JP2002533320A - Novel oxo-aminotetralin compounds useful for pain management - Google Patents

Abstract

(57) The present invention provides a novel oxo-formula of formula (I) wherein X, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are defined herein. It relates to an aminotetralin compound. The compounds of formula (I) are useful for pain management. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION

The present invention relates to compounds exhibiting analgesic activity, in particular compounds exhibiting analgesia due to the affinity of opioid receptors.

[0002]

BACKGROUND OF THE INVENTION

Numerous natural alkaloids and related analogs bind to specific opioid receptors and elicit an analgesic response similar to classic opiates. It has been shown that many different types of opioid receptors coexist in higher animals. For example, W.
Martin et al., J. Pharmacol.Exp.Ther., 197: 517 (1975) and J. Lord e
See al., Nature (London), 257: 495 (1977). Three opioid receptors have been identified. The first form, δ, shows a discriminating affinity for enkephalin-like peptides. The second μ type shows high selectivity for morphine and other polycyclic alkaloids. The third κ-type shows similar affinity for both groups of the above ligands, showing a preferential affinity for dinorphin. Generally, the analgesic effect seems to be relatively deeply related to the μ-type receptor. δ-type and κ-type receptors may also mediate analgesia, but δ-type receptors are thought to correspond to behavioral effects.

[0003] Each of the opioid receptors, when bound to an opiate, produces a specific biological response unique to that type of receptor. If the opiate activates more than one receptor, the biological response to each receptor is affected, thereby producing side effects.
The lower the specificity and selectivity of an opiate, the greater the opportunity for increased side effects from opiate administration.

[0004] Opiates can have serious, potentially fatal, side effects. Nonspecific interactions with central nervous system receptors cause side effects such as respiratory depression, tolerance, physical dependence, and sudden withdrawal syndrome. K. Budd, International Enc
yclopedia of Pharmacology and Therapeutics (International Encyclopedia of Pharmacology and Therapeutics)
:): NE Williams and H. Wilkinson, edited by Pergammon (Oxford) (112, 51)
1983). It is therefore an object of the present invention to provide compounds which have an analgesic effect, but have as few side effects as possible.

[0005]

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides novel oxo-aminotetralin compounds of formula (I) and pharmaceutically acceptable derivatives thereof:

Embedded image Wherein X is (i) a bond and (ii) —CR ₇ R ₈ — wherein R ₇ and R ₈ are independently H, OH, halogen, CN, COOH, CONH ₂ , amino, nitro , SH
C _1-6 alkyl optionally having one or more carbon atoms optionally substituted with one or more heteroatoms selected from O, S and N, one or more carbon atoms Wherein C _2-6 alkenyl optionally substituted with one or more heteroatoms selected from O, S and N, wherein one or more carbon atoms are selected from O, S and N C _2-6 alkynyl, optionally substituted with one or more heteroatoms, and COOR _c , wherein R _c is C _1-6 alkyl, C _2-6 alkenyl or C _{2-6 2-6} alkynyl);
R ₇ and R ₈ are bonded to form a C _3-8 cycloalkyl, a C _3-8 cycloalkenyl or 3
Capable of forming a saturated heterocyclic ring of ８8 atoms].

R ₁ is H, wherein one or more carbon atoms are selected from O, S and N
Or a C _1-12 alkyl optionally substituted with or more heteroatoms, 1
Or a C _2-12 alkenyl optionally having one or more carbon atoms optionally substituted with one or more heteroatoms selected from O, S and N, one or more carbon atoms being O 2 , of 1 or may be optionally substituted with more heteroatoms C _2-12 selected from S and N alkynyl, aryl C _6-12, aralkyl of C _6-12, a C _6-12 R ₂ and R ₃ are independently selected from the group consisting of aryloxy, C _1-12 acyl, heteroaryl having 6-12 atoms, and phosphoryl; wherein one or more carbon atoms is O, A C _1-6 alkyl optionally substituted with one or more heteroatoms selected from S and N, one or more carbon atoms wherein one or more carbon atoms are selected from O, S and N May be optionally substituted with more heteroatoms C _2-6 alkenyl, 1 or more carbon atoms is O, S optionally in an optionally substituted C _2-6 with 1 or more heteroatoms selected from and N alkynyl, C _{6 -12} aryl, C _{6 -12} aralkyl, selected from the group consisting of heteroaryl, and H having 6 to 12 atoms, or, R ₂ and R ₃ have the atoms 3-8 together May form a saturated heterocycle;

[0007] R ₄ and R ₅ are independently C _1- optionally one or more carbon atoms optionally substituted with one or more heteroatoms selected from O, S and N. ₆ alkyl, C _2-6 alkenyl, optionally having one or more carbon atoms optionally substituted with one or more heteroatoms selected from O, S and N, 1 or more carbon atoms selected from O, the group consisting of S and one or more optionally substituted also good C _2-6 and alkynyl with heteroatoms selected from N, and H; also, R ₄ and R ₅ is cycloalkyl of C _3-8 bonded to, may form a saturated heterocyclic ring having a cycloalkenyl or 3-8 atoms of C _3-8;

[0008] R₆Is selected from hydrogen, OH, one or more carbon atoms from O, S and N
Optionally substituted with one or more heteroatoms_1-6Al
A kill, one or more of which one or more carbon atoms are selected from O, S and N
C optionally substituted with more heteroatoms_2-6Alkenyl, 1 or
One or more hetero atoms wherein more carbon atoms are selected from O, S and N
C optionally substituted with a hydrogen atom_2-6Alkynyl, one or more charcoal
Optionally, one or more heteroatoms wherein the elementary atom is selected from O, S and N
OC which may be substituted_1-6Alkyl, one or more carbon atoms of which is O,
Optionally substituted with one or more heteroatoms selected from S and N
Good OC_2-6Alkenyl, one or more carbon atoms of O, S and N
O-C optionally substituted with one or more heteroatoms selected from _2-6 Alkynyl, halogen, CN, COOH, CONH_Two, Amino, nitro, or
Is SH; wherein 1) R_FourAnd R_FiveAre not H, 2) R_TwoAnd R_ThreeAt least one of
One is H or C_1-6Is an alkyl.

The compounds of the invention are useful in therapy, especially as analgesics. In another aspect, there is provided a method of treating pain in a mammal comprising administering to the mammal an analgesic effective amount of a compound or composition of the present invention. Yet another aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for treating pain. In another aspect, there is provided a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or adjuvant.

X is preferably —CR ₇ R ₈ —, wherein R ₇ and R ₈ are independently OH, halogen, CN, COOH, CONH ₂ , amino, nitro, SH, 1, or more C _1-6 alkyl, H and COOR _c , where many carbon atoms may be optionally substituted with one or more heteroatoms selected from O, S and N, wherein R _c is C _1- is selected from the group consisting of ₆ is alkyl); and, R ₇ and R ₈ may form a cycloalkyl of C _{3- 8} attached. X more preferably, -CR ₇ R ₈ - and is, wherein R ₇ and R ₈ is selected from the group consisting of alkyl and H of C _1-6 independent. X is most preferably -CH ₂ -.

R ₁ is preferably selected from the group consisting of H, C _1-12 alkyl, C _6-12 aryl and C _6-12 aralkyl. R ₁ is more preferably selected from the group consisting of C _1-6 alkyl, C _6-12 aryl and C _6-12 aralkyl. R ₁ is most preferably C _1-6 alkyl.

