring may be optionally substituted with one to three substituents independently selected from phenyl, naphthyl and a 5- to 6-membered heteroaryl ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be substituted with from, one to three (CrC^alkyl or C₃-C₈ cycloalkyl substituents; or when B is a phenyl, naphthyl or heteroaryl ring, each said ring may be optionally substituted with one to three substituents independently selected from (a) lactone formed from -(CH₂XOH with an ortho -COOH, wherein t is one, two or three; (b) -CONR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ are independently selected from (CτC₈)alkyl and benzyl, or R¹⁴ and R¹⁵ together with the nitrogen to which they are attached form a 5- to 7-membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the -CONR¹⁴R¹⁵ group, wherein when any of said heteroatoms is nitrogen it may be optionally substituted with (C₁-C₈)alkyl or benzyl, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms; (c) -(CH₂)_VNCOR¹⁶R¹⁷ wherein v is zero, one, two or three and -COR¹⁶ and R¹⁷ taken together with the nitrogen to which they are attached form a 4- to 6-membered lactam ring; and, (d) -(C₁-C₈)NR¹⁸R¹⁹ where each of R¹⁸ and R¹⁹ is selected, independently, from hydrogen and (C_rC₄)alkyl, or R¹⁸ and R¹⁹, together with the nitrogen to which they are attached, form a 4- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; wherein the broken lines indicate optional double bonds; n is one, two, or three; and a pharmaceutically acceptable salt or optical isomer thereof; and at least one active agent selected from (a) a selective serotonin re-uptake inhibitor (SSRI), (b) an alpha-2-delta (A2D) ligand or (c) a corticotropin releasing factor (CRF) antagonist.

2. A composition according to claim 1 wherein R³ is (CH₂)_gB wherein g is zero and B is selected from phenyl and pyridyl.

3. A composition according to claim 2 wherein said (C₃-C₈)cycloalkyl moiety of said (C₃-C₈)hydroxycycloalkyl-, (C₃-C₈)CyClOaIkOXy-, or (C₁-C₈)alkoxy-(C₃-C₈)cycloalkyl- substituents is selected from cyclobutyl, cyclopentyl and cyclohexyl.

4. A composition according to claim 2 wherein said heterocycloalkyl moiety having 4 to 8 atoms, of said one to three optional substituents, is selected from tetrahydropyranyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, diazepinyl, oxazepinyl, thiazepinyl, oxetanyl and tetrahydrofuranyl .

5. A composition according to claim 2 wherein said 5- to 6-membered heteroaryl ring of said one to three optional substituents is selected from pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl and oxadiazolyl.

6. A composition according to claim 1 wherein said compound of formula I is selected from the group consisting of selected from the group consisting of

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(6-morpholin-4-yl-pyridin-3-yi)-pyrrolidin-2- one,

1-[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one, 3-[2-(4-Methyi-piperazin-1 -yl)-benzyl]-1 -(4-morpholin-4-yl-phenyl)-pyrrolidin-2-one,

1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyi-piperazin-1-yl)-benzyl]-pyrrolidin- 2-one,

1-[4-(2-Hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one, 1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-[2-(4-methyI-piperazin-1 -yi)-benzyl]- pyrrolidin-2-one,

1 -[4-(1 -Methoxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- piperidin-2-one, 3-[2-Fluoro-6-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-cyclopentyl)-phenyl]- pyrrolidin-2-one,

1-[4.(1-Hydroxy-cyclopentyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trinnethyl-piperazin-1-yl)- benzyl]-pyrrolidin-2-one, 1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one,

1-[4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl- piperazin-1-yl)-benzyl]-pyrrolidin-2-one,

6'-(1 -Hydroxy-1 -methyl-ethyl)-3-[2-(4-methyi-piperazin-1 -yl)-benzyl]-3,4,5,6- tetrahydro-[1 ,3']bipyridinyl-2-one,

3-[2-Fluoro-6-(4-methyl-piperazin-1-yl)-benzyl]-1-[6-(1 -hydroxy-1 -methyl-ethyl)- pyridin-3-yl]-pyrrolidin-2-one,

1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1 - yl)-benzyl]-pyrrolidin-2-one, 3-[2-(4-Ethyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-1 -methyl-ethyl)-phenyl]- pyrrolidin-2-one,

1 -[6-(1 -Ethyl-1 -hydroxy-propyI)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-1 -[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]- pyrrolidin-2-one,

1 -[6-(1 -Hydroxy-cyclopentyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-pyrrolid intone, 1 -[5-(1 -Hydroxy-cyclopentyl)-pyridin-2-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

1-[4-(2-Methyl-oxazol-4-yl)-phenyI]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-piperidin-2- one,

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-[4-(piperidine-1-carbonyl)-phenyl]-pyrrolidin- 2-one,

and pharmaceutically acceptable salts and optical isomers thereof.

