FKBP inhibitors

Details FKBP inhibitors FKBP inhibitors

2000-10-30

2004-02-03

Rotman, Alan L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S316000, C514S322000, C544S130000, C546S187000, C546S199000

Reexamination Certificate

active

06686357

ABSTRACT:

This invention relates to 1-heteroaryl-pyrrolidine, -piperidine and -homopiperidine derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
It has been reported that the immunosuppressant FK-506 promotes neurite outgrowth in vitro in neuronal cell line and culture models (see Lyons et al, Pro. Natl. Acad. Sci., 1994, 91, 3191-95 and Snyder et al, Nature Medicine, 1995, 1, 32-37). International Patent Applications publication Nos. WO 96/40140, WO 96/40633 and WO 97/16190 disclose compounds that have neurotrophic activity but which lack inhibitory action at the protein phosphatase calcineurin and therefore which have no immunosuppressive activity.
It has been suggested in International Patent Applications publication numbers WO 96/40140 and WO 96/40633 that the neurotrophic effect of these compounds is mediated, at least in part, by a high affinity interaction with the FK-506 binding proteins, such as FKBP-12 or FKBP-52. However, the mechanism by which this interaction with FKBP-type immunophilins results in a neurotrophic effect is at present unknown. The range of neurotrophic activity that can be realised through this neurotrophic
on-immunosuppressant class of compounds has been explored and it has been found that axon regeneration can be promoted after facial nerve crush and sciatic nerve crush in the rat. It has also been observed that the functional regeneration of dopamine neurons damaged with the toxin MPTP was promoted by the compounds disclosed therein in mice. Additionally, it was reported that restoration of striatal innervation in the rat was promoted by the compounds disclosed therein following 6-hydroxydopamine lesioning of dopaminergic neurons (see Hamilton & Steiner, Current Pharmaceutical Design, 1997, 3, 405-428).
International Patent Applications publication numbers WO 98/00278, WO 98/13343, WO 98/13355, W098/20891, W098/20892 and W098/20893 describe various neurotrophic pyrrolidine, piperidine and homopiperidine derivatives having an acyl, amide, oxalyl, or similar linking group, at the 1-position of the heterocycle.
U.S. Pat. No. 5,721,256 describes various pyrrolidine, piperidine and homopiperidine derivatives having an SO
2
linking group at the 1-position of the heterocycle, as having affinity for rotamase enzymes.
European Patent Application publication number 0 657 451 A2 generically discloses a number of 2-(1-pyrrolidino)-benzoxazoles as leukotriene biosynthesis inhibitors, and specifically discloses methyl 1-(5-chloro-2-benzoxazolyl)proline.
It has now been found that the presently-disclosed substances are neurotrophic agents which have an affinity for FKBP-type immunophilins. In particular, they are potent inhibitors of the enzyme activity and especially of the cis-trans prolyl isomerase (rotamase) activity of FKBP-type immunophilins, particularly the immunophilins FKBP-12 and FKBP-52. The present substances do not significantly inhibit the protein phosphatase calcineurin and therefore lack any significant immunosuppressive activity.
The present substances moderate neuronal degeneration and promote neuronal regeneration and outgrowth and as such can be used for treating neurological disorders arising from neurodegenerative diseases or other disorders involving nerve damage. The neurological disorders that may be treated include senile dementia (Alzheimer's disease) and other dementias, amyotrophic lateral sclerosis and other forms of motor neurone disease, Parkinson's disease, Huntington's disease, neurological deficits associated with stroke, all forms of degenerative disease affecting the central or peripheral nervous system (e.g. cerebellar-brainstem atrophies, syndromes of progressive ataxias), all forms of muscular dystrophy, progressive muscular atrophies, progressive bulbar muscular atrophy, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), herniated, ruptured