ZA200502117B

ZA200502117B - Treatment of CNS disorders wth trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine and its formamide

Info

Publication number: ZA200502117B
Application number: ZA200502117A
Authority: ZA
Inventors: Thomas P Jerussi; Qun Kevin Fang; Mark Currie
Original assignee: Sepracor Inc
Priority date: 2002-09-16
Filing date: 2005-03-14
Publication date: 2006-05-31
Also published as: CN1688538A; CN100584818C

Description

oS TREATMENT OF CNS DISORDERS WITH trans 4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-1-NAPTHALENAMINE ' AND ITS FORMAMIDE

Field of the Invention

[001] The present invention relates to methods of treating central nervous system (CNS) disorders using (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydro-1-napthalenamine; (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydro-1-napthalenamine and the four isomers of N-[4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl] formamide.

Background of the Invention

[002] Clinicians recognize a distinction among central nervous system illnesses, and there have been many schemes for categorizing mental disorders. The

Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed., Text

Revision, (hereinafter, the “DSM-IV-TR™”) published by the American

Psychiatric Association, and incorporated herein by reference, provides a standard diagnostic system upon which persons of skill rely. According to the framework of the DSM-IV-TR™, the CNS disorders of Axis I include: disorders diagnosed in childhood (such as, for example, attention deficit disorder or “ADD” and attention deficit / hyperactivity disorder or “ADHD”) and disorders diagnosed in adulthood. CNS disorders diagnosed in adulthood include (1) schizophrenia and psychotic disorders; (2) cognitive disorders; '

IE (3) mood disorders; (4) anxiety related disorders; (5) eating disorders; (6) substance related disorders; (7) personality disorders; and (8) “disorders not yet o included” in the scheme.

[003] Of particular interest to the present invention are adulthood disorders of

DSM-IV-TR™ categories (1) through (7) and sexual disorders, currently classified in category (8). Mood disorders of particular interest include depression, seasonal affective disorder and bipolar disorder. Anxiety related disorders of particular interest are agoraphobia, generalized anxiety disorder, phobic anxiety, obsessive compulsive disorder (OCD), panic disorder, acute stress disorder, posttraumatic stress disorder, premenstrual syndrome, social phobia, chronic fatigue disorder, perimenopause, menopause and male menopause.

[004] In general, treatment for psychoses, such as schizophrenia, for example, is quite different than treatment for mood disorders. While psychoses are treated with Dj antagonists such as olanzapine (the “typical” and “atypical” antipsychotics), mood disorders are treated with drugs that inhibit the neuronal reuptake of monoamines, in particular, serotonin (5-HT), norepinephrine (NE) and dopamine (DA).

[005] Common therapeutic agents for mood disorders include, but are not limited to, selective serotonin reuptake inhibitors (SSRI’s), including fluoxetine, citalopram, nefazodone, fluvoxamine, paroxetine, and sertraline.

[006] Sertraline, whose chemical name (18S,4S)-cis 4-(3,4-dichlorophenyl)- } 1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, is approved for the treatment . of depression by the United States Food and Drug Administration, and is available under the trade name ZOLOFT® (Pfizer Inc., NY, NY, USA). In the

Co human subject, sertraline has been shown to be metabolized to (1S,4S)-cis 4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, also known as o desmethylsertraline or norsertraline. Desmethylsertraline has been described as “not contributing significantly to the serotonergic action of sertraline”

Ronfield et al., Clinical Pharmacokinetcs, 32:22-30 (1997). Reports from

Hamelin et al., Clinical Pharmacology & Therapeutics, 60:512 (1996) and

Serebruany et al., Pharmacological Research, 43:453-461 (2001), have stated that norsertraline is “neurologically inactive”. These statements appear to be based on results observed in serotonin-induced syndrome and ptosis in mouse models in vivo, whereas the original Pfizer research papers suggested on the basis of data in vitro that desmethylsertraline was a selective serotonin uptake inhibitor. Koe et al., JPET, 226:686-700 (1983). Sanchez et al., Cellular and

Molecular Neurobiology, 19: 467 (1999), speculated that despite its lower potency, desmethylsertraline might play a role in the therapeutic effects of sertraline but, there is presently no evidence in the literature to support this theory.