7. A composition according to claim 1 wherein said compound of formula I is selected from the group consisting of: (R)-3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-1 -(6-morpholin-4-yl-pyridin-3-yl)-pyrrolidin-

2-one, (R)-1-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-3-[2-(4-nnethyl-piperaziπ-1-yl)-benzyl]- pyrrolidin-2-one,

(^^-^-(^Methyl-piperazin-i-yO-benzyO-i-C^morpholin^-yl-phenyO-pyrrolidin-Z- one, (R)-1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one,

(R)-1-[4-(2-Hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one,

(R)-1-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1-yl)- benzyl]-pyrrolidin-2-one,

(R)-1 -[4-(1 -Methoxy-1 -methyl-ethyl )-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(R)-1 -[4-(1 -Hydroxy-1 -methyl-ethyI)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- piperidin-2-one, (R)-3-[2-Fluoro-6-(4-meth,yl-piperazin-1-yl)-benzyl]-1-[4-(1-hydroxy-cyclopentyl)- phenyl]-pyrrolidin-2-one,

(R)-1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one,

(R)-1-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1- yl)-benzyl]-pyrrolidin-2-one,

(R)-1-[4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl- piperazin-1-yl)-benzyI]-pyrrolidin-2-one,

(R)-6'-(1 -Hydroxy-1 -methyl-ethyl)-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-3,4,5,6- tetrahydro-[1 ,3']bipyridinyl-2-one, (R)-3-[2-Fluoro-6-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[6-(1 -hydroxy-1 -methyl-ethyl)- pyridin-3-yl]-pyrrolidin-2-one,

(R)-1-[6-(1 -Hydroxy-1 -methyl-ethyl )-pyridin-3-yl]-3-[2-((3R,5S)-3,4,5-trimethyl- piperazin-1-yl)-benzyI]-pyrrolidin-2-one,

(R)-3-[2-(4-Ethyl-piperazin-1-yl)-benzyl]-1-[4-(1 -hydroxy-1 -methyl-ethyl)-phenyl]- pyrrolidin-2-one,

(R)-1-[6-(1-Ethyl-1-hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one,

(R)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]- pyrrolidin-2-one, (R)-1 -[6-(1 -Hydroxy-cyclopentyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one, (^-^^-(i-Hydroxy-cyclobutyO-phenyll-a-p-C^methyl-piperazin-i-ylJ-benzyl]- pyrrolidin-2-one,

(R)-1-[5-(1-Hydroxy-cyclopentyl)-pyridin-2-yl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one, (R)-1-[4-(2-Methyl-oxazol-4-yl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- piperidin-2-one,

(R)-3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-1 -[4-(piperidine-1 -carbonyl)-phenyl]- pyrrolidin-2-one,

(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(6-morpholin-4-yl-pyridin-3-yl)-pyrrolidin- 2-one,

(S)-1 -[4-(1 -Hydroxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-(4-morpholin-4-yl-phenyl)-pyrrolidin-2- one, (S)-1 -[4-(1 -Hydroxy-cyclopentyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(S)-1-[4-(2-Hydroxy-2-methyl-propyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrolidin-2-one,

(S)-1-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1-yl)- benzyl]-pyrrolidin-2-one,

(S)-1 -[4-(1 -Methoxy-1 -methyl-ethyl)-phenyl]-3-[2-(4-methy!-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(S)-1 -[4-(1 -Hydroxy-1 -methyl-ethyl )-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- piperidin-2-one, (S)-3-[2-Fluoro-6-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-cyclopentyl)- phenyl]-pyrrolidin-2-one,

(S)-1-[4-(1-Hydroxy-cyclopentyl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)- benzyl]-pyrrolidin-2-one,

(S)-1-[4-(1 -Hydroxy-1 -methyl-ethyl )-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl-piperazin-1- yl)-benzyl]-pyrrolidin-2-one,

(S)-1-[4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-((3R,5S)-3,4,5-trimethyl- piperazin-1-yl)-benzyl]-pyrroIidin-2-one,

(S)-6'-(1 -Hydroxy-1 -methyl-ethyl)-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-3,4,5,6- tetrahydro-[1 ,3']bipyridinyl-2-one, (S)-3-[2-Fluoro-6-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[6-(1 -hydroxy-1 -methyl-ethyl)- pyridin-3-yl]-pyrrolidin-2-one, (S)-1 -[6-(1 -Hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-3-[2-((3R,5S)-3,4,5-trimethyl- piperazin-1-yl)-benzyl]-pyrrolidin-2-one,

(S)-3-[2-(4-Ethyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-1 -methyl-ethyl)-phenyl]- pyrrolidin-2-one, (S)-1-[6-(1-Ethyl-1-hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- pyrrol id in-2-one,

(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyI]-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]- pyrrol id in-2-one,

(S)-1 -[6-(1 -Hydroxy-cyclopentyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one,

(S)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrol id in-2-one,

(S)-1 -[5-(1 -Hydroxy-cyclopentyl)-pyridin-2-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrol id in-2-one, (S)-1 -[4-(2-Methyl-oxazol-4-yl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- piperidin-2-one,

(S)-3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-1 -[4-(piperidine-1 -carbonyl)-phenyl]- pyrroIidin-2-one, and pharmaceutically acceptable salts thereof.