R ₁ is

Embedded image Can also be, where, n is an integer between 1 to 5, Rx and Rx ₁ is independently, H, alkyl of C _1-6, alkenyl or C _2-6 of C _2-6 Is alkynyl. More preferably n is 1 or 2, Rx and Rx ₁ is alkyl C _1-6. Most preferably Rx and Rx ₁ is methyl or ethyl.

In another embodiment, R ₁ is CH ₃ , — (CH ₂ ) _n —CH ₃ , and — (CH ₂ ) _n —O
Is selected from the group consisting of -CH _3, this time n is an integer between 1 and 5. In another preferred embodiment, R ₁ is C _6-12 aryl or heteroaryl having 6 to 12 atoms.

In a further preferred embodiment, R ₁ is

Embedded imageSelected from the group consisting of: wherein A is C_1-6Alkyl, C_1-6Alkyl, C _2-6 Alkenyl, C_2-6Alkynyl, OC_1-6Alkyl, OC_2-6Al
Kenyl, OC_2-6Alkynyl, SC_1-6Alkyl, S—C_2-6The alkene
Le, S-C_2-6Alkynyl, NC_1-6Alkyl, N-C_2-6Alkenyl,
N-C_2-6Alkynyl, CF_Three, Fluoro, chloro, bromo, iodo, OH, S
H, CN, nitro, amino, aminoamidino, amidino, guanide, COOH,
And COOR_z(Where R_zIs C_1-6Alkyl, C_2-6Alkenyl or C_2-6of
Alkynyl).

In another embodiment, R ₁ is C _6-12 aralkyl or heteroaryl having 6-12 atoms.

More preferably, R ₁ is

Embedded image Selected from the group consisting of: wherein A is C _1-6 alkyl, C _1-6 alkyl,
C _2-6 alkenyl, C _2-6 alkynyl, OC _1-6 alkyl, OC _2-6 alkenyl, OC _2-6 alkynyl, SC _1-6 alkyl, alkenyl S-C _2-6, alkynyl of S-C _2-6, alkyl N-C _1-6, alkenyl of _{N-C 2-6, N-C} 2-6 alkynyl, CF _3, fluoro, Chloro, bromo, iodo, OH,
SH, CN, nitro, amino, aminoamidino, amidino, guanide, COOH
And COOR _z , wherein R _z is C _1-6 alkyl, C _2-6 alkenyl or C _2-6
Is selected from the group consisting of alkynyl is a), and Y is - (CH _{2) m} - and is,
Here, m is an integer between 1 and 5.

R ₁ is preferably

Embedded image Wherein A and Y are as defined above.

[0018] A is preferably alkyl of C _1-6, alkyl O-C _1-6, alkyl of S-C _1-6, OH, nitro, amino, Aminoamijino, amidino, guanido, COOH
And COOR _a , wherein R _a is C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl. A is more preferably selected from the group consisting of C _1-6 alkyl, OH, nitro, amino, aminoamidino, amidino, guanide, and COOH. A is most preferably selected from the group consisting of amidino, guanide and OH.

R_TwoAnd R_ThreeIs preferably H. R_FourAnd R_FiveIs preferably a hydroxyl
Replaced C_1-4Is an alkyl. R_FourAnd R_FiveIs preferably C_1-4The alkyl of
It is. In a further preferred embodiment, R_FourAnd R_FiveIs independently methyl, ethyl,
It is selected from the group consisting of isopropyl, propyl, butyl and isobutyl. R _Four And R_FiveIs preferably ethyl. R_FourAnd R_FiveIs preferably methyl.

R ₆ can be substituted at any position on the aromatic ring. More preferably, R ₆ is adjacent to the carbon with OH. In another embodiment, the present invention provides a compound of formula (II)
Or a compound of formula (III) and pharmaceutically acceptable derivatives thereof:

Embedded image[Where X, R₁, R_Two, R_Three, R_Four, R_FiveAnd R₆Is as defined above. R ₆ Is preferably H, methyl, halogen or OR_b(Where R_bIs C_1-6The alkyl of
, C_2-6Alkenyl or C_2-6Alkynyl). R₆Is most preferably H
It is.

The compounds of the present invention contain at least two chiral centers, which have the general formula (I
) Are marked with an asterisk (*) above. Thus, the compounds of formula (I) can be of different geometric isomers (ie trans and cis) and optical isomers (ie (+) or (
-) Enantiomer). Thus, when there are two chiral centers at the site marked by an asterisk, the compound may be in the form of the cis or trans isomer. The cis or trans isomer also exists as the (+) and (-) enantiomers, respectively. All such isomers, including racemic mixtures, enantiomers and mixtures thereof are included within the scope of the invention.

Preferably, the compounds of the invention are in the form of the trans isomer (between centers marked with an asterisk on general formula (I)). More preferably, the compounds of the present invention exist in trans (+) enantiomer and trans (-) enantiomer form.

Preferred compounds of the present invention include trans-7-amino-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 1); 7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 2); trans-7-amino-8,8-dimethyl-6-phenoxy -5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 3); trans-7-amino-6-isopropoxy-8,8-dimethyl-5,6,7,8
Trans-7-amino-8,8-dimethyl-6-propoxy-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 5) Trans-7-amino-8,8-dimethyl-6- (2-phenoxy-ethoxy) -5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 6); trans-7-amino- 6-ethoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 7); trans-7-amino-8,8-diethyl-6- (2-methoxy- Ethoxy)
-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 8); trans-7-amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalene- 2-ol (Compound No. 9); trans-7-amino-8,8-diethyl-6- (2-hydroxy-ethoxy) -5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 10) )
Trans-7-amino-8,8-spiropentanyl-6-methoxy-5,6,7,
8-tetrahydro-naphthalen-2-ol (Compound No. 11); trans-7-amino-6-methoxy-8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 12) Trans-7-amino-6-ethoxy-8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 13); trans-7-amino-6- (2- Phenoxy-ethoxy) -8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 14
Trans-3-amino-4,4-diethyl-1,2,3,4-tetrahydro-naphthalene-2,6-diol (Compound No. 15); (−) trans-3-ethoxy-1,1 chloride -Diethyl-7-hydroxy-1,
2,3,4-tetrahydro-naphthalen-2-yl-ammonium (Compound No. 1
6); (+) chloride trans-3-ethoxy-1,1-diethyl-7-hydroxy-1,
2,3,4-tetrahydro-naphthalen-2-yl-ammonium (Compound No. 1
7); 1,1-diethyl-7-hydroxy-3-trans- (3-hydroxy-chloride)
Propoxy) -1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium (Compound No. 18); 7-amino-6- (2-amino-ethoxy) -8,8-diethyl-5,6, 7,8
-Tetrahydro-naphthalen-2-ol bistrifluoroacetate (Compound No. 19); 3- (3-amino-4,4-diethyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yloxy ) -Propionic acid trifluoroacetate (
Compound No. 20); and pharmaceutically acceptable derivatives thereof, wherein the compound is (+
) Enantiomers, (-) enantiomers and mixtures of (+) and (-) enantiomers, including racemic mixtures.

More preferred compounds of the present invention are Compound No. 1, Compound No. 2, and Compound No. 3.
, Compound No. 4, Compound No. 5, Compound No. 6, Compound No. 7, Compound No. 8,
It is selected from the group consisting of Compound No. 9, Compound No. 12, Compound No. 16, Compound No. 17, Compound No. 18 and Compound No. 19.

The most preferred compounds of the present invention are Compound No. 1, Compound No. 2, and Compound No. 5.
, Compound No. 8, Compound No. 9, Compound No. 16, Compound No. 17, Compound No. 18, and Compound No. 19.

As used in this application, the term “pain” refers to actual or potential tissue damage, or unpleasant sensations and emotions associated with what is described in terms of such damage Express experience. The term "pain" also encompasses "acute pain" and chronic pain.

Acute pain is usually immediate and short-lived. Acute pain can also be traumatic,
It may be manifested by short-term illness, or surgical / medical procedures. Examples of acute pain include burns, fractures, muscle abuse, or post-surgical pain. Pain in cancer can be long-lasting, but it can also be acute due to ongoing tissue damage.

[0028] Some chronic pain is due to breakage or damage to the nerve fibers themselves (neuropathic pain). Chronic pain can be caused by diseases such as shingles and diabetes, trauma, surgery or amputation (
Fantasy pain). It can occur without known trauma or disease.

[0029] The present invention is directed to the treatment of all types of pain, including acute and chronic pain.

As used in this application, the term “alkyl” refers to unsubstituted or substituted [halogen, nitro, aminoamidino, amidino, guanide, CONH ₂ , COOH, O—C _1-6 alkyl, O—C _{2 -6} alkenyl, alkynyl O-C _2-6, amino, by hydroxyl or COOQ (wherein Q is an alkyl of C _1-6, alkenyl C _2-6, alkynyl of C _2-6)] of , Linear, branched or cyclic hydrocarbon moieties (eg, isopropyl, ethyl, fluorohexyl or cyclopropyl). The term alkyl is also meant to include alkyl wherein one or more hydrogen atoms are replaced by halogen, more preferably halogen is fluorine (eg, CF ₃ — or CF ₃ CH ₂ —).

The term “saturated heterocycle” refers to a carboxyl ring in which one or more of the ring's 3-8 atoms is an element other than carbon, such as N, S and O. The term "aryl" represents an aromatic ring having 6 to 12 carbon atoms, which alkyl C _1-6, alkenyl C _2-6, alkynyl of C _2-6, halogen, nitro, Aminoamijino, amidino, guanides, CONH _2, COOH, alkyl O-C _1-6, alkenyl of O-C _2-6, alkynyl of O-C _2-6, amino, hydroxyl or COOQ (wherein Q is as phenyl and naphthyl , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl).

The term "aralkyl", represents C _1-6 alkyl on adjacent atoms, alkenyl of C _1-6, an aryl group attached to an alkynyl of C _1-6 (e.g., benzyl). The term "aryloxy" refers to an aryl or aralkyl moiety covalently linked through an oxygen atom (eg, phenoxy). The term "heteroaryl" means that one or more of the ring's 6-12 atoms has O,
Represents an aromatic ring that is an element other than carbon, such as N and S (eg, pyridine, isoquinoline, or benzothiophene).

The term “acyl” refers to substitution [halogen (F, Cl, B
r, I), C _6-20 aryl or C _1-6 alkyl)] or a group derived from an unsubstituted carboxylic acid. As with the acids with which it is associated, the acyl group may be substituted (by halogen, _C1-5 alkoxyalkyl, nitro or OH) or unsubstituted aliphatic or aromatic, Whatever the structure of
The properties of the functional groups remain essentially the same (eg, acetyl, propionyl, isobutanoyl, pivaloyl, hexanoyl, trifluoroacetyl, chloroacetyl, and cyclohexanoyl).

The term “phosphoryl” refers to a method wherein at least one of —OH is replaced with a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _1-6 heteroalkyl, _{6-1 2} aryl represents a group derived from a phosphono moiety that can be replaced by a heteroaryl aralkyl and C _6-12 of C _6-12 (e.g., diethoxyphosphorylmethyl). The term "halogen" includes chloro, fluoro, bromo and iodo.

If sulfur atoms are present, the sulfur atoms can be at various oxidation levels, S, SO or S
It can be a O _2. All such oxidation levels are within the scope of the present invention.

The following abbreviations are used in this application: AcOEt ethyl acetate Boc t-butyloxycarbonyl DMAP 4-dimethylaminopyridine DME ethylene glycol dimethyl ether DMF dimethylformamide Et2O ether Hex hexane HPLC high-performance liquid chromatography LAH lithium aluminum hydrate LHMDS lithium bis (trimethylsilyl) amide NHMDS sodium bis (trimethylsilylamide) Ph phenyl PPTS pyridium p-toluenesulfonate PTSA p-toluenesulfonic acid r. t. Room temperature sat. Saturated TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography

[0037] In yet another aspect of the invention, there is provided a method of preparing a compound of formula (I). The method is illustrated in Scheme 1, wherein X, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined above, and P, P1, P2, and P3 are protecting groups. is there.

[0038]

Embedded image

Step 1 The starting ketone AA is dissolved in a suitable solvent such as DMF, acetonitrile, THF, DME and sodium hydride or other base such as potassium t-butoxide, sodium bis (trimethylsilyl) amide Processed. The resulting mixture was then treated with ethyl iodide or an alkyl halide such as methyl iodide, allyl bromide, butane diiodide to give compound A.

Step 2 Compound A is dissolved in a suitable solvent such as pyridine, DMF, ethanol and treated with hydroxylamine hydrochloride or other hydroxylamines such as hydroxylamine sulfate, hydroxylamine bromide to give compound B Obtained.

Step 3 Compound B is dissolved in a suitable solvent such as THF, dioxane, DME, and in the presence of diethylamine or other amines such as methylbutylamine, dipropylamine, such as LAH, or red-Al And other reducing agents. The mixture was then heated to 50 ° C. or higher to give compound C.

Step 4 Compound C is dissolved in a suitable solvent such as dichloromethane (CH ₂ Cl ₂ ) or other solvent such as dichloroethane and BBr ₃ or other demethylating agent such as BCl ₃ , HBr To give compound D.

Step 5 The amino group or hydroxyl group of compound D was protected with Boc or another protecting group to give compound E. Protecting groups are described in Greene, incorporated herein by reference.
And Wuts edited "Protective Groups in Organic Synthesis"
Syntheses), Second Edition (1991, John Wiley & Sons, New York).

Step 6 Compound E is dissolved in a suitable solvent such as ethanol or methanol, propanol,
Dissolved in other alcohols such as butanol, p- toluenesulfonic acid pyridinium (PPTS), or HCl, and obtain a BF ₃ .OEt _2, compound is treated with other acids or Lewis acids such as PTSA F. Alternatively, non-alcoholic solvents can be used in combination with an appropriate amount of alcohol and a suitable Lewis acid such as ytterbium triflate. For example, Tetrahedron Letters, Vol. 37, No. 43, pages 7717-7720 (1996), which is incorporated herein by reference.
Year).

Step 7 The protecting group of compound F is added under appropriate conditions, for example, with TFA or with HCl,
Compound I was obtained by removal with an acid such as PTSA.

It has been found that certain substituents require protection during synthesis and subsequent deprotection. For example, it may be necessary to protect the hydroxyl group by conversion to an alkoxy or ester, which may be followed by deprotection. Protecting groups for other substituents can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2nd Edition, 1991, John W.
iley & Sons, New York).

