SK17512001A3 - Tricyclic analgesics - Google Patents

Abstract

A tricyclic compound of Formula (I): wherein: R<1> is hydrogen or hydroxy; R<2> is hydrogen or hydroxy; or R<1> and R<2> together are oxygen; A is a bond, CH2, CH CH3, CH2 CH2 or C(CH3)2; R<3> and R<4> are the same or different and are hydrogen, halo, C1-C6 alkyl, C1-C4 alkoxy, trifluoromethyl, NO2, COR<6>, COOR<6> or NR<6>R<7>, wherein R<6> and R<7> are the same or different and are hydrogen, C1-C6 alkyl or benzyl; R<5> is hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, (O=C)-C1-6 alkyl, (O=C)-C2-6 alkenyl, (O=C)-C3-6 cycloalkyl, wherein said alkyl, alkenyl and cycloalkyl groups can be substituted by 1, 2 or 3 groups selected from halo, C3-C6 cycloalkyl, phenyl or substituted phenyl, and salts thereof, are particularly useful for treating, among other indications, neuropathic pain and other CNS disorders.

Description

Tricyclic analgesics

Technical field

The invention relates to organic compounds characterized by having a fused bicyclic ring system substituted with a third ring containing a spiro nitrogen atom. The compounds are effective for treating seizures and chronic pain in mammals.

BACKGROUND OF THE INVENTION

Although chronic pain is a common condition in the population, its pathophysiology is not well understood. · One possibility is that nociceptive spinal sensory neurons exert inappropriate activity after injury. Spinal sensory neurons become hyperexcitable and generate spontaneous impulses after injury in experimental animals and humans. Matzner and Devor (1992) suggested that hyperexcitability associated with chronic

has pain for result increase densities Na channels in place injury. She was also developed the hypothesis that changes in kinetics and features On the streams dependent at the voltage contribute AFTER injury nerve to formation ectopic impulse and

hyperexcitability of spinal sensory neurons. Dorsal root ganglion neurons (DRGs) have a complex complex of Na currents, including a fast tetrodotoxin sensitive current (TTXS) and a slow resistant TTX current (TTX-R). In rat DRG neurons, PGE ₂ , adenosine and serotonin, three agents that induce hyperalgesia in vivo, increase the magnitude of TTX-R current and shift its conductivity / voltage relationship to a hyperpolarized direction (Gold et al., 1996). After nerve injury, TTX-R currents in DRG neurons are attenuated and TTX-S currents are activated in the same animals (Cummings and Waxman, 1997). Using a Na channel-specific antibody, Devor et al. (1993) have shown evidence of Na channel accumulation in a neuron resulting from nerve cuts, Na channel accumulation at the injured axonal ends can explain the ectopic excitability of the channel and the resulting pain and paraesthesia, which often complicate peripheral nerve injury in humans.

The axon injury of spinal sensory neurons appears to modify the Na currents, substantially altering their excitability. Thus, selective Na channel blockers can be used to prevent or treat chronic pain in mammals. Sodium channel blockers have been shown to be effective in chronic pain syndromes including trigeminal neuralgia, diabetic neuropathy, migraine prophylaxis and cancer pain (reviewed by McQuay et al., 1995, British Medical Journal, 1995, 311: 1047-1052 and references here).

But the pain caused by acute or chronic injury: the nerve is difficult to treat and is often resistant to the usual analgesics. Such compounds contain some local anesthetics and anticonvulsants, for example lidocaine, etidocaine, benzocaine, tetracaine, riluzole, phenytoin and gabapentin. Most of them, even when these preparations modulate Na channels, have limited clinical use against the high risk of side effects. For example, lidocaine may induce cardiovascular collapse and resultant cardiac arrest. Benzocaine can cause respiratory distress, and such skin rashes, erythema and edema. The use of phenytoin for seizure disorders may result in hyperglycaemia.

Since there is no effective chemical treatment for neuropathic pain, e.g. chronic pain, and since this pain is typically associated with diseases such as cancer, as well as severe physical injuries and diabetic neuropathy, there remains a need to find compounds that can be used clinically without the consequences of serious side effects.

• e r e

r. C r * 9 <· rr rtt r r <· r r r f »f i · r

- r - r: - r

SUMMARY OF THE INVENTION

We have now discovered a number of tricyclic compounds that are potent neuronal Na channel antagonists. The compounds are characterized as fused bicyclic ring systems substituted with a third ring bond.

The invention thus provides tricyclic compounds of formula I:

where:

R ¹ is a hydrogen atom or a hydroxy group,

R ² is hydrogen or hydroxy or

R ¹ and R ² together are oxygen,

A is a bond, CH 2, CHCH ₃ , CH 2 CH 2 or C (CH ₃ ) 2,

R ³ and R ⁴ are the same or different and are hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, trifluoromethyl, NO 2, COR ⁶ , COOR ⁶ or NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a C 1-6 alkyl group or a benzyl group,

R ⁵ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (0 = C) -alkyl of 1 to 6 carbon atoms, (0 = (C) -alkenyl having 2 to 6 carbon atoms; (O = C) -cycloalkyl having 3 to 6 carbon atoms; wherein the alkyl, alkenyl, and cycloalkyl groups may be substituted with 1, 2 or 3 groups selected from the group consisting of halogen, cycloalkyl of 3 to 6 carbon atoms, phenyl, or substituted phenyl, and their pharmaceutically acceptable salts.

The compounds of the invention are useful in the clinical management and treatment of various medical conditions, such as seizure disorders, epilepsy, neuroprotection, preferably for the treatment of medical conditions such as cerebral ischemia, hypoxia and trauma, headache, local anesthesia, pain, preferably acute, chronic, neuropathic, visceral and somatic pain, irritable bowel syndrome (IBS), drug treatment, migraine and obsessive compulsive disorders.

Preferred compounds are those of formula I wherein R ⁵ is hydrogen, C 1 -C 6 alkyl optionally substituted by phenyl or C 3 -C 6 cycloalkyl.

Other preferred compounds are compounds of formula I wherein R ⁵ is C 1 -C 6 alkyl optionally substituted by phenyl or C 3 -C 6 cycloalkyl.

Other preferred compounds are compounds of formula I wherein R ⁵ is hydrogen, C 1 -C 6 alkyl optionally substituted by phenyl or C 3 -C 6 cycloalkyl, and R ³ is hydrogen or C 1 -C 4 alkoxy atoms.

Most preferred compounds of the invention are compounds of formula I wherein R ¹ and R ² together are oxygen and A is CH ₂ .

Other most preferred compounds are compounds of formula I wherein R ⁵ is H, C 1 -C 6 alkyl optionally substituted by phenyl or C 3 -C 6 cycloalkyl, and R ³ is hydrogen or C 1 -C 4 alkoxy .

A further embodiment of the invention is a pharmaceutical formulation comprising a compound of formula I mixed with a pharmaceutically acceptable carrier or diluent.

Another embodiment of the present invention is the treatment of a mammal. suffering from pain and in need of treatment, comprising administering an effective amount of a compound of Formula I.

Yet another embodiment of the invention is the treatment of a seizure disorder of a mammal in need of treatment, comprising administering a compound of Formula I.

The treatment of all other indications mentioned above is within the scope of the present invention.

As used herein, the term alkyl having 1 to 6 carbon atoms refers to a straight or branched carbon chain formed from one to six carbon atoms. Examples of the alkyl group having 1 to 6 carbon atoms are methyl, ethyl, isopropyl, sec-butyl, tert-butyl, isopentyl and n-hexyl.

The term (C 1 -C 6) alkoxy refers to the preceding alkyl groups bonded via oxygen, such as methoxy, isopropoxy and n-hexyloxy.

The term C 2 -C 6 alkenyl refers to a straight or branched carbon chain having two to six carbon atoms, with one double bond r r between two carbon atoms present in the chain. Examples are ethenyl, 2-propenyl, 1-methyl-3-pentenyl, 1-ethyl-2-butenyl and 5-hexenyl.

The term C 3 -C 6 cycloalkyl refers to a non-aromatic cyclic ring having three to six carbon atoms, exemplified by cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The foregoing alkyl, alkenyl and cycloalkyl groups may be substituted with 1, 2 or 3 groups selected from the group consisting of halogen, unsubstituted cycloalkyl of 3 to 6 carbon atoms, phenyl or substituted phenyl. The term halogen atom denotes a chlorine atom, a bromine atom, a fluorine atom and an iodine atom. The term substituted phenyl refers to a phenyl group having 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, nitro, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 6 alkoxy and NH ₂ .

Thus, examples of C 1 -C 6 alkyl substituted by cycloalkyl are cyclopropylmethyl, 1-cyclobutylethyl, 3-cyclohexylbutyl and 3,3-dicyclohexylpropyl. The alkyl groups substituted with a halogen atom form a chloromethyl group, a 1,2-dibromomethyl group, a trifluoromethyl group and a 1-bromo-3-chloro-6-iodo-hexyl group. Alkyl groups substituted by phenyl or substituted phenyl are benzyl, 1-phenylpropyl, 1-methyl-3-phenylbutyl, 3-chlorophenylmethyl, 2,3-dimethoxybenzyl.

Ί, 3- (2-methyl-5-fluoro-6-nitrophenyl) butyl and 3,3-diphenylpropyl.

Examples of substituted C 2 -C 6 alkenyl groups include 2-cyclobutylethenyl, 3-phenyl-2-butenyl, 1,1-dimethyl-3-chloro-3-butenyl, 4,4-diphenyl-3-butenyl 2- (3-chlorophenyl) -3-cyclobutyl-4-hexenyl and 1,2-difluoro-3- (2-phenylcyclobutyl) -4-pentenyl.

Examples of substituted C 3 -C 6 cycloalkyl groups include 3-cyclopentylcyclohexyl, 2-phenylcyclobutyl, 3-chlorocyclopentyl, 2,2-dibromo-3-nitrocyclohexyl and 2,2-di (3-methoxyphenyl) cyclopropyl.

Examples of substituted C 1 -C 6 alkoxy include trichloromethoxy, cyclopropylmethoxy, 1-methyl-2-phenylpropoxy and 2,3-di (2,4-dinitrophenyl) hexyloxy.

The alkyl, alkenyl and cycloalkyl substituent groups may be attached via a carbonyl group (O = O. Examples include acetyl, pivaloyl, 1-oxo-3pentenyl, 1-oxocyclobutylmethyl, 1-oxo-3-phenyl-4-cyclohexylpentyl and 1-oxo (3-phenylcyclopentyl) methyl.