or prolapsed intervertebrae disc syndromes, cervical spondylosis, plexus disorders, thoracic outlet syndromes, all forms of peripheral neuropathy (both diabetic and non-diabetic), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, all forms of auto-immune related disease resulting in damage of the central or peripheral nervous system (e.g. multiple sclerosis, myasthenia gravis, Guillain-Barre syndrome), AIDS related disorders of the nervous system, dapsone ticks, bulbar and retrobulbar affections of the optic nerve (e.g. retinopathies and retrobulbar neuritis), hearing disorders such as tinnitus, and prion diseases.
Preferably, the present substances can be used for treating senile dementia (Alzheimer's disease) or another dementia, amyotrophic lateral sclerosis or another form of motor neurone disease, Parkinson's disease, Huntingdon's disease, a neurological deficit associated with stroke, physical or traumatic damage to the central or peripheral nervous system (e.g. spinal cord), a peripheral neuropathy (either diabetic or non-diabetic), multiple sclerosis or a hearing disorder such as tinnitus.
The substances of the present invention are compounds of the formula (I):
or a pharmaceutically acceptable salt, or solvate of either entity, wherein:
X is O, S, NH or N(C
1-6
alkyl);
R
1
, R
2
, R
3
and R
4
are each independently H, OH, OCO(C
1-6
alkyl), CO
2
(C
1-6
alkyl), CONH
2
, CONH(C
1-6
alkyl), CON(C
1-6
alkyl)
2
, halo, C
3-7
cycloalkyl, C
3-7
cycloalkyloxy, C
2-6
alkenyl, aryl
1
, C
1-6
alkyl optionally substituted by one or more substituents selected from halo and C
3-7
cycloalkyl, and C
1-6
alkoxy optionally substituted by one or more substituents selected from fluoro and C
3-7
cycloalkyl;
A is unbranched C
3-5
alkylene optionally substituted by up to three C
1-6
alkyl groups;
D is O or S;
E is O, S, NH, N(C
1-6
alkyl) or CR
11
R
12
;
G is C
1-14
alkyl or C
2-14
alkenyl, each of which is optionally substituted by one or more substituents independently selected from halo, aryl, C
1-4
alkoxy, cycloalk, het and NR
5
R
6
,
R
2
and R
6
are either each independently H or C
1-6
alkyl, or are taken together to form, with the nitrogen atom to which they are attached, a 4 to 7-membered heterocyclic ring optionally containing another hetero-moiety selected from NR
7
, O and S(O)
p
, and which 4 to 7-membered heterocyclic ring is optionally substituted by up to 3 substituents independently selected from C
1-6
alkyl and C
1-6
alkoxy;
R
7
is H, C
1-6
alkyl, C
2-6
alkenyl, COR
8
, SO
2
R
8
, CONR
9
R
10
, CO
2
R
8
or SO
2
NR
9
R
10
;
R
8
is C
3-7
cycloalkyl, C
2-6
alkenyl, aryl
1
, or C
1-6
alkyl optionally substituted by C
3-7
cycloalkyl or aryl
1
;
R
9
and R
10
are each independently H, C
2-6
alkenyl, C
3-7
cycloalkyl, or C
1-6
alkyl optionally substituted by C
3-7
cycloalkyl or aryl;
R
11
and R
12
are each independently H, aryl, C
2-8
alkenyl or C
1-8
alkyl,
wherein said C
2-8
alkenyl and C
1-8
alkyl groups are optionally substituted by one or more substituents independently selected from halo, NO
2
, C
1-6
alkyl, C
2-6
alkenyl, cycloalk, OH, C
1-6
alkoxy, C
2-6
alkenyloxy, phenyloxy, benzyloxy, NH
2
, aryl and het;
p is 0, 1 or 2;
wherein “aryl” means phenyl or naphthyl, each of which is optionally substituted by up to 3 substituents independently selected from C
1-6
alkyl optionally substituted by one or more halo or C
3-7
cycloalkyl groups, C
2-6
alkenyl, C
1-6
alkoxy, C
2-6
alkenyloxy, OH, halo, NO
2
, phenyloxy, benzyloxy, phenyl and NH
2
;
“aryl” means phenyl, naphthyl or benzyl, each of which is optionally substituted by 1 or 2 substituents independently selected from C
1-6
alkyl optionally substituted by one or more halo or C
3-7
cycloalkyl groups, C
1-6
alkoxy and halo;
“cycloalk” is C
3-8
cycloalkyl optionally substituted by up to 3 substituents independently selected from C
2-6
alkenyl, C
1-6
alkoxy, C
2-6
alkenyloxy, OH, halo, and C
1-6
alkyl optionally substituted by one or more halo;
and “het” means a 5- or 6-membered monocyclic,

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