US5399565A — Pyrazolidinone CCK and gastrin antagonists and ph…

Claim 1

Independent Claim 422 words

A method for treating or preventing a condition associated with cholecystokinin modulation in a warm blooded vertebrate, comprising administering an effective amount of a compound of the formula ##STR24## wherein R and R 1 are independently hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl(C 1 -C 4 alkyl), phenyl(C 1 -C 4 alkoxy), phenylacetyl, C 1 -C 6 alkanoyl, cyano, carbamyl, nitro, C 1 -C 6 alkoxycarbonyl, methylenedioxy, C 3 -C 6 alkylene, amino, --NH(C 1 -C 4 alkyl or benzyl), and N(C 1 -C 4 alkyl) 2 ; R 2 is hydrogen, C 1 -C 6 alkyl, carboxymethyl, C 1 -C 4 alkoxycarbonylmethyl or a group of the formula ##STR25## wherein t is 1 or 0; A is --CH 2 --, --O--, --NH-- or --N(C 1 -C 6 alkyl)--; and Y is phenyl or substituted phenyl as defined above; R 4 is C 1 -C 6 alkyl, carboxymethyl, or C 1 -C 4 alkoxycarbonylmethyl; R 3 is hydrogen or a group of the formula ##STR26## wherein B is 0 or S; X is selected from the phenyl substituents defined above; m is 0, 1 or 2; n is 0 or 1; Q is --NH--, --N(C 1 -C 6 alkyl)--, --S--, or --O--; and R 5 is a group of the formula --[CH(R 6 )] q --(CH 2 ) r --R 7 wherein R 6 is hydrogen or C 1 -C 6 alkyl; q is 0 or 1; r is 0, 1 or 2; and R 7 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, pentafluorophenyl, pyridyl, tetrahydro-naphthyl, indolyl, quinolinyl, phenyl, naphthyl, or phenyl or naphthyl substituted with 1, 2 or 3 substituents as defined above for phenyl; or the group --(Q) n R 5 is 2-tetrahydroisoquinolinyl; and the pharmaceutically acceptable salts thereof; provided that at least one of the group R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is hydrogen only when the other of R and R 1 is substituted phenyl in which the substituent is phenyl; and provided further that at least one of the groups R 2 and R 3 is other than hydrogen, and when R 3 is a group of the formula ##STR27## R 2 is other than a group of the formula ##STR28##

Claim 2

Independent Claim 422 words

A method for treating or preventing a condition associated with cholecystokinin modulation in a warm blooded vertebrate, comprising administering an effective amount of a compound of the formula ##STR24## wherein R and R 1 are independently hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl(C 1 -C 4 alkyl), phenyl(C 1 -C 4 alkoxy), phenylacetyl, C 1 -C 6 alkanoyl, cyano, carbamyl, nitro, C 1 -C 6 alkoxycarbonyl, methylenedioxy, C 3 -C 6 alkylene, amino, --NH(C 1 -C 4 alkyl or benzyl), and N(C 1 -C 4 alkyl) 2 ; R 2 is hydrogen, C 1 -C 6 alkyl, carboxymethyl, C 1 -C 4 alkoxycarbonylmethyl or a group of the formula ##STR25## wherein t is 1 or 0; A is --CH 2 --, --O--, --NH-- or --N(C 1 -C 6 alkyl)--; and Y is phenyl or substituted phenyl as defined above; R 4 is C 1 -C 6 alkyl, carboxymethyl, or C 1 -C 4 alkoxycarbonylmethyl; R 3 is hydrogen or a group of the formula ##STR26## wherein B is 0 or S; X is selected from the phenyl substituents defined above; m is 0, 1 or 2; n is 0 or 1; Q is --NH--, --N(C 1 -C 6 alkyl)--, --S--, or --O--; and R 5 is a group of the formula --[CH(R 6 )] q --(CH 2 ) r --R 7 wherein R 6 is hydrogen or C 1 -C 6 alkyl; q is 0 or 1; r is 0, 1 or 2; and R 7 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, pentafluorophenyl, pyridyl, tetrahydro-naphthyl, indolyl, quinolinyl, phenyl, naphthyl, or phenyl or naphthyl substituted with 1, 2 or 3 substituents as defined above for phenyl; or the group --(Q) n R 5 is 2-tetrahydroisoquinolinyl; and the pharmaceutically acceptable salts thereof; provided that at least one of the group R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is hydrogen only when the other of R and R 1 is substituted phenyl in which the substituent is phenyl; and provided further that at least one of the groups R 2 and R 3 is other than hydrogen, and when R 3 is a group of the formula ##STR27## R 2 is other than a group of the formula ##STR28##

