Pharmaceutical for treatment of neurological and neuropsychiatric disorders

• US 7,019,024 B2
• Filed: 01/09/2001
• Issued: 03/28/2006
• Est. Priority Date: 05/31/1996
• Status: Expired due to Fees

• Current Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Original Assignee: Allelix Neuroscience, Inc. (Shire plc)
• Inventors: Zhang, Jing, Bell, Stanley Charles, Ognyanov, Vassil Iliya, Borden, Laurence A.
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US09/757,011
• Publication Number:
  US 20010012857A1
• Time in Patent Office: 1,904 Days
• Field of Search: 514/438, 514/466, 514/471, 549/77, 549/437, 549/496
• US Class Current: 514/438
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07C 229/14 to carbon atoms of carbon skeletons containing rings
• CPC Class Codes: C07C 229/16 to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
• CPC Class Codes: C07C 237/06 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 255/43 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07C 2603/32 Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 2603/88 Ethanoanthracenes; Hydrogenated ethanoanthracenes
• CPC Class Codes: C07C 303/40 by reactions not involving the formation of sulfonamide groups
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/02 condensed with one carbocyclic ring
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/65 attached in position 3 or 5
• CPC Class Codes: C07D 223/28 having a single bond between positions 10 and 11
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 279/24 : with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
• CPC Class Codes: C07D 279/26 : without other substituents attached to the ring system
• CPC Class Codes: C07D 295/03 : with the ring nitrogen atoms directly attached to acyclic carbon atoms
• CPC Class Codes: C07D 295/073 : with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/088 : to an acyclic saturated chain
• CPC Class Codes: C07D 307/14 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/42 : Singly bound oxygen atoms
• CPC Class Codes: C07D 317/64 : Oxygen atoms
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07F 9/3808 : Acyclic saturated acids which can have further substituents on alkyl

Abstract

The invention provides a pharmaceutical for treatment of neurological and neuropsychiatric disorders comprising a compound of the formula:
or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of the following formula:

or a pharmaceutically acceptable salt thereof,

wherein;

(1) C* is a substituted carbon;

(2) R² (a) is hydrogen, (C1–

C6) alkyl, (C1–

C6) alkoxy, cyano, (C2–

C7) alkanoyl, aminocarbonyl, (C1–

C6) alkylaminocarbonyl, or dialkylaminocarbonyl wherein each alkyl is independently C1 to C6, (b) is (where R¹ is not aminoethylene, —

O—

R⁸ or —

S—

R^8*) hydroxy, fluoro, chloro, bromo or (C2–

C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon from one of either R¹, R^xb or R^yb, or (d) is R^2a linked by R^2b to C*;

(2i) R^x is R^xa linked by R^xb to C*;

(2ii) R^y is R^ya linked by R^yb to C*;

(2iii) R^xa and R^ya are independently Ar, which is phenyl or naphthyl, heteroaryl, or a 5 to 7-membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen and sulfur, and R^2a, when present, is Ar, and wherein;

(a) heteroaryl is thienyl, furanyl, benzothienyl, benzofuryl or methylenedioxyphenyl,

(b) each of R^xa and R^ya can be independently substituted with one R^q, R^rO—

or R^sS—

, wherein each R^q, R^r and R^s are independently Ar, heteroaryl, adamantyl, or a 5 to 7-membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen and sulfur, and

(c) R^xa, R^ya, R^2a, R^q, R^r and R^s can be substituted or additionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1–

C6) N-alkyl substitutions, (C1–

C12) alkyl, (C2–

C12) alkenyl, amino, (C1–

C6) alkylamino, dialkylamino wherein each alkyl of dialkylamino is independently C1 to C6, (C1–

C6) alkoxy, (C2–

C7) alkanoyl, (C2–

C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2–

C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1–

C6) alkyl, (C1–

C6) alkylsulfonyl, or amidino wherein the amidino can be independently substituted with up to three (C1–

C6) alkyl groups, wherein;

(i.) the substitutions of R^xa and R^ya can be combined to form a second bridge between R^xa and R^ya in which the second bridge is (1) methylene or ethylene, or (2) —