-A- in formula I is defined as a bond, -CH ₂ -, -CH-CH 3, -CH- (CH ₃ ) _2, and -CH ₂ CH ₂ -, the compounds of the invention may thus have the following general structures:

(C)

-R5 (Id)

Preferred compounds of the present invention include the following compounds:

3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'piperidine], -cyclobutylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'piperidine], 1'-cyclohexylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'piperidine] 1'-phenylethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4 'piperidine], 1'-cyclopropylethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4' piperidine], 1'-cinnamyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1 '- (3,3-diphenylpropyl) -3,4-dihydro-1-oxospiro [naphthalene2] (1 H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-5,7-dimethyl-1-oxospiro [naphthalene-2 (1 H), 4'-piperidine],

1 '- (cyclopropylmethyl) -3, ^4-dihydro-i 6-methoxy-l-oxo-spiro [naphthalene-2 (H), 4'-piperidine], I' - (cyclopropylmethyl) -3,4-dihydro-5-methoxy -1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-7-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine] 1 '- (cyclopropylmethyl) -3,4-dihydro-7-nitro-1-oxospiro [naphthalene2 (1H), 4'-piperidine], 1' - (cyclopropylmethyl) -7-amino-3,4-dihydro-1 - oxospiro [naphthalene2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -7-chloro-3,4-dihydro-1-oxospiro [naphthalene2 (1H), 4'-piperidine],

3,4-dihydro-1'-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-allyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4 ' piperidine);

3,4-dihydro-1 '- (2-methylpropyl) -1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclopropionyl-3,4-dihydro-1-oxospiro (naphthalene-2 (IH)) (4'-piperidine);

3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine) -1'- (trans-2-phenylmethylcyclopropyl),

3,4-dihydro-1'-benzyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine),

3,4-dihydro-1 '- (di-p-fluorobenzhydryl) -oxospiro (naphthalene2 (IH), 4'-piperidine), 1'-cyclopropylmethyl-1,3,4-trihydro-1'-hydroxyspiro (naphthalene2 (IH), 4'-piperidine 1'-cyclopropylmethyl-1,2,3,4-tetrahydrospiro (naphthalene-2 (1H), 4 'piperidine), 1'-cyclopropylmethyl-1,3-dihydro-1-oxospiro [2H-indene-2 (1H), 4'-piperidine ], I '- (cyclopropylmethyl) -8,9-dihydrospiro [6H-benzocykloheptén6,4'-piperidin] 5 (7H) -one l ^of cyclopropylmethyl-3,4-dihydro-4-methyl-l-oxo-spiro ( naphthalene2 (1H), 4'-piperidine),

6-chloro-1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclopropylmethyl-3,4-dihydro-6-fluoro-oxospiro (naphthalene2 (IH), 4'-piperidine), 1'-cyclopropylmethyl-3,4-dihydro-6,7-dimethoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1 '- (1'-cyclopropyl-ethyl) -3,4 -dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1 '- (3-pentene) -3,4-dihydro-1-oxospiro (naphthalene-2 (1 H), 4'-piperidine), 1'- (3-Phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4 'piperidine), 1'-cinnamyl-3,4-dihydro-6-methoxy-oxospiro (naphthalene-2 (IH)) 4'-cyclopropylethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine),

1'-cyclobutylmethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine),

1'-cyclohexylmethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine),

1'-cinnamyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4 'piperidine), 1' - (2-phenylethyl) -3,4-dihydro-5-methoxy-1 -oxospiro (naphthalene2 (1H), 4'-piperidine), 1 '- (3-phenylpropyl) -3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1' - ( 3,3'-diphenylpropyl) -3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-6-methoxy-1 -oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclohexylmethyl-3,4 -dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cinnamyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4 'piperidine )

1 '- (2-phenylethyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1' - (3-phenylpropyl) -3,4-dihydro-6- l-methoxy-oxospiro (naphthalene-2 (H), 4'-piperidine),

1 '- (3,3'-diphenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-7 -methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine),

1'-cyclohexylmethyl-3,4-dihydro-7-methoxy-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine);

1'-cinnamyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine),

1 '- (2-phenylethyl) -3,4-dihydro-7-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1' - (3-phenylpropyl) -3,4-dihydro-7- methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1 '- (3,3'-diphenylpropyl) -3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (IH), 4 1'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-4-methyl-1- oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclohexylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine),

1'-cinnamyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'piperidine), 1 '- (2-phenylethyl) -3,4-dihydro-4-methyl-1 -oxospiro (naphthalene2 (1H), 4'-piperidine), 1 '- (3-phenylpropyl) -3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1' - ( 3,3-diphenyl-propyl) -3,4-dihydro-4-methyl-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine);

6-chloro-1'-cyclopropylethyl-3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine),

6-chloro-1'-cyclobutylmethyl-3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine)

6-Chloro-cyclohexylmethyl-3,4-dihydro-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine);

6-chloro-1'-cinnamyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4 'piperidine),

6-chloro-1 '- (2-phenylethyl) -3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine),

6-chloro-1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine); and

6-chloro-1 '- (3,3'-diphenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine),

3,4-dihydro-6-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine].

More preferred compounds of the invention include the following compounds:

1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1'-cyclopropylethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4 'piperidine ], l-cinnamyl-3,4-dihydro-l-oxo-spiro [naphthalene-2 (H), ^r 4 -piperidine], I '- (3,3-diphenyl-propyl) -3, 4-dihydro-l-oxo-spiro [naphthalene-2 ( 1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-5,7-dimethyl-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1' - (cyclopropylmethyl) - 3,4-dihydro-6-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-5-methoxy-1-oxospiro [naphthalene-2 (1 H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-7-methoxy-1-oxospiro [naphthalene-2 (1 H), 4'-piperidine],

1 '- (cyclopropylmethyl) -3,4-dihydro-7-nitro-1-oxospiro [naphthalene 2 (1H), 4'-piperidine],

1 '- (cyclopropylmethyl) -7-amino-3,4-dihydro-1-oxospiro [naphthalene 2 (1H), 4'-piperidine],

1 '- (cyclopropylmethyl) -7-chloro-3,4-dihydro-1-oxospiro [naphthalene 2 (1H), 4'-piperidine], 1'-cyclopropylmethyl-1,3,4-trihydro-1-hydroxyspiro (naphthalene2) (H), 4'-piperidine);

1'-cyclopropylmethyl-1,2,3,4-tetrahydrospiro (naphthalene-2 (1H), 4 'piperidine), 1'-cyclopropylmethyl-1,3-dihydro-1-oxospiro [2H-indene-2 (IH), 4'-piperidine], 1 '- (cyclopropylmethyl) -8,9-dihydrospiro [6H-benzocycloheptene-6,4'-piperidine] -5 (7H) -one,

1'-cyclopropylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine), β-chloro-1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro (naphthalene2 ( 1H), 4'-piperidine),

1'-cyclopropylmethyl-3,4-dihydro-6-fluoro-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine);

1'-cyclopropylmethyl-3,4-dihydro-6,7-dimethoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1 '- (1-cyclopropyl-1-ethyl) -3,4- dihydro--oxo-spiro (naphthalene-2 (H), 4'-piperidine);

1 '- (3-pentene) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4' piperidine), 1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene) -2 (1H), 4 'piperidine), 1'-cinnamyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (IH), 4' piperidine), e 9

1'-cyclopropylethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine),

1'-cyclobutylmethyl-3,4-dihydro-5-methoxy-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine);

1'-cinnamyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4 'piperidine),

1 '- (3-phenylpropyl) -3,4-dihydro-5-methoxy-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine);

1 '- (3,3'-diphenylpropyl) -3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-6 methoxy-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine);

1'-cyclobutylmethyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cinnamyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene- 2 (1H), 4 'piperidine),

1'- (3-phenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1 '- (3,3'-diphenylpropyl) -3,4-dihydro 6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine) 1'-cinnamyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (1 H), 4 'piperidine), 1' - (3-phenylpropyl) -3,4-dihydro-7-methoxy-1 -oxospiro (naphthalene-2 (1H), 4'-piperidine), 1- (3,3'-diphenylpropyl) -3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine 1'-cyclopropylethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2) (1H), 4'-piperidine), 1'-cinnamyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (IH), 4 'piperidine),

1 '- (3-phenylpropyl) -3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1' - (3,3'-diphenylpropyl) -3,4-dihydro -4-methyl-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine);

6-chloro-1'-cyclopropylethyl-3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine);

6-chloro-1'-cinnamyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4 'piperidine),

6-chloro-1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine); and

6-chloro-1 '- (3,3'-diphenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine),

3,4-dihydro-6-methoxy-l-oxo-spiro [naphthalene-2 (H), 4'-piperidine].

Most preferred compounds of the invention include the following compounds:

1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4 'piperidine], 1'-cyclopropylethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4' piperidine ]

1'-cinnamyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'piperidine], 1 '- (3,3-diphenylpropyl) -3,4-dihydro-1-oxospiro [naphthalene2 (IH) 1 ', 4'-piperidine], 1' - (cyclopropylmethyl) -3,4-dihydro-6-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1 '- (3-phenylpropyl) -3 4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), l-cyclopropylethyl-3,4-dihydro-6-methoxy-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine);

1'-cyclobutylmethyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine),

1 '- (3-phenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-7-methoxy-1- oxospiro (naphthalene-2 (H), ^r 4 piperidine);

3,4-dihydro-6-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine].

reactions

Typical acceptable salts

The compounds of formula I are characterized by being bicyclic rings having a spirocycle as a substituent group. The spiro cycle contains a nitrogen atom (i.e., NR ⁵ ), which may be basic in nature when R ⁵ is a group such as an alkyl group, an alkenyl group or a cycloalkyl group. Such basic compounds readily form pharmaceutically acceptable salts with conventional inorganic and organic acids.

Useful for making pharmaceuticals of the invention include acids:

hydrochloric, sulfuric, sulfamic, phosphoric, citric, succinic, glutamic, maleic, lactic, tartaric, p-toluenesulfonic, benzoic, oxalic and salicylic acids. The salts are prepared simply by contacting the spirobase with a suitable acid, generally in a solvent such as methanol or diethyl ether. The salts are generally highly crystalline, readily precipitate and are obtained by filtration. If desired, they can be further purified by recrystallization from a conventional acid solvent such as methanol, ethyl acetate, acetone and tetrahydrofuran.

The compounds of the invention of formula I are readily prepared by methods known in the art of organic chemistry. It is preferred to first prepare a compound in which R ⁵ is a hydrogen atom simply and then react the compound with R ⁵ -alkylating or -acylating agent. Such a reaction is shown in Scheme 1 below, e

wherein R ¹ , R ² , R ³ , R ⁴ and A are as defined above and L is a normal leaving group (e.g. a halogen atom such as a chlorine or bromine atom, or a silyl derivative such as a trimethylsilyl group).

The foregoing reaction is carried out by combining an approximately equimolar amount of spiroamine with an alkylating or acylating agent (i.e., LR ⁵ ), generally in a non-reactive organic solvent such as tetrahydrofuran, dimethylsulfoxide or N, N-dimethylformamide. If desired, a base such as triethylamine or NaHCO 3 may be used to act as an acid scavenger. Essentially, the reaction is typically. completed after about 2 to 20 hours when operated at a temperature of about 25 ° C to about 60 ° C. The product is readily isolated by removal of the reaction solvent and, if desired, further purification by normal means such as salt formation, crystallization and chromatography can be achieved.

The desired starting material, i. spiroamine, can be synthesized from readily available reactants, using any of several methods:

In one method, the N-protected form of a derivatized diethylamine is reacted with a bicyclic ketone according to Scheme 2:

Γ Γ e Γ yy yy

Γ · · <.

Scheme 2

HO

HBl ->

in.

Protective group

-> Br

In Scheme 2 above, P is an amine protecting group that is readily removed, for example, an ethoxycarbonyl or benzyl group. The protected diethylamine derivative readily reacts with a bicyclic ketone in the presence of a strong base such as NaH. This reaction results in the formation of a spiroamino derivative which is readily deprotected by conventional means, for example by reaction with hydrochloric acid.

Scheme 2 illustrates the preparation of ketosubstituted starting materials; wherein R ¹ and R ² together are oxo groups. These compounds are readily converted to the corresponding alcohol (R is H, R ² is OH) by reaction with a reducing agent such as NaBH ₄ , generally in a solvent such as methanol or ethanol.

The alcohol can be further reduced by catalytic hydrogenation, for example by reaction with hydrogen gas in the presence of 10% palladium on carbon. These reactions are shown in Scheme 3.

r c

Alternatively, the compounds of the invention of formula I may be prepared starting with a suitably substituted piperidine derivative as shown in Scheme 4.

Scheme 4

R3

The cyclization reaction is carried out by reacting substituted piperidine with strong dehydrating agents, such as phosphorus pentoxide and titanium tetrachloride, generally in a non-reactive organic solvent, such as rrrrr · o.

Pc is benzene, toluene, xylene or chloroform. Normally, the reaction is complete in 2 hours when carried out at 30 ° C to 60 ° C.

The cyclized product is a compound of formula I wherein R ¹ and R ² together are oxo, which, as outlined in Scheme 3 above, can be reduced to the corresponding alcohol or alkane (R ¹ and R ² are both hydrogen).

The substituted piperidine necessary for the above reaction is readily prepared as shown in Scheme 5.