[007] The primary clinical use of sertraline is in the treatment of depression. In addition, United States Patent 4,981,870 discloses and claims the use of sertraline and norsertraline, as well as (1R,4S)-trans 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-N-methyl-1-napthalenamine and (1S,4R)-trans 4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl- 1-napthalenamine for the treatment of psychoses, psoriasis, rheumatoid arthritis and inflammation. The receptor pharmacology of the individual (15,4R) and (1R,4S) enantiomers of trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine is described by Welch et al., J Med. Chem., 27:1508-1515 (1984).

Summary of the Invention

[008] It has now been discovered that (1R,4S)-trans 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-napthalenamine (P) and (1S,4R)-trans 4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydro- 1 -napthalenamine (Q) are useful in the treatment of CNS-related disorders that are modulated by monoamine activity, and produce diminished side effects as compared to the current standards of treatment. Treatable CNS disorders include, but are not limited to, mood disorders (e.g., depression), anxiety disorders (e.g., OCD), behavioral disorders (e.g., ADD and ADHD), eating disorders, substance abuse disorders and sexual function disorders. The compounds are also useful for the prophylaxis of migraine.

[009] Compounds P and Q are represented by the formulae:

NH, NH,

Cl Cl

P and Q

[0010] In one aspect, the present invention relates to a method for treating CNS disorders, which involves the administration of a therapeutically effective amount of P or Q, or a pharmaceutically acceptable salt of either. - [0011] In another aspect, the invention relates to trans- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-napthalenamine of the formula (PQ):

Ne NH; “

Cl

PQ)

[0012] In another aspect, the invention relates to a process for preparing 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro- 1-napthalenamine, which involves: (a) reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone with an excess of formic acid and formamide to provide N-[4-(3,4- dichloro phenyl)-1,2,3,4-tetrahydronaphthalen- 1 -yl]Jformamide; and (b) hydrolyzing the N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro naphthalen-1-yl]formamide with aqueous acid, and thereby yielding 4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro- 1-napthalenamine.

Detailed Description of the Invention

[0013] The present invention provides several embodiments of a method for treating one or more CNS disorders. The method encompasses administering pure P or pure Q, or any mixture thereof. Administration of either compound or any combination thereof, including the racemic mixture of trans isomers, results in a broad therapeutic profile and avoidance of side effects that are associated with an imbalance among the distribution of activity between norepinephrine, serotonin and dopamine receptors. ’ [0014] Preparation of compounds of the present invention is illustrated below in

Scheme 1 and its accompanying narrative.

Scheme 1 0 90 Oxg wR (R)-RSONH, oS" —_— Y

Ti(OEt)

Po TO op

Cl

J R

®) .R Cl 0 ANY

Ose rd NL Ss

Cl HCI/MeOH Cl jo hydrolysis ' 0

S-isomer Reisomer =

J Cl CL

Cl Cl

HCONH, / HCOOH

NHCHO 160-170 C N NHCHO ; Cl SW

NHCHO / Cl \ NHCHO NHCHO / Cl \ NHCHO

Flash N = 90 Column CI) <Q Flash orl

Luss ALR Tarar) on E(1S4R) ’ 9

Cl Cl

NH; NH, or HCl J 6NHCL80C er HCI JeNtcl 80 C (1R 4S) X Cl (15,4R) ,

Cl Cl -6- : 3

Corrected Sheet: 23.09.05 i. [0015] In the compound

OsemR

NS! ; Cl

Ci of Scheme 1,

Rr <R’,

Ris R, wherein R', R? and R® are each independently alkyl. In a preferred embodiment of the compounds, R is tert-butyl.

[0016] N-[4-(3,4-dichlorophenyl)-1,2,3 4-tetrahydronaphthalen-1-yl)formamide, the intermediate in the synthesis shown in Scheme 1, exists in four stereoisomeric forms:

NHCHO NHCHO

Cl : ~Cl

Cl Cl

A (1S,4R) B (1R,4S)

NHCHO NHCHO

Cl CL, , Cl Cl

C (18,45) D (1R,4R)

ie [0017] When N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1- yl]formamide is synthesized from achiral starting materials via non- 3 stereoselective syntheses, all four isomers will be produced. The mixture can be readily separated into a racemic cis diastereomer and a racemic trans diastereomer by means, such as recrystallization or chromatography on achiral media, that rely on chemical and physical differences.

[0018] The trans diastereomer, represented as E below, is a 1:1 mixture of A and

B. When E is hydrolyzed, PQ is produced; when A is hydrolyzed, P is produced; when B is hydrolyzed, Q is produced. The cis diastereomer, represented as F below, is a 1:1 mix of C and D.