CH═

CH—

, or (3) sulfur, or (4) oxygen, or wherein R^xa and R^ya can be directly linked by a single bond,

(d) wherein at least one of R^xa, R^ya, R^q, R^r or R^s is heteroaryl, or the second bridge between R^xa and R^ya is sulfur or oxygen as set forth in (c)(i), or Ar substituted with a methylenedioxy;

(2iv) R^xb and R^2b are independently a single bond or (C1–

C2) alkylene;

(2v) R^yb is a single bond, oxy, (C1–

C2) alkylene, ethenylene or —

CH═

(where the double bond is with C*), thio, methyleneoxy or methylenethio, or either —

N(R⁶) or —

CH₂—

N(R^6*)—

, wherein R⁶ and R^6* are hydrogen or (C1–

C6) alkyl;

(3) R¹ is;

a straight-chained (C2–

C3) aliphatic group;

═

N—

O-(ethylene), wherein the unmatched double bond is linked to C*;

—

O—

R⁸ or —

S—

R^8* wherein R⁸ or R^8* is a ethylene or ethenylene and O or S is bonded to C*;

or aminoethylene where the amino is bonded to C*;

wherein R¹ can be substituted with up to one hydroxy, up to one (C1–

C6) alkoxy or up to one (C2–

C7) alkanoyloxy, with up to two independent (C1–

C6) alkyl, with up to one oxo, up to one (C1–

C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy or oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen;

wherein if R¹ contributes a heteroatom linked to C*, then R^yb does not contribute a heteroatom linked to C*; and

wherein the alkyl or alkylidene substituents of R¹ can be linked to form a 3 to 7-membered non-aromatic ring;

(4) R³ (a) is hydrogen, (C1–

C6) alkyl, or phenyl or phenylalkyl wherein the alkyl is C1 to C6 and the phenyl or phenyl of phenylalkyl can be substituted with the same substituents defined above for Ar of R^xa, (b) is —

R¹²C(R^xx)(R^yy)(R¹¹), wherein R¹² is bonded to N, R^xx is independently the same as R^x, R^yy is independently the same as R^y, respectively, R¹¹ is independently the same as R², and R¹² is independently the same as R¹;

(5) R⁴ and R^4* are independently hydrogen or (C1–

C6) alkyl, or one of R⁴ and R^4* can be (C1–

C6) hydroxyalkyl; and

(6) R⁵ is (CO)NR¹³R¹⁴, (CO)OR¹⁵, (CO)SR¹⁶, (SO₂)NR¹⁷R¹⁸, (PO)(OR¹⁹)(OR²⁰), (CR²²)(OR²³)(OR²⁴) or CN, wherein (a) R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ are independently hydrogen, (C1–

C8) alkyl which can include a (C3–

C8) cycloalkyl, wherein the carbon of R¹⁵ that is linked to oxygen or the carbon of R¹⁶ that is linked to sulfur has no more than secondary branching, (C2–

C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1–

C6) alkyls, Ar-alkyl wherein the alkyl is C1–

C6, or Ar, and (b) R²² is hydrogen or OR²⁵ and R²³, R²⁴ and R²⁵ are independently (C1–

C6) alkyl, phenyl, benzyl or acetyl;

wherein the phenyl or naphthyl groups of R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²², R²³ or R²⁴ can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, hydroxy, trifluoromethyl, amidosulfonyl which can have up to two independent (C1–

C6) N-alkyl substitutions, (C1–

C6) alkyl, (C2–

C6) alkenyl, (C1–

C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1–

C6) alkoxy, (C2–

C7) alkanoyl, (C2–

C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2–

C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1–

C6) alkyl, (C1–

C6) alkylsulfonyl, or amidino that can be substituted with up to three (C1–

C6) alkyl.