η c r r

Γ ŕ

In Scheme 5, methyl 4-piperidine formate was reacted with an amine protecting agent (i.e., to insert P). Typical amine protecting groups are tert-butoxycarbonyl, benzyl and trimethylsilyl. The protected piperidine derivative is further reacted with a phenylalkyl halide, for example phenylethyl bromide (where A is CH ₂ ) or 2-phenylpropyl iodide (where A is CH-CH ₃ ) or 3-phenylpropyl iodide (where A is CH ₂ CH ₂ ), in the presence a strong base such as NaH or lithium diisopropylamide (LDA), generally in a non-reactive solvent such as tetrahydrofuran or benzene. The reaction, carried out at about -20 ° C, is generally substantially complete after about 2 to 4 hours. The alkylated piperidine may then be deprotected (L-deprotected) and cyclized by reaction with PCl5 and TlCl4 or may be cyclized first and then the L-deprotected.

The following detailed examples illustrate the synthesis of the specific compounds provided by this invention. The examples are merely representative and in no way intended to be limiting.

Examples

Example 1

3,4-dihydro-l-oxo-spiro [naphthalene-2 (H), 4'-piperidine]

NH

Step 1: Bis (2-bromoethyl) amine hydrobromide

• »ŕ p P β p r p r y r

O C P r C O Γ r »'

157.5 g (1.5 mol) of diethanolamine, and then, with stirring, 1.35 L of 48% HBr (exothermic reaction) are placed in a 2-L three-necked flask which can be equipped with either refluxing or for distillation. The solution was heated in a 180-200 ° C bath to distill a volume of 350 mL at a steam temperature of 122 ° C. The apparatus was brought to reflux and held for 1 hour. Further distillation was carried out as above to beat the collected distillate 465 ml. The apparatus was again refluxed for 3.75 hours, and then 400 mL was distilled off. The mixture was cooled and 300 mL of ethyl acetate was added to the residue. The suspension was stirred for 1 hour in an ice bath. The precipitate was filtered off and then washed with ethyl acetate. 367 g of a white crystalline product were obtained. Yield = 78.5%, mp. (° C) = 130-135 ° C;

Step 2: Ethyl bis (2-bromoethyl) carbamate

367 g (1.17 mol) of the product obtained in the previous step, then 108 ml, i.e. the title compound is obtained. 122.6 g (1.13 mol) of ethyl chloroformate were added to the 4 L reactor containing 1.8 L of water / ice mixture with stirring. About 1.3 L of 2N sodium hydroxide solution was added to the solution over a period of 5 minutes to achieve a constant pH of 11, keeping the temperature below 5 ° C. The mixture was stirred for 5 minutes, and then acidified to pH 1 with concentrated HCl. Extraction was carried out three times with 1 L of ethyl ether. The organic phase was washed three times with 500 ml of demineralized water, and then dried over Na ₂ SO ₄ . The solvent was evaporated. The residue was chromatographed eluting with CH 2 Cl 2. 208.5 g of product were obtained. Yield = 58%, TLC (CH ₂ C1 _{2): Rf} = 0, 6,

NMR: CDCl ^{3 3?} ((Ppm): 1.2 (t, 3H), 3.4-3.55 (m, 4H), 3.6-3.7 (m,

4H), 4.1-4.2 (q, 2H)).

e e e »

Step 3: ethyl 3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine] -1'-carboxylate.

g (0.472 mol) of 1-tetralone and 234 ml of DMF, previously dried on a molecular sieve, were charged to a moisture-protected reactor under an inert atmosphere. The solution was cooled to -15 ° C in a dry ice / acetone bath and 34.6 g (1.15 mol) of 80% sodium hydride was added as a dispersion in mineral oil. The temperature was allowed to rise to approximately 20-25 ° C (exothermic reaction). The reaction mixture was stirred for 1.5 hours below 30 ° C.

At the same time, a solution of 208 g (0.69 mol) of ethyl bis (2-bromoethyl) carbamate in 234 ml of DMF (pre-dried on a molecular filter) in a moisture-protected reactor under inert atmosphere was cooled to -25 ° C. in a dry ice / acetone bath. The reaction solutions prepared simultaneously were added under nitrogen and the reaction was allowed to proceed for 10 minutes at -25 ° C. The temperature was allowed to rise (exothermic reaction with temperature increase to 45 ° C). The reaction mixture was then cooled to maintain approximately 30 ° C. It was then brought to 50 ° C for 2 hours, and then the solvent was evaporated at 50 ° C under a vacuum of less than 1 mm Hg. The residue was taken up in 1.2 L of ice-cold water and extracted three times with 600 ml of ether. The organic phase was washed three times with 500 ml of demineralized water, and then dried over Na ₂ SO ₄ . Evaporation of the solvent gave a dark brown oily residue which was purified by flash chromatography eluting with CH ₂ Cl ₂ gradually enriched with acetone. 57.7 g (0.2 mol) of the product were obtained (yield =

42.5%), TLC (97/3 _{CH2 Cl2} / acetone): _Rf = 0.45.

r * r * * rece r c f ~>

c r r - - - - - r>

- r c r • - r - - r. r r r

NMR CDC1 ₃ ^x H ((ppm): 1.15 (t, 3H), 1.4 (m, 2H), 1.8-2.0 (m,

4H), 2.85-2.95 (m, 2H), 3.45-3.55 (m, 4H), 4.0-4.1 (q, 2H),

7.1 (d, 1H), 7.2 (dd, 1H), 7.35 (dd, 1H), 7.9 (d, 1H)).

Step 4: 3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]

57.7 g (0.2 mol) of ethyl 3,4-dihydro-1-oxospiro [naphthalene2 (1H), 4'-piperidine] -1'-carboxylate, and then 1.6 L of 6N HCl were charged to the reactor. The mixture was stirred and refluxed for 14 hours. It was then cooled and extracted twice with 500 ml of ethyl ether. The aqueous phase was basified with NaOH until cold, and extracted three times with 500 mL of ethyl ether. The organic phase was washed and dried over Na ₂ SO ₄ . After evaporation of the solvent, the residue was purified by chromatography eluting with CH ₂ Cl _{2 with} sequentially enriched methanol containing 10% NH ₄ OH.

Weight: 31 g, Yield = 72%, TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.2-0.35.

NMR: CDCl ₃ ³ H ((ppm) base: 1.35-1.45 (m, 2H), 1.8-1.9 (m, 2H),

2.0 (t, 2H), 2.1 (s, 1H), 2.75-2.85 (m, 2H), 2.85-3.0 (m, 4H),

7.1 (d, 1H), 7.2 (dd, 1H), 7.35 (dd, 1H), 7.9 (d, 1H)).

The hydrochloride is prepared by addition of approximately 5N ethereal hydrochloric acid to a solution of the product in CH ₂ C1 _2nd The mixture was concentrated to dryness, and then the product was crystallized from a mixture of methanol and ether.

White powder, m.p. = 235 ° C, TLC (90/10 CH ₂ Cl ₂ / MeOH containing

10% _NH4 OH) _Rf = 0.35.

Analysis confirmed C ₁₄ H ₁₀ ClNO.

IR: 2995, 2700, 1675, 1600, 1440, 1395, 1210, 1090, 990, 750,

0 cm ' ¹ r <* rrc ··

Example 2 1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4 'piperidine]

g (46.4 mmol) of 3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], and then 80 mL of DMF and 36.2 mL of THF were charged to a three-necked flask. It was added 6.89 g (51 mmol) of (bromomethyl) cyclopropane and 7.8 g (92.8 mmol) of NaHCO _third The suspension was brought to reflux and then held for 1.5 hours. The solvents were evaporated at 50 ° C under a vacuum of less than 1 mm Hg. The residue was taken up in 200 ml of water and extracted three times with 100 ml of ether. The ether phase was extracted with 100 ml of 1N HCl and then twice with 50 ml of water. The aqueous phase was basified with concentrated NaOH until cold, and extracted three times with 100 mL of ether. The organic phase was washed with NaCl solution and dried over Na ₂ SO ₄ . When the solvent was evaporated, 12 g of an oily residue were obtained. The hydrochloride is prepared by addition of approximately 5N ethereal hydrochloric acid to a solution of the crude product in CH ₂ C1 _2nd The mixture was concentrated to dryness, and then the product was crystallized by adding 20 ml of ether to a methanol solution of the product, the crystallization was allowed to proceed overnight at 20-25 ° C, and then the product was filtered off and washed with water. After drying, 8.4 g of product were obtained. White powder, m.p.

243 ° C, TLC (95/5 CH ₂ Cl ₂ / MeOH containing

10% NH ₄ OH): R _f = 0.55.

Analysis confirmed C18H24CINO.

p o p c r <p e p e - f

P r-r r r r * r p 0 'Γ

- Γ t P r

NMR: ^{CDCl3; H} ((ppm) HCI: 0.4-0.55 (m, 2H), from 0.75 to 0.8 (m, 2H);

1.3-1.4 (m, 1H), 2.1-2.2 (m, 4H), 2.4-2.55 (m, 2H), 2.85-2.9 (m, 2H) ), 3.0-3.05 (m, 2H), 3.2-3.3 (m, 2H), 3.5-3.6 (m, 2H),

7.2-7.25 (m, IH), 7.3-7.35 (m, IH), 7.5-7.6 (m, IH), 7.95-8.0 (m, IH) 12.0-12.2 (m, 1H).

IR: 2990, 2700, 1675, 1600, 1420, 1395, 1320, 1080, 980, 900,

760, 740 cm ¹

The corresponding iodomethylate was also obtained. Mp: 162 ° C

Example 3 1'-cyclobutylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]

The method described in Example 2 using cyclobutylmethyl bromide results in the hydrochloride product. Beige powder, mp. Melting point = 235 DEG.

TLC (92/8 CH ₂ Cl ₂ / MeOH containing 10% _{NH4OH): Rf} = 0.7. Analysis confirmed C19H26CINO.

NMR: CDCl 3 ¹ H ((ppm) HCl: 1.8-2.25 (m, 10H), 2.4-2.5 (m, 2H),

2.95-3.1 (m, 2H), 3.1-3.25 (m, 2H), 3.25-3.35 (m, 2H), 7.27.35 (m, 2H), 7.45-7.55 (m, 1H), 7.9-8.0 (m, IH), 11, 95-12.15 (m, 1H))

IR: 3400, 2900, 2650, 2500, 1680, 1590, 1430, 1360, 1300,

1220, 1140, 1100, 1040, 960, 930, 900, 800, 770, 740, 640 cm ¹ or R eeerc r.

Example 4 1'-cyclohexylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4 'piperidine]

The method described in Example 2 using cyclohexylmethyl bromide results in the hydrochloride product. Beige powder, mp. Melting point = 265 DEG.

TLC (93/7 CH ₂ Cl 2 / MeOH containing 10% _{NH4OH): Rf} = 0.8. Analysis confirmed C ₂₁ H ₃₀ ClNO.

NMR CDC1 ₃ ^X H ((ppm) HCI: 0.95-1.3 (m, 5H), 1.6-2.1 (m, 10 H);

2.5-2.65 (m, 2H), 2.7-2.8 (m, 2H), 2.9-3.0 (m, 2H), 3.1-3.2 (m, 2H) ), 3.3-3.4 (m, 2H), 7.15-7.3 (m, 2H), 7.4-7.5 (m, 1H),

7.9-7.95 (m, 1H), 11.6-11.8 (m, 1H))

IR: 3400, 2900, 2500, 1680, 1600, 1440, 1360, 1300, 1220,

1150, 1110, 1060, 980, 910, 760, 735 cm ^&lt; -1 ^&gt;.

Example 5

1'-Phenylethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4 'piperidine]

The method described in Example 2 using phenethyl bromide results in the hydrochloride product. Beige powder, mp.

c r f - e c r Γ - r Γ «» n r

C r> f * f. rre. 30 => 275 ° C, yield = 55%. TLC: (95/5 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R f = 0.85. Analysis confirmed C ₂₂ H ₂₆ ClNO.