NHCHO NHCHO

Cl Cl

Cl Ci

E=A+B F=C+D

[0019] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Machr, J. Chem.

Ed, 62:114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but not implying any absolute stereochemistry; and wedge outlines and dotted or broken lines denote enantiomerically pure - compounds of indeterminate absolute configuration.

- [0020] Thus, formula PQ above indicates any mixture of the individual isomers P and Q, which share the trans relative configuration. Clearly, the most , convenient mixture is the 1:1 racemate. When a single enantiomer is to be employed, it is preferred that the mixture include greater than 90% of the desired enantiomer, more preferably greater than 95%, and most preferably, greater than 98%. The percentages refer to the optical purity of the single enantiomer.

[0021] According to the present invention a therapeutically effective amount of N- [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide, which may be a pure isomer or a mixture of any or all of A, B, C and D, may also be administered to a person a need of therapy

[0022] Disorders treatable with the compounds of the present invention include, but are not limited to: depression, bipolar disorder, chronic fatigue disorder, seasonal affective disorder, agoraphobia, generalized anxiety disorder, phobic anxiety, obsessive compulsive disorder (OCD), panic disorder, acute stress disorder, social phobia, posttraumatic stress disorder, premenstrual syndrome, menopause, perimenopause and male menopause.

[0023] Depression, for example, is characterized by changes in mood, and by feelings of intense sadness or pessimistic worry. Symptoms include insomnia, anorexia, CNS slowing, as well as a loss of drive, enthusiasm, and libido.

[0024] Studies have shown that an increase in body monoamine levels, especially an increase in the level of norepinephrine, appears to reduce the symptoms associated with the aforementioned disorders. Thus, the compounds of the present invention are believed to provide their therapeutic activity by ) simultaneously blocking the reuptake of norepinephrine, serotonin and dopamine.

[0025] In addition to their beneficial therapeutic effects, compounds of the present . invention provide the additional benefit of avoiding one or more of the adverse effects associated with conventional mood disorder treatments. Such side effects include, for example, insomnia, breast pain, weight gain, extrapyramidal symptoms, elevated serum prolactin levels and sexual dysfunction (including decreased libido, ejaculatory dysfunction and anorgasmia).

[0026] The compounds of the present invention are also effective for treating disruptive behavior disorders, such as attention deficit disorder (ADD) and attention deficit disorder / hyperactivity (ADHD), which is in accordance with its accepted meaning in the art, as provided in the DSM-IV-TR™. These disorders are defined as affecting one’s behavior resulting in inappropriate actions in learning and social situations. Although most commonly occurring during childhood, disruptive behavior disorders may also occur in adulthood.

[0027] The term ADD, as used herein, includes both attention deficit disorder and attention deficit / hyperactivity disorder (ADHD), and is used in accordance with its accepted meaning in the art, which is defined in the DSM-IV-TR™.

Accordingly, as used herein, the term attention deficit disorder includes

ADHD: DSM-IV-TR™ categories 314.xx (which includes 314.01, 314.00 and 314.9); conduct disorder: DSM-IV-TR™ categories 312.xx (which includes 312.81, 312.82 and 312.89, as well as 312.9 - disruptive behavior disorder); and oppositional defiant disorder: DSM-IV-TR™ category 313.81. The skilled artisan will recognize that there are alternate nomenclatures, nosologies, and classification systems for pathological conditions and that these systems evolve with medical scientific progress.

. [0028] Methylphenidate (RITALIN® ; Novartis Pharmaceuticals Corporation,

East Hanover, NJ, USA) is typically the drug of choice for the treatment . and/or prevention of ADD. Tricyclic antidepressants (such as, for example, imipramine), caffeine, dextroamphetamine, and other psychostimulants (such as, for example, pemoline) are less preferred alternatives to methylphenidate.

Common side effects of methylphenidate include sleep disturbances, depression or sadness, headache, stomachache, suppression of appetite, elevated blood pressure, and, with large continuous doses, a reduction of growth. Accordingly, alternate means of treating or preventing attention deficit disorders would be of great benefit. Due to their strong dopaminergic component, compounds of the present invention not only provide effective treatment of disruptive behavior disorders, but also, avoid many of the adverse effects associated with conventional treatments.

[0029] The term “treating” when used in connection with the foregoing disorders means amelioration, prevention or relief from the symptoms and / or effects associated with these disorders and includes the prophylactic administration of a compound of formula P or Q, a mixture thereof, or a pharmaceutically acceptable salt of either, to substantially diminish the likelihood or seriousness of the condition.