In another aspect, the present invention acts or activates an opioid receptor in a mammal, comprising administering to the mammal an opioid receptor activating or activating amount of a compound or composition of the invention. Provide a way.

Also provided is a pharmaceutically acceptable composition comprising a compound of the present invention and derivatives thereof, together with a pharmaceutically acceptable carrier, diluent or adjuvant. Depending on the "derivative", the compound of formula (I) or (II) or, when administered to a recipient, a compound of formula (I) or (II)
Or a pharmaceutically acceptable salt, ester or salt of such an ester, of a compound of formula (I) or any other compound capable of providing (directly or indirectly) an active metabolite or residue thereof. I do.

The present invention also provides a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and preferably a pharmaceutically acceptable carrier, diluent or adjuvant. . By the term "pharmaceutically effective amount" is meant the amount of a compound required to be administered to a mammal to induce analgesia. The term “amount acting on an opioid receptor” also refers to the amount of a compound administered to a mammal required to bind to and / or activate the opioid receptor in vivo.

The methods of treatment of the present invention include treating a patient with such a compound or composition in a pharmaceutically acceptable manner. Such compositions may be in the form of tablets, capsules, caplets, powders, granules, troches, suppositories, reconstitutable powders, or liquid preparations such as oral solutions or sterile injectable solutions or suspensions. Good.

To achieve consistency of administration, the compositions of the invention are preferably in unit dosage form. Unit dosage forms for oral administration may be tablets and capsules and may contain conventional excipients. Binders such as gum arabic, gelatin, sorbitol or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet lubricants such as magnesium stearate; starch, polyvinylpyrrolidone; Disintegrants such as sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate.

The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, sucrose and the like. The compounds may be administered orally in the form of a solution which may contain coloring and / or flavoring agents. The active ingredient is mixed with the sugar or corn syrup, flavoring and pigment, respectively, and the compound is administered sublingually in the form of a lozenge or lozenge, sufficiently dehydrated to produce a mixture suitable for compression into a solid form. You may.

Solid oral compositions may be prepared by conventional methods, such as mixing, filling, making tablets and the like. Repeated mixing operations may be used to distribute the active ingredient throughout such compositions using large amounts of filler. Such operations are, of course, conventional in the art. The tablets may be coated, especially with an enteric coating, according to methods well known in normal pharmaceutical practice.

[0054] Liquid oral formulations may be in the form of emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or another suitable solvent before use. Such liquid formulations may or may not contain conventional additives. For example, suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fat; emulsifying agents such as sorbitan monooleate or akasi; almond oil; Non-aqueous vehicles such as coconut oil and oily esters selected from the group consisting of glycerin, propylene glycol, ethylene glycol and ethyl alcohol, which may include edible oils; for example, methyl parahydroxybenzoate of sorbic acid, ethyl para Preservatives such as hydroxybenzoate, n-propyl parahydroxybenzoate, or n-butyl parahydroxybenzoate; and, if desired, conventional flavoring and coloring agents.

The compound may be injected parenterally; this may be intramuscular, intravenous or subcutaneous.
For parenteral administration, the compounds may be used in the form of a sterile solution containing other saline, for example, sufficient saline or glucose to make the solution isotonic. For parenteral administration, solutions in unit dosage form may be prepared using the compound and sterile vehicle, depending on the concentration employed, and may be suspended or dissolved in the vehicle.
Once in solution, the compound may be injected and the filter sterilized before filling into vials or ampoules and sealing the carrier or storage container. Adjuvants such as a local anaesthetic, preservative or buffering agents may be dissolved in the vehicle before use. The stability of a pharmaceutical composition may be enhanced by freezing the composition after filling into vials and removing the water under vacuum (eg, lyophilization of the composition). Parenteral suspensions may be prepared by substantially the same methods, except that the compound should be suspended, rather than dissolved in the vehicle, and sterilization cannot be achieved by filtration. However, the compounds may be sterilized by exposure to ethylene oxide before suspension in a sterile vehicle. Surfactants or wetting solutions may be advantageously included in the composition to promote uniform distribution of the compound.

A pharmaceutical composition of the invention comprises a pharmaceutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. It typically contains from about 0.01% to about 99% by weight, preferably from about 10% to about 60% by weight, of the compound of the present invention, depending on which method of administration is employed.

The compounds of the present invention can be administered in combination with one or more additional therapeutic agents. Preferably, the one or more additional therapeutic agents are from non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, narcotics, antidepressants, anticonvulsants, corticosteroids, tramadol, samatriptan, and capsaicin. Selected from the group consisting of:

[0058] Without limitation, NSAIDs include aspirin (anacin, Bayer, bufferin), ibuprofen (motolin, advil, nuprine), naproxen sodium (Alebe) and ketoprofen (Ordis KT). Without limitation, narcotics include drugs derived from opiates (opiates) such as morphine and codeine, and synthetic narcotics (opioids) such as oxycodone, methadone and meperidine (demerol).

[0059] Without limitation, antidepressants include amitriptyline (elavir), trazodone (decylel), and imipramine (tofranil) may be used with other analgesics. Such agents are particularly useful for neuropathic headache and cancer pain. Without limitation, anticonvulsants include drugs developed for epilepsy, such as phonation (dilantin) and carbamazepine (tegretor), which can also be useful for chronic neuralgia.

Tramadol (Ultrum) is a synthetic analgesic used primarily for chronic pain, but is also prescribed for acute pain. Samatriptan (imitrex) may reduce pain from migraine by constricting blood vessels.

Capsaicin (ZOSTRIX) is a topical cream made from red pepper extract and can help reduce the sensitivity of the skin resulting from shingles. Capsaicin can also be used to treat arthritis, cluster headache, pain from diabetic neuropathy and post-mastectomy pain.

[0062] In another aspect of the invention, the compounds may be used to distinguish opioid receptors from non-opioid receptors. For such use, the compounds of the invention are radiolabeled, for example, by incorporating ³ H or ¹⁴ C into their structure, or by attaching ¹²⁵ I. Such a radiolabeled form can be used to directly identify the presence of the opioid receptor, especially the μ-type opioid receptor in the receptor population. This is achieved by incubating the membrane preparation with a radiolabeled inventive compound. The presence or amount of opioid receptor in the preparation is determined from the difference in membrane bound radioactivity relative to a control preparation lacking the opioid receptor. In addition, by measuring the ability of a test ligand to displace a radiolabeled compound of the invention, the radiolabeled form of the compound can be used to screen for more potential opioid ligands.

The following non-limiting examples are provided to further assist in understanding the present invention. Certain abbreviations are used throughout the examples and can be found in the catalogs of Aldrich Chemical Company and Bachem.

Example 1

Embedded image

Example 1 trans-7-amino-8,8-diethyl-6-methylsulfanyl-5,6 hydrochloride
Synthesis of 1,7,8-dihydro-naphthalen-2-ol Step 1: 1,1-Diethyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-one (A) 7-methoxy-2-tetralone (4.26 g, 24.18 mmol) of DMF (
100 ml) solution at 0 ° C. with 1 equivalent of sodium hydride (60% in oil) (1 g
, 41.6 mmol). After 30 minutes, 1.25 equivalents of iodoethane (2.5 m
l, 30.2 mmol), then 30 minutes later, another equivalent of sodium hydride (1 g) was added, and after 30 minutes, iodoethane (2.5 ml, 30.2 mmol) was added. The resulting purple solution was stirred at 0 ° C. for 1 hour and at room temperature overnight. The mixture was quenched with water and then diluted with ether. Then wash the organic layer with H ₂ O, brine, dried over MgSO _4, filtered and evaporated. The residue was purified by flash chromatography (5% AcOEt / Hex) (4.40 g, 7
8%). ¹ H NMR (CDCl ₃ ): 7.12 (1H, d, J = 8.0 Hz), 6.78 (2H, m), 3.84 (3H, s), 2.
97 (2H, t, J = 6.0 Hz), 2.6 (2H, t, J = 6.0 Hz), 2.10 (2H, m), 1.71 (2H, m),
0.63 (6H, t, J = 7.5 Hz)

Step 2: 1,1-Diethyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-one oxime (B) 1,1-Diethyl-7-methoxy-3 in dry pyridine (20 ml) , 4-Dihydro-1H-naphthalen-2-one (4.40 g, 18.96 mmol) was heated at 80 ° C. with hydroxyamine hydrochloride (10.54 g, 151.7 mmol) for 1 day. The mixture was cooled to room temperature and then pyridine was removed under reduced pressure. The green rubber was dissolved in AcOEt, washed with H ₂ O, 10% HCl, H ₂ O, brine,
dried over MgSO _4, and filtered through a small pad of silica. The crude compound was used without further purification (4.69 g, 100%). _{^{1 H NMR (CDCl 3):}} 7.94 (1H, s), 7.06 (1H, d, J = 8 Hz), 6.84 (1H, d, J = 2.5
Hz), 6.73 (1H, dd, J = 2.5 and 8 Hz), 3.83 (3H, s), 2.80-2.75 (4H, m), 2.
08 (2H, m), 1.85 (2H, m), 0.68 (6H, t, J = 7.5 Hz)

Step 3: 7,7-diethyl-5-methoxy-1a, 2,7,7a-tetrahydro-1H-1-aza-cyclopropa [b] naphthalene (C) 1,1-diethyl-7-methoxy- 3,4-dihydro-1H-naphthalene-2-
To a solution of onoxime (4.68 g, 18.96 mmol) in dry THF (100 ml) at 0 ° C. was added diethylamine (4.9 ml, 47.4 mmol) and LAH (95% powder) (2.16 g, 56.9). Mmol). The mixture was stirred at 0 ° C. for 15 minutes, then heated to reflux for 3 hours. The gray solution was cooled to 0 ° C., quenched with brine and diluted with AcOEt. Gently pour the organic layer, H ₂ O (2 times),
Washed with brine, dried over MgSO ₄ , filtered and evaporated. The residue was purified by flash chromatography (3% MeOH / CH ₂ Cl ₂ ) (3.889 g, 89%) ¹ H NMR (CDCl ₃ ): 6.99 (1 H, d, J = 8 Hz), 6.76 (2H , m), 3.13 (2H, m), 2.40
(1H, bs), 2.10-2.05 (2H, m), 1.84 (1H, m), 1.62 (4H, m), 1.02 (3H, t, J
= 7.5 Hz), 0.75 (3H, t, J = 7.5 Hz)

Step 4: 7,7-Diethyl-1a, 2,7,7a-tetrahydro-1H-1-aza-
Cyclopropa [b] naphthalen-5-ol (D) 7,7-diethyl-5-methoxy-1a, 2,7,7a-tetrahydro-1H
1-aza - cyclopropa [b] naphthalene (3.889g, 16.81 mmol) (1M in CH ₂ Cl ₂₎ BBr ₃ at -78 ° C. in CH ₂ Cl ₂ (170ml) solution of
(33.6 ml, 33.62 mmol) was added. Mixture at -78 ° C for 30 minutes,
It was then kept at 0 ° C. for 1.5 hours. The mixture is quenched with NaHCO ₃ and Ac
Diluted with OEt. The organic layer was washed with H ₂ O, brine, dried over MgSO _4, filtered and then evaporated. Flash chromatography (3% MeOH /
The residue was purified by (CH ₂ Cl ₂ ) (2.917 g, 80%) ¹ H NMR (CDCl ₃ ): 6.93 (1 H, d, J = 8.0 Hz), 6.68 (1 H, d, J = 2.5 Hz). , 6.64 (
1H, dd, J = 8 and 2.5 Hz), 3.12 (2H, m), 2.42 (1H, bs, 2.14 (1H, bs), 2.0
4 (1H, m), 1.82 (1H, m), 1.65 (4H, m), 1.02 (3H, t, J = 7.5 Hz), 0.75 (3H,
t, J = 7.5 Hz)

Step 5: 5-tert-butoxycarbonyloxy-7,7-diethyl-1a, 2
, 7,7a-Tetrahydro-1-aza-cyclopropa [b] naphthalene-1-carboxylic acid tert-butyl ester (E) 7,7-diethyl-1a, 2,7,7a-tetrahydro-1H-1-aza- CH ₂ C of cycloprop [b] naphthalen-5-ol (1.5 g, 6.90 mmol)
To a solution of 12 (30 ml) at room temperature was added (Boc) 2O (3.77 g, 17.26 mmol), triethylamine (3.85 ml, 27.6 mmol) and DMAP (cat
) Was added. The mixture was stirred overnight at room temperature. The mixture was quenched with NH ₄ Cl and diluted with AcOEt. The organic layer was washed with H ₂ O, brine, dried over MgSO _4, filtered and then evaporated. Flash chromatography (5% ~
The residue was purified by 25% AcOEt / Hex) (2.44 g, 84%).
) ¹ H NMR (CDCl ₃ ): 7.05-6.95 (3H, m), 3.29 (1H, d, J = 17 Hz), 3.04 (1H, dd)
, J = 2 and 17 Hz), 2.94 (1H, m), 2.67 (1H, d, J = 6.5 Hz), 2.05-1.95 (2H,
m), 1.65-1.50 (11H, m), 1.43 (9H, s), 1.11 (3H, t, J = 7.5 Hz), 0.72 (3H,
t, J = 7.5 Hz)

Step 6: 7-tert-butoxycarbonylamino-trans-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-yl ester carbonate tert-butyl ester carbonate (F) 5-tert-butoxycarbonyloxy-substituted under argon at room temperature
7,7-Diethyl-1a, 2,7,7a-tetrahydro-1-aza-cyclopropa [
b] naphthalene-1-carboxylic acid tert-butyl ester (224.0 mg, 0.1
54 mmol) was dissolved in absolute ethanol (8.0 ml). To this solution, a catalytic amount of pyridinium p-toluenesulfonate was added. The reaction mixture was stirred overnight.
The next day, the reaction mixture was poured into aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered to remove the solvent. Using hexane: ethyl acetate (9: 1) then (8: 2) as eluent,
The crude was purified by flash chromatography. The isolated product is a solid (129 mg, 55%).

