3-Azabicyclo[3.1.0]hexane derivatives useful in...

Details 3-Azabicyclo[3.1.0]hexane derivatives useful in... 3-Azabicyclo[3.1.0]hexane derivatives useful in...

1999-12-20

2001-11-06

Gerstl, Robert (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S141000, C546S272400, C548S126000, C548S243000, C548S255000, C548S267200, C548S305100, C548S312100, C548S454000, C548S455000

Reexamination Certificate

active

06313312

ABSTRACT:

This invention relates to pharmaceutically useful compounds, in particular compounds that bind to opiate receptors (e.g. mu, kappa and delta opioid receptors). Compounds that bind to such receptors are likely to be useful in the treatment of diseases modulated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors have also been indicated in the treatment of eating disorders, opiate overdoses, depression, smoking and alcohol addiction, sexual dysfunction, shock, stroke, spinal damage and head trauma.
There is a particular need for an improved treatment of itching. Itching, or pruritus, is a common dermatological symptom that can give rise to considerable distress in both humans and animals. Pruritus is often associated with inflammatory skin diseases which may be caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mite or pollen; by bacterial and fungal infections of the skin; or by ectoparasite infections.
Existing treatments that have been employed in the treatinent of pruritus include the use of corticosteroids and antihistamines. However, both of these treatments are known to have undesirable side effects. Other therapies that have been employed include the use of essential fatty acid dietary supplements, though these have the disadvantages of being slow to act, and of offering only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed, but with limited success.
Thus, there is a continuing need for alternative and/or improved treatments of pruritus. Certain 4-arylpiperidine-based compounds are disclosed in inter alia European patent applications EP 287339, EP 506468 and EP 506478 as opioid antagonists. In addition, International Patent Application WO 95/15327 discloses azabicycloalkane derivatives useful as neuroleptic agents.
According to the invention there is provided a compound of formula I,
wherein the “Ar” ring represents an optionally benzo-fused phenyl or 5- or 6-membered heteroaryl ring;
R
1
when taken alone is H, halogen, NO
2
, NH
2
, NY
2
WY
1
, Het
1
, AD, CO
2
R
7
, C(O)R
8
, C(═NOH)R
8
, or OE,
Y
2
is H, C
1-6
alkyl, C
3-6
alkenyl (each of which alkyl and alkenyl is optionally substituted by aryl, aryloxy or Het
1
),
W is SO
2
, CO, C(O)O, P(Y
1
)═O, P(Y
1
)═S,
Y
1
is C
1-10
alkyl (optionally substituted by one or more substituents independently selected from halogen, OH, C
1-4
alkoxy, C
1-6
alkanoyloxy, CONH
2
, C
1-6
alkoxycarbonyl, NH
2
, aryl, mono- or di(C
1-4
alkyl)arnino, C
3-8
cycloalkyl, phthalimidyl, Het
1
), Het
1
, aryl (optionally substituted by one or more substituents independently selected from C
1-4
alkyl, C
1-4
haloalkyl and halogen), NH
2
, N(C
1-6
alkyl)
2
or NH(C
1-6
alkyl),
Het
1
is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaryl group, optionally benzo- or pyrido-fused heteroaryl), optionally substituted by one or more substituents independently selected from C
1-6
alkyl, C
1-6
alkoxy, C
3-6
cycloalkyl, C
1-6
haloalkoxy, C
1-6
haloalkyl, C
3-6
halocycloalkyl, ═O, OH, halogen, NO
2
, SiR
19a
R
19b
R
19c
, CON
20a
R
20b
, NR
20a
R
20b
, SR
21a
, NR
21b
SO
2
R
22a
, NR
21c
C(O)OR
22b
, NR
21d
COR
22d
, and C
1-6
alkoxycarbonyl, and if a S atom is present in a ring, it can be present as part of a —S—, S(O)— or —S(O
2
)— group, and carbon atoms in the ring can be present as a part of a carbonyl moiety;
R
19a
, R
19b
, R
19c
each independently represent C
1-6
alkyl or aryl,
R
20a
and R
20b
each independently represent H, C
1-6
alkyl, aryl, (C
1-4
alkyl)phenyl, each of which alkyl, aryl and alkylphenyl are optionally substituted by one or more C