[0030] Compounds of the present invention are also effective for treating eating disorders. Eating disorders are defined as a disorder of one’s appetite or eating habits or of inappropriate somatotype visualization. Eating disorders include, but are not limited to, anorexia nervosa; bulimia nervosa, obesity and cachexia.

[0031] Compounds of the invention are also effective for treating cerebral a function disorders. The term cerebral function disorder, as used herein; includes cerebral function disorders involving intellectual deficits, and may be

,- exemplified by senile dementia, Alzheimer’s type dementia, memory loss, amnesia / amnestic syndrome, epilepsy, disturbances of consciousness, coma, 2 lowering of attention, speech disorders, Parkinson’s disease and autism.

[0032] The compounds of formulae P and Q are also effective for treating sexual dysfunction in both males and females. Disorders of this type include, for example, erectile dysfunction and orgasmic dysfunction related to clitoral disturbances.

Compounds of the present invention are also useful in the treatment of substance abuse, including for example addiction to cocaine, heroin, nicotine, alcohol, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phenylcyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine addiction of all known forms, such as, for example, nicotine addiction resulting from cigarette, cigar and / or pipe smoking, as well as addiction resulting from tobacco chewing. In this respect, due to their activity as norepinephrine and dopamine uptake inhibitors, the compounds of the present invention function in a manner similar to that of buproprion (ZYBAN®,

GlaxoSmithKline, Research Triangle Park, NC, USA), by reducing the craving for the nicotine stimulus. As a benefit beyond the therapeutic activity of buproprion, however, the compounds of the present invention provide an additional serotonergic component.

[0033] Compounds of the present invention are also effective in the prophylaxis of migraine : [0034] The magnitude of a prophylactic or therapeutic dose of a compound of formula A-F, P or Q will vary with the nature and severity of the condition to i be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of

Claims

. CLAIMS

: 1. A compound of formula PQ: NH,

5 . Cl PQ .

2. A compound according to claim 1, of formula P or Q: NH, NH; ‘ CL. Cl P or cl Q.

3. (15,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine according to claim 1.

4. (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine according to claim 1.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any of claims 1 to 4.

6. A tablet or capsule according to claim 5.

7. A compound: (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH; x o Cl P; (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine oo g Cl Cl Q; (c) a mixture of P and Q; or (d) a pharmaceutically acceptable salt thereof, for use in a method for treating CNS disorders in a human, the method comprising administering to a person in need of treatment for a CNS disorder, a therapeutically effective amount of the compound.

8. The compound according to claim 7, wherein the CNS disorder is a mood disorder.

9. The compound according to claim 8, wherein the mood disorder is depression.

10. The compound according to claim 7, wherein the CNS disorder is an anxiety- related disorder. -27- Amended Sheet: 23.09.05

11. The compound according to claim 10, wherein the anxiety-related disorder is obsessive compulsive disorder.

12. The compound according to claim 7, wherein the CNS disorder is a disruptive behavior disorder.

13. The compound according to claim 12, wherein the disruptive behavior disorder is one of attention deficit disorder (ADD) or attention deficit / hyperactivity disorder (ADHD).

14. The compound according to claim 7, wherein the CNS disorder is a sexual dysfunction.

15. The compound according to claim 7, wherein the CNS disorder is a substance abuse disorder.

16. The compound according to claim 7, wherein the CNS disorder is an eating disorder.

17. The compound according to claim 7, wherein the CNS disorder is premenstrual syndrome disorder.

18. A compound chosen from: (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH, % (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine -28 - Amended Sheet: 23.09.05 co g Cl Cl Q; (c) a mixture of P and Q; and (d) a pharmaceutically acceptable salt thereof, for use in a method for the prophylaxis of migraine in a human, the method comprising administering to a person at risk or in need of therapy for a migraine, a therapeutically effective amount of the compound.

19. A compound: (a) (1R,4S5)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH; % Cl (b) (15,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH» g Cl Cl Q; (©) a mixture of P and Q ; or (d a pharmaceutically acceptable salt thereof, together with (e) a therapeutically effective amount of a D, antagonist, or a pharmaceutically acceptable salt thereof,

-29. Amended Sheet: 23.09.05 for use in a method for treating psychoses in a human, the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of the compound.