2. The compound of claim 1, wherein at least one of R^xa, R^ya, R^q, R^r and R^s is thienyl or furanyl.

3. The compound of claim 1, wherein at least one of R^xa and R^ya is thienyl or furanyl.

4. The compound of claim 1, wherein

(A) at least one of R^xa, R^ya and R^2a is substituted with fluoro, chloro, bromo, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or (C3–

C8) alkyl, or

(B) at least one of R^xa and R^ya is substituted with R^q, R^rO—

or R^sS—

, or

(C) R³ is hydrogen, (C1–

C6) alkyl, or phenyl or phenylalkyl wherein the alkyl is C1 to C6 and either such phenyl can be substituted with

(1) one R^q, R^rO—

or R^sS—

, wherein each R^q, R^r and R^s are independently Ar, heteroaryl, adamantyl, or a 5 to 7-membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, and sulfur, and

(2) wherein either phenyl of R³, R^q, R^r and R^s can be substituted or additionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1 C6) N alkyl substitutions, (C1–

C12) alkyl, (C2–

C12) alkenyl, amino, (C1–

C6) alkylamino, dialkylamino wherein each alkyl of dialkylamino is independently C1 to C6, (C1–

C6) alkoxy, (C2–

C7) alkanoyl, (C2–

C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2–

C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1–

C6) alkyl, (C1–

C6) alkylsulfonyl, or amidino wherein the amidino can be independently substituted with up to three (C1–

C6) alkyl groups, or

(D) the ring structures of R^xa, R^ya and R^2a, including substituents thereto, otherwise include at least two aromatic ring structures that together include from 15 to 20 ring atoms.

5. The compound of claim 4, wherein at least one of R^xa, R^ya, R^q, R^r and R^s is substituted with fluoro, trifluoromethyl, trifluoromethoxy, nitro, cyano, or (C3–

C8) alkyl.

6. The compound of claim 1, wherein at least one of R^xa and R^ya is substituted with R^q, R^rO—

, or R^sS—

.

7. The compound of claim 1, wherein an Ar of at least one of R^xa, R^ya and R^2a is phenyl.

8. The compound of claim 1, wherein R^yb is oxy, methyleneoxy, thio, or methylenethio.

9. The compound of claim 8, wherein R^yb is oxy or thio.

10. The compound of claim 1, wherein R⁵ is (CO)NR¹³R¹⁴, (CO)OR¹⁵ or (CO)SR¹⁶.

11. The compound of claim 10, wherein R⁵ is (CO)OR¹⁵ and R¹⁵ is (C2–

C6) alkyl, (C2–

C4) hydroxyalkyl, phenyl, phenylalkyl wherein the alkyl is C1–

C3, or aminoalkyl where the alkyl is C2–

C6 and the amino can be substituted with up to two independent (C1–

C3) alkyls, wherein the phenyl or the phenyl of phenylalkyl can be substituted.

12. The compound of claim 10, wherein R⁵ is (CO)OR¹⁵ and R¹⁵ is hydrogen.

13. The compound of claim 1, wherein R⁴ is hydrogen, methyl or hydroxymethyl and R^4* is hydrogen.

14. The compound of claim 1, wherein R¹ is —

O—

R⁸ or —

S—

R⁸*.

15. The compound of claim 14, wherein R^xa—

R^xb—

, R^ya—

R^yb— and

C* form;

wherein A and B are Ar ring structures consistent with the definitions of R^xa and R^ya, respectively, and Y is C* wherein R²¹ either (i.) completes a single bond linking two Ar rings of R^xa and R^ya, or (ii.) is methylene, ethylene or —

CH═

CH—

, and wherein R^xa and R^ya can be substituted.

16. The compound of claim 15, wherein R²¹ is ethylene or CH═

CH.

17. The compound of claim 1, wherein R^xa and R^ya together can be substituted with up to six substituents, R^2a, R^q, R^r and R^s can each be substituted with up to 3 substituents, and wherein the presence of each of R^q, R^rO—

or R^sS—

is considered a substitution to the respective ring structure of R^xa and R^ya.

18. The compound of claim 1, wherein a phenyl of R³ is substituted with up to three substituents.

19. The compound of claim 1, wherein the Ar of R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ or R²⁰ is substituted with up to three substituents.