NMR: CDCl 3 ((ppm) HCl: 2.0-2.15 (m, 4H), 2.3-2.45 (m, 2H),

2.9-3.0 (m, 2H), 3.05-3.25 (m, 6H), 3.4-3.5 (m, 2H), 7.1-7.3 (m, 7H) ), 7.4-7.45 (m, 1H), 7.85-7.9 (m, 1H), 12.25-12.45 (m, 1H))

IR: 3400, 2900, 2500, 1670, 1600, 1450, 1360, 1290, 1220, 1110, 1010, 960, 820, 800, 740, 700cm ^-1

Example 6 1'-cyclopropylethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]

0.94 g (4.36 mmol) of 3,4-dihydro-1-oxospiro [naphthalene2 (1H), 4'-piperidine], and then 10 mL of DMF were charged to a three necked flask. To the obtained solution was added 1.3 g (8.7 mmol) of (bromomethyl) cyclopropane in 2 mL of DMF, followed by 0.73 g (8.7 mmol) of NaHCO 3. The suspension was brought to reflux and then held for 1.5 hours. The solvents were removed at 50 ° C under a vacuum of less than 1 mm Hg. The residue was taken up in 50 ml of water and extracted three times with 50 ml of ether. The ether phase was extracted with 100 ml of 1N HCl and then twice with 50 ml of water. The aqueous phase was basified with concentrated NaOH until cold, and extracted three times with 50 ml of ether. The organic phase was washed with NaCl solution and dried over Na ₂ SO ₄ . The solvent was removed. The oily residue was purified by flash chromatography eluting with CH ₂ Cl ₂ enriched with methanol.

Γ r *

This left 0.6 g, hydrochloride salt was prepared by addition of approximately 5N ethereal hydrochloric acid to a solution of the crude product in CH ₂ C1 _2nd The mixture was concentrated to dryness, and then the product was crystallized by adding 30 ml of ether to a solution of the product in 5 ml of isopropanol. Crystallization was allowed to proceed for 14 hours at 20-25 ° C, and then the product was filtered off and washed with ether. After drying, 0.5 g of a white powder was obtained, m.p. = 244 ° C

TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% _{NH4OH): Rf} = 0.35. Analysis confirmed C ₁₉ H ₂₆ ClNO.

NMR: CDCl 3 ^Χ ((ppm) HCl: 0.1-0.3 (m, 2H), 0.45-0.65 (m, 2H),

0.7-0.8 (m, 1H), 1.6-2.6 (m, θΗ), 2.9-3.5 (m, 8H), 7.2-7.4 (m, 2H) 7.4-7.6 (t, 1H), 7.9-8.05 (d, 1H), 12.15, (1H))

IR: 2900, 2450, 1670, 1600, 1430, 1290, 1220, 950, 890, 740 cm ^{@ -1}

Example 7

1'-Cinnamyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4 'piperidine]

Prepared according to the method described in Example 2 with cinnamyl bromide, then purified by chromatography and crystallization of the hydrochloride. White powder, m.p. Melting point = 228 DEG.

TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% _{NH4OH): Rf} = 0.55. Analysis confirmed C ₂ 3 H ₂₆ ClNO.

r r r r r r r r r r r r r rf r - 'r r f · f r

NMR: CDCl 3 ^Χ ((ppm) HCl: 2.0-2.25 (m, 4H), 2.3-2.5 (m, 2H),

2.9-3.85 (m, 8H), 6.4-6.6 (m, 1H), 6.6-6.8 (d, 1H), 7.1-7.6 (m, 8H) ), 7.9-8.0 (d, 1H), 12.1 (IH))

IR: 2900, 2400, 1670, 1590, 1420, 1290, 1220, 970, 730, 690 cm ^-1

Example 8 1 '- (3,3-Diphenylpropyl) -3,4-dihydro-1-oxospiro [naphthalene 2 (1H), 4'-piperidine]

Prepared according to the method described in Example 6 with 3,3-diphenylpropyl bromide and preparation of the hydrochloride. A white powder was obtained, mp-257 ° C, TLC (95/5 CH ₂ Cl 2 / MeOH): R _f = 0.35. Analysis confirmed C29H32CINO.

NMR: ^{CDCl3; H} ((ppm) HCI: 2.0-2.2 (m, 4H), 2,4-3,5 (m, 12H);

3.9-4.05 (m, 1H), 7.2-7.4 (m, 12H), 7.4-7.6 (m, 1H), 7.9-8.0 (m, IH) ), 12.3 (IH)

IR: 2900, 2350, 1670, 1590, 1450, 1300, 1220, 910, 740, 700 ^cm-1

Example 9

1 '- (cyclopropylmethyl) -3,4-dihydro-5,7-dimethyl-1-oxospiro [naphthalene-2 (1H), 4'-piperidine] trans-piperidin-2-one; Pr pprpt · -> y

3,4-dihydro-5,7-dimethyl-1-oxospiro [naphthalene-2 (1H), 4'-piperidine] was prepared according to the method described for the synthesis of Example 1. The N alkylation was identical to the alkylation described in Example 6. Hydrochloride was obtained as a white powder, m.p. Mp > 260 ° C.

TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% _{NH4OH): Rf} = 0.5. Analysis confirmed C20H28CINO.

N MR: CDC1 ₃ ^X H ((ppm) HCI: 0.3-0.4 (m, 2H), 0.7-0.8 (m, 2H), 1.1-1.3 (m, 1H), 2.0-2.1 (m, 4H), 2.2 (s, 3H), 2.3 (s, 3H), 2.35-2, 45 (m, 2H), 2, 7-2.85 (m, 4H), 3.0-3.2 (m, 2H), 3.4-3.5 (m, 2H), 7.15 (s, 1H), 7.6 ( s, IH), 12.15 (IH)

IR: 3400, 2900, 2500, 1670, 1605, 1470, 1430, 1280, 1180,

1020, 970, 950, 880, 830 cm ^&lt; -1 ^&gt;.

Example 10 1 '- (cyclopropylmethyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1 H), 4'-piperidine]

/ h ₃ c

By the method of the example powder, m.p. Mp > 255 ° C.

hydrochloride was obtained. White yyyy r c · · · · yyyy r yy <· * yyyy

- C r • ·· r · c f

TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.35. The analysis confirmed CigH ₂₆ ClNO _second

NMR: CDCl _{3 3} H ((ppm) HCl: 0.4-0.5 (m, 2H), 0.75-0.85 (m, 2H),

1.25-1.4 (m, 1H), 2.05-2.2 (m, 4H), 2.35-2.5 (m, 2H), 2.8-2.95 (m, 2H) 2.95-3.05 (m, 2H), 3.2-3.4 (m, 2H), 3.45-3.6 (m, 2H),

3.85 (s, 3H), 6.7 (s, 1H), 6.85 (d, 1H), 7.9-8.0 (d, 1H),

12.15 (IH))

IR: 2900, 2420, 1660, 1590, 1430, 1250, 1220, 960, 830,

600 cm ^-1

Example 11 1 '- (cyclopropylmethyl) -3,4-dihydro-5-methoxy-1-oxospiro [naphthalene-2 (1 H), 4'-piperidine]

Following the same procedure as in Example 10, the hydrochloride was obtained. White powder, m.p. Melting point = 244 DEG.

TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH 4 OH): R _f = 0.75. The analysis confirmed the C ₉ H ₂ 6ClNO _second

NMR CDC1 ₃ ¹ H ((ppm) HCI: 0.4-0.5 (m, 2H), 0.75 to 0, 85 (m, 2H);

1.25-1.4 (m, 1H), 2.05-2.2 (m, 4H), 2.35-2.5 (m, 2H), 2.8-3.0 (m, 4H) ), 3.1-3.3 (m, 2H), 3.5-3.6 (m, 2H), 3.85 (s, 3H), 7.07.1 (m, 1H), 7, 25-7.35 (m, 1H), 7.5-7.6 (m, 1H), 12.1-12.2 (IH))

IR: 2930, 2560, 2360, 1680, 1580, 1470, 1435, 1260, 1060, 970,

750 cm ^-1

r. p r r r r c e <- r-, - .-.

rrf 'rp .- ς crp »r»' rf Γ η c Γ · r ·; _C

P C r · · · r. c c · '’· -1 ·

Example 12 1 '- (methylcyclopropyl) -3,4-dihydro-7-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]

Using the same methods as in Example 10, the hydrochloride was obtained. White powder, m.p. Melting point = 235 DEG.

TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.70-0.75. Analysis confirmed C19H26CINO2.

NMR: CDCl ^{3 3} H ((ppm) HCl: 0.4-0.5 (m, 2H), 0.75-0.85 (m, 2H),

1.25-1.4 (m, 1H), 2.05-2.2 (m, 4H), 2.35-2.5 (m, 2H), 2.8-3.0 (m, 4H), 3.2-3.3 (m, 2H), 3.5-3.6 (m, 2H), 3.80 (s, 3H), 7.07.1 (m, 1H), 7 , 15-7.25 (m, 1H), 7.4 (s, 1H), 12.1-12.2 (1H))

IR: 2930, 2510, 2445, 1670, 1610, 1495, 1415, 1250, 1025 cm ^{@ -1}

Example 13

1 '- (cyclopropylmethyl) -3,4-dihydro-7-nitro-1-oxospiro [naphthalene2 (1H), 4'-piperidine]

Step 1: 2.4 g (8.35 mmol) of ethyl 3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine] -1'-carboxylate, prepared according to the method described in Step 3 of Example 1, and 35 ml of concentrated sulfuric acid were placed in a three-necked flask. 0.79 g (12.5 mmol) of fuming nitric acid are much β · R · Γ · L · e fre ^fc β r rr R <

σ c ŕ fr - C C r r ^{1 1} * added to the solution cooled to 0 ° C. The mixture was stirred for 1 hour at 0 ° C and then for 2 hours at 2025 ° C. The solution was precipitated from 100 mL of water and ice, and then extracted three times with 100 mL of CH 2 Cl 2. The organic phase was washed successively with water and saturated NaCl solution. After drying over Na ₂ SO ₄ and evaporation of the solvent, 2.75 g of an oil was obtained, which was chromatographed eluting with CH ₂ Cl ₂ gradually enriched with acetone. 1.5 g of ethyl 3,4-dihydro-7-nitro-loxospiro [naphthalene-2 (1H), 4'-piperidine] -1'-carboxylate was obtained as an oily residue which crystallized. Yield = 54%, TLC (98/2 CH ₂ Cl ₂ / acetone): R _f = 0.3.

NMR: CDCl 3 ¹ H ((ppm): 1.15 (t, 3H), 1.4 (m, 2H), 1.8-2.0 (m,

4H), 2.9-3.0 (m, 2H), 3.45-3.55 (m, 4H), 4.0-4.1 (q, 2H), 7.3 (d, 1H) 8.2 (d, 1H), 8.8 (s, 1H)).

Step 2: 1.5 g of the product from the previous step were hydrolyzed as described in Step 4, Example 1. After chromatography with CH ₂ Cl ₂ sequentially enriched in methanol containing 10% NH ₄ OH, 0.45 g was isolated. TLC (90/10 1 CH ₂ Cl ₂ / MeOH containing 10% NH 4 OH): R _f = 0.1.

Step 3: The 0.22 g (0.845 mmol) of the 3,4-dihydro-7-nitro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine] obtained in the previous step was suspended in 3 mL of acetonitrile. A solution of 0.343 g (2.54 mmol) of cyclopropylmethyl bromide in 0.5 ml of acetonitrile was added with stirring. The reaction mixture was brought to reflux and maintained for approximately 5 hours. The solvent was removed and the residue was taken up in 20 mL of CH ₂ Cl ₂ and extracted with 20 mL of N / 1 HCl. The acid phase was basified until cold with a dilute sodium hydroxide solution to pH 12 and extracted three times with 20 ml CH ₂ C1 _2nd

After washing, drying and removal of the solvent, the residue was chromatographed eluting with CH ₂ Cl ₂ successively enriched with methanol containing 10% NH ₄ OH. 0.130 g of 3,4dihydro-1 '- (cyclopropylmethyl) -7-nitro-1-oxospiro [naphthalene2 (1H), 4'-piperidine] was obtained. TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH 4 OH): R _f = 0.7.

