Prodrugs of muscarinic agonists and methods of treatment of neuropsychiatric disorders

• US 20070105836A1
• Filed: 10/31/2006
• Published: 05/10/2007
• Est. Priority Date: 10/31/2005
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Ohlsson, Jorgen, Pettersson, Lars, Gaubert, Gilles
• Application Number:
  US11/590,559
• Publication Number:
  US 20070105836A1
• Time in Patent Office: Days
• US Class Current: 514/211.130
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07D 243/38 [b, e]- or [b, f]-condensed with six-membered rings
• CPC Class Codes: C07D 267/20 [b, f]-condensed
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds are described that are prodrugs to active compounds that modulate a muscarinic receptor. In some cases, the compounds are prodrugs to N-desmethylclozapine. The compounds may be used to treat neuropsychiatric disorders.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein;

X is selected from the group consisting of NR¹⁰, O, CR¹⁰R¹¹, C═

CR¹⁰R¹¹, and C═

O;

A and B are independently selected from the group consisting of hydrogen and mono-substituted, poly-substituted or unsubstituted, cyclic or acyclic, straight or branched chain variants of the following residues;

C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₂-C₆ alkoxy;

A and B may optionally be bound together to form a cycloalkyl, heterocyclyl, heteroaryl, or aryl ring fused to the piperazine ring;

L is a cleavable linker moiety capable of being metabolically cleaved from the piperazine nitrogen;

Y is selected from the group consisting of hydrogen;

halogen;

cyano;

—

C(O)R¹⁰;

—

C(O)OR¹⁰;

—

C(O)NR¹⁰R¹¹;

—

NR¹²C(O)NR¹⁰R¹¹;

—

SO₂NR¹⁰R¹¹;

—

SO₂R¹⁰;

—

OSO₂R¹⁰;

—

NO₂, —

NR¹⁰COR¹¹;

mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues;

C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₁-C₂₄ alkoxy, C₁-C₂₄ heteroalkyl, C₁-C₂₄ perhaloalkyl, C₁-C₂₄ perhaloalkoxy, acyl, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, arylalkoxy, C₁-C₂₄ alkoxyalkyl, C₁-C₂₄ alkylthio, C₃-C₂₄ heterocycloalkyl-alkyl, and C₃-C₂₄ heterocycloalkenyl-alkyl; and

mono-substituted, poly-substituted or unsubstituted variants of the following residues;

acyloxy, aryloxycarbonyloxy, C₃-C₂₄ cycloalkyl, C₃-C₂₄ cycloalkenyl, C₂-C₂₄ cycloalkoxy, aryl, heteroaryl, C₂-C₂₄ heterocycloalkyl, C₂-C₂₄ heterocycloalkenyl, carbonyl, amino, aminocarbonyl, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, arylthio, carboxy, thio, acyl mono-radicals derived from naturally occurring amino acids or from lipoic acid, —

CH₂CH₂SC(O)OR¹⁰, and —

CH₂CH₂SC(O)R¹⁰, with the proviso that -L-Y is not unsubstituted alkyl;

R¹, R², R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are each independently selected from the group consisting of hydrogen;

halogen;

—

OH;

—

SH;

—

CN;

—

C(O)R¹⁰;

—

C(O)OR¹⁰;

—

C(O)NR¹⁰R¹¹;

—

NR¹²C(O)NR¹⁰R¹¹;

—

SO₂NR¹⁰R¹¹;

—

SO₂R¹⁰;

—

OSO₂R¹⁰;

—

NO₂;

—

NR¹⁰C(O)R¹¹; and

mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues;

C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkyloxy, C_1-6 heteroalkyl, C_1-6-alkoxyalkyl, C_1-6 alkylthio, C_1-6 perhaloalkyl, and C_1-6 perhaloalkoxy,

independently R¹ and R², R² and R³, R³ and R⁴, R⁶ and R⁷, R⁷ and R⁸, or R⁸ and R⁹ may optionally be taken together, along with the ring carbons to which they are attached, to form a five-membered or six-membered cycloalkyl, heterocyclyl, or heteroaryl ring, or a six-membered aryl ring,

independently R¹⁰ in X may optionally be bound to R⁴ or R⁶ to form a five-membered optionally substituted heterocyclyl or heteroaryl ring system;

R¹⁰, R¹¹, and R¹² are each independently selected from a group consisting of hydrogen and mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues;

C_1-6 alkyl, C_3-6 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, arylalkyl, C_2-6alkylcarbonyl, C_2-6 alkoxycarbonyl, C_6-10 aryl, and C_5-10 heteroaryl.

