SPIROCYCLIC HETEROCYCLIC DERIVATIVES AND METHODS OF THEIR USE

1 . A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

2 . A pharmaceutical composition according to claim 1 , wherein the compound of formula XXVIII has the following structure:

3 . A pharmaceutical composition according to claim 1 , further comprising an opioid, an agent for the treatment of neuralgia/neuropathic pain, an agent for the treatment of depression, an agent for the treatment of incontinence, or an anti-Parkinson's agent.

4 . A pharmaceutical composition according to claim 3 , wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tramadol, a diastereoisomer thereof, a pharmaceutically acceptable salt thereof, a complex thereof, or a mixture thereof.

5 . A pharmaceutical composition according to claim 3 , wherein said agent for the treatment of neuralgia/neuropathic pain is a mild OTC analgesic, a narcotic analgesic, an anti-seizure medication or an anti-depressant.

6 . A pharmaceutical composition according to claim 3 , wherein said agent for the treatment of depression is a selective serotonin re-uptake inhibitor, a tricyclic compound, a monoamine oxidase inhibitor, or an antidepressant compound belonging to the heterocyclic class.

7 . A pharmaceutical composition according to claim 3 , wherein said agent for the treatment of urge incontinence is an anticholinergic agent, an antispasmodic medication, a tricyclic antidepressant, a calcium channel blocker or a beta agonist.

8 . A pharmaceutical composition according to claim 3 , further comprising:

an antibiotic, antiviral, antifungal, anti-inflammatory, anesthetic, or mixture thereof.

9 . A method of binding opioid receptors in a patient in need thereof, comprising the step of:

administering to said patient an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

10 . A method according to claim 9 , wherein said compound binds δ opioid receptors.

11 . A method according to claim 10 , wherein said δ opioid receptors are located in the central nervous system.

12 . A method according to claim 10 , wherein said δ opioid receptors are located peripherally to the central nervous system.

13 . A method according to claim 9 , wherein said binding modulates the activity of said opioid receptors.

14 . A method according to claim 13 , wherein said binding agonizes the activity of said opioid receptors.

15 . A method according to claim 12 , wherein said compound does not substantially cross the blood-brain bather.

16 . A method of preventing, inhibiting or treating a condition, comprising the step of:

administering to a patient in need thereof an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof;

said condition selected from any one of the group consisting of: pain, gastrointestinal dysfunction, a urogenital disorder, an immunomodulatory disorder, an inflammatory disorder, a mood disorder, anxiety, a respiratory function disorder, a stress-related disorder, attention deficit hyperactivity disorder, a sympathetic nervous system disorder, tussis, a motor disorder, stroke, cardiac arrhythmia, glaucoma, sexual dysfunction, and substance addiction.

17 . A method of preventing, inhibiting or treating a condition, comprising the step of:

administering to a patient in need thereof an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof;

said condition selected from any one of the group consisting of: shock, brain edema, cerebral ischemia, cerebral deficits subsequent to cardiac bypass surgery and grafting, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy, and rejection in organ transplants and skin grafts.

18 . A method of improving organ and cell survival, comprising the step of:

administering to a patient in need thereof an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

19 . A method of preventing, inhibiting or treating pain, comprising the step of:

administering to a patient in need thereof an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

20 . A method of preventing, inhibiting or treating a urogenital disorder, comprising the step of:

administering to a patient in need thereof an effective amount a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

21 . A method of preventing, inhibiting or treating an inflammatory disorder, comprising the step of:

administering to a patient in need thereof an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

22 . A method of preventing, inhibiting or treating a mood disorder, comprising the step of:

administering to a patient in need thereof an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

23 . A method of preventing, inhibiting or treating anxiety, comprising the step of:

administering to a patient in need thereof an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

24 . A method of preventing, inhibiting or treating a motor dysfunction, comprising the step of:

administering to a patient in need thereof an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

25 . A method according to claim 24 , wherein the motor dysfunction is Parkinson's disease.

26 . A method according to claim 24 , wherein the motor dysfunction is tremors, Tourette's syndrome, or dyskinesia.

27 . A method of preventing, inhibiting or treating cardiac arrhythmia, comprising the step of:

administering to a patient in need thereof an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

28 . A method of preventing, inhibiting or treating sexual dysfunction, comprising the step of:

administering to a patient in need thereof an effective amount of a compound according to formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

p is 1;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

29 . A method according to claim 19 wherein the pain is selected from the group consisting of acute pain and chronic pain.

30 . A method according to claim 29 wherein the pain is acute pain.

31 . A method according to claim 29 wherein the pain is chronic pain.

32 . A method according to claim 19 wherein the pain is selected from the group consisting of nociceptive pain, inflammatory pain, visceral pain, somatic pain, neuralgia, neuropathic pain, AIDS pain, cancer pain, phantom pain, psychogenic pain, pain resulting from hyperalgesia, pain caused by rheumatoid arthritis, migraine and allodynia.

33 . A method according to claim 32 wherein the pain is neuropathic pain.

34 . A method according to claim 32 wherein the pain is migraine.

35 . A method according to claim 9 , wherein said compound has the following structure:

36 . A method according to claim 16 , wherein said compound has the following structure:

37 . A method according to claim 17 , wherein said compound has the following structure:

38 . A method according to claim 18 , wherein said compound has the following structure:

39 . A method according to claim 19 , wherein said compound has the following structure:

40 . A method according to claim 20 , wherein said compound has the following structure:

41 . A method according to claim 21 , wherein said compound has the following structure:

42 . A method according to claim 22 , wherein said compound has the following structure:

43 . A method according to claim 23 , wherein said compound has the following structure:

44 . A method according to claim 24 , wherein said compound has the following structure:

45 . A method according to claim 25 , wherein said compound has the following structure:

46 . A method according to claim 28 , wherein said compound has the following structure:

47 . A method according to claim 29 , wherein said compound has the following structure:

48 . A method according to claim 30 , wherein said compound has the following structure:

49 . A method according to claim 31 , wherein said compound has the following structure:

50 . A method according to claim 32 , wherein said compound has the following structure:

51 . A method according to claim 33 , wherein said compound has the following structure:

52 . A method according to claim 34 , wherein said compound has the following structure:

53 . A pharmaceutical composition according to claim 1 , wherein the compound of formula XXVIII is selected from the group consisting of:

54 . A pharmaceutical composition according to claim 53 , wherein the compound of formula XXVIII is selected from the group consisting of:

55 . A method according to claim 9 , wherein the compound of formula XXVIII is selected from the group consisting of:

56 . A method according to claim 55 , wherein the compound of formula XXVIII is selected from the group consisting of: