BG106162A - Tricyclic analgesics - Google Patents

Abstract

A tricyclic compound of formula wherein: R1 is hydrogen or hydroxy; R2 is hydrogen or hydroxy; or R1 and R2 together are oxygen; A1 is a bond, CH2, CH CH3, CH2 CH2 or (C(CH3)2; R3 and R4 are the same or different and are hydrogen, halo, C1-C6 alkyl, C1-C4 alkoxy, trifluoromethyl, NO2, COR6, COOR6 or NR6R7, wherein R6 and R7 are the same or different and are hydrogen, C1-C6 alkyl or benzyl; R5 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. 13 claims

Description

TECHNICAL FIELD

The invention relates to organic compounds characterized as having a fused bicyclic ring system substituted with a nitrogen-containing third ring. The compounds are effective in treating acute and chronic mammalian pain.

BACKGROUND OF THE INVENTION

Although chronic pain is a common condition in the population, its pathophysiology is not well understood. One possibility is that nasal-responsive spinal sensory neurons generate inappropriate activity after damage. Spinal sensory neurons become hyper-excitable and generate spontaneous impulses after damage in experimental animals and humans. Matzner and Devor (1992) suggest that hyper-excitability associated with chronic pain leads to an increase in Na channel density on the lesion side. Another hypothesis is that, after nerve damage, changes in kinetic and electrically dependent charge

characteristics of Na currents contribute to the generation of ectopic impulse and hyper excitability of spinal sensory neurons. The dorsal root ganglia (DRG) have a complex mixture of Na currents, including a highly tetrodotoxin-sensitive (TTX-S) current and a weak TTX-resistant (TTX-R) current. In rat DRG neurons, PGE ₂ , adenosine and serotonin, three agents that produce hyperalgesia in vivo increase the magnitude of TTX-R current and shift its conductivity / voltage ratio in the direction of hyperpolarization (Gold et al., 1996). After nerve damage, TTX-R currents are down-regulated in DRG neurons, and, in the same animals, TTX-S currents are up-regulated (Coming and Waxman, 1997). Using a specific Na channel antibody, Devor et al. (1993) show an accumulation of Na channels in the neuroma leading to a cross section of the nerve; accumulation of Na channels on damaged axonal tips may explain ectopic excitability of the canal, and lead to pain and paresthesia, which often complicates peripheral nerve damage in humans.

Axonal damage to the spinal sensory neurons appears to modify Na currents, significantly altering their excitability; Thus, selective Na channel blockers can be used to prevent or treat chronic pain in mammals. Sodium channel blockers have been found to be effective in chronic pain syndromes, including in triphminus neuralgia, Tfi diabetic neuropathy, in the prevention of mcren, and b | 5 and pain in cancer (reviewed by McQuay et al., 1995, British Medical Journal, 1995; 311: 1047 - 1052, and references cited therein).

However, pain due to acute or chronic nerve damage is difficult to treat and is often resistant to conventional analgesics. Such compounds include some topical anesthetics and anticonvulsants, for example, lidocaine, ethidocaine, benzocaine, tetracaine, riluzole, phenytoin, and gabapentin. Most of them, even when they are Na channel modulating agents, have limited clinical use due to the high risk of adverse effects. Lidocaine, for example, can cause cardiovascular collapse and, consequently, heart failure. Petrol can cause respiratory distress as well as skin rash, erythema, or edema. The use of phenytoin in diseases with apoplectic stroke can lead to hyperglycemia.

Because there is no effective chemical treatment for neuropathic pain, such as chronic pain, and since such pain is typically associated with diseases such as cancers, as well as severe physical injury and diabetic neuropathy, the need to search for compounds that can to be used clinically without serious adverse effects.

SUMMARY OF THE INVENTION

The invention now discloses a series of tricyclic compounds that are potent antagonists of neuronal Na channels. The compounds are characterized as condensed bicyclic ring systems, and have a third moiety substituted in the third ring.

The invention therefore provides tricyclic compounds of formula I:

where:

R ¹ is hydrogen 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 , CH CH ₃ , CH ₂ CH ₂ , or C (CH ₃ ) ₂ ;

R ³ and R ⁴ are the same or different and are hydrogen, halo, 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, C1-C6 alkyl, or benzyl;

R ⁵ is hydrogen, C 1 -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, (O = C) -C 1. ₆ alkyl, (O = C) -C ₂ . ₆ alkenyl, (O = C) -C ₃ . 6 cycloalkyl, wherein said alkyl, alkenyl and cycloalkyl groups may be substituted by 1, 2, or 3 groups selected from the group consisting of halo, C ₃ -C ₆ cycloalkyl, phenyl, or substituted phenyl, and their pharmaceutically acceptable salts.

The compounds of the invention are used in the clinical management and treatment of various conditions, such diseases as seizures (apoplectic stroke), epilepsy, neuroprotection, preferably lyric disorders such as cerebral ischemia, hypoxia and cardiac trauma, local anesthesia, pain, preferably acute. , chronic, neuropathic, acute internal organ pain, and somatic pain, inflammatory bowel syndrome (IBS), treatment for drug dependence, migraine, and compulsive compulsive diseases.

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

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

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

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 those of formula I wherein R ⁵ is H, C 1 -C 6 alkyl optionally substituted by a phenyl or C 3 -C 6 cycloalkyl group, and R ³ is hydrogen or C 1 -C 4 alkoxy.

Another embodiment of the present invention is a pharmaceutical composition comprising a compound of formula I mixed with a pharmaceutically acceptable carrier or diluent.

Another embodiment of the present invention is a method of treating mammals suffering from pain and in need of such treatment, which method consists in administering an effective amount of a compound of formula I.

Yet another embodiment of the present invention is a method of treating a seizure disorder (apoplectic stroke) in a mammal in need of such treatment, which method consists in administering an effective amount of a compound of formula I.

Methods for treating all other indications refer to the foregoing and are also within the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "C 1 -C ₆ alkyl" means a straight or branched carbon chain consisting of one to six carbon atoms. Examples of Ci - C ₆ alkyl groups include methyl, ethyl, isopropyl, sec-butyl, tert-butyl, isopentyl and n-hexyl.

"C ₁ -C ₆ alkoxy" means the preceding alkyl groups linked to oxygen, for example, methoxy, isopropoxy, and n-hexyloxy.

"C ₂ - C ₆ alkenyl" means straight or branched carbon chain consisting of two to six carbon atoms having one double carbon-carbon bond in the chain. Examples include ethenyl, 2-propenyl, 1-methyl-3-pentenyl, 1-ethyl-2-butenyl, and 5-hexenyl.

"C ₃ - C ₆ cycloalkyl" means a non-aromatic cyclic ring having from three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The above alkyl, alkenyl and cycloalkyl groups may be substituted by 1, 2, or 3 groups selected from the group consisting of halogen, unsubstituted Q ₃ -C ₆ cycloalkyl, phenyl, or substituted phenyl. "Halogeno" means chloro, bromo, fluoro, and iodo. "Substituted phenyl" means a phenyl group having 1, 2, or 3 substituents selected from the group consisting of halo, hydroxy, nitro, unsubstituted Ci - C ₆ alkyl, unsubstituted Ci - C ₆ alkoxy, and NH ₂ group.

Examples of a - C ₆ alkyl group substituted by cycloalkyl include cyclopropylmethyl, 1-cyclobutylethyl, 3-cyclohexylbutyl and 3,3-dicyclohexylpropyl. Halo-substituted alkyl groups include chloromethyl, 1,2-dibromoethyl, trifluoromethyl, and 1-bromo-3-chloro-6-iodohexyl. Alkyl groups substituted by phenyl or substituted phenyl include benzyl, 1-phenylpropyl, 1-methyl-3-phenyl-butyl,

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

Examples of substituted Cz-C _Q 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-phenyl-cyclobutyl) -4-pentenyl.

Examples of substituted C ₃ - C ₆ cycloalkyl groups include 3-tsiklopentiltsikpoheksilova, 3-feniltsiklobutilova, 3-hlortsiklopentilova, 2,2-dibromo-H-nitrocyclohexyl, and 2,2-di- (3-methoxyphenyl) -tsiklopropilova.

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

The alkyl, alkenyl and cycloalkyl substituted groups may be linked to a carbonyl group (O = C). Examples include acetyl, pivaloyl, 1-oxo-3-pentyl yl, 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 -, -CHCH 3, -CH- (CH ₃ ) _2, and -CH ₂ CH ₂ -; so the compounds of the invention may have the following general structures:

(la)

(Ic)

Preferred compounds of the present invention include the following:

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

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

'-Cyclobutylmethyl-3,4-dihydro-1-oxospiro [naphthalene2 (1H), 4'-piperidine];

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

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

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

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

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

- (cyclopropylmethyl) -3,4-dihydro-5,7-dimethyl-1-oxospiro [naphthalene-2 (1H), 4'-piperidine];

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

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

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

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

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

- (cyclopropyl methyl) -7-chloro-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine];

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

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

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

-cyclopropionyl-3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine);

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

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

3,4-dihydro-1 '- (di-p-fluorobenzhydryl) -1-oxospiro (naphthalene-2 (1H), 4'-piperidine);

'-cyclopropylmethyl-1,3,4-trihydro-1-hydroxy-spiro (naphthalene-2 (1H), 4'-piperidine);

'-cyclopropylmethyl-1,2,3,4-tetrahydro-spiro (naphthalene-2 (1H), 4'-piperidine);

'-cyclopropylmethyl-1, 3-dihydro-1-oxospiro- [2H-indene -2,4'-piperidine];

1 '- (cyclopropyl methyl) -1,8,9-dihydrospiro [6H-benzocycloheptene-6,4'-piperidine] -5 (7H) -one;

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

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

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

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

'- (1-cyclopropyl-1-ethyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine);

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

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

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

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

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

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

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

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

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

'- _(3! 3 ' difenilprolil) -3,4-dihydro-5-methoxy-1 oksospiro- (naphthalene-2 (1H), 4'-piperidin ^ n);

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

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

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

1 -14aminyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine);

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

'- (3,3'-diphenylpropyl) -3,4-dihydro-4-methyl-1 oxospiro (naphthalen-2 (1H), 4'-piperidine);

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

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

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

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

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

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

More preferred compounds of the invention include the following:

'-Cyclopropyl methyl-3,4-dihydro ro-1-oxospiro [naphthalene -2 (1H), 4'-piperidine];

'-Cyclopropylethyl-3,4-dihydro-1-oxospiro [naphthalene2 (1H), 4'-piperidine];

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

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

'- (cyclopropylmethyl) -3,4-dihydro-5,7-dimethyl-1-oxospiro [naphthalene-2 (1H), 4'-piperidine];

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

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

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

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

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

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

'-cyclopropylmethyl-1,3,4-trihydro-1-hydroxy-spiro (naphthalene-2 (1H), 4'-piperidine);

'-cyclopropylmethyl-1,2,3,4-tetrahydro-spiro (naphthalene-2 (1H), 4'-piperidine);

1-Cyclopropylmethyl-1,3-dihydro-1-oxosgifo [2Ninden-2,4'-piperidine];

N- (cyclopropylmethyl) -8,9-dihydrospiro- [6H-benzocycloheptene-6,4'-piperidine] -5 (7H) -one;

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

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

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

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

'- (1-cyclopropyl-1-ethyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine);

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

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

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

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

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

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

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

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

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

'-cyclobutylmethyl-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);

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

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

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

β 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);

'- (3,3'-diphenylpropyl) -3,4-dihydroO'7-methoxy-1-oxo 5 spiro (naphthalene-2 (1H), 4'-piperidine);

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

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

^w 1'-cinnamyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine);

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

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

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

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

6-chloro-1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); and '- (cyclopropylmethyl) -7-chloro-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); and '-cyclopropyl methyl-1,3,4-trihydro-1-hydroxy-spiro (naphthalene-2 (1H), 4'-piperidine);

'-cyclopropylmethyl-1,2,3,4-tetrahydro-spiro (naphthalene-2 (1H), 4'-piperidine);

'-Cyclopropylmethyl-1, 3-dihydro-1-oxospiro- [2Nindene-2,4'-piperidine];

1 '- (cyclopropylmethyl) -8,9-dihydrospiro- [6H-benzocycloheptene-6,4'-piperidine] -5 (7H) -one;

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

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

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

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

'- (1-cyclopropyl-1-ethyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine);

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

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

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

N-cyclopropylethyl-3,4-dihydro-5-methoxy-1-xospiro (naphthalene-2 (1H), 4'-piperidine);

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

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

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

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

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

'-cyclobutylmethyl-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);

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

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

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

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

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

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

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

1-Cyclobutylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4H-pyridium);

1-cinnamyl-3,4-dihydro-4-methyl-1-oxospiro- (naphthalene2 (1H), 4'-piperidine);

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

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

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

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

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

6-chloro-1 '- (3,3'-diphenylpropyl) _-3> 4-dihydro-1 -oksospiro (naphthalene-2 (1H), 4'-piperidine); and

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

Most preferred compounds of the invention include the following:

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

'-Cyclopropylethyl-3,4-dihydro-1-oxospiro [naphthalene2 (1H), 4'-piperidine];

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

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

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

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

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

'-Cyclobutylmethyl-3 D-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine;

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

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

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

The compounds of formula I are characterized in that they are cyclic rings having a spiro ring as a substituent group. The spiro ring contains a nitrogen atom (for example, Ν-R ⁵ ) which may be basic when R ⁵ is such a group as alkyl, alkenyl, or cycloalkyl. Such basic compounds readily form pharmaceutically acceptable salts by reaction with ordinary mineral and organic acids. Typical acids used to form pharmaceutically acceptable salts of the invention include hydrochloric, sulfuric, sulfamic, phosphoric, citric, succinic, glutamic, maleic, lactic, tartaric, p-toluenesulfonic, benzoic, oxalic and salicylic acids. Salts are prepared by simply contacting the spiro base with the appropriate acid, usually in a solvent such as methanol or diethyl ether. The salts are usually crystalline, easily precipitated, and collected by filtration. They can then be purified by recrystallization from ordinary solvents such as methanol, ethyl acetate, acetone and tetrahydrofuran.

The compounds of the formula I according to the invention are readily prepared by methods well known in the field of organic chemistry. It is generally preferred to first obtain a compound in which R ⁵ is hydrogen and then react with the compound with P ⁵ -alkylating or -acylating agents. Such a reaction is shown in Scheme 1 below:

Where R ¹ , R ² , R ³ , R ⁴ , and A have the meaning indicated above, and "L" is a leaving group (e.g., halogen such as chloro or bromo or silyl derivative such as trimethylsilyl).

The above reaction is effected by combining approximately equimolar amounts of spiro amine with an alkylating or acylating agent (e.g., L-R ⁵ ), typically in a reaction-inert organic solvent such as tetrahydrofuran, dimethylsulfoxide, or N, N-dimethylformyl. Bases such as triethylamine or NaHCO ₃ can be used to act as an acid binding agent if desired. The reaction is typically substantially complete until about 2 - 20 hours when carried out at a temperature of about 25 ° C to about 60 ° C. The product is easily isolated by removing the solvent of the reaction, and then, if desired, purification can be carried out in normal ways, such as salt formation, crystallization, and chromatography.

The necessary starting material, such as spiro amine, can be synthesized from readily available reagents using any of several methods:

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

Scheme 2

According to Scheme 2 above, P is an amine protecting group that is easily removed, for example, ethoxycarbonyl or benzyl. The protected dimethylamine 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 spiro amino derivative which is readily deprotected by conventional means, for example, by reaction with hydrochloric acid.

Scheme 2 illustrates the preparation of keto substituted starting materials, for example, R ¹ and R ² together are oxo. Such © compounds are readily converted to the corresponding alcohol (R ¹ is H, R ² is OH) by reacting with a reducing agent such as NaBH ₄ , typically in a solvent such as methanol or ethanol.

Further, the alcohol can be reduced by catalytic hydrogenation, for example by reacting with hydrogen gas in the presence of 10% palladium on carbon. These reactions are illustrated in Scheme 3:

Scheme 3

The compounds of formula I according to the invention can alternatively be prepared starting from a suitably substituted piperidine derivative, as shown in Scheme 4:

Scheme 4

The cyclization reaction is effected by reacting the substituted piperidine with a highly dehydrating agent such as phosphorus pentachloride and titanium tetra

is chloride, usually in a reaction-inert organic solvent such as benzene, toluene, xylene, or chloroform. Typically, the reaction is complete within 2 hours when carried out at a temperature of 30 ° C to 60 ° C.

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

The substituted piperidine required for the above reaction is readily prepared according to the scheme shown in Scheme 5:

Figure 5

According to Scheme 5, methyl 4-piperidine formate is reacted with an amine protecting agent (e.g., to include P). Typical amine protecting groups include tert-butoxy carbonyl, benzyl and trimethylsilyl. The protected piperidine derivative is then reacted with a phenyl alkyl 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 of a strong base such as NH or lithium diisopropylamide (LDA), typically in a reaction-inert organic solvent such as tetrahydrofuran or benzene. The reaction, carried out at -20 ° C, generally essentially ends completely after approximately 2-4 hours. The alkylated piperidine can then be deprotected (removed by the L-protecting group) and cyclized by reacting with PCl ₅ and TiCl ₄₎ or, first, it may be cyclized and then L- the protecting group.

The following detailed examples illustrate the synthesis of specific compounds provided by this invention. The examples are only representative and do not in any way limit the invention.

EXAMPLE 1

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

Step 1: Bis (2-bromoethyl) amine hydrobromide.

157 g (1.5 mol) of diethanolamine, stirring from time to time, 1.35 (1.5 mol) of 48% HBr (exothermic reaction) were placed in a 2 L three-necked flask, which could be adapted for heating under reflux, it was for distillation. The solution was heated at a bath temperature of the order of 180 - 200 ° C in order to distil a volume of 350 mL at a vapor temperature of 122 ° C. SetTy adjust to reflux and hold for 1 hour. Further distillation as above was carried out in order to collect a distillate of 465 mL. The plant was adjusted again to the reflux temperature for 3.75 hours and then distilled 400 mL. 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 are obtained. Yield = 78.5%, mp (° C) = 130-135 ° C.

Step 2: Ethyl bis (2-bromoethyl) amine carbamate.

367 g (1.17 mol) of the product obtained in the previous step and then 108 mL, i.e., 122.6 g (1.13 mol), ethyl chloroformate, were added, with stirring, to a 4L reactor containing 1 , 8 L water / ice mixture. Approximately 1.3L of 2N sodium hydroxide solution was poured into the solution for 5 minutes in order to reach a constant pH of 11 while maintaining the temperature below 5 ° C. The mixture was stirred for 5 minutes and then acidified to pH 1 with concentrated HCl. Extraction is carried out with 3 times 1 L ethyl ether. The organic phase was washed 3 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 are obtained. Yield = 58%, (CH ₂ Cl ₂ ): R _f = 0.6,

N.M.R. : CDCI3 Ή ((ppm): 1.2 (t, 3H), 3.4-3.55 (m, 4H), 3.6 -3.7 (m, 4H), 4.1-4.2 (q, 2H)).

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

g (0.47 mol) of 1-tetralone and 234 mL of DMF, previously dried over a molecular sieve, were introduced into a moisture-proofed 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 dispersed in mineral oil were added thereto. The temperature was allowed to rise to approximately 20-25 ° C (exothermic reaction). The reaction mixture was stirred for 1.5 hours at a temperature below 30 ° C.

At the same time, a solution of 208 g (0.69 mol) of ethyl bis (2bromethyl) carbamate in 234 mL of DMF (previously dried over a molecular sieve) was cooled in a moisture-proofed reactor under an inert atmosphere. to -15 ° C in a dry ice / acetone bath. The reaction liquors, obtained in the same way, were introduced by transfer to a nitrogen atmosphere and reacted for 10 minutes at -25 ° C. the temperature was allowed to rise (exothermic reaction with temperature rise to 45 ° C). The reaction mixture was then cooled to maintain at approximately 30 ° C. It was then brought to 50 ° C for 2 hours, and then the solvent was evaporated at 50 ° C in vacuo at less than 1 mm Hg. The residue was dissolved in 1.2 L of ice-cold water and extracted 3 times with 600 mL of ether. The organic phase was washed 3 times with 500 mL of demineralized water, and then dried over Na ₂ SO ₄ . Evaporation of the solvent gave a brown oily residue, which was purified by crude oil.

graphy eluting with CH ₂ Cl ₂ gradually enriched with acetone. 57.7 g (0.2 mol) of the product are obtained.

(Yield = 42.5%), TLC (97/3 CH ₂ Cl ₂ / acetone): K _z = 0.45.

NMR: CDCI ₃ ¹ 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, 1 Η), 7.35 (dd, 1 Η), 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- [naphthalene 2- (1H), 4'-piperidine] -1'-carboxylate, and then 1.6 L 6N HCl are introduced into 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 while cold with NaOH, and extracted 3 times with 500 ml of ethyl ether each time. 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 , gradually enriched with 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: CDCI3 ¹ 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), 2.80-3.0 (m, 4H), 7.1 (d, 1 Η), 7.2 (dd, 1 Η) , 7.35 (dd, 1H), 7.9 (d, 1H).

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

White powder, mp = 235 ° C, TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.35.

The analysis corresponds to Ci ₄ Hi ₈ CINO.

IR: 2995,2700,1675, 1600, 1440, 1395, 1210, 1090, 990, 750 740 cm ^'1.

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

g (46.4 mol) of 3,4-dihydro-1-oxospiro- [naphthalene-2 (1H), 4'-piperidine] and then 80 mL of DMF and 36.2 mL of THF were introduced into a three-necked flask. 6.89 g (51 mol) of (bromomethyl) cyclopropane and 7.8 g (92.8 mol) of NaHCO _{3 were added} . The suspension was refluxed and maintained for 1.5 hours. The solvents were evaporated at 50 ° C in vacuo at less than 1 mm. The residue was dissolved in 200 mL of water and extracted 3 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 while cold with NaOH, and extracted 3 times with 100 ml of ethyl ether. The organic phase was washed with NaCl solution and dried over Na ₂ SO ₄ . Evaporation of the solvent gave 12 g of an oily residue. The hydrochloride is obtained by the addition of approximately 5N ethereal hydrochloric acid to a solution of the crude product in CH ₂ Cl ₂ . The mixture was concentrated to dryness and then the product was crystallized by adding 20 mL of ether to a solution of the product in methanol, allowing the crystallization to proceed overnight at 20-25 ° C, and then filtering the product. and washed with water. After drying, 8.4 g of product are obtained.

White powder, mp = 243 ° C, TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): Rf = 0.55.

Analysis corresponds to Ci ₈ H ₂₄ CINO.

NMR: CDCI ₃ ¹ H ((ppm) HCl: 0.4-0.55 (m, 2H), 0.75-0.8 (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, 1Η), 7.3 - 7.35 (m, 1Η), 7.5 - 7.6 (m, 1Η), 7.95-8.0 (m, 1H), 12.0-12.2 (m, 1H).

IR: 2990, 2700, 1675, 1600, 1420, 1395, 1320, 1080, 980, 900, 760 740 cm ^'1.

Appropriate iodomethylates were also obtained. Mp 162 ° C.

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

The method described in Example 2 using cyclobutylmethyl bromide produced the product in the form of hydrochloride. Beige powder, mp = 235 ° C.

TLC (92/8 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.7.

Analysis corresponds to Ci ₉ H ₂₆ CINO.

NMR: CDCI3 ¹ H ((ppm) HCl: 1.8-2.25 (m, 10H), 2.4-2.5 (m, 2H), 2.95-3.1 (m, 5H), 3.1-3.25 (m, 2H), 3.25-3.35 (m, 2H),

7.2 - 7.35 (m, 2H), 7.45 - 7.55 (m, 1 Η), 7.9 - 8.0 (m, 1 Η), 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 .

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

The method described in Example 2 using cyclohexylmethyl bromide produced the product in the form of hydrochloride. Beige powder, mp = 265 ° C.

TLC (93/7 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.8. Analysis corresponds to C ₂ H ₃ oCINO.

NMR: CDCl3 ¹ H ((ppm) HCl: 0.95-1.3 (m, 5H), 1.6-2.1 (m, 10H), 2.5-2.65 (m, 2H), 2.7-2.8 (m, 2H), 2.9-3.0 (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 ' ¹ .

Example 5 '-phenylethyl-3,4-dihydro-1-oxospiro [naphthalene-2- (1H), 4'-piperidine].

The method described in Example 2 using phenethyl bromide produced the product in the form of hydrochloride. Beige powder, mp => 275 ° C, yield 55%.

TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.85. Analysis corresponds to C ₂₂ H ₂₆ CINO.

NMR: CDCI ₃ ¹ H ((ppm) HCl: 2.0-2.15 (m, 10H), 2.5-2.65 (m, 4H), 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, 1 Η), 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, 700, cm ' ¹ .

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

0.94 g (4.36 mmol) of 3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine] and then 10 mL of DMF were introduced into a three-necked flask. To the resulting solution was added 1.3 g (8.7 mmol) of (bromomethyl) cyclopropane in 2 mL of DMF, and then 0.73 g (8.7 mmol) of NaHCO ₃ . The suspension was refluxed and maintained for

1.5 hours. The solvents were evaporated at 50 ° C in a vacuum of less than 1 mm. The residue was dissolved in 50 ml of water and extracted 3 times with 50 ml of ether each. The ether phase was extracted with 100 ml of 1N HCl, and then twice with 50 ml of water each. The aqueous phase was basified while cold with concentrated NaOH and extracted 3 times with 50 ml of ethyl 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 chromatography, extracting with CH ₂ Cl ₂ enriched in methanol. 0.6 g of product are obtained, and its hydrochloride is obtained by adding approximately 5N ether hydrochloric acid to a solution of the crude product in CH ₂ Cl ₂ . 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. The crystallization was allowed to proceed for 14 h at 20-25 ° C, then the product was filtered off and washed with ether. After drying, 0.5 g of white powder is obtained, mp = 244 ° C,

TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.35. Analysis corresponds to Ci ₉ H ₂₆ CINO.

NMR: CDCI ₃ ¹ H ((ppm) HCl: 0.1 - 0.3 (m, 2H), 0.45 - 0.65 (m, 2H), 0.7 - 0.8 (m, 1 Η ), 1.6 - 2.6 (m, 8Η) 2.9 - 3.5 (m, 8H), 7.2 - 7.4 (m, 2H), 7.4 - 7.6 (t, 1 Η), 7.9 - 8.05 (d, 1 Η), 12.15 (1 Η)).

IR: 2900, 2450, 1670, 1600, 1430, 1290, 1220, 950, 890 740 cm ^'1.

Example of Ί ′-cinnamyl-3,4-dihydro-1-oxospiro [naphthalene-2- (1H), 4′-piperidine].

It was prepared according to the method described in Example 2 with cinnamyl bromide, and then purified by chromatography and crystallization of the hydrochloride.

white powder, mp = 228 ° C,

TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.55. Analysis corresponds to C ₂₃ H ₂₆ CINO.

NMR: CDCI ₃ ¹ H ((ppm) HCl: 2.0-2.25 (m, 4H), 2.3-2.5 (m, 2H), 2.9-3.85 (m, 8H) , 6.4 - 6.6 (d, 1 Η), 7.1 - 7.6 (m, 8Η), 7.9-8.0 (d, 1H), 12.1 (1H).

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

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

Oh

Obtained according to the method described in Example 6 with 3,3-diphenylpropyl bromide to give the hydrochloride. A white powder was obtained, mp = 257 ° C, TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.35.

Analysis corresponds to C ₂₉ H ₃₂ CINO.

NMR: CDCI3 ¹ H ((ppm) HCl: 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, 1H), 12.3 (1H).

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

Example 9 '- (cyclopropylmethyl) -3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine].

3,4-Dihydro-5,7-dimethyl-1-oxospiro [naphthalene-2- (1H), 4n-piperidine] is obtained according to the method described in the synthesis of Example 1. "N" alkylation is identical to described in Example 6. The hydrochloride is obtained in the form of a white powder, mp> 260 ° C.

TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.5. Analysis corresponds to C ₂₀ H ₂₈ CINO.

N.M.R. : CDCI3 'H ((ppm) HCl: 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 3, 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, 1H), 12.15 (1H)).

IR: 3,400, 2900, 2500, 1670, 1605, 1470, 1430, 1280, 11.80, 1020, 970, 950, 880, 830 cm ^'1.

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

According to the method of Example 9, the hydrochloride was obtained.

White powder, mp> 255 ° C.

TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.35. Analysis corresponds to Ci ₉ H ₂₆ CINO ₂ .

NMR: CDCI ₃ ¹ H ((ppm) HCl: 0.4 -0.5 (m, 2H), 0.75-0.85 (m, 2H), 1.25-1.4 (m, 1 Η ), 2.05 - 2.2 (m, 4Η), 2.35 - 2.5 (m, 2H), 2.8 - 2.95 (m, 4H), 2.95 - 3.05 (m , 2H), 3.2 - 3.4 (m, 2H), 3.45 -

3.6 (m, 2H), 3.85 (S, 3H), 6.67 (s, 1H), 6.85 (d, 1H), 7.90 - 8.0 (d, 1H), 12 , 15 (1H)).

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- (1H), 4'-piperidine].

The same method as in Example 10; hydrochloride is obtained.

White powder, mp = 244 ° C.

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

NMR: CDCI3 ¹ 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), 3.1 - 3.3 (m, 2H) ), 3.5 - 3.6 (m, 2H), 3.85 (S, 3H), 7.0 - 7.1 (m, 1H), 7.25 - 7.35 (m, 1H), 7.5 - 7.6 (m, 1 Η), $ 12.1-12.2 (1 Η)).

IR: 2930, 2560, 2360, 1680, 1580, 1470, 1435, 1260, 1060, 970, cm @ ^-1 .

I

I

I * Example 12 ί 1 '- (methylcyclopropyl) -3,4-dihydro-7-methoxy-1-oxospiro [naphthalene-2- (1 Η), 4′-piperidine].

Using the same method as in Example 10, hydrochloride a was obtained.

White powder, mp = 235 ° C.

TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% ΝΗ ₄ ΟΗ):

R _f = 0.70 - 0.75. The assay was for C19H26CINO2.

NMR: CDCI3 ¹ H ((ppm) HCl: 0.4 -0.5 (m, 2H), 0.75-0.85 (m, 2H), 1.25-1.4 (m, 1 Η) , 2.05 - 2.2 (m, 4Η), 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), 7.0 - 7.1 (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 '- (cyclopropylmethyl) -3,4-dihydro-7-nitro-1-oxospiro [naphthalene-2- (1H), 4'-piperidine].

Step 1: 2.4 g (8.35 mmol) of ethyl 3,4-dihydro-7-nitro-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 introduced into a three-necked flask. 0.79 g (12.5 mmol) of fuming nitric acid was added to the solution cooled to 0 ° C. The mixture was stirred for 1 hour at 0 ° C, and then for 2 hours at 20-25 ° C. the solution was precipitated with 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 evaporating the solvent, 2.75 g of an oil is obtained, which is chromatographed, eluting with CH ₂ Cl ₂ , gradually enriched with acetone. 1.5 g of ethyl 3,4-dihydro-7-nitro-1-oxospiro- [naphthalene-2 (1H), 4'-piperidine] -1-carboxylate are obtained in the form of an oily crystalline residue. Yield = 54%,

TLC (8/2 CH ₂ Cl ₂ / acetone): R _f = 0.3.

NMR: CDCI ₃ ¹ H ((ppm): 1.15 (t, 1H), 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 of the preceding step was hydrolyzed by the method described in Step 4, Example 1. After chromatography, eluting with CH ₂ Cl ₂ , gradually enriched with methanol containing 10% NH ₄ OH, was isolated

O, 45 g. TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): Rr = 0.1.

Step 3: 0.22 g (0.845 mmol) of 3,4-dihydro-7-nitro-1-oxospiro- [naphthalen-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 refluxed and maintained for approximately 5 hours.

The solvent was removed, and the residue was dissolved in 20 ml of CH ₂ Cl ₂ and extracted with 20 ml of N / 1 HCl. The acidic phase was basified while cold with a dilute solution of sodium hydroxide to pH 12, and extracted 3 times with 20 ml of CH ₂ Cl _{2 each} . After washing, drying and removal of the solvent, the residue is chromatographed, eluting with CH ₂ Cl ₂ , gradually enriched with methanol containing 10% NH ₄ OH. 0.130 g was obtained. 3,4-dihydro-1 '- (cyclopropylmethyl) -7-nitro-1 oxospiro [naphthalene-2- (1H), 4'-piperidine].

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, mp = 256 ° C.

TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.7. Analysis corresponds to Ci8H ₂ 3CIN ₂ O ₃ .

NMR: CDCl3 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 - 4.6 (m, 2H), 7.45 (d, 1H), 8.3 (d, 1H), 8.8 (S, 1H), 12.1 (1H)).

IR: 2940, 2500, 2440, 1690, 1610, 1520, 1410, 1345, 1220, 1105 960 cm ^'1.

Example 14 '- (cyclopropylmethyl) -7-amino-3,4-dihydro-7-nitro-1-oxospiro- [naphthalene-2- (1 Η), 4′-piperidine].

mg (0.845 mmol) of 3,4-dihydro-1 '- (methylcyclopropyl) -

7-Nitro-1-oxospiro- [naphthalen-2- (1H), 4'-piperidine], prepared as described in Example 13, was dissolved in 1 ml of THF, and then tin chloride hydrate was added with stirring. . The solution was brought to reflux for 1 h. It is fed to the reaction liquors

NaHCO ₃ to saturated solution, and extracted 3 times with CH ₂ Cl ₂ . The organic phase was washed and dried over Na ₂ SO ₄ . The solvent was evaporated, and the resulting residue was chromatographed, eluting with CH ₂ Cl ₂ , gradually enriched with methanol containing 10% NH 4 OH. 29 mg of product are obtained.

NMR: CDCl3 ¹ H ((ppm): 0.1 -0.2 (m, 2H), 0.4-0.55 (m, 2H),

O, 85-1.0 (m, 1H), 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, O (d, 1H), 7.2 (S, 1H)).

The hydrochloride crystallizes from ether. 26 mg of a yellow powder are obtained.

mp = 200 ° C, decomposed. TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.45.

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

Step 1: Piperidine-1,4-dicarboxylic acid, 4-ethyl 1t-butyl ester.

g (0.381 mol) of ethyl isonepecotate and 400 mL of THF were placed in a three-necked, moisture-proofed flask in an inert atmosphere and 18.3 g (0.458 mol) of sodium hydroxide pellets were added. A solution of 100 g (0.458 mol) of difButyl dicarbonate in 170 mL of THF was added to the suspension for 1 h with stirring. The temperature reaches 45 ° C. The reaction mixture was left stirring for 14 h at 20-25 ° C and then poured into 2I water and ice, and extracted 3 times with 500 ml of ether each. The organic phase was extracted 3 times with 250 ml of saturated NaCl solution, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by chromatography, extracted with CH ₂ Cl ₂ enriched gradually with acetone, and then distilled in vacuo at 0.09 mm Hg, and at vapor temperature.

95-102 ° C. 82 g (yield = 83.6%) are obtained.

TLC (95/5 CH ₂ Cl ₂ / acetone): R _f = 0.60.

NMR: CDCI ₃ ¹ H ((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, 2H), 2.7-2.85 (m, 2H),

3.9 - 3.40 (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 diisopropylamine and 174 mL of THF, dried over a molecular sieve, were introduced by transfer into a nitrogen atmosphere in a three-necked, moisture-proofed flask in an inert atmosphere. The solution was cooled to -10 ° C, and 24.3 ml of 2.5N n-butyllithium in hexane (60.9 mmol) were added thereto. The mixture was stirred for 15 minutes at -10 ° C, and cooled to -70 ° C, a solution of 10.4 g (40.6 mmol) of the product obtained in the previous step was poured inside for 20 minutes. 1, in 86 ml of THF. The mixture was stirred for 10 minutes at -70 ° C, and then 10.9 g (60.9 mmol) of NMRT was added. The mixture was left at -70 ° C with stirring for 1.5 hours, poured inside for 20 minutes, a solution of 4-chlorophenethyl bromide (10.7 g,

48.7 mmol) in 86 ml THF at -70 ° C. The mixture was stirred at 20-25 ° C for 14 hours, then poured onto 350 ml of water, and extracted 3 times with ether. The organic phase was washed with N / 1 HCl solution and then with saturated NaCl solution. After drying and concentration, 17 g of an orange oil are obtained, which is chromatographed, eluting with CH ₂ Cl ₂ , gradually enriched with hexane and then with acetone. Obtained 11.8 g (Yield = 80%), TLC (95/5 CH ₂ Cl ₂ / aqeTOH): R _f = 0.70.

NMR: CDCI 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), 2.7-2.9 (m, 2H), 3, 7 - 3.9 (m, 2H), 4.05 - 4.15 (q, 2H), 6.9 - 7.0 (m, 2H), 7.1-7.2 (m, 2H)) .

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

10.8 g of the product obtained according to the preceding step and 50 ml of CH ₂ Cl ₂ were introduced into a three-necked flask that was protected from moisture. The mixture was stirred and 25 ml of trifluoroacetic acid were added at 20-25 ° C. The mixture was left stirring for 30 minutes, then concentrated to dryness, and the residue dissolved 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 crystallized oil are obtained. TLC (90/10 CH ₂ Cl ₂ / methanol containing 10% NH ₄ OH): R _f = 0.45. NMR: CDCI3 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-chlorophenyl) piperidine-4-carboxylate

3.4 g (11.5 mmol) of the product obtained according to the previous step 3, 3.87 mL of THF, dried over a molecular sieve, and then, with stirring, 14.9 ml of triethylamine and

2.4 ml (20.9 mmol) of 85% (bromomethylBicyclopropane are successively introduced into a moisture-proof, round-bottomed flask under a nitrogen atmosphere. The mixture is heated at reflux for 14 hours. , then concentrated to dryness and the residue dissolved in water and extracted twice with ether. The organic phase, washed with saturated NaCl solution and dried, was concentrated to give 3 g of product which was chromatographed (eluent: CH ₂ Cl ₂ gradually enriched with methanol containing 10% NH ₄ OH) to give 2.6 g of an oily product. Yield = 65%.

TLC (95/5 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.50.

• NMR: CDCI3 ¹ H ((ppm): 0.0 - 0.1 (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), 1.7-1.8 (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 (q , 2H), 6.9 - 7.0 (dd, 2H), 7.1 - 7.2 (dd, 2H)).

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

2.2 g (6.28 mmol) of the preceding ester and 6.6 mL of anhydrous dimethyl sulfoxide were introduced into a round-bottomed flask that was protected from moisture and which was in a nitrogen atmosphere. A solution of t-butoxide 4.4 g (39 mmol) in 30 ml dimethyl sulfoxide was added with stirring. The mixture was stirred for 2 hours at 20-25 ° C. The reaction mixture was brought to 200 ml with water and then 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 Cl ₂ / methanol. Mp = 250 ° C

N.M.R. : CDCh Ή ((ppm): 0.2 - 0.3 (m, 2H), 0.5 - 0.6 (m, 2H), 1.07-1.1 (m, 2H), 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) -1oxospiro- [naphthalene-2- (1H), 4'-piperidine].

0.3 g (0.9 mmol) of the acid obtained previously and 6 ml of benzene were introduced into a moisture-proof, round-bottom flask under a nitrogen atmosphere. 0.24 g of PCI ₅ and 6 ml of CH ₂ Cl _{2 are added} , followed by another 0.24 g of PCI _5. The mixture is stirred for 2 hours at 20-25 ° C. The mixture was cooled to 0 ° C, 0.44 ml of tin tetrachloride (abundant precipitate) was added, 12 ml of CH ₂ Cl _{2 was added} , and the mixture was left at 0 ° C for 1 hour and then at 20 - 25 ° C for 14 hours. The solvents were removed and the residue was dissolved with water. The aqueous phase was washed with water, 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 gradually enriched with methanol containing 10% ΝΗ ₄ ΟΗ. 22 mg of the product is obtained, the product is treated with a solution of CH ₂ Cl ₂ with 5N hydrochloric acid. After crystallization from ethyl acetate, the product was filtered off and dried at 50 ° C in vacuo.

White powder. TLC (90/10 CH ₂ Cl ₂ / MeOH containing 10% NH ₄ OH): R _f = 0.55, mp = 263 ° C.

NMR: CDCI3 ¹ H ((ppm) HCl: 0.4 - 0.5 (m, 2H), 0.7 - 0.8 (m, 2H),

1.2-1.3 (m, 1H), 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),

7.2-7.3 (m, 1H), 7.4-7.5fB, 1Η), 7, θ (έ, 1H), 12.2 (1H))

More ····

IR: 2930, 2440, 1720, 1490, 1230, 1185, 1095, 1025, 810 cm @ -1.

Examples 16-34

Following the general methods described above, the following compounds are listed in Table 1

Table 1

An example R ¹ R ² R ³ R ⁴ A R ⁵ 16 = 0 n. N. dream ₂ CH3 17 = 0 n N. dream ₂ CH ₂ CH = CH ₂ 18 = 0 n N. dream ₂ / CH, SN, SN 'CH, 19 = 0 n N. dream ₂ 20 = 0 n n dream ₂

Table 1 (continued)

An example R * R ² R ⁵ R ⁴ A R ⁵ 21 = 0 N. N. CH ₂ ^CH > -O 22 = 0 N. N. CH ₂ 23 N. HE N. N. CH ₂ dream ₂ - <

24 N. n n N. dream ₂ dream ₂ - <1 25 = 0 '· n N. Bond vr & o dream ₂ - < '26 = 0 n n CH ₂ CH ₂ dream ₂ - <| 27 = 0 n n dream 1 · dream ₃ dream _{2 -} oh 28 = 0 6-C1 1 n CH ₂ CH ₂ - <1 29 = 0 6-F n CH ₂ dream ₂ - < ³⁰ = 0 6: 0CH ₃ 7: OCH ₃ dream ₂ dream ₂ - < 31 = 0 N. N. dream ₂ n 32 = 0 N. N. dream ₂ 33 = 0 N. N. dream ₂ X ) 34 = 0 bOCHs n dream ₂ X

The m.p. and NMR data of the compounds of Examples 16 through are provided below:

Example 16

Mp = 240 - 243 ° C

R. M. N. CDCI ₃ ¹ H δ (ppm) base: 1.5-1.6 (m, 1 Η), 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, 1 Η), 7.9-7.95 (m, 1H))

Example 17 © Melting point = 242 - 244 ° C

R.M.N. CDCI3 ¹ H δ (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 - 3.6 (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, 1H), 7.9 - 7, 95 (m, 1H), 12.3 - 12.45 (m, 1H).

Example 18

Mp = 244-245 ° C

R. M. N. CDCI3 Ή 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, 1H), 11.7 - 11.8 (m, 1H).

Example 19

M.P. = 95 - 97 ° C

RMN CDCI ₃ ¹ H δ (ppm) base: 0.6-0.7 (m, 2H), 0.8-0.9 (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, w

Example 20

Τ. τ. = 220 - 221 ° C

R. Μ. Ν. CDCI ₃ ¹ Η δ (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), 7.0-7.6 (m, 8H), 7.9-8.1 (m, 1H) , 12.2-12.4 (m, 1H), 1);

Example 21

Τ. τ. = 261-262 ° C

RMN CDCI3 ¹ H δ (ppm) HCl: 2.0 - 2.1 (m, 4H), 2.4 - 2.5 (m, 2H), 2.95 - 3.05 (m, 2H), 3 , 1 - 3.25 (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

Τ. τ. > 250 ° C

RMN CDCI3 ¹ H δ (ppm) base: 1.4 - 1.55 (m, 2H), 1.9 - 2.05 (m, 4H), 2.2 - 2.35 (m, 2H), 2.4 - 2.55 (m, 2H), 2.8 - 2.95 (m, 2H),

4.2 (S, 1H), 6.8-7, (rn, 4H), 7.15 (d, 1H), 7.2-7.35 (m, 5H), 7.4 (t, 1H). 7.9 (d, 1H), 1);

Example 23

Τ. τ. = 91 - 93 ° C

RMN CDCI3 ¹ H δ (ppm) base: -0.05 - 0.05 (m, 2H), 0.35 0.45 (m, 2H), 0.7 - 0.85 (m, 1H), 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), 7.0- 7.3 (m, 4H).

Example 24

Τ. τ. = 256-258 ° C

RMN CDCI3 ¹ H δ (ppm) base: 0.0 - 0.01 (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

Τ. τ. = 241 ° C

R. Μ. Ν. CDCI ₃ ¹ Η δ (ppm) HCl: 0.0 - 0.01 (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, 2H), 2.9 (s, 2H), 3.0 (d, 2H), 7. 25 (t, 1H), 7.35 (d, 1H), 7.5 (t, 1H), 7.65 (d, 1H), 12.1-12.2 (1H).

Example 26

Τ. τ, = 242 - 243 ° C

RMN CDCI3 ¹ H δ (ppm) HCl: 0.4 - 0.5 (m, 2H), 0.7 - 0.8 (m, 2H), 1.2 - 1.35 (m, 1H), 1 , 85 - 2.0 (m, 4H), 2.2 - 2.3 (m, 2H), © 2.7 - 2.9 (m, 6H), 3.4 - 3.5 (m, 2H) ), 7.15 - 7.4 (m, 4H), 12.1 12.3 (1H) "

Example 27

Τ. τ. = 234 ° C

RMN CDCI3 ¹ H δ (ppm) HCl: 0.45 (m, 2H), 0.75 (m, 2H), 1.35 (m, 1H), 1.4 (dd, 3H), 1.85 ( m, 2H), 2.1 (m, 3H), 2.3 (m, 1H), 2.75 (m, 2H), 2.9 (m, 2H), 3.25 (m, 1H), 3.45 - 3.8 (m, 3H), 7.3 - 7.45 j (m, 2H), 7.6 (m, 1H), 8.0 (dd, 1H), 12.1 (1H) ).

ii Example 28: Τ. τ. > 250 ° C and ® RMN CDCI ₃ ¹ H δ (ppm) HCl: 0.4 - 0.5 (m, 2H), 0.75 - 0.85 [(m, 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

Τ. τ. = 227 ° C

RMN CDCI ₃ Ή δ (ppm) HCl: 0.45 - 0.5 (m, 2H), 0.75 - 0.85 (m, 2H), 1.3-1.4 (m, 1H), 2 , 0-2.2 (m, 4H), 2.4-2.6 (m, 2H),

2.85 - 2.95 (m, 2H), 3.0 - 3.1 (m, 2H), 3.2 - 3.3 (m, 2H), 3.5 - 3.6 (m, 2H) ), 6.90 - 7.0 (m, 1 Η), 7.0 - 7.1 (m, 1H), 7.95 - 8.05 (m, 1H),

12.1 (1H),.

Example 30

Mp = 229 ° C

R. M. N. CDCI ₃ ¹ H δ (ppm) HCl:: 0.45 (m, 2H), 0.75 (m, 2H), 1.35 (m, 1H), 2.15 (m, 4H), 2.45 (dt, 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, 1H), 12.05 (1H) "

Example 31

Mp = 189-191 ° C © R. M. N. CDCI ₃ ¹ H δ (ppm) HCl: 0.2 - 0.3 (m, 1H), 0.6 - 0.7 (m, 1H), 0.7-0.8 (m, 1H), 0.8-09 (m, 1H), 1.1-1.2 (m, 1H), I 1.55 (d, 3H). 1.6-1.7 (m, 1H), 2.1-2.2 (m, 4H), 2.5-2.7 (m, 2H),

J 3.0 - 3.1 (m, 2H), 3.3 - 3.6 (m, 4H), 7.2 - 7.25 (m, 1H), 7.3 - 7.35

I (m, 1H), 7.45-7.5 (m, 1H), 8.0-8.05 (m, 1H), 11.85 (1H) "| Example 32 and TT> 235 ° C j; RMN CDCI3 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, 1H), 7.5-7.6 (m, 1H), 7.95-8.0 (m, 1H), 12.2 (1H);

Example 33

T. t. = 209 ° C

RMN CDCI3 'Η δ (ppm) HCl: 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, 7H), 7.5 (m , 1H), 7.95 (m, 1H), 11.95 (1H);

Example 34

Τ. τ. = 228 ° C

R. Μ. N. CDCI ₃ Ή 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, 1H), 7.35 (m, 3H), 7.45 (d, 2H), 7.95 (d, 1 Η), 11.95 (1H);

Examples 35-69

Following techniques well known in the art, some of the tetralones described above were alkylated to give the following compounds listed in Table 2.

Table 2

An example R ¹ -R ² R ₃ r ₄ Rs A Rf 35 = 0 5: OCH ₃ N. (CH ₂ ) ₂ -C-C ₃ H ₅ dream ₂ 0.7 36 = 0 5: OCH ₃ N. CH ₂ -C-C ₄ H ₇ dream ₂ 0.5 37 = 0 5: OCH ₃ N. _CH2 -c-SbN11 dream ₂ 0.8 38 = 0 5: OCH ₃ N. CH ₂ -CH = CH-with _b n ₆ dream ₂ 0.7 39 = 0 5: OCH ₃ N. CH ₂ -CH ₂ -C ₆ H ₆ dream ₂ 0.7 40 = 0 5: OCH ₃ N. dream _{2 -} dream ₂ = dream ₂ - dream ₆ n ₆ dream ₂ 0.7 41 = 0 5: OCH ₃ N. (CH ₂ ) ₂ - CH- (C ₆ H ₆ ) ₂ dream ₂ 0.7 42 = 0 6: OCH ₃ N. (CH ₂ ) ₂ -C-C 3 H ₅ dream ₂ 0.7 43 = 0 6: OCH ₃ N. CH ₂ -C-C ₄ H ₇ dream ₂ 0.7 44 = 0 6: OCH ₃ n CH ₂ -c-CbHz dream ₂ 0.7 45 = 0 6: OCH ₃ n dream _{2 -} dream ₂ = dream ₂ - dream ₆ n ₆ dream ₂ 0.7 46 = 0 6: OCH ₃ n dream _{2 -} dream _{2 -} dream - ₆ dream ₆ dream ₂ 0.7 47 = 0 6: OCH ₃ n dream ₂ 0.7

48 = 0 6: OCH ₃ N. (CH ₂ ) ₂ - CH- (C ₆ H ₆ ) ₂ dream ₂ 0.7 49 = 0 7: OCH ₃ N. (CH ₂ ) ₂ -C-C ₃ H ₅ dream ₂ 0.7 50 = 0 7: OCH ₃ N. CH ₂ -C-C ₄ H ₇ dream ₂ 0.7 51 = 0 7: OCH ₃ N. CH ₂ -c-CbHz dream ₂ 0.7 52 = 0 7: OCH ₃ N. CH ₂ -CH = CH- _{6 6} CH ₆ dream ₂ 0.7 53 = 0 7: OCH ₃ N. CH ₂ -CH ₂ -C ₆ H ₆ dream ₂ 0.7 54 = 0 7: OCH ₃ N. CH ₂ CH ₂ CH ₂ C ₆ H ₆ dream ₂ 0.7 55 = 0 7: OCH ₃ N. (CH ₂ ) ₂ - CH- (C ₆ H ₆ ) ₂ dream ₂ 0.7

Table 2 (continued)

An example R ¹ -R ² R ₃ r ₄ Rs A Rf 56 = 0 Η h (CH ₂ ) ₂ -cC ₃ H ₅ dream ₂ 0.7 57 = 0 Η H CH ₂ -cC ₄ H ₇ dream ₂ 0.7 58 = 0 Η H CH ₂ -c-CbHz dream ₂ 0.7 59 = 0 Η H CH ₂ -CH = CH-C ₆ H ₆ dream ₂ 0.7 60 = 0 Η H CH ₂ CH ₂ - with _b n ₆ dream ₂ 0.7 61 = 0 Η H CH ₂ -CH ₂ -CH ₂ -C ₆ H ₆ dream ₂ 0.7 62 = 0 Η H (CH ₂ ) ₂ - CH- (C ₆ H ₆ ) ₂ dream ₂ 0.7 63 = 0 6: CI H (CH ₂ ) ₂ -C-C 3 H ₅ dream ₂ 0.7 64 = 0 6: CI H CH ₂ -C-C ₄ H ₇ dream ₂ 0.7 65 = 0 6: CI H CH ₂ -C-CeH 1 dream ₂ 0.7 66 = 0 6: CI H CH ₂ -CH = CH- _{6 6} CH ₆ dream ₂ 0.7 67 = 0 6: CI H CH ₂ CH ₂ - ₆ H ₆ dream ₂ 0.7 68 = 0 6: CI H CH ₂ -CH ₂ -CH ₂ -C ₆ H ₆ dream ₂ 0.7 69 = 0 6: CI H <CH ₂ ) ₂ - CH- (CH ₆ ) ₂ dream ₂ 0.7

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 for step 3, where 6-methoxytetralone was used instead of 1-tetralone.

NMR: CDCI ₃ ¹ H ((ppm) base: 1.9 - 2.3 (m, 6H), 2.9 - 3.1 (t, 2H), 3.3 - 3.6 (t, 4H) , 3.85 (s, 3H), 6.65 (s, 1H), 6.8-6.9 (t, 1H), 7.9-8.0 (dd, 1H), 9.5 (bs , 2H).

Mp = 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 stated above, the compounds of the invention of formula I are used to treat chronic pain and other CNS diseases such as seizures, such as epilepsy. The compounds were evaluated in a standard assay to measure their ability to block individual Na neural channels in mammals, as well as their ability to be antagonists of prostaglandin E ₂ (PGE ₂ ) production. Both studies have been routinely used to demonstrate the clinical utility of compounds for the treatment of chronic pain and other CNS diseases (see Tonelian et al., Anesthesiology, 24: 949-1991).

Example 71 Sodium Channel Binding Assay [ ³ H] -Batrachotoxin (BTX)

Sprague-Dawley male rat cerebral cortex was homogenized in a Teflon-type homogenizer in 10 volumes of ice-cold 0.32 M sucrose, 5 mM K2HPO4 (pH 7.4 at 4 ° C). The homogenate was centrifuged at 1000 g for 10 minutes, the pellets were resuspended in the same amount of sucrose, and centrifuged again. The pellets were removed, and the two supernatants obtained from these two centrifugations were combined and centrifuged at 20000 g for 10 minutes. The resulting pellets were resuspended in Na-free assay buffer containing 50 mM HEPES, 5.4 mM KCI, 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 pg synaptosomal protein to assay buffer containing 25 pg scorpion venom (Leirus quinquestriatus), 0.1% BSA, and 10 nM [ ³ H] bathrachotoxin (40 Ci / mmol, NEN) in the presence or absence of different concentrations of unlabeled drugs (250 pl final volume). Non-specific binding was determined in the presence of 0.3 mM veratridine. The reactions were incubated for 90 minutes at 25 ° C and the bound ligand was removed from the free by vacuum filtration through Whatman GF / B filters; the filters were washed with 2 x 5 ml buffer (5 mM HEPES, 1.8 mM CaCl ₂ , 0.8 mM MgSO4, 130 mM choline chloride, 0.01% BSA; pH 7.4 at 25 ° C) and bound ligand is evaluated by liquid scintillation spectrometry.

Example 72

Suction of ²² Na ⁺ into SK-N-SH neuroblastoma cells

Characterization of Na ⁺ channel activity is accomplished using human SK-N-SH cells in 96-well culture dishes. The effect of the test compounds in terms of intake of Na ⁺ in Na ⁺ -Te channels are evaluated in the simulation with veratridine. SK-N-SH cells were pre-incubated for 15 minutes at 37 ° C in the presence of test compounds in 25 mM hepes / Tris pH 7.5 buffer containing 5.4 mM KCI, 0.8 mM MgSO ₄ . 1.8 CaCl ₂ , 5 mM glucose, 0.01% BSA, 140 mM choline chloride. Na ⁺ uptake was induced by incubation for 10 minutes at 37 ° C of SK-N-SH cells in the presence of test compound and veratridine in the incubation buffer to which 1 μΜ ubaine, 10 mM NaCl, 130 mM choline was added. chloride and ²² Na ⁺ (Jacques, Y, Fosset, M and Lazdunski, M., (1978), Molecular properties of the action potential of Na ⁺ ionophore in neuroblastoma cells. J. Biol. Chem., 253, 7383-7392).

After ²² Na ⁺ extraction, the cells were washed with 0.1 mM MgCl 2. The radioactivity was then measured with a microplate counter (Topcount, Packard) after the addition of scintillation fluid (Microscin 40, Packard). The reference compound is a tetrodotoxin assayed at 7 concentrations ranging from 10 ^'10 M to 10' ⁷ M in order to determine the IC 50 value of Example 73.

Analgesic activity on chronic hyperalgesia induction by PGE ₂ in rats

The study consists in determining the analgesic effect of the test compound in rats by the test of

Randall and Selitto, in which chronic hyperalgesia was ejected by intraplantar injection of PGE ₂ for 4 days in the leg, according to a protocol adapted by Nakamura-Craig et al (Pain, 63: 33-37, 1995). The assay was performed on batches of 120-140 g Sprague-Dawley rats, to which 100 ng of PGE _{2 were administered} , in a volume of 100 μΙ, by implantation, for 4 consecutive days twice daily, causing chronic leg hyperalgesia from day 5 for at least one week. On the day of the test, in the morning, the threshold for the pain response was checked using the Randall and Selitto test, and the animals whose threshold was ψ100 arbitrarily determined units were separated. In the afternoon, the measurement is repeated after being previously applied by s. (subcutaneous) route a solution of the compound being tested; this application is performed 30 minutes before the pain threshold is measured. For each batch, analgesic activity (%) was calculated from threshold values measured before and after treatment, compared with those of control animals that received vehicle alone.

The following Table 3 shows the Na channel binding and analgesic activity of the representative compounds of the invention when measured in the above study.

Table 3: Pharmacological activities

Compound From Example No Assay [ ³ H] vm Na ⁺ channel Ki (nM) coupling Intake of ²² Na IC50 (μΜ) PGE ₂ assay: analget Activity at 10 mg / kg SC (%) 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

The biological data mentioned above show that the compounds of formula I are particularly useful for the treatment of mammalian CNS diseases, in particular pain, trigeminal neuralgia, diabetic neuropathy, sciatic neuropathy and strokes. The compounds are extremely well suited for 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 migraines.

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The compounds of the invention may be administered to a person in need of treatment for a condition of chronic pain or stroke, in two ways, or orally or parenterally, for example, as tablets or capsules, or as subcutaneous or intravenous injections. The compounds may be administered in an amount that is effective in controlling and treating a stroke disease or alleviating the sensation of neuropathic pain. Such effective amounts are typically from about 0.1 to about 2000 mg / kg of mammalian body weight. Typically, the prescribed dosages for administration are from about 5 mg / kg to about 500 mg / kg. Such dosage amounts may be administered to an adult person from 1 to 4 times daily to relieve neuropathic pain and stroke. The exact dosage to be used depends on the specific compound of formula I being used, the specific conditions of the subject to be treated, and is usually administered by the treating physician or other medical practitioner.

Formulations can be formulated from the compounds by normal methods of suitable oral or parenteral dosage. Typical oral forms are tablets, capsules, elixirs, syrups, suspensions and sustained release controlled forms, for example, by osmotic pumps. The compounds can also be formulated for intraperitoneal, subcutaneous, intramuscular, transdermal, sublingual, or intravenous administration. The compounds can be formulated using conventional diluents, excipients, carriers, and binding agents (b) used in the pharmaceutical field. For example, the compounds may be admixed with carriers, diluents, and excipients, such such as starch, cellulose, PVP, methylcellulose, sugar, wax, talc, and with stabilizers and binders such as Mg stearate, MdO, CaCO ₃ , methyl-p-hydroxybenzoate (methylparaben), and n-propyl-p-hydrobenzoate ( propyl paraben).

The following examples illustrate typical pharmaceutical dosage forms provided by this invention.

Example 74

Getting a tablet

Compound according to Example 10 25.0mg

Microcrystalline cellulose 50,0mg

Modified cereal starch 50.0mg

Magnesium stearate 1.0 mg

The above constituents are mixed to a uniform mixture, and compressed into a tablet. Such tablets are administered from 1 to 4 times daily to a person suffering from chronic pain.

Example 75

Preparation of an intravenous dosage form

The compound of Example 2 400 mg Acetate buffer 20 ml Diluted aqueous solution of 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 is poured into a sterile, soft plastic container fitted with a dropper. The solution is administered IV to a patient suffering from diabetic nephropathy.

Claims (13)

1. A tricyclic compound of formula I: where: 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, CH ₂ , CH CH ₃ , CH ₂ CH ₂ , or C (CH ₃ ) ₂ ; R ³ and R ⁴ are the same or different and are hydrogen, halo, 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 are the same or different and are hydrogen, C1-C6 alkyl or benzyl; R ⁵ is hydrogen, C 1-6 alkyl, C ₂ . ₆ alkenyl, C ₃ _b cycloalkyl, (0 = C) -C i-alkyl, (D - C) -C ₂ -C 6 alkenyl, (0 = C) -C ₃ -D cycloalkyl, wherein said alkyl, alkenyl and cycloalkyl groups may be substituted by 1, 2, or 3 groups selected from the group consisting of halo, C ₃ -C ₆ cycloalkyl, phenyl, or substituted phenyl, and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R ⁵ is a C 1 -C ₆ alkyl optionally substituted by phenyl or a C ₃ -C ₆ cycloalkyl group. A compound according to claim 1 or 2, wherein R ³ is hydrogen, halo or C 1 -C ₄ alkoxy. A compound according to any one of claims 1 to 3, characterized in that R ¹ is C ^ alkyl, C ₂ -e alkenyl or Sz_b cycloalkyl optionally substituted by 1, 2 or 3 groups selected from the group consisting of halo, 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, characterized in that R ⁴ is hydrogen. 6. 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]; 1 '-cyclobutylmethyl-3,4-dihydro-1-oxospiro [naphthalene2 (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 [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 (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 [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]; 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 (naphthalene2 (1H), 4'-piperidine); 1-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-1-oxospiro (naphthalene-2 (1H), 4'-piperidine) 3,4-dihydro-1 '- (di-p-fluorobenzhydryl) -1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1 '-cyclopropylmethyl-1,3,4-trihydro-1-hydroxy-spiro (naphthalene-2 (1H), 4'-piperidine); 1'-cyclopropylmethyl-1,2,3,4-tetrahydro-spiro (naphthalene-2 (1H), 4'-piperidine); 1 '-cyclopropylmethyl-1,3-dihydro-1-oxospiro- [2H-indene -2,4 ^l- piperidine]; 1 '- (cyclopropylmethyl) -1,8,9-dihydrospiro [6H-benzocycloheptene-6,4'-piperidine] -5 (7H) -one; 1'-cyclopropylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 6-chloro-1'-cyclopropylmethyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-cyclopropylmethyl-3,4-dihydro-6-fluoro-1-oxospiro (naphthalene-2 (1H), 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 (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 (1H), 4'-piperidine); 1'-cyclopropylethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-Cyclobutylmethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1 '-cyclohexylmethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-cinnamyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); N- (2-phenylethyl) -3,4-dihydro-5-methoxy-1-oxpiro (naphthalene-2 (1H), 4'-piperidine); 1 '- (3-phenylpropyl) -3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (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 (naphthalene-2 (1H), 4'-piperidine); 1'-Cyclobutylmethyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (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 (naphthalene-2 (1H), 4'-piperidine); 1 '- (3-phenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); N- (3,3'-diphenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro- (naphthalene-2 (1H), 4'-piperidine); 1'-cyclopropylethyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-Cyclobutylmethyl-3,4-dihydro-7-methoxy-1-oxospiro (naphthalene-2 (1H), 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 (1H), 4'-piperidine); 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 (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 (naphthalene-2 (1H), 4'-piperidine); 1'-Cyclobutylethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-cyclohexylethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-cinnamyl-3,4-dihydro-4-methyl-1-oxospiro- (naphthalene2 (1H), 4'-piperidine); 1 '- (2-phenylethyl) -3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1 '- (3-phenylpropyl) -3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); T- (3,3'-diphenylpropyl) -3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 6-chloro-1'-cyclopropylethyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 6-chloro-1'-cyclobutylmethyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 6-chloro-1'-cyclohexylmethyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 6-chloro-1'-cinnamyl-3,4-dihydro-1-oxospiro- (naphthalene2 (1H), 4'-piperidine); 6-chloro-1 '- (2-phenylethyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 6-chloro-1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); and 6-chloro-N- (3,3'-diphenylpropyl) -3,4-d11hydro-1-oxospiro (naphthalene-2 (1H), 4'-piperides). 3,4-dihydro-6-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine] 7. 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 [naphthalene2 (1H), 4'-piperidine]; 1'-cinnamyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]; © 1 '- (3,3'-diphenylpropyl) -3,4-dihydro-1-oxospiro [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 (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 [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-hydroxy-spiro (naphthalene-2 (1H), 4'-piperidine); 1'-cyclopropylmethyl-1,2,3,4-tetrahydro-spiro (naphthalene-2 (1H), 4'-piperidine); 1 '-cyclopropylmethyl-1,3-dihydro-1-oxospiro- [2Ninden-2,4'-piperidine]; N- (cyclopropylmethyl) -8,9-dihydrospiro- [6H-benzocycloheptene-6,4'-piperidine] -5 (7H) -one; 1'-cyclopropylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 6-chloro-1-cyclopropylmethyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1 '-cyclopropylmethyl-3,4-dihydro-6-fluoro-1-oxospiro (naphthalene-2 (1H), 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 (1H), 4'-piperidine); 1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene 2 (1H), 4'-piperidine); 1'-cinnamyl-1-ethyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1 '-cyclopropylethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-Cyclobutylmethyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-cinnamyl-3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); N- (3-phenylpropyl) -3,4-dihydro-5-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1 '- (3,3'-diphenylpropyl) -3,4-dihydro-N + Aetoxy-1-oxospiro- (naphthalene-2 (1H), 4'-piperidine); 1'-cyclopropylethyl-3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-Cyclobutylmethyl-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 '- (3-phenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (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 (naphthalene-2 (1H), 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); 1 '-cyclopropylethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1 '-cyclobutylmethyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-cinnamyl-3,4-dihydro-4-methyl-1-oxospiro (naphthalene2 (1H), 4'-piperidine); 1 '- (3-phenylpropyl) -3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1 '- (3,3'-diphenylpropyl) -3,4-dihydro-4-methyl-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 6-chloro-1'-cyclopropylethyl-3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); IMMSMM 6-chloro-1'-cinnamyl-3,4-dihydro-1-oxospiro (naphthalene2 (1H), 4'-piperidine); 6-chloro-1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); and ^6-chloro-1 - ₍₃₎ 3'-diphenylpropyl) -3,4-dihydro-1 -oksospiro (naphthalene-2 (1H), 4'-piperidine); 3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 8. Compounds 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- (naphthalene2 (1H), 4'-piperidine); 1'-cinnamyl-3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]; 1 '- (3,3-diphenylpropyl) -3,4-dihydro-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]; 1 '- (cyclopropylmethyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine; 1 '- (3-phenylpropyl) -3,4-dihydro-1-oxospiro- (naphthalene2 (1H), 4'-piperidine); 1'-cyclobutylmethyl-3,4-dihydro-5-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]; 1'-cyclopropylethyl-3,4-dihydro-6-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]; 1'-cyclobutylmethyl-3,4-dihydro-6-methoxy-1-oxospiro [naphthalene-2 (1H), 4'-piperidine]; 1 '- (3-phenylpropyl) -3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); 1'-cyclopropylethyl-3,4-dihydro-7-methoxy-1 oxospiro (naphthalene-2 (1H), 4'-piperidine); 3,4-dihydro-6-methoxy-1-oxospiro (naphthalene-2 (1H), 4'-piperidine); A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 mixed with a pharmaceutically acceptable carrier, diluent, or carrier thereof. 10. A method of treating mammals suffering from pain and 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. 12. The method of claim 10, wherein the pain is diabetic neuropathy. A method for treating mammals suffering from a seizure-related disease, comprising administering to an effective amount of a compound according to any one of claims 1 to 8.