20. The compound according to claim 19, wherein the D, antagonist is olanzapine.

21. A compound: (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH N (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH» g Cl Clq; (©) a mixture of P and Q ; or (d) apharmaceutically acceptable salt thereof, together with (e) a therapeutically effective amount of a typical antipsychotic agent, or a pharmaceutically acceptable salt thereof, for use in a method for treating psychoses in a human, the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of the compound.

22. A compound: (a) (1R,48)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- -30- Amended Sheet: 23.09.05 napthalenamine NH Ca Cl P; (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine QQ Cl Q; (©) a mixture of P and Q ; or (d) a pharmaceutically acceptable salt thereof, together with (e) a therapeutically effective amount of an atypical antipsychotic agent, or a pharmaceutically acceptable salt thereof, for use in a method for treating psychoses in a human, the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of the compound.

23. A process for preparing 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1 - napthalenamine, the process comprising: (a) reacting 4-(3,4-dichlorophenyl)-3 4-dihydro-l-naphthalenone with an excess of formic acid and formamide to provide N-[4-(3,4- dichloro phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl}formamide; and (b) hydrolyzing the N-[4-~(3,4-dichlorophenyl)-1,2,3,4-tetrahydro naphthalen-l-yl]formamide with aqueous acid, yielding 4-(3,4- dichlorophenyl)- 1,2,3,4-tetrahydro-1 -napthalenamine.

24. A compound of formula: 231 - Amended Sheet: 23.09.05

NHCHO Cl Cl )

25. A compound according to claim 24, of formula E: NHCHO Cl Cl E.

26. A compound according to claim 24, of formula F: NHCHO Cl Cl F .

27. A compound according to claim 24, of formula A, B, C, or D:

-32. Amended Sheet: 23.09.05

NHCHO NHCHO NHCHO NHCHO Cl Cl Cl Cl Cl A, Cl B, Cl C, or Cl D.

28. (18,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl] formamide according to claim 24.

29. (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl] formamide according to claim 24.

30. (18,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl}formamide according to claim 24.

31. (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide according to claim 24.

32. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any of claims 24 to 31.

33. A tablet or capsule according to claim 32.

34. N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide for use in a method for treating CNS disorders in a human, wherein the method comprises administering to a person in need of treatment for a CNS disorder, a therapeutically effective amount of the compound.

35. A compound according to claim 34, which is: (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- -33- Amended Sheet: 23.09.05 tetrahydronaphthalen-1-yl]formamide NHCHO 8 Cl b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (c) (1S,45)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl}formamide -34- Amended Sheet: 23.09.05

NHCHO Cl (e) a mixture of A and B; ® a mixture of C and D; or (2) a pharmaceutically acceptable salt thereof, wherein the method comprises administering to a person in need of treatment for a CNS disorder, a therapeutically effective amount of the compound.

36. The compound according to claim 34, wherein the CNS disorder is a mood disorder.

37. The compound according to claim 36, wherein the mood disorder is depression.

38. The compound according to claim 34, wherein the CNS disorder is anxiety- related disorder.

39. The compound according to claim 38, wherein the anxiety-related disorder is obsessive compulsive disorder.

40. The compound according to claim 34, wherein the CNS disorder is a disruptive behavior disorder.

41. The compound according to claim 40, wherein the disruptive behavior disorder is one of attention deficit disorder (ADD) or attention deficit / hyperactivity disorder (ADHD). -35- Amended Sheet: 23.09.05

42. The compound according to claim 34, wherein the CNS disorder is a sexual dysfunction.

43. The compound according to claim 34, wherein the CNS disorder is a substance abuse disorder.

44. The compound according to claim 34, wherein the CNS disorder is an eating disorder.

45. The compound according to claim 34, wherein the CNS disorder is premenstrual syndrome disorder.

46. N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl] formamide for use in a method for the prophylaxis of migraine in a human, the method comprising administering to a person at risk or in need of therapy for a migraine, a therapeutically effective amount of the compound.

47. A compound according to claim 46, which is: (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl Cl A; (b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yljformamide -36- Amended Sheet: 23.09.05

NHCHO Cl (©) (15,45)-N-{4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (d (1R4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (e) a mixture of A and B; ® a mixture of C and D; or (2) apharmaceutically acceptable salt thereof, wherein the method comprises administering to a person at risk or in need of therapy for a migraine a therapeutically effective amount of the compound. -37- Amended Sheet: 23.09.05

48. N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl] formamide for use in a method for treating psychoses in a human, the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of the compound.