The hydrochloride was prepared as described above. White powder, m.p. Melting point = 256 DEG C. TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH 4 OH): R _f = 0.7.

Analysis confirmed CibH ₂ 3ClN ₂ O ₃ .

NMR: CDCl 3 ¹ H (ppm) HCl: 0.4-0.5 (m, 2H); 0.7-0.8 (m, 2H); 1,2- 1.4 (m, 1H) 2-2.25 (m, 4H), 2.4-2.6 (m, 2H), 2.8-2.9 (m, 2H), 3, 05 -3.3 (m, 4H), 4.5-4, Δ (m, 2H), 7.45 (d, 1H), 8.3 (d, IH), 8.8 (s, IH) 12.1 (IH)

IR: 2940, 250Q, 2440, 1690, 1610, .1520, 1410, 1345, 1220,

1105, 960 cm ¹

Example 14

1 '- (cyclopropylmethyl) -7-amino-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]

mg (0.19 mmol) of 3,4-dihydro-1 '- (methylcyclopropyl) -7-nitro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine] obtained as described in Example 13 was dissolved in 1 ml of THF, and then 0.21 g of stannous chloride hydrate was added with stirring. The solution was brought to reflux for 1 hour. Saturated NaHCO 3 solution was added to the reaction mixture, and the mixture was extracted three times with CH ₂ Cl ₂ . The organic phase was washed and dried over Na ₂ SO ₄ . The solvent was evaporated and the obtained residue was chromatographed eluting with CH ₂ Cl 2 sequentially enriched with methanol containing 10% NH ₄ OH. 29 mg of product were obtained.

NMR CDC1 ₃ ^J H ((ppm): 0.1-0.2 (m, 2H), 0.4-0.55 (m, 2H), 0,851,0 (m, IH), 1,6- 1.7 (m, 2H), 1.9-2.1 (m, 4H), 2.3-2.4 (m, 2H), 2.5-2.75 (m, 4H), 2, 8-2.9 (m, 2H), 3.6-3.8 (2H), 6.8 (d,

1H), 7.0 (d, 1H), 7.2 (s, 1H)).

The hydrochloride was crystallized from ether. 26 mg of a yellow powder were obtained.

tt. Melting point = 200 ° C. TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10%

NH 4 OH) _Rf = 0.45.

Example 15 1 '- (Cyclopropylmethyl) -7-chloro-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]

Cl

Step 1: Piperidine-1,4-dicarboxylic acid 4-ethyl-t-butyl diester g (0.381 mol) of ethyl isonipipotate and 400 ml of THF were placed in a three-necked, vial-protected, inert-atmosphere flask added 18.3 g (0.458 mol) of sodium hydroxide pellets. A solution of 100 g (0.458 mol) of di-t-butyl dicarbonate in 170 ml of THF was added after stirring for 1 hour to form a suspension. The temperature reached 45 ° C. The reaction mixture was left under stirring for 14 hours at 20-25 ° C and then poured into 2 L of water and back and extracted three times with 500 mL of ether. The organic phase was washed three times with 250 ml of saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated.

r> r

The residue was chromatographed eluting with CH 2 Cl 2 sequentially enriched with acetone and then distilled under a vacuum of 0.09 mm Hg and a steam temperature of 95-102 ° C. 82 g (yield = 83.6%) were obtained. TLC (95/5 _{CH2 Cl2} / acetone): _Rf = 0.60.

NMR CDC1 ₃ * Η ((ppm): 1.2-1.3 (t, 3H), 1.4 (s, 9H), 1.5-1.6 (m,

2H), 1.8-1.9 (m, 2H), 2.35-2.45 (m, 1H), 2.7-2.85 (m, 2H),

3.9-4.0 (m, 2H); 4.05-4.15 (q, 2H)).

Step 2: 4- (4-chlorophenethyl) piperidine-1,4-dicarboxylic acid 4-ethyl-1- t -butyl diester

6.16 g (60.9 mmol) of di isopropyl amine and 174 ml of THF, dried on a molecular filter, were added under a nitrogen atmosphere to a three-necked vial protected from moisture under an inert atmosphere. The solution was cooled to -10 ° C and 24.3 mL (60.9 mmol) of 2.5 N n-butyllithium in hexane was added. The mixture was stirred for 15 minutes at 10 C and cooled to 70 ^e C and a solution of 10.4 g (40.6 mmol) of the product of Step 1 in 86 ml THF for. about 20 minutes. The mixture was stirred for 10 minutes at -70 ° C, and then 10.9 g (60.9 mmol) of HMPT was added. The mixture was kept under stirring at -70 ° C for 1.5 hours and a solution of 10.7 g (48.7 mmol) of 4-chlorophenethyl bromide in 86 mL of THF was added over 20 minutes at -70 ° C. The mixture was stirred at 20-25 ° C for 14 hours and then poured into 350 ml of water and extracted three times with ether. The organic phase was washed with N / 1 HCl solution and then with saturated NaCl solution. After drying and concentration to obtain 17 g of an orange oil which was chromatographed eluting with CH ₂ C1 ₂ gradually enriched with hexane, and then with acetone. 11.8 g (yield = 80%) were obtained. TLC (95/5 _{CH2 Cl2} / acetone): _Rf = 0.70.

NMR: CDCl 3 ¹ H ((ppm): 1.2-1.3 (t, 3H), 1.4 (s, 9H), 1.3-1.4 (m,

2H), 1.7-1.8 (m, 2H), 2.0-2.1 (m, 2H), 2.3-2.4 (m, 2H), 2.7e r · Λ Γ

2.9 (m, 2Η), 3.7-3.9 (m, 2Η), 4.05-4.15 (q, 2Η),

2Η), 7.1-7.2 (m, 2Η)).

6.9-7.0 (m,

Step 3: Ethyl 4- (4-chlorophenethyl) piperidine-4-carboxylate

10.8 g of the product from step 2 above and 50 ml of CH 2 Cl 2 were placed in a three-necked flask protected from moisture. The solution was stirred and 25 mL of trifluoroacetic acid at 20-25 ° C was added. The mixture was kept under stirring for 30 minutes and then concentrated to dryness and the residue taken up in ether. The organic phase was washed with 10% sodium hydroxide solution and then with saturated NaCl solution. After drying and concentration, 9 g of an oil was obtained which crystallized.

TLC (90/10 CHCl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.45.

NMR: CDCl 3 ¹ H ((ppm): 1.1-1.25 (t, 3H), 1.3-1.4 (m, 2H), 1.7-1.8 (m, 2H), 2 1-2.2 (m, 2H); 2.35-2.45 (m, 2H); 2.6-2.7 (m, 2H);

2.9-3.0 (m, 2H), 3.3 (1H), 4.1-4.2 (q, 2H), 6.9-7.0 (dd, 2H), 7.1- 7.2 (dd, 2H).

Step 4: ethyl 1- (cyclopropylmethyl) -4- (4-chlorophenethyl) piperidine-4-carboxylate

3.4 g (11.5 mmol) of the product of previous step 3, ml of THF, dried on a molecular filter, and then with stirring

14.9 ml of triethylamine and 2.4 ml (20.9 mmol) of 85% (bromomethyl) cyclopropane were sequentially charged to a moisture-protected, round-bottomed flask under nitrogen. The mixture was refluxed for 14 hours and then concentrated to dryness and the residue taken up in water and extracted twice with ether. The organic phase, washed with saturated NaCl solution and dried, was concentrated. 3 g of crude product were obtained, which was chromatographed (eluent: CH ₂ Cl ₂ gradually enriched in methanol containing 10% NH ₄ OH). 2.6 g of an oily product were obtained. Yield = 65%.

TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% _{NH4OH): Rf} = 0.50.

NMR: CDCl 3 ^X H ((ppm): 0-0.1 L) [m, 2H] 0.35-0.45 (M, 2H) / 0,7- 0, 8 (m, 1H), 1.1-1.2 (t, 3H) , 1,4-1, 5 (m, 2H) , 1 , 7 to 1.8 (M, 2H), 1.9-2.1 (m, 2H); 2.1-2.2 (m, 2H) , 2,3-2,4 (M, 2H), 2,7- 2, 85 (m, 2H), 4.1-4.2 (g, 2H); 6, 9-7.0 (dd, 2H). 7 1 to 7.2 (Dd,

2H)).

Step 5: 1- (Cyclopropylmethyl) -4- (4-chlorophenethyl) -piperidine-4-carboxylic acid

2.2 g (6.28 mmol) of the previous ester and 6.6 mL of anhydrous dimethylsulfoxide were charged to a round-bottomed, moisture-proof, round-bottomed flask under a nitrogen atmosphere. A solution of 4.4 g (39 mmol) of potassium t-butoxide in 30 ml of dimethylsulfoxide was added with stirring. The mixture was left under stirring for 2 hours at 20-25 ° C. To the reaction mixture was added 200 mL of water, and then the mixture was washed with ether. The aqueous phase was acidified to pH 5-7 with 10% HCl. The precipitate was filtered off and washed with water. The resulting acid was crystallized from a mixture of CH ₂ C1 ₂ and methanol. Tt. Melting point = 250 DEG.

NMR: CDCl 3 ¹ H ((ppm): 0.2-0.3 (m, 2H), 0.5-0.6 (m, 2H), 1.07-1.1 (m, 1H), 1 6-1.9 (m, 4H), 2.25-2.35 (m, 2H), 2.5-2.6 (m, 2H), 2.65-2, 75 (m, 2H) 2.8-2.9 (m, 2H), 3.3-3.4 (m, 2H), 6.9-7.0 (dd, 2H), 7.1-7.2 (dd, 2H)).

IR: 3370, 1490, 1445, 1380, 1240, 1170, 1095, 965, 805 cm ^{@ -1}

Step 6: 7-chloro-3,4-dihydro-1 '- (cyclopropylmethyl) -1-oxospiro [naphthalene-2 (1H), 4'-piperidine]

0.3 g (0.9 mmol) of the acid obtained in the previous step and ml of benzene were charged to a round-bottomed flask which was e.

R Π '· I r r protected from moisture and which was in a nitrogen atmosphere. 0.24 g of PCl5 and 6 mL of CH 2 Cl 2 were added, followed by others

0.24 g PCI5. The mixture was stirred for 2 hours at 20-25 ° C. The mixture was cooled to 0 ° C and 0.44 mL of chloride was added

For example, tin (II) (solid precipitation), 12 mL of CH ₂ Cl ₂ was added and the mixture was maintained at 0 ° C for 1 hour, and then at 20-25 ° C for 14 hours. The solvents were removed and the residue was taken up in water. The aqueous phase was washed with ether and then basified to pH 12 with NaOH and extracted with ether. The organic phase was washed, dried and concentrated. The crude product was chromatographed eluting with CH ₂ Cl ₂ sequentially enriched with methanol containing 10% NH ₄ OH. 22 mg of the product was obtained, and this product was treated with 5N ethereal hydrogen chloride solution in CH 2 Cl 2. After crystallization from ethyl acetate, the product was filtered off and dried at 50 ° C under vacuum.

White powder. TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.55. Tt. Melting point = 263 DEG.

NMR: ^{CDCl3; H} ((ppm) HCI: 0.4-0.5 (m, 2H), 0.7-0.8 (m, 2H), 1,21.3 (m, IH), 2.0- 2.15 (m, 4H), 2.4-2.55 (m, 2H), 2.8-2.9 (m,

2H), 2.95-3.05 (m, 2H), 3.1-3.3 (m, 2H), 3.5-3.6 (m, 2H), 7.27.3 (m, 1H) 7.4-7.5 (m, 1H); 7.9 (s, 1H); 12.2 (1H))

IR: 2930, 2440, 1720, 1490, 1230, 1185, 1095, 1025, 810 cm ^{&lt; 1} &gt;

r · r r * r

Examples 16-34

The following additional compounds listed in Table 1 were prepared according to the general procedures described above.