8. A composition according to any of claims 1 to 7, wherein said active agent is a selective serotonin reuptake inhibitor.

9. A composition according to claim 8 wherein said selective serotonin reuptake inhibitor is selected from sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, d,l- fenfluramine, femoxetine, trazodone, cericlamine, ifoxetine, cyanodothiepin litoxetine, indalpine, indeloxazine, milnacipran, sibutramine zimeldine norfluoxetine, escitalopram, dapoxetine, nefazodone, trazodone, analogs, derivatives, prodrugs and pharmaceutically acceptable salts thereof. ^!

10. A composition according to any of claims 1 to 7, wherein said active agent is an alpha-2-delta (A2D) ligand.

11. A composition according to claim 10 wherein said A2D ligand is selected from the group consisting of: gabapentin, pregabalin, vigabatrin, baclofen, muscimol, progabide, riluzole, valproic acid, tiagabine, lamotrigine, phenytoin, carbamazepine, topiramate and analogs, derivatives, prodrugs and pharmaceutically acceptable salts thereof.

12. A composition according to any of claims 1 to 7, wherein said active agent is a corticotropin releasing factor (CRF) antagonist.

13. A composition according to claim 12 wherein said CRF antagonist is a compound of formula II:

Formula Il or a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof,

Y is selected from -NR₂₂R₂₃. -OR₂₂₁ -CR₂₂R₂₄R₂₄, -C(O)R₂₂, -S(O)_mR₂₂, -NR₂₂C(O)R₂₃, or -NR₂₂S(O)_nR₂₃; r is 0,1 or 2;

Ar is selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R₂0, R₂₁, and each R₂₄ are independently selected from halogen, -NO_2ι -CN, -R_a, - OR₃, -S(O)_rR_a, -NR₃R₃, -C(O)NR₃R₃, -C(S)NR₃R₃ -S(O)_rNR₃R_a, -NR₃S(O)_nR₃, -NR₃C(O)OR₃, - OC(O)NR₃R₃, -NR₃C(O)NR₃R₃, -NR₃C(S)NR₃R₃, -C(O)OR₃, -C(S)OR₃, Or -OC(O)OR₃; R₂₂ and R₂₃ are independently selected from R_3i heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, substituted aryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl provided at least one of R₂₂θr R₂₃ are heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl; each R₃ is independently selected from H, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substituted with 1 to 5 of R_t, -OR_t, -S(O)_rR_t, NR_tR_t, oxo (=O), thione (=S), phenyl, heteroaryl, or heterocycloalkyl where phenyl, heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5 independently taken from R_t; each R_t is independently selected from H, halogen, -NO₂, -NH₂, -OH, -SH, -CN, -

C(O)NH₂, -C(O)-N Haikyl, -C(O)Nalkylalkyl, -Oalkyl, NHalkyl, Nalkylalkyl, -StO^lkyl, SO₂NH₂,

SO₂NHalkyl and SO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl, heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryl and heterocycloalkyl may be optionally substituted with alkyl or halogen; and aryl is either phenyl or naphthyl.

14. A pharmaceutical composition for use in treating a disorder or condition in a mammal selected from depression, anxiety, depression with concomitant anxiety, dysthymia, post traumatic stress disorder, panic phobias, obsessive compulsive disorder (OCD), OCD with comorbid Tourette's Syndrome, borderline personality disorder, sleep disorder, psychosis, seizures, dyskinesis, symptoms of Huntington's or Parkinson's diseases, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, faintness attacks, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, premenstrual syndrome (PMS) associated mood and appetite disorder, inflammatory bowel disease, modification of feeding behavior, blocking carbohydrate cravings, late luteal phase dysphoric disorder, tobacco withdrawal-associated symptoms, panic disorder, bipolar disorder, sleep disorders, jet lag, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions selected from dependencies on, or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine; pathological gambling; trichotilomania; headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising an amount of a composition according to any of claims 1 to 13.

15. A method of treating a disorder or condition in a mammal selected from depression, anxiety, depression with concomitant anxiety, dysthymia, post traumatic stress disorder, panic phobias, obsessive compulsive disorder (OCD), OCD with comorbid Tourette's Syndrome, borderline personality disorder, sleep disorder, psychosis, seizures, dyskinesis, symptoms of Huntington's or Parkinson's diseases, spasticity, suppression of seizures resulting from epilepsy, cerebral ischemia, anorexia, faintness attacks, hypokinesia, cranial traumas, chemical dependencies, premature ejaculation, premenstrual syndrome (PMS) associated mood and appetite disorder, inflammatory bowel disease, modification of feeding behavior, blocking carbohydrate cravings, late luteal phase dysphoric disorder, tobacco withdrawal-associated symptoms, panic disorder, bipolar disorder, sleep disorders, jet lag, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, chemical dependencies and addictions selected from dependencies on, or addictions to nicotine or tobacco products, alcohol, benzodiazepines, barbiturates, opioids or cocaine; pathological gambling; trichotilomania; headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome, comprising administering to a mammal in need of such treatment an amount of a composition according to any of claims 1 to 13 that is effective in treating such disorder or condition.