49. A compound according to claim 48, which is: (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO : Cl (b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl}formamide NHCHO Cl (¢) (1S,45)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide -38- Amended Sheet: 23.09.05

NHCHO Cl (d (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (e) a mixture of A and B; ® a mixture of C and D; or (€9) a pharmaceutically acceptable salt thereof, together with (h) a therapeutically effective amount of a D, antagonist, or a pharmaceutically acceptable salt thereof, wherein the method comprises administering to a person in need of treatment for a psychoses, a therapeutically effective amount of the compound.

50. The compound according to claim 49, wherein the D, antagonist is olanzapine.

51. A compound according to claim 48, which is: (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide

-39.- Amended Sheet: 23.09.05

NHCHO 8 Cl (b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl ©) (1S,45)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (d (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide -40 - Amended Sheet: 23.09.05

NHCHO Cl (e) a mixture of A and B; ® a mixture of C and D; or (2) a pharmaceutically acceptable salt thereof, together with (h) a therapeutically effective amount of an antipsychotic agent, or a pharmaceutically acceptable salt thereof, wherein the method comprises administering to a person in need of treatment for a psychoses, a therapeutically effective amount of the compound.

52. A process for preparing N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen- 1-yl]formamide comprising reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone with an excess of formic acid and formamide to provide N-[4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydronaphthalen-1-yl]formamide.

53. The process according to claim 52, wherein the 4-(3,4-dichlorophenyl)-3,4- dihydro-1-naphthalenone is of the (S) configuration and the N-[4-(3,4-dichloro phenyl)- 1,2,3,4-tetrahydronaphthalen-1-yl]formamide is a 1:1 mixture of (1R,45)- N-[4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and (15,45)-N-[4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.

54. The process according to claim 53, further comprising separating the (1R,4S)-N- [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl] formamide and (1S,45)-N-[4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl] formamide.

55. The process according to claim 52, wherein the 4-(3,4-dichlorophenyl)-3,4- dihydro-1-naphthalenone is of the (R) configuration and the N-[4-(3,4-dichloro phenyl)- 1,2,3,4-tetrahydronaphthalen-1-yl]formamide is a 1:1 mixture of (1R,4R)- N-[4-(3,4- -41 - Amended Sheet: 23.09.05 dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]Jformamide and (1S,4R)-N-[4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.

56. The process according to claim 55, further comprising separating the (1R,4R)-N- [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and (1S,4R)-N-[4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl] formamide.

57. The process according to claim 52, wherein the 4-(3,4-dichlorophenyl)-3,4- dihydro-1-naphthalenone is racemic and the process further comprises separating the N- [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl] formamide into cis N-[4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl] formamide and trans N-[4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.

58. Use of a compound: (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH; o Cl P; (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH» g Cl Cl Q; (©) a mixture of P and Q; or (d) a pharmaceutically acceptable salt thereof, -42 - Amended Sheet: 23.09.05 in the manufacture of a medicament for use in a method for treating CNS disorders in a human.

59. The use according to claim 58, wherein the CNS disorder is a mood disorder.

60. The use according to claim 59, wherein the mood disorder is depression.

61. The use according to claim 59, wherein the CNS disorder is anxiety-related disorder.

62. The use according to claim 61, wherein the anxiety-related disorder is obsessive compulsive disorder.

63. The use according to claim 58, wherein the CNS disorder is a disruptive behavior disorder.

64. The use according to claim 63, wherein the disruptive behavior disorder is one of attention deficit disorder (ADD) or attention deficit / hyperactivity disorder (ADHD).

65. The use according to claim 58, wherein the CNS disorder is a sexual dysfunction.

66. The use according to claim 58, wherein the CNS disorder is a substance abuse disorder.

67. The use according to claim 58, wherein the CNS disorder is an eating disorder.

68. The use according to claim 58, wherein the CNS disorder is premenstrual syndrome disorder.

69. Use of a compound chosen from: (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine -43 - Amended Sheet: 23.09.05

NH; N Cl P; b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH» g Cl Cl Q; ©) a mixture of P and Q; and (d) a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for the prophylaxis of migraine in a human.

70. Use of a compound: (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH; 5 N Cl P; (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine -44 - Amended Sheet: 23.09.05

NH» g Cli Cl Q; (c) a mixture of P and Q ; or d) a pharmaceutically acceptable salt thereof, together with (e) a therapeutically effective amount of a D, antagonist, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for treating psychoses in a human.

