Spiroazabicyclic heterocyclic compounds

• US 6,110,914 A
• Filed: 10/29/1998
• Issued: 08/29/2000
• Est. Priority Date: 07/18/1997
• Status: Expired due to Term

• Current Assignee: Astra AB (Astrazeneca PLC)
• Original Assignee: Astra AB (Astrazeneca PLC)
• Inventors: Mack, Robert, Phillips, Eifion, Semus, Simon, Macor, John
• Primary Examiner(s): Ramsuer, Robert W.
• Application Number:
  US09/171,983
• Time in Patent Office: 670 Days
• Field of Search: 544/70, 546/18, 514/233.2
• US Class Current: 514/233.2
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• 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: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings

Abstract

A compound of formula ##STR1## wherein n is 0 or 1; m is 0 or 1; p is 0 or 1; X is oxygen or sulfur; Y is CH, N or NO; W is oxygen, H₂ or F₂ ;

A is N or C(R²); G is N or C(R³); D is N or C(R⁴);

with the proviso that no more than one of A, G, and D is nitrogen, but at least one of Y, A, G, and D is nitrogen or NO;

R¹ is hydrogen or C₁ to C₄ alkyl;

R², R³, and R⁴ are independently hydrogen, halogen, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, aryl, heteroaryl, OH, OC₁ -C₄ alkyl, CO₂ R¹, --CN, --NO₂, --NR⁵ R⁶, --CF₃, --OSO₂ CF₃ or R² and R³, or R³ and R⁴, respectively, may together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively, containing between zero and two nitrogen atoms, and substituted with one to two of the following substituents: independently hydrogen, halogen, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, aryl, heteroaryl, OH, OC₁ -C₄ alkyl, CO₂ R¹, --CN, --NO₂, --NR⁵ R⁶, --CF₃, --OSO₂ CF₃ ; R⁵ and R⁶ are independently hydrogen, C₁ -C₄ alkyl, C(O)R⁷, C(O)NHR⁸, C(O)OR⁹, SO₂ R¹⁰ or may together be (CH₂)_j Q(CH₂)_k where Q is O, S, NR¹¹, or a bond; j is 2 to 7, k is 0 to 2; R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently C₁ -C₄ alkyl, aryl, or heteroaryl, or an enantiomer thereof,

and the pharmaceutically acceptable salts thereof, processes for preparing them, composition containing them, and their use in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders.

Claims

1. A compound of formula I ##STR8## wherein n is 0 or 1;

m is 0 or 1;

p is 0 or 1;

X is oxygen or sulfur;

Y is CH, N or NO;

W is oxygen, H₂ or F₂ ;

A is N or C(R²);

G is N or C(R³);

D is N or C(R⁴);

with the proviso that no more than one of A, G, and D is nitrogen but at least one of Y, A, G, and D is nitrogen or NO;

R¹ is hydrogen or C₁ -C₄ alkyl;

R², R³, and R⁴ are independently hydrogen, halogen, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, aryl, heteroaryl, OH, OC₁ -C₄ alkyl, CO₂ R¹, --CN, --NO₂, --NR⁵ R⁶, --CF₃, --OSO₂ CF₃, or R² and R³, or R³ and R⁴, respectively, may together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively, containing between zero and two nitrogen atoms, and substituted with one to two of the following substituents;

independently hydrogen, halogen, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, aryl, heteroaryl, OH, OC₁ -C₄ alkyl, CO₂ R¹, --CN, --NO₂, --NR⁵ R⁶, --CF₃, --OSO₂ CF₃ ;

R⁵ and R⁶ are independently hydrogen, C₁ -C₄ alkyl, C(O)R⁷, C(O)NHR⁸, C(O)OR⁹, SO₂ R¹⁰ or may together be (CH₂)_j Q(CH₂)_k where

Q is O, S, NR¹¹, or a bond;

j is 2 to 7;

k is 0 to 2;

R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently C₁ -C₄ alkyl, aryl, or heteroaryl,

or an enantiomer thereof, and the pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein m is 1.

3. A compound according to claim 1 wherein n is 0.

4. A compound according to claim 1 wherein p is 0.

5. A compound according to claim 1 wherein X is oxygen.

6. A compound according to claim 1 wherein A is C(R²);

G is C(R³); and

D is C(R⁴).

7. A compound according to claim 1 wherein m is 1;

n is 0;

p is 0;

X is oxygen;

A is C(R²);

G is C(R³);

D is C(R⁴).