Claim 3

Dependent Claim 22 words

A method of claim 1 wherein the condition is a response produced by cessation and withdrawal from the use of a benzodiazepine.

Claim 4

Dependent Claim 21 words

A method of claim 1 wherein the condition is a response produced by cessation and withdrawal from the use of nicotine.

Claim 5

Dependent Claim 13 words

A method of claim 1 wherein the condition is a neuroleptic related disorder.

Claim 6

Dependent Claim 22 words

A method of claim 4 wherein the neuroleptic related disorder is selected from the group consisting of dystonia, dyskinesia, akathisia, and Parkinsonism.

Claim 7

Dependent Claim 11 words

A method of claim 1 wherein the condition is a psychosis.

Claim 8

Dependent Claim 236 words

A method of claim 6 wherein the condition is selected from the group consisting of Moderate Mental Retardation; Severe Mental Retardation; Profound Mental Retardation; Autistic Disorder; Pervasive Development Disorder NOS; Conduct Disorder, Group Type; Conduct Disorder, Solitary Agressive Type; Tourette's Disorder; Primary Degenerative Dementia of the Alzheimer Type, Senile Onset, with Delirium; Primary Degenerative Dementia of the Alzheimer Type, Senile Onset, with Delusions; Schizophrenia, Catatonic, Subchronic; Schizophrenia, Catatonic, Chronic; Schizophrenia, Catatonic, Subchronic with Acute Exacerbation; Schizophrenia, Catatonic, Chronic with Acute Exacerbation; Schizophrenia, Catatonic, in Remission; Schizophrenia, Catatonic, Unspecified; Schizophrenia, Disorganized, Subchronic; Schizophrenia, Disorganized, Chronic; Schizophrenia, Disorganized, Subchronic with Acute Exacerbation; Schizophrenia, Disorganized, Chronic with Acute Exacerbation; Schizophrenia, Disorganized, in Remission; Schizophrenia, Disorganized, Unspecified; Schizophrenia, Paranoid, Subchronic; Schizophrenia, Paranoid, Chronic; Schizophrenia, Paranoid, Subchronic with Acute Exacerbation; Schizophrenia, Paranoid, Chronic with Acute Exacerbation; Schizophrenia, Paranoid, in Remission; Schizophrenia, Paranoid, Unspecified; Schizophrenia, Undifferentiated, Subchronic; Schizophrenia, Undifferentiated, Chronic; Schizophrenia, Undifferentiated, Subchronic with Acute Exacerbation; Schizophrenia, Undifferentiated, Chronic with Acute Exacerbation; Schizophrenia, Undifferentiated, in Remission; Schizophrenia, Undifferentiated, Unspecified; Schizophrenia, Residual, Subchronic; Schizophrenia, Residual, Chronic; Schizophrenia, Residual, Subchronic with Acute Exacerbation; Schizophrenia, Residual, Chronic with Acute Exacerbation; Schizophrenia, Residual, in Remission; Schizophrenia, Residual, Unspecified; Delusional (Paranoid) Disorder; Brief Reactive Psychosis; Schizophreniform Disorder; Schizoaffective Disorder; Induced Psychotic Disorder; Psychotic Disorder NOS (Atypical Psychosis);Bipolar Disorder, Hixed, with Psychotic Features; Bipolar Disorder, Hanic, with Psychotic Features; Bipolar Disorder, Depressed, with Psychotic Features; Bipolar Disorder NOS; Personality Disorders, Paranoid; Personality Disorders, Schizotypal; and Personality Disorders, Borderline.