71. The use according to claim 70, wherein the D, antagonist is olanzapine.

72. Use of a compound: (a) (1R,48)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH x "Cl Cl P; (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH» g Cl Cl Q; ©) a mixture of Pand Q ; or 45 - Amended Sheet: 23.09.05

(d) a pharmaceutically acceptable salt thereof, together with (e) a therapeutically effective amount of a typical antipsychotic agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for treating psychoses in a human.

73. Use of a compound: (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH, Ca Cl P: (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine NH, A Cl Q; (©) a mixture of Pand Q ; or d a pharmaceutically acceptable salt thereof, together with (e) a therapeutically effective amount of an atypical antipsychotic agent, or a pharmaceutically acceptable salt thereof, in the manufacture of as medicament for use in a method for treating psychoses in a human.

74. Use of N-[4-(3,4-dichlorophenyl)-1,2,3 4-tetrahydronaphthalen-1-yl]formamide in the manufacture of a medicament for use in a method for treating CNS disorders in a human. _46 - Amended Sheet: 23.09.05

75. Use according to claim 74, wherein the method comprises administering to a person in need of treatment for a CNS disorder, a therapeutically effective amount of: (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO i Cl ®) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (c) (1S,48)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl Cl C; (d (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl}formamide -47 - Amended Sheet: 23.09.05

NHCHO Cl (e) a mixture of A and B; ® a mixture of C and D; or (2) a pharmaceutically acceptable salt thereof.

76. The use according to claim 74, wherein the CNS disorder is a mood disorder.

77. The use according to claim 76, wherein the mood disorder is depression.

78. The use according to claim 74, wherein the CNS disorder is anxiety-related disorder.

79. The use according to claim 78, wherein the anxiety-related disorder is obsessive compulsive disorder.

80. The use according to claim 74, wherein the CNS disorder is a disruptive behavior disorder.

81. The use according to claim 80, wherein the disruptive behavior disorder is one of attention deficit disorder (ADD) or attention deficit / hyperactivity disorder (ADHD).

82. The use according to claim 74, wherein the CNS disorder is a sexual dysfunction.

83. The use according to claim 74, wherein the CNS disorder is a substance abuse disorder. -48 - Amended Sheet: 23.09.05

84. The use according to claim 74, wherein the CNS disorder is an eating disorder.

85. The use according to claim 74, wherein the CNS disorder is premenstrual syndrome disorder.

86. Use of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide in the manufacture of a medicament for use in a method for the prophylaxis of migraine in a human .

87. Use according to claim 86, wherein the method comprises administering to a person at risk or in need of therapy for a migraine, a therapeutically effective amount of a compound chosen from: (@ (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3.4- tetrahydronaphthalen-1-yl]formamide NHCHO : Cl (db) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yljformamide NHCHO Cl (c) (15,45)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl}formamide -49 - Amended Sheet: 23.09.05

NHCHO Cl (d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (e) a mixture of A and B; ® a mixture of C and Dj; or (2) a pharmaceutically acceptable salt thereof.

88. Use of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide in the manufacture of a medicament for use in a method for treating psychoses in a human.

89. Use according to claim 88, wherein the method comprises administering to a person in need of treatment for a psychoses, a therapeutically effective amount of: (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide -50- Amended Sheet: 23.09.05

NHCHO : Cl (b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (©) (18,45)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (6) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen- 1-yl]formamide -51- Amended Sheet: 23.09.05

NHCHO Cl (e) a mixture of A and B; ® a mixture of C and D; or (2) a pharmaceutically acceptable salt thereof, together with (h) a therapeutically effective amount of a D; antagonist, or a pharmaceutically acceptable salt thereof.

90. The use according to claim 89, wherein the D, antagonist is olanzapine.

91. Use according to claim 88, wherein the method comprises administering to a person in need of treatment for a psychoses, a therapeutically effective amount of: (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl}formamide NHCHO 8 Cl (b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide

-52.- Amended Sheet: 23.09.05

NHCHO Cl (©) (15,45)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO Cl (d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide NHCHO : Cl Cl D; (e) a mixture of A and B; ® a mixture of C and D; or (8) a pharmaceutically acceptable salt thereof, together with (h) a therapeutically effective amount of an antipsychotic agent, or a pharmaceutically acceptable salt thereof. -53- Amended Sheet: 23.09.05