Table 1

Example R ¹ R ² R ³ R ⁴ A R ⁵ 16 = 0 H. H ch ₂ ch ₃ 17 «= 0 H H ch ₂ ch ₂ ch = ch ₂ 18 = o H H ch ₂ / CH 19 = 0 H H ch ₂ 20 = 0 H H ch ₂

Table 1 - continued

Example R '| R ' R ^J R ⁴ A R ^J 21 = 0 H H ch ₂ 'H-H 22 = 0 H H ch ₂ / Or ^{F 9H} X X> _F 23 H OH H H ch ₂ ch ₂ - <

r. , · P e <* e r o C c y r y r e i <'y r

24 H H H H ch ₂ ch ₂ - < 25 = 0 ** H H weave ch ₂ - <3 26 = 0 H H CH ₂ CH ₂ ch ₂ - <] 27 ABOUT H H CH 1 CH _S ch ₂ - < 28. = 0 6-C1 1 H ch ₂ ch ₂ - <J 29 = 0 6-F H ch ₂ ch ₂ - <] 30 «= 0 6: OCH ₃ 7: OCH ₃ ch ₂ ch ₂ - ^ 3 31 = 0 H H CH ₂ ) - « 32 = 0 H H ch ₂ 33 = 0 H H CHI 'ABOUT 34 = 0 6: OCH H CH ₂ Ό0

Melting point (tt) and NMR data for Examples 16-34 are provided below:

compound

Example 16 mp = 240-243 ° C

NMR CDCl 3 ¹ H δ (ppm) base: 1.5-1.6 (m, 2H), 1.95-2.05 (m, 4H),

2.25 (s, 3H), 2.3-2.4 (m, 2H), 2.45-2.55 (m, 2H), 2.9-2.95 (m, 2H), 7, 1-7.15 (m, 1H), 7.2-7.25 (m, 1H), 7.35-7.4 (m, 1H),

7.9-7.95 (m, 1H) .delta. . c / / * r

Example 17 mp = 242-244 ° C

NMR CDCl 3 ¹ ? (Ppm) HCl: 2.05-2.15 (m, 4H), 2.3-2.45 (m, 2H)

3.0-3.1 (m, 2H), 3.1-3.25 (m, 2H), 3.35-3.5 (m, 2H), 3.55-3, (m, 2H) 5.4-5.55 (m, 2H); 6.1-6.25 (m, 1H); 7.2-7.35 (m, 2H)

7.45-7.5 (m, IH), 7.9-7.95 (m, IH), 12.3-12.45 (m, IH)

Example 18 mp = 244-245 ° C

NMR CDCl 3 ¹ H δ (ppm) HCl: 1.15 (d, 6H), 2.0-2.1 (m, 4H), 2.15

2.3 (m, 1H), 2.55-2, 65 (m, 2H), 2.75-2.8 (m, 2H), 2.95-3.0 (m 2H), 3.1 -3.25 (m, 2H), 3.35-3.45 (m, 2H), 7.2-7.35 (m, 2H)

7.45-7.5 (m, 1H), 7.9-7.95 (m, IH), 11.7-11.8 (m, IH)

Example 19 mp = 95-97 ° C NMR CDCl 3 ^X H δ (ppm) base: 0.6-0.7 (m, 2H), 0.8-0.95 (m, 2H) 1.4-1.5 (m, 2H); 1.6-1.7 (m, 1H); 1.8-2.1 (m, 4H); 2.9-3.5 (m 2H), 3.4-3.8 (m, 4H), 7.1-7.3 (m, 2H), 7.35-7.45 (m, 1H), 7.9 8.0 (m, 1H)

Example 21 mp = 261-262 ° C

Example 20 mp = 220-221 ° C

NMR CDCl 3 ^Τ Η ppm (ppm) HCl: 1.05-1.3 (m, 2H), 1.5-1.9 (m, 1H)

2.0-2.2 (m, 5H), 2.3-2.55 (m, 2H), 2.9-3.4 (m, 6H), 3.4-3, (m, 2H) 7.0-7.6 (m, 8H), 7.9-8.1 (m, 1H), 12.2-12.4 (m, 1H)

NMR CDCl 3 ^γ H δ (ppm) HCl: 2.0-2.1 (m, 4H), 2.4-2.5 (m, 2H), 2.95-3.05 (m, 2H), 3 1-3.35 (m, 2H), 3.3-3.4 (m, 2H), 4.1-4.15 (m, 2H), 7.2-7.35 (m, 2H) 7.4-7.5 (m, 4H); 7.65-7.7 (m, 2H);

7.9-7.95 (m, 1H); 12.25-12.5 (m, 1H)

Example 22 mp> 250 ° C

NMR CDCl 3 ¹ H δ (ppm) base: 1.4-1.55 (m, 2H), 1.9-2.05 (m, 4H),

, 35 (M, 2H), 2 4 to 2.55 (M, 2H), 2.8-2.95 (M, 2H); 4.2 6, 8 -7.0 (M, 4H) , 7.15 (D, IH), 7.2-7.35 (M, 5H), 7.4 7.9 (D, H)

Example 23 mp = 91-93 ° C

NMR CDC1 ₃ ^x H δ (ppm) Base: -0, 05-0, 05 (m, 2H), 0, 35-0, 45 (m, 2H), 0.7-0.85 (m, H) 1.25-1.85 (m, 7H), 2.2 (d, 2H), 2.2-2.4 (m, 2H), 2.5-2.6 (m, 1H), 2 6-2.7 (m, 3H); 4.2 (s, 1H); 7.07.3 (m, 4H)

Example 24 mp = 256-258 ° C

NMR CDCl 3 δ (ppm) base: 0.0-0.1 (m, 2H), 0.4-0.5 (m, 2H),

0.75-0.85 (m, 1H), 1.45-1.55 (m, 4H), 1.6-1.65 (m, 2H), 2.2 (d, 2H), 2, 35-2.6 (m, 6H), 2.7-2.8 (m, 2H), 6.9-7.05 (m, 4H)

Example 25 mp = 241 ° C

NMR CDCl 3 δ (ppm) HCl: 0.0-0.15 (m, 2H), 0.4-0.55 (m, 2H),

0.75-0.9 (m, 1H); 1.35 (d, 2H); 1.9-2.15 (m, 4H); 2.25 (d, 1H);

Γ Γ ·

Γ Γ ΓΓ Ρ

2Η), 2.9 (s, 2Η), 3.0 (d, 2Η), 7.25 (t, 1Η), 7.35 (d, 1Η), 7.5 (t, 1Η), 7, 65 (d, 1Η), 12.1-12.2 (1Η)

Example 26 mp = 242-243 ° C

NMR CDCl ₃ Ô (ppm) HCl: 0.4-0.5 (m, 2H), 0.7-0.8 (m, 2H), 1.21.35 (m, 1H), 1.85- 2.0 (m, 4H), 2.2-2.3 (m, 2H), 2.3-2.4 (m,

2H), 2.7-2.9 (m, 6H), 3.4-3.5 (m, 12.3 (IH) 2H), 7.15-7.4 (m, 4H); 12,1- Example 27 F mp = 234 ° C NMR CDCl 3 ¹ H δ (ppm) HCl: 0.45 (m, 2H), 0.75 (m, 2H), 1.35 (m, 2H) 1H), 1.4 (dd, 3H), 1.85 (m, 2H), 2.1 (m, 3H); 2.3 (m, IH), 2.75 (m, 2H); 2.9 (m, 2H); 3.25 (m, 1H), 3.45-3.8 (m, 3H); 7.3-7.45 (m, 2H), 7.6 (m, 1H), 8.0 (dd, IH), 12.1 (IH) Example 28 mp> 250 ° C NMR CDCl 3 ^X H δ (ppm) HCl: 0.4-0.5 (m, 2H), 0.75-0.85 (m, 2H) 2H), 1.3-1.4 (m, 1H), 2.1-2.2 (m, 4H), 2.4-2.55 (m, 2H), 2.9 -2, 95

(m, 2H), 3.0-3.05 (m, 2H), 3.2-3.3 (m, 2H), 3.5-3.6 (m, 2H),

7.25-7.3 (m, 2H), 7.9-7.95 (m, 1H), 12.2 (1H)

Example 29 mp = 227 ° C

NMR CDCl 3 δ H ^X (ppm) HCI: 0.4-0.5 (m, 2H), 0.75 to 0.8? 5 (m, 2H);

1.3-1.4 (m, 1H), 2.0-2.2 (m, 4H), 2.4-2.6 (m, 2H), 2.85-2.95 r (m, 2H), 3.0-3.1 (m, 2H), 3.2-3.3 (m, 2H), 3.5-3.6 (m, 2H),

6.9-7.0 (m, 1H), 7.0-7.1 (m, IH), 7.95-8.05 (m, IH), 12.1 (IH)

Example 30 mp = 229 ° C

NMR CDCl ₃ ¹ H δ (ppm) HCl: 0.45 (m, 2H), 0.75 (m, 2H), 1.35 (m, 1H), 2.15 (m, 4H), 2.45 (td, 2H), 2.9 (m, 2H), 2.95 (m, 2H),

3.3 (m, 2H), 3.55 (m, 2H), 4.85 (s, 3H), 4.95 (s, 3H), 6.65 (s, 1H), 7.45 (s) , IH), 12.05 (IH)

Example 31 mp = 189-192 ° C

NMR CDCl 3 ^Χ Η δ (ppm) HCl: 0.2-0.3 (m, IH), 0.6-0.7 (m, IH), 0.70.8 (m, IH), 0.8 -0.9 (m, 1H), 1.1-1.2 (m, 1H), 1.55 (d, 3H),

1.6-1.7 (m, 1H), 2.1-2.2 (m, 4H), 2.5-2.7 (m, 2H), 3.0-3.1 (m, 2H) ), 3.3-3.6 (m, 4H), 7.2-7.25 (m, 1H), 7.3-7.35 (m, 1H),

7.45-7.5 (m, 1H), 8.0-8.05 (m, 1H), 11.85 (1H)

Example 32 mp> 235 ° C

NMR CDCl ₃ ¹ H δ (ppm) HCl: 1.7 (d, 3H), 2.1-2.2 (m, 4H), 2.4-2.5 (m, 2H), 2.6- 2.7 (m, 2H), 2.9-3.1 (m, 4H), 3.2-3.3 (m, 2H),

3.4-3.5 (m, 2H), 5.3-5.4 (m, 1H), 5.6-5.7 (m, 1H), 7.2-7.3 (m, 1H) ), 7.3-7.35 (m, IH), 7.5-7.6 (m, IH), 7.95-8.0 (m, IH), 12.2 (IH)

Example 33 tt = 209 ° C rerer r r r ľ f Γ - r '- ·· r «-.n r · r- f ·

NMR CDCl ^{Χ Η δ} (ppm) HCI: 2,1 (m, 4H), 2.25 (m, 2H), 2.45 (m, 2H), 2.7 (m, 2H), 2.9 ( m, 2H), 3.0 (m, 2H), 3.15 (m, 2H), 3.4 (m, 2H), 7.1-7.35 (m, 7Η), 7.5 (m 1 H, 7.95 (m, 1H), 11.95 (IH)

Example 34 mp = 228 ° C

NMR CDCl 3 ¹ H δ (ppm) HCl: 2.0-2.2 (m, 4H), 2.4 (td, 2H), 3.0 (m,

2H), 3.3 (qd, 2H); 3.45 (m, 2H), 3.75 (T, 2H), 3.85 (s, 3H); 6, 55 (qt, 1H); 6.7 (m, 2H); 6, 85 (Dd, IH), 7.35 (m, 3H) 7.45 (D, 2H), 7.95 (d, 1H), 11.95 (IH).

Examples 35-69

According to procedures known in the art, some of the tetralones described above have been alkylated to give the following additional compounds listed in Table 2.