Claim 9

Dependent Claim 191 words

A method of claim 7 wherein the condition is selected from the group consisting of Schizophrenia, Catatonic, Subchronic; Schizophrenia, Catatonic, Chronic; Schizophrenia, Catatonic, Subchronic with Acute Exacerbation; Schizophrenia, Catatonic, Chronic with Acute Exacerbation; Schizophrenia, Catatonic, in Remission; Schizophrenia, Catatonic, Unspecified; Schizophrenia, Disorganized, Subchronic; Schizophrenia, Disorganized, Chronic; Schizophrenia, Disorganized, Subchronic with Acute Exacerbation; Schizophrenia, Disorganized, Chronic with Acute Exacerbation; Schizophrenia, Disorganized, in Remission; Schizophrenia, Disorganized, Unspecified; Schizophrenia, Paranoid, Subchronic; Schizophrenia, Paranoid, Chronic; Schizophrenia, Paranoid, Subchronic with Acute Exacerbation; Schizophrenia, Paranoid, Chronic with Acute Exacerbation; Schizophrenia, Paranoid, in Remission; Schizophrenia, Paranoid, Unspecified; Schizophrenia, Undifferentiated, Subchronic; Schizophrenia, Undifferentiated, Chronic; Schizophrenia, Undifferentiated, Subchronic with Acute Exacerbation; Schizophrenia, Undifferentiated, Chronic with Acute Exacerbation; Schizophrenia, Undifferentiated, in Remission; Schizophrenia, Undifferentiated, Unspecified; Schizophrenia, Residual, Subchronic; Schizophrenia, Residual, Chronic; Schizophrenia, Residual, Subchronic with Acute Exacerbation; Schizophrenia, Residual, Chronic with Acute Exacerbation; Schizophrenia, Residual, in Remission; Schizophrenia, Residual, Unspecified; Delusional (Paranoid) Disorder; Brief Reactive Psychosis; Schizophreniform Disorder; Schizoaffective Disorder; Induced Psychotic Disorder; Psychotic Disorder NOS (Atypical Psychosis);Bipolar Disorder, Mixed, with Psychotic Features; Bipolar Disorder, Manic, with Psychotic Features; Bipolar Disorder, Depressed, with Psychotic Features; Bipolar Disorder NOS; with Psychotic Features; Personality Disorders, Paranoid; Personality Disorders, Schizotypal; and Personality Disorders, Borderline.

Claim 10

Dependent Claim 154 words

A method of claim 8 wherein the condition is selected from the group consisting of Schizophrenia, Catatonic, Subchronic; Schizophrenia, Catatonic, Chronic; Schizophrenia, Catatonic, Subchronic with Acute Exacerbation; Schizophrenia, Catatonic, Chronic with Acute Exacerbation; Schizophrenia, Catatonic, in Remission; Schizophrenia, Catatonic, Unspecified; Schizophrenia, Disorganized, Subchronic; Schizophrenia, Disorganized, Chronic; Schizophrenia, Disorganized, Subchronic with Acute Exacerbation; Schizophrenia, Disorganized, Chronic with Acute Exacerbation; Schizophrenia, Disorganized, in Remission; Schizophrenia, Disorganized, Unspecified; Schizophrenia, Paranoid, Subchronic; Schizophrenia, Paranoid, Chronic; Schizophrenia, Paranoid, Subchronic with Acute Exacerbation; Schizophrenia, Paranoid, Chronic with Acute Exacerbation; Schizophrenia, Paranoid, in Remission; Schizophrenia, Paranoid, Unspecified; Schizophrenia, Undifferentiated, Subchronic; Schizophrenia, Undifferentiated, Chronic; Schizophrenia, Undifferentiated, Subchronic with Acute Exacerbation; Schizophrenia, Undifferentiated, Chronic with Acute Exacerbation; Schizophrenia, Undifferentiated, in Remission; Schizophrenia, Undifferentiated, Unspecified; Schizophrenia, Residual, Subchronic; Schizophrenia, Residual, Chronic; Schizophrenia, Residual, Subchronic with Acute Exacerbation; Schizophrenia, Residual, Chronic with Acute Exacerbation; Schizophrenia, Residual, in Remission; Schizophrenia, Residual, Unspecified; Delusional (Paranoid) Disorder; Brief Reactive Psychosis; Schizophreniform Disorder; Schizoaffective Disorder; and Personality Disorders, Schizotypal.