2. The compound of claim 1, wherein L is selected such that the piperizine nitrogen together with L form a tertiary amine, a carbamate, a urea, an amide, an enamine, a sulfamide, a sulfonamide, an aminal, a hydrazine, or a hydroxylamine.

3. The compound of claim 1, wherein L is selected from the group consisting of carboxy, carbonyl, and alkoxy.

4. The compound of claim 3, wherein L is selected from the group consisting of —

C(O)O—

, —

C(O)—

, and —

(CH₂)₂O—

.

5. The compound of claim 1, wherein L is selected from a group consisting of —

C(O)—

, —

C(O)O—

, —

C(O)NR¹⁰—

, —

NR¹⁰C(O)NR¹¹—

, —

NR¹⁰C(O)—

, —

NR¹⁰—

, —

CR¹⁰R¹¹OC(O)—

, —

CR¹⁰R¹¹C(O)O—

,

and

6. The compound of claim 1, wherein -L-Y is hydroxyalkyl.

7. The compound of claim 1, wherein Y is selected from a group consisting of hydrogen;

mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues;

C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₁-C₂₄ alkoxy, C₁-C₂₄ heteroalkyl, C₁-C₂₄ perhaloalkyl, C₁-C₂₄ perhaloalkoxy, phenyl-C_1-2-alkyl, C₃C₂₄ heterocycloalkyl-alkyl, and C₃-C₂₄ heterocycloalkenyl-alkyl; and

mono-substituted, poly-substituted or unsubstituted variants of the following residues;

C₃-C₂₄ cycloalkyl, C₃-C₂₄ cycloalkenyl, C₂-C₂₄ cycloalkoxy, C₂-C₂₄ heterocycloalkyl, C₂-C₂₄ heterocycloalkenyl, acyl mono-radicals derived from naturally occurring amino acids or from lipoic acid, —

CH₂CH₂SC(O)OR¹⁰, and —

CH₂CH₂SC(O)R¹⁰.

8. The compound of claim 1, wherein R² is H or F.

9. The compound of claim 1, wherein R⁸ is Cl, Br, or I.

10. The compound of claim 1, wherein R⁴ is Cl or Me.

11. The compound of claim 1, wherein X is NH.

12. The compound of claim 1, wherein X is O.

13. The compound of claim 1, selected from the group consisting of:

15. A method of modulating the activity of a muscarinic receptor, comprising administering to a subject a compound of claim 1 or 14.

16. The method of claim 15, wherein administration of the compound causes activation of the muscarinic receptor.

17. The method of claim 15, wherein administration of the compound causes inhibition of the muscarinic receptor.

18. The method of claim 15, wherein administration of the compound causes formation of a second compound in vivo that is an agonist of the muscarinic receptor.

19. The method of claim 15, wherein administration of the compound causes formation of a second compound in vivo that is an antagonist of the muscarinic receptor.

20. A method of treating or preventing a neuropsychiatric disorder, comprising administering to a subject a compound of claim 1 or 14.

21. The method of claim 20, wherein the neuropsychiatric disorder is selected from the group consisting of one or more of psychosis, cognitive impairment associated with psychosis, hallucination, delusion, disordered thought, behavioral disturbance, aggression, neuropathic pain, anhedonia, a psychiatric disturbance secondary to dementia or cognitive impairment, a behavioral disturbance secondary to dementia or cognitive impairment, schizophrenia, an idiopathic psychosis, anxiety, a sleep disorder, an appetite disorder, an affective disorder, Tourette'"'"'s Syndrome, drug-induced psychosis, psychosis secondary to a neurodegenerative disorder, and cognitive impairment secondary to a neurodegenerative disorder.

22. The method of claim 21, wherein the affective disorder is selected from one or more of major depression, bipolar disorder, mania, flattening of affect, suicidality, and depression with psychotic features.

23. The method of claim 21, wherein the neurodegenerative disorder is selected from one or more of Alzheimer'"'"'s and Huntington'"'"'s disease.

24. A method of treating or preventing glaucoma, comprising administering to a subject a compound of claim 1 or 14.

25. A pharmaceutical composition, comprising a compound of claim 1 or 14.

26. The composition of claim 25, wherein the composition comprises one or more of a physiologically acceptable carrier, diluent, or excipient.

14. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein;

D is absent or is selected from the group consisting of —

NH(CH₂)_n— and

—

(CH₂)_n—

;

E is selected from the group consisting of;

Z is nitrogen, CH, or CH₂;

Z′

is C or CH, wherein when Z′

is C, there is a double bond between Z and Z′ and

wherein when Z′

is CH, there is a single bond between Z and Z′

;

Z″

is N or CH;

each n is separately selected from the group consisting of 0, 1, 2, 3, and 4;

m is selected from the group consisting of 1, 2, and 3;

X is selected from the group consisting of NR¹⁰, O, CR¹⁰R¹¹, C═

CR¹⁰R¹¹, and C═

O;

A and B are independently selected from the group consisting of hydrogen and mono-substituted, poly-substituted or unsubstituted, cyclic or acyclic, straight or branched chain variants of the following residues;

C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and C₂-C₆ alkoxy;

A and B may optionally be bound together to form a fused cycloalkyl, heterocyclyl, heteroaryl, or aryl ring;

L is a cleavable linker moiety capable of being metabolically cleaved from the nitrogen to which it is attached;

Y is selected from the group consisting of hydrogen;

halogen;

cyano;

—

C(O)R¹⁰;

—

C(O)OR¹⁰;

—

C(O)NR¹⁰R¹¹;

—

NR¹²C(O)NR¹⁰R¹¹;

—

SO₂NR¹⁰R¹¹;

—

SO₂R¹⁰;

—

OSO₂R¹⁰;

—

NO₂, —

NR¹⁰COR¹¹;

mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues;

C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₁-C₂₄ alkoxy, C₁-C₂₄ heteroalkyl, C₁-C₂₄ perhaloalkyl, C₁-C₂₄ perhaloalkoxy, acyl, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, arylalkoxy, C₁-C₂₄ alkoxyalkyl, C₁-C₂₄ alkylthio, C₃-C₂₄ heterocycloalkyl-alkyl, and C₃-C₂₄ heterocycloalkenyl-alkyl; and

mono-substituted, poly-substituted or unsubstituted variants of the following residues;

acyloxy, aryloxycarbonyloxy, C₃-C₂₄ cycloalkyl, C₃-C₂₄ cycloalkenyl, C₂-C₂₄ cycloalkoxy, aryl, heteroaryl, C₂-C₂₄ heterocycloalkyl, C₂-C₂₄ heterocycloalkenyl, carbonyl, amino, aminocarbonyl, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, arylthio, carboxy, thio, acyl mono-radicals derived from naturally occurring amino acids or from lipoic acid, —

CH₂CH₂SC(O)OR¹⁰, and —

CH₂CH₂SC(O)R¹⁰, with the proviso that -L-Y is not unsubstituted alkyl;

a, b, c, and d are each separately selected from the group consisting of carbon, nitrogen, oxygen, and sulfur, or each is separately absent,

provided that at least three of a, b, c, or d are present,

provided that at least one of a, b, c, or d is carbon, and

provided that no two adjacent a, b, c, or d are both oxygen or both sulfur;

e, f, g, and h are each separately selected from the group consisting of carbon, nitrogen, oxygen, and sulfur, or each is separately absent,

provided that at least three of e, f, g, or h are present,

provided that at least one of e, f, g, or h is carbon, and

provided that no two adjacent e, f, g, or h are both oxygen or both sulfur;

R¹, R², R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are each independently selected from the group consisting of hydrogen;

halogen;

—

OH;

—

SH;

—

CN;

—

C(O)R¹⁰;

—

C(O)OR¹⁰;

—

C(O)NR¹⁰R¹¹;

—

NR¹²C(O)NR¹⁰R¹¹;

—

SO₂NR¹⁰R¹¹;

—

SO₂R¹⁰;

—

OSO₂R¹⁰;

—

NO₂;

—

NR¹⁰C(O)R¹¹; and

mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues;

C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkyloxy, C_1-6 heteroalkyl, C_1-6-alkoxyalkyl, C_1-6 alkylthio, C_1-6 perhaloalkyl, and C_1-6 perhaloalkoxy,

independently R¹ and R², R² and R³, R³ and R⁴, R⁶ and R⁷, R⁷ and R⁸, or R⁸ and R⁹ may optionally be taken together, along with the ring carbons to which they are attached, to form a five-membered or six-membered cycloalkyl, heterocyclyl, or heteroaryl ring, or a six-membered aryl ring,

independently R¹⁰ in X may optionally be bound to R⁴ or R⁶ to form a five-membered optionally substituted heterocyclyl or heteroaryl ring system;

R¹⁰, R¹¹, and R¹² are each independently selected from a group consisting of hydrogen and mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues;

C_1-6 alkyl, C_3-6 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, arylalkyl, alkylcarbonyl, C_2-6 alkoxycarbonyl, C_6-10 aryl, and C_5-10 heteroaryl; and

any bond represented by a dashed and solid line represents a bond selected from the group consisting of a carbon-carbon single bond and a carbon-carbon double bond.