Step 7: 7-tert-butoxycarbonylamino-trans-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-yl ester carbonate tert-butyl ester anhydrous chloroformate 15.0 ml) with 5-tert placed under nitrogen
-Butoxycarbonyloxy-7,7-diethyl-1a, 2,7,7a-tetrahydro-1-aza-cyclopropa [b] naphthalene-1-carboxylic acid tert-butyl ester (346.0 mg, 0.83 mmol) Dissolve, then 0.5 equivalent of ytterbium trifluoromethanesulfonate (257.0 mg, 0.42 mmol)
Was added. The reaction mixture was stirred overnight at room temperature. The next day, it was poured into aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude was purified by flash chromatography using hexane: ethyl acetate (9: 1) then (8: 2) as eluent. The isolated product is a solid (275 mg, 71%). ¹ H NMR (400 MHz) (CDCl ₃ ; d; ppm): 7.06 (1 H, d, J = 8.3 Hz), 6.93-6.99 (2H, m
), 4.33 (1H, d, J = 10.4 Hz), 4.06 (1H, dd, J1 = J2 = 10.0 Hz), 3.72 (1H, m),
3.64 (1H, m), 3.54 (1H, m), 3.22 (1H, dd, J1 = 6.0 Hz, J2 = 16.2 Hz), 2.79
(1H, dd, J1 = 9.5 Hz, J2 = 16.2 Hz), 2.79 (1H, dd, J1 = 9.5 Hz, J2 = 16.0 Hz), 1
.72 (3H, m), 1.51 (1H, m), 1.55 (9H, s), 1.47 (9H, s), 1.22 (3H, t, J = 7.
0 Hz); 0.74 (3H, t, J = 7.5 Hz); 0.69 (3H, t, J = 7.3 Hz)

Step 8: trans-3-ethoxy-1,1-diethyl-7-hydroxy-1, chloride
2,3,4-tetrahydro-naphthalen-2-yl-ammonium (Compound No. 1
7) 7-tert-butoxycarbonylamino-carbonate placed under nitrogen at room temperature
Trans-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester (200 mg, 0.43 mmol) was dissolved in tetrahydrofuran (5.0 ml). , Then trifluoroacetic acid (
3.0 ml) was added and the reaction mixture was stirred for about 1 hour. The solvent was evaporated under reduced pressure and a solution of hydrochloric acid in ether (1.0 M) (50 ml) was added. The reaction mixture thus obtained was stirred for another hour. The solvent was removed under reduced pressure and the solid isolated with ether and then dichloromethane was washed several times. The isolated product is a yellow powder (145 mg,> 99%). ^{1 H NMR (400MHz) (CDCl} 3; d; ppm): 6.98 (1H, d, J = 8.9 Hz), 6.68 (2H, m), 3.
96 (1H, m), 3.87 (1H, m), 3.56 (1H, m), 3.39 (2H, m), 2.57 (1H, dd, J1 = 1
0.0 Hz, J2 = 15.5 Hz), 2.07 (1H, m), 1.73 (1H, m), 1.66 (2H, m), 1.30 (3H,
t, J = 7.0 Hz); 0.80 (3H, t, J = 7.4 Hz); 0.70 (3H, t, J = 7.3 Hz)

Example 2

Embedded image

Step 1: Trans-7-amino-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (231 mg, 0.88 mmol) was added at room temperature to nitrogen at room temperature. And dissolved in anhydrous acetonitrile (20 ml). 0.25 ml of triethylamine (1.75 mmol) and 504 mg of chiral auxiliary (1.75 mmol) are added. The reaction mixture thus obtained was heated to reflux overnight. The next day, the reaction mixture was cooled to room temperature, then poured into aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with 0.1N HCl, brine, and then dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure. The crude was purified by flash chromatography using hexane: ethyl acetate (9: 1) then (8: 2) as eluent. The isolated product is a colorless oil (72%). (Less polar isomer) ¹ H NMR (400 MHz) (CDCl ₃ ; d; ppm): 7.41 (10H, m), 7.03
(1H, m), 6.94 (2H, m), 5.84 (2H, m), 4.54 (1H, d), 4.10 (1H, m), 3.61 (2
H, m), 3.39 (1H, m), 3.19 (1H, m), 2.72 (1H, m), 1.71 (2H, m); 1.64 (3H,
d); 1.50-1.62 (2H, m), 1.57 (3H, d); 0.98 (3H, t, J = 7.0 Hz); 0.72 (6H,
2t) (isomer with much polarity) ¹ H NMR (400 MHz) (CDCl ₃ ; d; ppm): 7.37 (10H, m), 7.03 (1
H, m), 6.95 (2H, m), 5.82 (2H, m), 4.51 (1H, d), 4.10 (1H, m), 3.71 (2H,
m), 3.55 (1H, m), 3.23 (1H, dd), 2.80 (1H, dd), 1.40-1.78 (4H, m), 1.67
(3H, d); 1.56 (3H, d); 1.22 (3H, t); 0.68 (6H, 2t)

Step 2: (−) trans-3-ethoxy-1,1-diethyl-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium chloride (Compound No. 16) Trans-6-ethoxy-8,8-diethyl-7- (1-phenyl-ethoxycarbonylamino) -5,6,7,8-tetrahydro-naphthalen-2-yl ester 1 placed under nitrogen -Phenyl-ethyl ester (a less polar isomer) (31 mg, 0.055 mmol) was dissolved in dichloromethane (8.0 ml), trifluoroacetic acid (3.0 ml) was added and the reaction mixture was stirred for about 1 hour. .
The solvent was then evaporated under reduced pressure and a solution of hydrochloric acid (1.0 M) in ether (7 ml) was added. The reaction mixture thus obtained was stirred for another hour. The solvent was removed under reduced pressure, and the isolated solid was washed several times with ether, hexane, and then dichloromethane. The isolated product is a yellow powder (15.7 mg, 95%). ¹ H NMR (400 MHz) (CD ₃ OD; d; ppm): 6.98 (1 H, d, J = 8.9 Hz, aromatic), 6.68 (2
H, m, aromatics), 3.96 (1H, m, CH-NH ₂ ), 3.87 (1H, m), 3.56 (1H, m), 3.39
(2H, m), 2.57 (1H, dd, J1 = 10.0 Hz, J2 = 15.5 Hz), 2.07 (1H, m), 1.73 (1H,
m), 1.66 (2H, m), 1.30 (3H, t, J = 7.0 Hz); 0.80 (3H, t, J = 7.4 Hz); 0.70
(3H, t, J = 7.3 Hz). [Α] D + 43.00 ° C = 0.2

Step 2A (+) Trans-3-ethoxy-1,1-diethyl-7-hydroxy-1,2 chloride
, 3,4-Tetrahydro-naphthalen-2-ylammonium (Compound No. 16) trans-6-ethoxy-8,8-diethyl-7- (1-phenyl-ethoxycarbonyl carbonate carbonate at room temperature under nitrogen Amino) -5,6,7,8-tetrahydro-naphthalen-2-yl ester 1-phenyl-ethyl ester (the more polar isomer) (32 mg, 0.057 mmol) was dissolved in dichloromethane (5.0 ml). , Trifluoroacetic acid (3.0 ml) was added and the reaction mixture was stirred for about 1 hour. The solvent was evaporated under reduced pressure and then a solution of hydrochloric acid (1.0 M) in ether (10 ml) was added. The reaction mixture thus obtained was stirred for another hour. The solvent was removed under reduced pressure, and the isolated solid was washed several times with pentane, hexane, and then dichloromethane. The isolated product is a yellow powder (10.3 mg, 60%). ¹ H NMR (400 MHz) (CD ₃ OD; d; ppm): 6.98 (1 H, d, J = 8.9 Hz, aromatic), 6.68 (2
H, m), 3.96 (1H, m), 3.87 (1H, m), 3.56 (1H, m), 3.39 (2H, m), 2.57 (1H,
dd, J1 = 10.0 Hz, J2 = 15.5 Hz), 2.07 (1H, m, CH ₂ ), 1.73 (1H, m), 1.66 (2H,
m), 1.30 (3H, t, J = 7.0 Hz); 0.80 (3H, t, J = 7.4 Hz); 0.70 (3H, t, J = 7.3
Hz). [Α] D −43.68 ° C. = 0.19 In a similar manner, the following compounds were prepared:

Compound No. 2 (±) trans-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-
Tetrahydro-naphthalen-2-ol hydrochloride

Embedded image ¹ H NMR (400 MHz) (DMSO-d6; d; ppm): 9.24 (1H, bs), 8.30 (3H, bs), 6.88 (1H
, d, J = 9.3 Hz), 6.74 (1H, d, J = 2.2 Hz), 6.59 (1H, dd, J = 2.2 and 9.3 Hz)
, 3.65 (1H, m), 3.43 (3H, s), 3.40 (1H, m), 3.27 (1H, m), 3.13 (1H, m),
1.40 (3H, s); 1.17 (3H, s)

Compound No. 3 (±) trans-7-amino-8,8-dimethyl-6-phenoxy-5,6,7,8
-Tetrahydro-naphthalen-2-ol TFA salt

Embedded image ¹ H NMR (400 MHz) (DMSO-d6; d; ppm): 9.26 (1H, bs), 8.31 (3H, bs), 7.34 (2H
, t, J = 8.5 Hz), 7.15 (2H, d, J = 8.1 Hz), 7.01 (1H, t, J = 7.2 Hz), 6.88 (1H
, d, J = 8.4 Hz), 6.78 (1H, d, J = 2.4 Hz), 6.60 (1H, dd, J = 2.4 and 8.4 Hz)
, 4.74 (1H, m), 3.51 (1H, m), 3.30 (1H, dd, J = 5.4 and 10.3 Hz), 2.72 (1
H, dd, J = 5.4 and 10.3 Hz), 1.47 (3H, s), 1.24 (3H, s)

Compound No. 4 1,1-Diethyl-7-hydroxy-trans-3-isopropoxy-1,1,2 chloride
, 3,4-tetrahydro-naphthalen-2-yl-ammonium

Embedded image ¹ H NMR (400 MHz) (CD ₃ OD; d; ppm): 6.98 (1 H, d, J = 9.0 Hz, aromatic), 6.67 (
2H, m), 4.04 (1H, m), 3.97 (1H, m), 3.34 (1H, m), 3.32 (1H, m), 2.58 (1H
, dd, J1 = 10.0 Hz, J2 = 15.6 Hz), 2.05 (1H, m), 1.76 (1H, m), 1.68 (2H, dd,
J1 = 7.5 Hz, J2 = 15.1 Hz), 1.28 (3H, d, J = 6.1 Hz); 1.25 (3H, d, J = 6.0 Hz),
0.79 (3H, t, J = 7.5 Hz), 0.69 (3H, t, J = 7.2 Hz)

Compound No. 5 (±) chloride 1,1-diethyl-7-hydroxy-trans-3-propoxy-1,
2,3,4-tetrahydro-naphthalen-2-yl-ammonium

Embedded image ¹ H NMR (400 MHz) (CD ₃ OD; d; ppm): 6.97 (1 H, d, J = 8.7 Hz, aromatic), 6.66 (
2H, m), 3.94 (1H, m), 3.72 (1H, m), 3.48 (1H, dd, J1 = 7.0 Hz, J2 = 14.1 Hz)
, 3.39 (1H, m), 3.73 (1H, m), 2.55 (1H, dd, J1 = 9.8 Hz, J2 = 15.3 Hz), 2.06
(1H, m), 1.67 (5H, m), 1.00 (3H, t, J = 7.3 Hz), 0.78 (3H, t, J = 7.3 Hz),
0.68 (3H, t, J = 7.0 Hz)

Compound No. 6 (±) 1,1-Diethyl-7-hydroxy-trans-3- (2-phenoxy-ethoxy) -1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium chloride

Embedded image ¹ H NMR (400 MHz) (CD ₃ OD; d; ppm): 7.29 (2H, m), 6.96 (4H, m), 6.69 (2H, m)
, 4.23 (2H, m), 4.13 (2H, m), 3.93 (1H, m), 3.45 (2H, m), 2.64 (1H, dd,
J1 = 9.9 Hz, J2 = 15.5 Hz), 2.07 (1H, m), 1.72 (1H, m), 1.67 (2H, m), 0.80 (
3H, t, J = 7.5 Hz), 0.70 (3H, t, J = 7.2 Hz)

(±) Compound No. 7 7-amino-trans-6-ethoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol hydrochloride

Embedded image ¹ H NMR (400 MHz) (CD ₃ OD; d; ppm): 6.94 (1 H, d, J = 8.3 Hz), 6.79 (1 H, d, J = 2
.4 Hz), 6.64 (1H, dd, J1 = 2.4 Hz, J2 = 8.3 Hz), 3.87 (1H, m), 3.77 (1H, m),
3.56 (1H, m), 3.35 (1H, m), 3.23 (1H, dd, J1 = 0 Hz, J2 = 10.8 Hz), 2.63 (1
H, dd, J1 = 10.4 Hz, J2 = 15.3 Hz), 1.49 (3H, s), 1.31 (3H, t, J = 7.0 Hz), 1.
28 (3H, s)

Compound No. 8 (±) 1,1-diethyl-7-hydroxy-trans-3- (2-methoxy-ethoxy) -1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium chloride

Embedded image ¹ H NMR (400 MHz) (DMSO-d6; d; ppm): 9.24 (1H, bs), 7.97 (3H, bs), 6.91 (1H
, d, J = 8.2 Hz), 6.60 (2H, m), 3.89 (1H, m), 3.79 (1H, m), 6.66 (1H, m),
3.54 (2H, m), 3.45 (2H, m), 3.28 (3H, s), 3.20 (1H, m), 1.84 (2H, m), 1.
35 (2H, m), 0.66 (3H, t, J = 7.3 Hz), 0.56 (3H, t, J = 7.1 Hz)

Compound No. 9 (±) 1,1-Diethyl-7-hydroxy-trans-3-methoxy-1,2 chloride
, 3,4-tetrahydro-naphthalen-2-yl-ammonium

Embedded image ¹ H NMR (400 MHz) (CD ₃ OD; d; ppm): 7.00 (1 H, d, J = 6.4 Hz), 6.68 (2H, m), 3.
87 (1H, m), 3.53 (3H, s), 3.41 (2H, m), 2.54 (1H, dd, J1 = 10 Hz, J2 = 16 Hz
), 2.07 (1H, m), 1.71 (1H, m), 1.66 (2H, m), 0.80 (3H, t, J = 7.5 Hz), 0.7
0 (3H, t, J = 7.3 Hz)

Compound No. 10 (±) 1,1-Diethyl-7-hydroxy-trans-3- (2-hydroxy-ethoxy) -1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium chloride

Embedded image ¹ H NMR (400 MHz) (DMSO-d6; d; ppm): 9.22 (1H, bs), 7.96 (3H, bs), 6.91 (1H
, d, J = 8.2 Hz), 6.60 (2H, m), 4.70 (1H, bs), 3.89 (1H, m), 3.79 (1H, m),
3.66 (1H, m), 3.54 (2H, m), 3.45 (2H, m), 3.20 (1H, m), 1.83 (2H, m), 1
.58 (2H, m), 0.66 (3H, t, J = 7.3 Hz), 0.57 (3H, t, J = 7.1 Hz)

