Heterocyclic compounds as inhibitors of rotamase enzymes

Details Heterocyclic compounds as inhibitors of rotamase enzymes Heterocyclic compounds as inhibitors of rotamase enzymes

2002-01-23

2003-05-13

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C546S064000, C546S273400, C548S306100, C548S309100, C548S301700

Reexamination Certificate

active

06562964

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). WO-A-96/40140, WO-A-96/40633 and WO-A-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. U.S. Pat. No. 5,721,256 discloses sulphonamides, and WO-A-98/13343 and WO-A-98/13355 disclose heterocycles, that have neurotrophic activity but which do not exert any significant immunosuppressive activity. WO-A-92/21313 discloses sulphonamides with immunosuppressive activity.
It has been suggested in WO-A-96/40140 and WO-A-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).
It has now been found that the present compounds 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 immunophilin FKBP-12. The present compounds do not significantly inhibit the protein phosphatase calcineurin and therefore lack any significant immunosuppressive activity.
The present compounds therefore moderate neuronal degeneration and promote neuronal regeneration and outgrowth and 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 neuron 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-Barré 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 compounds can be used for treating senile dementia (Alzheimer's disease) or another dementia, amyotrophic lateral sclerosis or another form of motor neuron 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 present invention provides a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
A is unbranched C
3
-C
5
alkylene optionally substituted by C
1
-C
6
alkyl;
X is O, S, NH or N(C
1
-C
6
alkyl);
Y is O, S, NH or N(C
1
-C
6
alkyl);
R is a C-linked, 4- to 6-membered ring, non-aromatic, heterocyclic group containing one nitrogen heteroatom, said group being optionally substituted by 1, 2 or 3 substituent(s) each independently selected from C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
3
-C
7
cycloalkyl, aryl, het, —CO
2
(C
1
-C
6
alkyl), —CO(het), —CONR
5
R
6
and —CO(aryl), said alkyl and alkenyl being optionally substituted by 1 or 2 substituent(s) each independently selected from C
3
-C
7
cycloalkyl, aryl, het, —O(aryl), —O(C
1
-C
2
alkylene)aryl, —CO(het), —CONR
5
R
6
and —CO(aryl);
R
1
, R
2
, R
3
and R
4
are each independently selected from H, halo, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, halo(C
1
-C
6
)alkyl, C
1
-C
6
alkoxy, —CONR
5
R
6
, C
3
-C
7
cycloalkoxy, C
3
-C
7
cycloalkyl-(C
2
-C
4
)alkylene, C
3
-C
7
cycloalkyl(C
2
-C
4
)alkoxy and —CO
2
(C
1
-C
6
alkyl);
R
5
and R
6
are either each independently selected from H and C
1
-C
6
alkyl or, when taken together, represent unbranched C
3
-C
5
alkylene;
“aryl” means phenyl, optionally substituted by 1, 2 or 3 substituent(s) each independently selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo, —CONR
5
R
6
, halo(C
1
-C
6
alkyl) and —NR
5
R
6
; and
“het” means a 5- or 6-membered monocyclic, or 8-, 9- or 10-membered bicyclic, ring heterocyclic group containing from 1 to 3 heteroatoms each independently selected from N, O and S, said group being optionally substituted by 1, 2 or 3 substituent(s) each independently selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo, halo(C
1
-C
6
alkyl), phenyl and —NR
5
R
6
.
Throughout the above definitions, “halo” means fluoro, chloro, bromo or iodo and alkyl, alkoxy, alkenyl and alkylene groups containing the requisite number of carbon atoms, except where indicated, can be unbranched- or branched-chain.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.
The pharmaceutically acceptable solvates of the compounds of the formula (I) include the hydrates thereof.
Also included within the present scope of the compounds of the formula (I) are polymorphs and radiolabelled derivatives thereof.
A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. Where a compound of the formula (I) contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur. The present invention includes the individual stereoisomers of the compounds of the formula (I) and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof.
Separation of d

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