8. A compound according to claim 1, said compound being:

spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyrdine];

5'"'"'-bromospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-phenylspiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-nitrospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

'"'"' -chlorospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]isoquinoline];

5'"'"'-(phenylcarboxamido)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-(phenylaminocarbonylamino)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-(phenylsulfonylamido)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-aminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-N-methylaminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-N,N-dimethylaminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-N,N-diethylaminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-N-ethylaminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-N-benzylaminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-N-formamidospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-N-acetamidospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]isoquinoline];

spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]quinoline];

5'"'"'-ethenylspiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-(E)-(phenylethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-(4-morpholino)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-(1-azetidinyl)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

'"'"' -(E)-(2-(4-pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-(E)-(2-(2-pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-(2-trimethylsilylethynyl(spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-ethynylspiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-(2-furyl)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-(3-pyridyl)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-methylspiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-3'"'"'H)-furo[2,3-b]pyridine-5'"'"'carbonitrile];

spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine-5'"'"'carboxamide];

5'"'"'-N'"'"'-(3chlorophenyl)ureidoaminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

5'"'"'-N'"'"'-(2-nitrophenyl)ureidoaminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

4'"'"'chlorospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

4'"'"'-methoxyspiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

4'"'"'-phenylthiospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

4'"'"'-(N-2-aminoethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

4'"'"'-Phenylaminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

4'"'"'-methylaminospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

'"'"' -(4-N-methylpiperazin-1-yl)spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[2,3-b]pyridine];

4'"'"'-chloro-spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[3,2-c]pyridine];

spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'-(3'"'"'H)-furo[3,2-c]pyridine];

6'"'"'-fluorospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'(3'"'"'H)-furo[2,3-b]pyridine];

spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'(3'"'"'H)-furo[2,3-b]pyridine-6'"'"'-carbonitrile];

6'"'"'-chlorospiro[1-azabicyclo[2.2.2]octane-3,2'"'"'(3'"'"'H)-furo[2,3-b]pyridine];

or an enantiomer, or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 in which Y is NO.

10. A compound according to claim 9, being spiro[1-azabicyclo[2.2.2]octane-3,2'"'"'(3'"'"'H)-furo[2,3-b]pyridine-7'"'"'-oxide];

or a pharmaceutically acceptable salt, or an enantiomer, thereof.

11. A pharmaceutical composition including a compound as defined in claim 1, in admixture with an inert pharmaceutically acceptable diluent or carrier.

12. A method of treatment or prophylaxis of human diseases or conditions in which activation of the α

7 nicotinic receptor is beneficial which comprises administering a therapeutically effective amount of a compound as defined in claim 1.

13. A method of treatment or prophylaxis of psychotic disorders or intellectual impairment disorders, which comprises administering a therapeutically effective amount of a compound as defined in claim 1.

14. The method as claimed in claim 13, wherein the disorder is Alzheimer'"'"'s disease, learning deficit, cognition deficit, attention deficit, memory loss, or Attention Deficit Hyperactivity Disorder.

15. The method as claimed in claim 13, wherein the disorder is Parkinson'"'"'s disease, Huntington'"'"'s disease, Tourette'"'"'s syndrome, or neurodegenerative disorders in which there is loss of cholinergic synapses.

16. The method as claimed in claim 13, wherein the disorder is anxiety, schizophrenia or mania or manic depression.

17. A method of treatment or prophylaxis of jetlag, cessation of smoking, nicotine addiction, pain, and for ulcerative colitis which comprises administering a therapeutically effective amount of a compound as defined in claim 1.

18. A process for preparation of a compound of formula I, as defined in claim 1, wherein Y is N, or an enantiomer thereof, or a pharmaceutically acceptable salt, which comprises:

removal of a borane complex in a compound of formula II using acid in a suitable solvent or heating the complex in an alcoholic solvent ##STR9## and when W=F₂ allowed by reaction with diethylaminosulfur trifluoride, and where desired or necessary converting the resultant compound of formula I, or enantiomer thereof or an acid addition salt thereof, to a pharmaceutically acceptable acid addition salt thereof, or converting the resultant racemic mixture of the compound of formula I to an enantiomer thereof.

19. A process for the preparation of a compound of the formula I as defined in claim 1 wherein R¹ is hydroxyl and Y is N, by rearrangement of a compound of the formula I as defined in claim 1, wherein Y is NO, by reacting with a carboxylic anhydride in a suitable solvent.

20. A process for the preparation of a compound of the formula I as defined in claim 1 wherein R¹ is chloro and Y is N, by rearrangement of a compound of the formula I as defined in claim 1, wherein Y is NO, by reacting with a chlorinating source in a suitable solvent.

21. A process for the preparation of a compound of the formula I as defined in claim 1 wherein R¹ is cyano and Y is N, by rearrangement of a compound of the formula I as defined in claim 1, wherein Y is NO, by reacting with a source of cyanide in a suitable solvent.

22. A process for the preparation of a compound of formula I as defined in claim 20 wherein said chlorinating source is phosphorous oxychloride.

23. A process for the preparation of a compound of the formula I as defined in claim 21 wherein said source of cyanide is trimethylsilyl cyanide.