Table 2

Pr. R ¹ -R ² R ^J R ⁵ A Rf 35 = 0 5: OCH ₃ H (CH ₂ ) ₂ -C ₃ H ₅ CH ₂ 0.7 36 = 0 5: OCH ₃ H CH ₂ --C ₄ H ₇ ch ₂ 0.5 37 = 0 5: OCH3 H CH ₂ -C ₆ Hh ch ₂ oo 0 38 = 0 5: OCH3 H ch ₂ -ch = ch-c ₆ h ₆ ch ₂ 0.7 39 = 0 5: OCH ₃ H ch ₂ -ch ₂ -c ₆ h ₅ ch ₂ 0.7 40 = 0 5: OCH 3 H ch ₂ -ch ₂ -ch ₂ -c ₆ h ₆ ch ₂ 0.55 41 = 0 5: OCH 3 H (CH ₂ ) ₂ -CH- (C ₆ H ₆ ) ₂ ch ₂ 0, 90 42 = 0 6: OCH ₃ H (CH ₂ ) ₂ -C ₃ H ₅ ch ₂ 0.4

β PP cepeerrpeoee ^Λ rrrrrrrc

43 = 0 6: 0CH ₃ H CH ₂ --C ₄ H ₇ ch ₂ 0, 3 44 Q = 6: 0CH ₃ H CH ₂ -C ₆ Hu ch ₂ 0, 55 45 = 0 6: 0CH ₃ H ch ₂ -ch = ch-c ₆ h ₆ ch ₂ 0, 5 46 = 0 6: OCH ₃ H ch ₂ -ch ₂ -c ₆ h ₆ ch ₂ 0, 5 47 = 0 6: 0CH ₃ H ch ₂ -ch ₂ -ch ₂ -c ₆ h ₆ ch ₂ 0.4 48 = 0 6: 0CH ₃ H (CH ₂ ) ₂ -CH- (C ₆ H ₆ ) ₂ ch ₂ 0.7 49 = 0 7: OCH ₃ H, (CH ₂ ) ₂ -C ₃ H ₅ ch ₂ 0, 5 50 = 0 7: OCH ₃ 'H CH ₂ --C ₄ H ₇ ch ₂ 0.2 51 = 0 7: 0CH ₃ H CH ₂ -c ₆ Hii ch ₂ 0.4 52 = 0 7: 0CH ₃ H ch ₂ -ch = ch-c ₆ h ₆ ch ₂ 0.4 53 = 0 7: 0CH ₃ H ch ₂ -ch ₂ -c ₆ h ₆ ch ₂ 0.4 54 = 0 7: 0CH ₃ H ch ₂ -ch ₂ -ch ₂ -c ₆ h ₆ ch ₂ 0.3 55 = 0 7: OCH ₃ H (CH ₂ ) ₂ -CH- (C ₆ H ₆ ) ₂ ch ₂ 0, 65

Table 2 (continued)

Pr. R @ 2 --R @ ² R ^J R ⁴ R ^b A Rf 56 = 0 H H (CH ₂ ) ₂ -C ₃ H ₅ CHCH ₃ 0.4 57 = 0 H H CH ₂ -C ₄ H ₇ CHCH ₃ 0.2 58 = 0 H H CH ₂ -C ₆ Hu CHCH ₃ 0.5 59 = 0 H H ch ₂ -ch = ch-c ₆ h ₆ chch ₃ 0.45 60 = 0 H H CH ₂ CH ₂ -C ₆ H 6 CHCH ₃ 0.5 61 = 0 H H ch ₂ -ch ₂ -ch ₂ -c ₆ h ₆ CHCH ₃ 0.4 62 = 0 H H (CH ₂ ) ₂ -ch- (C ₆ H ₆ ) 2 CHCH ₃ 0.7 63 = 0 6: C1 H (CH ₂ ) ₂ -C ₃ H ₅ ch ₂ 0.5 64 = 0 6: C1 H CH ₂ --C ₄ H ₇ ch ₂ 0.3 65 = 0 6: C1 H CH ₂ -C ₆ Hn ch ₂ 0, 65

r e c.? · o

66 = 0 6: C1 H ch ₂ -ch = ch-c ₆ h ₆ ch ₂ 0.55 67 = 0 6: C1 H ch ₂ -ch ₂ -c ₆ h ₆ ch ₂ 0, 65 68 = 0 6: C1 H ch ₂ -ch ₂ -ch ₂ -c ₆ h ₆ ch ₂ 0, 5 69 = 0 6: C1 H (CH ₂ ) ₂ -ch- (C ₆ H ₆ ) ₂ ch ₂ 0.85

Example 70

3,4-dihydro-6-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]

The synthesis was similar to that described in Example 1 except step 3, where 6-methoxy-tetralone was used instead of 1-tetralone.

NMR CDC1 ₃ ^X H ((ppm) Base: 1.9-2.3 (m, 6H), 2.9-3.1 (m, 2H);

3.3-3.6 (m, 4H), 3.85 (s, 3H), 6.65 (s, 1H), 6.8-6.9 (m, 1H),

7.9-8.0 (dd, 1H), 9.5 (bs, 2H)).

tt. = 236-237 ° C, TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.25.

IR: 2724, 1657, 1595, 1446, 1258, 1223, 1086, 978, 906,

839 cm ^-1

As mentioned above, the compounds of the invention have the formula

I are useful for the treatment of chronic pain and other disorders

CNS, such as seizure disorders, e.g. epilepsy.

Compounds were evaluated in standard assays to measure the ability to block isolated mammalian Na neuronal channels, and e r.

their ability to antagonize the production of prostaglandin E ₂ (PGE ₂ ). Both assays are routinely used to recommend the clinical utility of compounds for the treatment of chronic pain and other CNS disorders (see Tonelian et al., Anesthesioloy, 24: 949-951, 1991).

Example 71

[ ³ H] Batrachotoxin (BTX) Sodium Channel Binding Assay

Cerebral cortexes of male Sprague-Dawley rats were homogenized in a glass / teflon homogenizer in 10 volumes of ice-cold 0.32M sucrose, 5mM K ₂ HPO ₄ (pH 7.4 at 4 ° C). The homogenate was centrifuged at 1000 g for 10 minutes, the pellet was resuspended in an equal volume of sucrose and centrifuged again. The pellet was discarded and the two supernatants resulting from the two centrifugations were pooled and centrifuged at 20,000 g for 10 minutes. The resulting pellet was resuspended in assay buffer free of Na containing 50 mM HEPES, 5.4 mM KCl, 0.8 mM MgSO ₄ , 5.5 mM glucose and 130 mM choline chloride (pH 7.4 at 25 ° C). The binding assay was initiated by adding 150-200 μς of synaptosomal protein to assay buffer containing 25. μς scorpion venom (Leirus chinquestriatus), 0,1% BSA and 10 nM [ ³ H] batrachotoxin (40 Ci / mmol, NEN) in the presence or absence of different concentrations of unlabeled drugs (final volume 250 μΐ). Non-specific binding was detected in the presence of 0.3 mM veratridine. The reactions were incubated for 90 minutes at 25 ° C and bound ligand was separated from free ligand by vacuum filtration through Whatman GF / B filters, the filters were washed with 2x5 ml buffer (5mM HEPES, 1.8mM CaCl ₂ , 0.8mM MgSO ₄ , 130mM choline chloride, 0.01% BSA, pH 7.4 at 25 ° C) and bound ligand was evaluated by liquid scintillation spectrometry.

Example 72 ²² Na ⁺ influx into SK-N-SH neuroblastoma cells

Characterization of Na ⁺ channel activity using human SK-N-SH cells in culture plates. The effect of the tested influx across Na ⁺ channels was evaluated by veratridine.

96 well compounds were converted to Na ⁺ upon stimulation

SK-N-SH cells were preincubated for 15 minutes at 37 ° C in the presence of test compound in 25 mM HEPES / Tris pH 7.5 buffer containing 5.4 mM KCl, 0.8 mM MgSO 4, 1.8 mM CaCl 2/5 mM glucose , 0.1% BSA, 140 mM choline chloride.

Influx Na ⁺ was induced by incubating SK-N-SH cells for 10 minutes at 37 ° C in the presence of test compound and veratridine in incubation buffer supplemented with ΙμΜ ouabain, 10 mM NaCl, 130 mM choline chloride and ²² Na ⁺ (Jacques, Y, Fosset, M Lazdunski, M., (1978), Molecular properties of the Na ⁺ ion potential acce potential in neuroblastoma cells (J. Biol. Chem., 253, 7383-7392).

After this uptake of ²² Na ⁺ , cells were washed with 0.1 mM MgCl ₂ . Radioactivity was then measured on a microplate reader (Topcount, Packard) after addition of scintillation fluid (Microscint 40, Packard).

The reference compound was tetrodotoxin tested at 7 concentrations ranging from 10 ^-10 M to 10 ⁷ M to determine the IC 50 value.

β e e f ο fl ŕ f

C r r c r r r r r

Example 73

Analgesic activity on chronic hyperalgesia induced by PGE ₂ in rats

The assay is to determine the analgesic effect of the test compound on rats by the Randall and Selitta test in which chronic hyperalgesia was induced by intraplantar injection of PGE ₂ into the limb for 4 days, according to a protocol modified by Nakamura-Craig et al. (Pain, 63: 33-37, 1995).

The study was conducted on groups of Sprague-Dawley rats weighing 120-140 g, administered 100 ng of PGE ₂ in a volume of 100 μΐ intraplantar, for 4 consecutive days twice daily, inducing chronic hyperalgesia in the limb from day 5 after for at least one week. On the morning of the test, the pain response threshold was examined by the Rapdalla and Selitta test, and animals whose threshold was ψ100 arbitrarily defined units were selected. After lunch, the measurements were repeated after the previous administration of the sc solution of the test compound, this administration was carried out 30 minutes before the measurement of the pain threshold. For each group, analgesic activity (%) was calculated from the average of the threshold values measured before and after treatment, compared to the means of control animals receiving vehicle only.

The following Table 3 shows the Na channel binding and analgesic activity of representative compounds of the invention as measured in previous assays.

Γ Γ <* Γ Γ

Table 3

Pharmacological activity

compound [ ^J H] BTX test: ²² To influx PGE ₂ test: from the example Na ⁺ channel binding IC ₅₀ (μΜ) Anälgetic activity no. Ki (nM) at 10 mg / kg s.c. (%) 2 876 10.7 49 6 1435 3.4 67 7 366 0, 94 57 8 397 0.97 47 10 3890 30 100 33 291 1/2 81 36 475 3.4 51 42 ND 4.3 46 43  ND 6 39 47 ND 0, 6 66 49 2183 7.6. 38 70 ND ND 46

ND = unspecified

Previous biological data has determined that compounds of Formula I are particularly useful for treating CNS disorders in mammals, particularly neuropathic pain, trigeminal neuralgia, diabetic neuropathy, ischaatic neuropathy and seizures. In particular, the compounds are very useful in the treatment of diabetic neuropathy, which is the most common complication accompanying diabetes mellitus. The compounds are also useful for the prophylaxis and treatment of migraine.

f Γ

The compounds of the invention may be administered to humans in need of treatment for chronic pain or seizure disorders, by oral and parenteral routes, for example, as tablets or capsules or as subcutaneous or intravenous injections. The compounds are administered in an amount effective to control and treat a seizure disorder or to relieve neuropathic pain. This effective amount is generally from about 0.1 to about 2000 mg / kg of mammalian body weight. Generally, prescribed doses are from about 5 mg / kg to about 500 mg / kg. This dosage amount can be administered to adults 1 to 4 times daily to relieve neuropathic pain and seizure disorders. The precise dose employed is dependent upon the specific compound of Formula I used, the particular condition of the patient being treated, and is generally determined by the attending physician or other practitioner.

The compounds may be formulated by conventional methods for conventional oral or parenteral dosing. Typical oral forms are tablets, capsules, lozenges, elixirs, syrups, suspensions, and sustained release forms such as an osmotic pump. The compounds may also be formulated for administration intraperitoneally, subcutaneously, intramuscularly, transdermally, sublingually, or intravenously. The compounds are formulated using conventional diluents, excipients, carriers and binders routinely used in the pharmaceutical art. For example, the compounds may be admixed with carriers, diluents and excipients such as starch, cellulose, PVP, methylcellulose, saccharide, wax, talc, and stabilizers and binders such as magnesium stearate, MgO, CaCO 3, methyl-p- hydroxybenzoate (methylparaben) and n-propyl p -hydrobenzoate (propylparaben).

The following further examples show typical pharmaceutical formulations of the invention.

·> T- i r · r

Example 74

Tablet preparation

Example 10 25.0 mg

Microcrystalline cellulose 50.0 mg

Modified edible corn starch 50.0 mg

Magnesium stearate 1.0 mg

The above ingredients are uniformly mixed and compressed into a tablet. These tablets are administered 1 to 4 times a day to a person suffering from chronic pain.

Example 75

Intravenous preparation

Example compound 400 mg

Acetate buffer 20 ml

Dilute aqueous HCl or NaOH to pH 6.5

Sterile isotonic saline qs 1000 ml

The compound of the invention was dissolved in acetate buffer and the pH was adjusted to 6.5. Isotonic saline was added to a volume of 1000 mL. The solution was filled with a sterile flexible plastic container equipped with a dropping tube. The solution was administered i. in. a patient suffering from diabetic neuropathy.

Claims (13)

PATENT CLAIMS 1. A tricyclic compound of formula I: R ¹ R ² KR ⁵ (D where: R ¹ is a hydrogen atom or a hydroxy group, R ² is a hydrogen atom or a hydroxy group, or R ¹ and R ² together are oxygen, A is a bond, CH ₂ , CHCH ₃ , CH 2 CH 2 or C (CH ₃ ) ₂ , R ³ and R ⁴ are the same or different and are hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, trifluoromethyl, NO ₂ , COR ⁶ , COOR ⁶ or NR ⁶ R ⁷ where R ⁶ and R ⁷ are the same or different and are hydrogen, C 1 -C 6 alkyl or benzyl, R ⁵ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a (O = C) -alkyl group having 1 to 6 carbon atoms, (0) = C) -alkenyl of 2 to 6 carbon atoms, (O = C) -cycloalkyl of 3 to 6 carbon atoms, wherein the alkyl, alkenyl and cycloalkyl groups may be substituted with 1, 2 or 3 groups selected from the group consisting of, which is a halogen atom, a C 3 -C 6 cycloalkyl group, a phenyl group or a substituted phenyl group, and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R ⁵ is C 1 -C 6 alkyl optionally substituted by phenyl or C 3 -C 6 cycloalkyl. A compound according to claim 1 or 2, wherein R ³ is a hydrogen atom, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms. A compound according to any one of claims 1 to 3, wherein R ¹ is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or a cycloalkyl group having 3 to 6 atoms. carbon, optionally substituted with 1, 2 or 3 groups selected from the group consisting of halogen, C 3 -C 6 cycloalkyl, phenyl or substituted phenyl, and R ₂ is hydrogen. A compound according to any one of claims 1 to 4, wherein R ⁴ is hydrogen. 6. A compound selected from the group consisting of: 3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'piperidine], Γ r r c 1'-cyclobutylmethyl-3,4-dihydro-l-oxo-spiro [naphthalene-2 (H), 4'-piperidin], 1'-cyclohexylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'piperidine], 1'-phenylethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (IH), 4 ' piperidine], 1'-cyclopropylethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'piperidine], 1'-cinnamyl-3,4-dihydro-1-oxospiro [naphthalene-2 (IH), 4 ' piperidine], 1 '- (3,3-diphenylpropyl) -3,4-dihydro-1-oxospiro [naphthalene2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-5,7-dimethyl-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1' - (cyclopropylmethyl) -3,4-dihydro-6- methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-5-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine ], 1 '- (cyclopropylmethyl) -3,4-dihydro-7-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-7-nitro-1-oxospiro [naphthalene2 (1H), 4'-piperidine], 1' - (cyclopropylmethyl) -7-amino-3,4-dihydro-1- oxospiro [naphthalene2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -7-chloro-3,4-dihydro-1-oxospiro [naphthalene2 (1H), 4'-piperidine], 3,4-dihydro-1'-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-allyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'- piperidine); 3,4-dihydro-1 '- (2-methylpropyl) -1-oxospiro (naphthalene-2 (1H), 4'-piperidine), C 6 -C 8 -cyclopropionyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine) -1 '- (trans-2-phenylmethylcyclopropyl), 3,4-dihydro-1'-benzyl-oxospiro (naphthalene-2 (1H), 4'-piperidine), 3,4-dihydro-1 '- (di-p-fluorobenzhydryl) -1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclopropylmethyl-1,3,4-trihydro-1-hydroxyspiro (naphthalene2 (IH), 4'-piperidine), 1'-cyclopropylmethyl-1,2,3,4-tetrahydrospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclopropylmethyl-1,3-dihydro-1-oxospiro [2H-indene- 2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -8,9-dihydrospiro [6H-benzocycloheptene-6,4'-piperidine] -5 (7H) -one, 1'-cyclopropylmethyl-3,4-dihydro-4 methyl-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine); 6-chloro-1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclopropylmethyl-3,4-dihydro-6-fluoro-oxospiro (naphthalene2 (IH), 4'-piperidine), 1'-cyclopropylmethyl-3,4-dihydro-6,7-dimethoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1 '- (1'-cyclopropyl-ethyl) -3,4 -dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1 '- (3-pentene) -3,4-dihydro-1-oxospiro (naphthalene-2 (1 H), 4'-piperidine), 1'- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), rr · 1'-cinnamyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4 'piperidine), 1'-cyclopropylethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2) (H), 4'-piperidine); 1'-cyclobutylmethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclohexylmethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cinnamyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene- 2 (1H), 4 'piperidine), 1' - (2-phenylethyl) -3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1 '- (3-phenylpropyl) -3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1' - (3,3'-diphenylpropyl) -3,4-dihydro -5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine) 1'-cyclobutylmethyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclohexylmethyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cinnamyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene- 2 (1H), 4 'piperidine), 1' - (2-phenylethyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'- (3-phenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'- (3,3'-diphenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), r. e'-cyclopropylethyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-7-methoxy-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine); 1'-cyclohexylmethyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cinnamyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene- 2 (H), 4'-piperidin) 1'- (2-phenylethyl) -3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1 '- (3-phenylpropyl) -3,4-dihydro- 7-methoxy-1-oxospiro (naphthalene-2 (IH), 4'-piperidine), 1- (3,3'-diphenylpropyl) -3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (IH) 4'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclohexylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 ( 1H), 4'-piperidine), 1'-cinnamyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1 '- (2-phenylethyl) -3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1' - (3-phenylpropyl) -3,4-dihydro-4- methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1 '- (3,3-diphenyl-propyl) -3,4-dihydro-4-methyl-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine); 6-chloro-1'-cyclopropylethyl-3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 6-chloro-D-cyclobutylmethyl-3,4-dihydro-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine); 6-Chloro-cyclohexylmethyl-3,4-dihydro-l-oxo-spiro (naphthalene-2 (IH), 4 / piperidine); 6-chloro-1'-cinnamyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4 'piperidine), 6-chloro-1 '- (2-phenylethyl) -3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 6-chloro-1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine); and 6-chloro-1 '- (3,3'-diphenylpropyl) -3,4-dihydro-oxospiro (naphthalene-2 (1H), 4'-piperidine), 3,4-dihydro-6-methoxy-l-oxo-spiro [naphthalene-2 (H), 4'-piperidine] 7. A compound selected from the group consisting of: 1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4 'piperidine], 1'-cyclopropylethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4' piperidine 1'-cinnamyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4 'piperidine], 1' - (3,3-diphenylpropyl) -3,4-dihydro-1-oxospiro [naphthalene2 ( 1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-5,7-dimethyl-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1' - (cyclopropylmethyl) -3,4- dihydro-6-methoxy-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-5-methoxy-oxospiro [naphthalene-2 (1H), 4'-piperidine ], rece 1 '- (cyclopropylmethyl) -3,4-dihydro-7-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -3,4-dihydro-7-nitro-oxospiro [naphthalene2 (1H), 4'-piperidine], 1' - (cyclopropylmethyl) -7-amino-3,4-dihydro-1-oxospiro [ naphthalene2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -7-chloro-3,4-dihydro-1-oxospiro [naphthalene2 (IH), 4'-piperidine], 1'-cyclopropylmethyl-1,3, 4-trihydro-1-hydroxyspiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclopropylmethyl-1,2,3,4-tetrahydrospiro (naphthalene-2 (1H), 4 'piperidine), 1'-cyclopropylmethyl-1,3-dihydro-1-oxospiro [2H-indene-2 (1H), 4'-piperidine], 1 '- (cyclopropylmethyl) -8,9-dihydrospiro [6H-benzocycloheptene-6,4'-piperidin] -5 (7H) -one, 1'-cyclopropylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 ( 1H), 4'-piperidine), 6-chloro-1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclopropylmethyl-3,4-dihydro-6-fluoro-1-oxospiro (naphthalene2 (IH) 1 ', 4'-piperidine), 1'-cyclopropylmethyl-3,4-dihydro-6,7-dimethoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1' - (1-cyclopropyl- 1-ethyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1 '- (3-pentene) -3,4-dihydro-1-oxospiro (naphthalene-2 (IH)) 4'-piperidine), 1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), R η f> β-Γ-cinnamyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4 'piperidine), 1'-cyclopropylethyl-3,4-dihydro-5-methoxy -1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cinnamyl-3 4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4 'piperidine), 1' - (3-phenylpropyl) -3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H) ), 4'-piperidine); 1 '- (3,3'-diphenylpropyl) -3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-6 -methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cinnamyl -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4 'piperidine), 1' - (3-phenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2) (1H), 4'-piperidine), 1 '- (3,3'-Diphenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-4 (1H), 4'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-7 methoxy-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine); 1'-cinnamyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (1H), 4 'piperidine), 1' - (3-phenylpropyl) -3,4-dihydro-7-methoxy-1 -oxospiro (naphthalene-2 (1H), 4'-piperidine), 1 '- (3,3'-diphenylpropyl) -3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine ) r r- rppf C r .. P 1'-cyclopropylethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 ( 1H), 4'-piperidine), 1'-cinnamyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4 'piperidine), 1' - (3-phenylpropyl) -3,4 dihydro-4-methyl-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine); 1 '- (3,3'-diphenylpropyl) -3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine), 6-chloro-D-cyclopropylethyl-3,4-dihydro-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine); 6-chloro-1'-cinnamyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4 'piperidine), 6-chloro-1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine); and 6-chloro-l- (3,3-diphenyl-propyl) -3,4-dihydro-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine); 3,4-dihydro-6-methoxy-l-oxo-spiro [naphthalene-2 (H), 4'-piperidine]. 8. A compound selected from the group consisting of: 1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1 H), 4 'piperidine], 1'-cyclopropylethyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1 H), 4' piperidine 1 ', 1' ^- cinnamyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1 H), 4' piperidine], 1 '- (3,3-diphenylpropyl) -3,4-dihydro-1-oxospiro [naphthalene 2] (H), 4'-piperidine], C 1 '- (cyclopropylmethyl) -3,4-dihydro-6-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine], 1' - (3-phenylpropyl) -3,4-dihydro-1 -oxospiro (naphthalene-2 (1H), 4'-piperidine), 1'-cyclobutylmethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclopropylethyl-3, 4-dihydro-6-methoxy-l-oxo-spiro (naphthalene-2 (H), 4'-piperidine); 1'-cyclobutylmethyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 1 '- (3-phenylpropyl) -3,4-dihydro-6-methoxy-1- oxospiro (naphthalene2 (1H), 4'-piperidine), 1'-cyclopropylethyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene2 (1H), 4'-piperidine), 3,4-dihydro-6-methoxy-l-oxo-spiro [naphthalene-2 (H), 4'-piperidine]. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 admixed with a pharmaceutically acceptable carrier or diluent. A method of treating a mammal suffering from a pain in need of treatment comprising administering an effective amount of a compound according to any one of claims 1 to 8. The method of claim 10, wherein the pain is neuropathic pain. The method of claim 10, wherein the pain is diabetic neuropathy. r π r «r c * r 13. A method of treating a mammal suffering from a seizure disorder comprising administering an effective amount of a compound according to any one of claims 1 to 8.