Claim 11

Dependent Claim 12 words

A method of claim 1 wherein the condition is an anxiety disorder.

Claim 12

Dependent Claim 72 words

A method of claim 10 wherein the condition is selected from the group consisting of Anxiety Disorders, Panic Disorder, Panic Disorder with Agoraphobia, Panic Disorder without Agoraphobia , Agoraphobia without History of Panic Disorders, Social Phobia, Simple Phobia, Obsessive Compulsive Disorder , Post-Traumatic Stress Disorder, Generalized Anxiety Disorder, Anxiety Disorder NOS, Organic Anxiety Disorder , Psychoactive Substance Anxiety Disorder, Separation Anxiety Disorder, Avoidant Disorder of Childhood or Adolescence , and Overanxious Disorder.

Claim 13

Dependent Claim 37 words

A method of claim 11 wherein the condition is selected from the group consisting of Panic Disorder; Social Phobia; Simple Phobia; Organic Anxiety Disorder; Obsessive Compulsive Disorder; Post-traumatic Stress Disorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS.

Claim 14

Dependent Claim 28 words

A method of claim 1 wherein the condition is a pathological psychological condition wherein delusions, hallucinations, disorganized behavior, or anxiety are a consistent manifestation of the pathological condition.

Claim 15

Independent Claim 434 words

A method for treating or preventing a functional bowel disorder associated with motility disorders in a warm-blooded vertebrate comprising administering an effective amount of a compound of the formula ##STR29## wherein R and R 1 are independently hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl(C 1 -C 4 alkyl), phenyl(C 1 -C 4 alkoxy), phenylacetyl, C 1 -C 6 alkanoyl, cyano, carbamyl, nitro, C 1 -C 6 alkoxycarbonyl, methylenedioxy, C 3 -C 6 alkylene, amino, --NH(C 1 -C 4 alkyl or benzyl), and N(C 1 -C 4 alkyl) 2 ; R 2 is hydrogen, C 1 -C 6 alkyl, carboxymethyl, C 1 -C 4 alkoxycarbonylmethyl or a group of the formula ##STR30## wherein t is 1 or 0; A is --CH 2 --, --O--, --NH-- or --N(C 1 -C 6 alkyl)--; and Y is phenyl or substituted phenyl as defined above; R 4 is C 1 -C 6 alkyl, carboxymethyl, or C 1 -C 4 alkoxycarbonylmethyl; R 3 is hydrogen or a group of the formula ##STR31## wherein B is O or S; X is selected from the phenyl substituents defined above; m is 0, 1 or 2; n is 0 or 1; Q is --NH--, --N(C 1 -C 6 alkyl )--, --S--, or --O--; and R 5 is a group of the formula --[CH(R 6 )] q --(CH 2 ) r --R 7 wherein R 6 is hydrogen or C 1 -C 6 alkyl; q is 0 or 1; r is 0, 1 or 2; and R 7 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, pentafluorophenyl, pyridyl, tetrahydro-naphthyl, indolyl, quinolinyl, phenyl, naphthyl, or phenyl or naphthyl substituted with 1, 2 or 3 substituents as defined above for phenyl; or the group --(Q) n R 5 is 2-tetrahydroisoquinolinyl; and the pharmaceutically acceptable salts thereof; provided that at least one of the group R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is hydrogen only when the other of R and R 1 is substituted phenyl in which the substituent is phenyl; and provided further that at least one of the groups R 2 and R 3 is other than hydrogen, and when R 3 is a group of the formula ##STR32## R 2 is other than a group of the formula ##STR33## provided that the gastrointestinal disorder is not irritable bowel syndrome.