1-4
alkyl, C
1-4
alkoxy, OH, NO
2
, NH
2
and/or halogen, or R
20a
and R
20b
can be taken together with the N atom to which they are attached, to form a 4- to 6-membered ring optionally substituted by one or more substitutuents independently selected from one or more C
1-4
alkyl, C
1-4
alkoxy, OH, ═O, NO
2
, NH
2
and/or halogen,
R
21a, b, c and d
each independently represent H, C
1-6
alkyl, aryl or C
1-4
alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more C
1-4
alkyl, C
1-4
alkoxy, OH, NO
2
, halogen, NH
2
,
R
22a, b and c
each independently represent C
1-6
alkyl, aryl or C
1-4
alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more C
1-4
alkyl, C
1-4
alkoxy, OH, NO
2
, halogen, NH
2
,
A is C
1-4
alkylene, C
2-4
alkenylene or C
2-4
alkynylene, each of which is optionally substituted by one or more C
1-4
alkyl, C
1-4
alkoxy, halogen and/or OH,
D is H, OH, CN, NR
25
R
26
, CONR
25
R
26
, NHR
27
, CO
2
R
28
, COR
29
, C(═NOH)R
29
,
or AD is CN, NR
25
R
26
, CONR
25
R
26
,
where R
25
and R
26
are either each independently H, C
1-3
alkyl, C
3-8
cycloalkyl, aryl, C
1-4
alkylphenyl (each of which C
1-3
alkyl, C
3-8
cycloalkyl, aryl and C
1-4
alkylphenyl are optionally substituted by one or more NO
2
, halogen, C
1-4
alkyl and/or C
1-4
alkoxy, (each of which latter C
1-4
alkyl and C
1-4
alkoxy is optionally substituted by one or more halogen)), or R
25
and R
26
are taken together with the N atom to which they are attached and can form a 4- to 7-membered heterocyclic ring optionally incorporating one or more further hetero atoms selected from N, O and S, and which ring is optionally substituted by one or more C
1-4
alkyl, OH, ═O, NO
2
, NH
2
and/or halogen,
R
27
is COR
30
, CO
2
R
31a
, SO
2
R
31b
,
R
28
and R
29
are each independently H, C
1-6
alkyl, C
3-8
cycloalkyl, aryl or C
1-4
alkylphenyl, each of which C
1-6
alkyl, C
3-8
cycloalkyl, aryl and C
1-4
alkylphenyl are optionally substituted by one or more NO
2
, halogen, C
1-4
alkyl, C
1-4
alkoxy (each of which latter C
1-4
alkyl and C
1-4
alkoxy are optionally substituted by one or more halogen),
R
30
is H, C
1-4
alkyl, C
3-8
cycloalkyl, C
1-4
alkoxy, C
3-8
cycloalkyloxy, aryl, aryloxy, C
1-4
alkylphenyl, phenyl(C
1-4
)alkoxy, (each of which C
1-4
alkyl, C
3-8
cycloalkyl, C
1-4
alkoxy, C
3-8
cycloalkyloxy, aryl, aryloxy, C
1-4
alkylphenyl and phenyl(C
1-4
)alkoxy are optionally substituted by one or more NO
2
, halogen, C
1-4
alkyl, C
1-4
alkoxy (which latter alkyl and alkoxy are optionally substituted by one or more halogen)),
R
31a
and R
31b
are each independently C
1-4
alkyl, C
3-8
cycloalkyl, aryl or C
1-4
alkylphenyl, each of which is optionally substituted by one or more NO
2
, halogen, C
1-4
alkyl or C
1-4
alkoxy, each of which latter alkyl and alkoxy is optionally substituted by one more halogen E is H, CONR
32
R
33
, CSNR
32
R
33
, COR
34
, CO
2
R
34
, COCH(R
34a
)NH
2
, R
35
, CH
2
CO
2
R
35a
, CHR
35b
CO
2
R
35a
, CH
2
OCO
2
R
35c
, CHR
35d
OCO
2
R
35c
, COCR
36
═CR
37
NH
2
, COCHR
36
CHR
37
NH
2
, or PO(OR
38
)
2
,
R
32
and R
33
are each independently H, C
3-10
alkylalkenyl, C
3-7
cycloalkyl (optionally substituted by C
1-4
alkyl), phenyl (optionally substituted by (X)
n
), C
1-10
alkyl (optionally substituted by C
4-7
cycloalkyl (optionally substituted by C
1-4
alkyl) or phenyl optionally substituted by (X)
n
),
or R
32
and R
33
can be taken together with the N atom to which they are attached and can form a 5- to 8-membered heterocycle optionally comprising fuirther hetero atoms selected from N, O and S, which heterocycle is optionally substituted by C
1-4
alkyl, optionally substituted by one or more halogen,
R
34
is H, C
4-7
cycloalkyl (optionally substituted by one or more C
1-4
alkyl), phenyl (optionally substituted by (X)
n
, C
1-4
alkanoyloxy, NR
32
R
33
, CONR
32
R
33
and/or OH), or C
1-6
alkyl (optionally substituted by one or more halogen, C
4-7
cycloalkyl (optionally substitute

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