20. The compound of claim 1, wherein R³ is hydrogen, (C1–

C6) alkyl, or phenyl or phenylalkyl wherein the alkyl is C1 to C6 and the phenyl or phenyl of phenylalkyl can be substituted with;

one of R^q, R^rO—

or R^sS—

, wherein each of R^q, R^r and R^s are independently Ar, heteroaryl (wherein heteroaryl comprises thienyl, furanyl, benzothienyl, benzofuryl, or methylenedioxyphenyl), adamantyl, or a 5 to 7-membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, and sulfur, and

one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1–

C6) N-alkyl substitutions, (C1–

C12) alkyl, (C2–

C12) alkenyl, amino, (C1–

C6) alkylamino, dialkylamino wherein each alkyl of dialkylamino is independently C1 to C6, (C1–

C6) alkoxy, (C2–

C7) alkanoyl, (C2–

C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2–

C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1–

C6) alkyl, (C1–

C6) alkylsulfonyl, or amidino wherein the amidino can be independently substituted with up to three (C1–

C6) alkyl groups.

21. The compound of claim 1, wherein the compound is an optically pure enantiomer.

22. The compound of claim 1 wherein:

(1) R² is hydrogen or wherein R² forms a double bond with an adjacent carbon from R¹,

(2) R^xa and R^ya are phenyl, thienyl or furanyl, and can be substituted,

(3) R^xb is a single bond and R^yb is a single bond or oxy, and

(4) R⁵ is (CO)NR¹³R¹⁴ or (CO)OR¹⁵, wherein R¹³, R¹⁴, and R¹⁵ are independently hydrogen;

(C1–

C8) alkyl which can include a (C3–

C8) cycloalkyl, wherein the carbon of R¹⁵ linked to oxygen of (CO)OR¹⁵ has no more than secondary branching;

(C2–

C6) hydroxyalkyl or aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1–

C6) alkyl or phenylalkyl, wherein the alkyl is C1–

C6 and the phenyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, hydroxy, trifluoromethyl, amidosulfonyl which can have up to two independent (C1–

C6) N-alkyl substitutions, (C1–

C6) alkyl, (C2–

C6) alkenyl, (C1–

C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1–

C6) alkoxy, (C2–

C7) alkanoyl, (C2–

C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2–

C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1–

C6) alkyl, (C1–

C6) alkylsulfonyl, amidino that can substituted with up to three (C1–

C6) alkyl.

23. The compound of claim 22, wherein R² forms a double bond with an adjacent carbon from R¹.

24. The compound of claim 1, wherein R¹ is a straight-chained (C2–

C3) aliphatic group.

25. The compound of claim 24, wherein R² forms a double bond with an adjacent carbon from R¹.

26. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

27. The pharmaceutical composition of claim 26, wherein the compound is present in an effective amount for:

(1) treating schizophrenia,

(2) treating epilepsy,

(3) treating spasticity,

(4) treating muscle spasm,

(5) treating pain,

(6) treating mood disorders,

(7) enhancing memory or learning, or

(8) treating learning disorders.

28. The pharmaceutical composition of claim 27, wherein the compound is present in an effective amount for treating schizophrenia.

29. A method of (1) treating schizophrenia comprising administering a schizophrenia treating effective amount of a compound of claim 1, (2) treating epilepsy comprising administering an epilepsy treating effective amount of the compound, (3) treating spasticity comprising administering a spasticity treating effective amount of the compound, (4) treating muscle spasm comprising administering a muscle spasm treating effective amount of the compound, (5) treating pain comprising administering a pain treating effective amount of the compound, (6) treating mood disorders comprising administering a mood disorder treating effective amount of the compound, (7) enhancing memory or learning comprising administering a memory or learning enhancing effective amount of the compound, or (8) treating learning disorders, comprising administering an amount effective for said treating or enhancing of the compound.

30. The method of claim 29, wherein the spasticity is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury or dystonia.

31. The method of claim 29 of (1) treating schizophrenia comprising administering a schizophrenia treating effective amount of a compound, (5) treating pain comprising administering a pain treating effective amount of a compound or (6) treating mood disorders comprising administering a mood disorder treating effective amount of a compound.

32. The method of claim 29 of treating schizophrenia comprising administering a schizophrenia treating effective amount of the compound.

33. The method of claim 31, wherein the mood disorder is depression.

34. The method of claim 29, wherein the learning disorders are attention deficit disorders.