Claim 16

Independent Claim 434 words

A method for treating or preventing a functional bowel disorder associated with motility disorders in a warm-blooded vertebrate comprising administering an effective amount of a compound of the formula ##STR29## wherein R and R 1 are independently hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl(C 1 -C 4 alkyl), phenyl(C 1 -C 4 alkoxy), phenylacetyl, C 1 -C 6 alkanoyl, cyano, carbamyl, nitro, C 1 -C 6 alkoxycarbonyl, methylenedioxy, C 3 -C 6 alkylene, amino, --NH(C 1 -C 4 alkyl or benzyl), and N(C 1 -C 4 alkyl) 2 ; R 2 is hydrogen, C 1 -C 6 alkyl, carboxymethyl, C 1 -C 4 alkoxycarbonylmethyl or a group of the formula ##STR30## wherein t is 1 or 0; A is --CH 2 --, --O--, --NH-- or --N(C 1 -C 6 alkyl)--; and Y is phenyl or substituted phenyl as defined above; R 4 is C 1 -C 6 alkyl, carboxymethyl, or C 1 -C 4 alkoxycarbonylmethyl; R 3 is hydrogen or a group of the formula ##STR31## wherein B is O or S; X is selected from the phenyl substituents defined above; m is 0, 1 or 2; n is 0 or 1; Q is --NH--, --N(C 1 -C 6 alkyl )--, --S--, or --O--; and R 5 is a group of the formula --[CH(R 6 )] q --(CH 2 ) r --R 7 wherein R 6 is hydrogen or C 1 -C 6 alkyl; q is 0 or 1; r is 0, 1 or 2; and R 7 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, pentafluorophenyl, pyridyl, tetrahydro-naphthyl, indolyl, quinolinyl, phenyl, naphthyl, or phenyl or naphthyl substituted with 1, 2 or 3 substituents as defined above for phenyl; or the group --(Q) n R 5 is 2-tetrahydroisoquinolinyl; and the pharmaceutically acceptable salts thereof; provided that at least one of the group R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is hydrogen only when the other of R and R 1 is substituted phenyl in which the substituent is phenyl; and provided further that at least one of the groups R 2 and R 3 is other than hydrogen, and when R 3 is a group of the formula ##STR32## R 2 is other than a group of the formula ##STR33## provided that the gastrointestinal disorder is not irritable bowel syndrome.

Claim 17

Dependent Claim 22 words

A method of claim 14 wherein the disorder is selected from the group consisting of colonic hypermotility, non-ulcer dyspepsia, and idiopathic constipation.

Claim 18

Dependent Claim 14 words

A method of claim 15 wherein the disorder is non-ulcer dyspepsia or idiopathic constipation.

Claim 19

Dependent Claim 21 words

A method of claim 15 wherein the compound inhibits CCK-induced colonic motility and does not significantly alter CCK-induced gall bladder emptying.

Claim 20

Dependent Claim 10 words

A method of claim 14 wherein the compound is (±)-trans-l-phenylaminocarbonyl-4,5-diphenyl-3pyrazolidinone.

Claim 21

Dependent Claim 14 words

A method of claim 18 wherein the disorder is non-ulcer dyspepsia or idiopathic constipation.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1998-03-20	1998-09-19	1999-03-21	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2002-03-20	2002-09-19	2003-03-21	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2006-03-20	2006-09-19	2007-03-21	$7700.00	Window Closed / Lapsed

Pyrazolidinone CCK and gastrin antagonists and pharmaceutical formulations therof

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