Compound No. 11 Trifluoroacetic acid (±) 1,1-spiropentanyl trans-7-hydroxy-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium

Embedded image ^{1 H NMR (MeOD): 6.95} (1H, d, J = 8.5 Hz), 6.73 (1H, d, J = 2.5 Hz), 6.63 (1
H, dd, J = 2.5 Hz and 8.5 Hz), 3.66 (1H, m), 3.53 (3H, s), 3.45-3.35 (2H,
m), 2.65 (1H, dd, J = 10 Hz and 16 Hz), 2.20 (1H, m), 2.15-1.95 (5H, m),
1.80-1.65 (2H, m)

Compound No. 12 Trifluoroacetic acid (±) 7-hydroxy-3-methoxy-1,1-dipropyl-
1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium

Embedded image ^{1 H NMR (MeOD): 6.99} (1H, d, J = 8.0 Hz), 6.70-6.65 (2H, m), 3.84 (H, qd,
J = 6.0 Hz and 10.0 Hz), 3.53 (3H, s), 3.45-3.35 (2H, m), 2.54 (1H, dd,
J = 10.0 Hz and 15.5 Hz), 1.95 (1H, m), 1.73 (1H, m), 1.65-1.45 (2H, m),
1.30-1.05 (3H, m), 0.95-0.90 (4H, m), 0.86 (3H, t, J = 7.0 Hz)

Compound No. 13 Trifluoroacetic acid (±) 3-ethoxy-7-hydroxy-1,1-dipropyl-
1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium

Embedded image ^{1 H NMR (MeOD): 6.98} (1H, d, J = 8.0 Hz), 6.70-6.65 (2H, m), 4.00-3.85 (2
H, m), 3.57 (1H, m), 3.39 (2H, m), 2.57 (1H, dd, J = 10.0 Hz and 15.5 Hz)
, 1.95 (1H, m), 1.77 (1H, m), 1.65-1.50 (2H, m), 1.31 (3H, t, J = 7.0 Hz),
1.30-1.05 (3H, m), 0.95-0.90 (4H, m), 0.86 (3H, t, J = 7.0 Hz)

Compound No. 14 Trifluoroacetic acid (±) 7-hydroxy-3- (2-phenoxy-ethoxy)-
1,1-dipropyl-1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium

Embedded image ^{1 H NMR (MeOD): 7.31} (2H, t, J = 8.0 Hz), 7.05-6.95 (4H, m), 6.70-6.65 (2
H, m), 4.25 (2H, t, J = 5.0 Hz), 4.20-4.05 (2H, m), 3.95 (1H, m), 3.50-3.4
5 (2H, m), 2.64 (1H, dd, J = 10.0 Hz and 15.5 Hz), 1.95 (1H, m), 1.80-1.
0 (3H, m), 1.30-1.05 (4H, m), 0.95-0.90 (4H, m), 0.86 (3H, t, J = 7.0 Hz)

Compound No. 15 (±) trans

Embedded image

Compound No. 16 (−) trans-3-ethoxy-1,1-diethyl-7-hydroxy-1,2 chloride
, 3,4-tetrahydro-naphthalen-2-yl-ammonium

Embedded image

Compound No. 17 (+) trans-3-ethoxy-1,1-diethyl-7-hydroxy-1,2 chloride
, 3,4-tetrahydro-naphthalen-2-yl-ammonium

Embedded image

Compound No. 18 1,1-Diethyl-7-hydroxy-3-trans- (3-hydroxy-propoxy) -1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium chloride

Embedded image ^{NMR (1 H, DMSO):} 9.22 (bs, 1H), 7.96 (s, 3H), 6.91 (m, 1H), 6.59 (m, 2H)
, 4.65 (m, 1H), 4.00-3.00 (m, 8H), 2.10-1.70 (m, 4H), 1.54 (m, 2H), 0.66
(t, J = 7.2 Hz, 3H), 0.57 (t, J = 6.9 Hz, 3H)

Compound No. 19 7-amino-6- (2-amino-ethoxy) -8,8-diethyl-5,6,7,8-
Tetrahydro-naphthalen-2-ol bis-trifluoroacetate

Embedded image ^{1 H NMR (DMSO): 9.28} (1H, s), 7.91 (3H, broad), 7.80 (3H, broad), 6.93
(1H, d, J = 8.5 Hz), 6.64 (2H, m), 4.00-3.90 (2H, m), 3.60 (1H, m), 3.30 (
2H, m), 3.20-3.05 (2H, m), 1.92 (1H, m), 1.84 (1H, m), 1.61 (2H, m), 0.6
9 (3H, t, J = 7.5 Hz), 0.59 (3H, t, J = 7.5 Hz)

Compound No. 20 3- (3-amino-4,4-diethyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yloxy) -propionic acid; trifluoroacetate

Embedded image ^{NMR (1 H, DMSO):} 9.25 (bs, 1H), 7.87 (s, 3H), 6.93 (m, 1H), 6.60 (m, 2H)
, 3.90 (m, 2H), 3.71 (m, 2H), 3.30 (m, 1H), 3.20 (m, 1H), 2.60 (m, 2H),
2.48 (m, 1H), 1.88 (m, 1H), 1.77 (m, 1H), 1.54 (m, 2H), 0.67 (t, J = 7.2 H
z, 3H), 0.58 (t, J = 6.9 Hz, 3H)

Biological Assays A. Affinity for Receptor-Radioligand Binding Assay Schiller et al., Biophys. Res. Commu, incorporated herein by reference.
n., 85: 1322 (1975), using rat brain membrane preparations to determine affinity for μ and δ opioid receptors in vitro by a radioligand binding assay. Was. Sprague weighing 350-450 g by inhaling CO ₂
Dawley male rats were sacrificed. Decapitate the rat, remove the cerebellum, remove the brain,
Place in ice-cold saline, then ice-cold 50 mM Tris buffer (pH 7.
4) Homogenized in (10 ml / brain). The membrane was centrifuged at 14000 rpm for 30 minutes at 4 ° C. About 6 ml of ice-cold 50 mM Tris buffer (pH 7) per brain
The pellet was resuspended in .4) and stored at -78 C until use. For protein quantification of brain homogenate, use the purchased protein assay kit (Bio-Rad)
Was performed according to

As radioligands for the μ and δ receptors, (3H) -DA respectively
MGO and (3H) DAGLE were used. 50 μl radioligand, 100 μm membrane
1 and serially diluted test compounds were incubated for 1 hour at 22 ° C. Non-specific binding was determined using a 500-fold excess of unlabeled ligand in the presence of tracer and membrane. Filtered through Whatman GF / B filter paper (pre-soaked in 1% aqueous polyethyleneimine) and ice-cold 50 mM T using a Brandel cell harvester.
Free ligand was separated from bound by rinsing with ris buffer (pH 7.4). The filters were dried and the radioactivity was measured in a 24-well macroplate in the presence of 500 ml of scintillant per well. Radioactivity was measured using a Wallac 1450 microbeta counter.
Inhibition constants of various compounds (Ki) was determined from the IC ₅₀ based on the equation of Cheng and Prusoff.

B. Central and Peripheral Analgesia—PBQ Writhing Assay Sigmund et al., Proc. Soc. Exp. Biol, incorporated herein by reference.
Med., 95: 729 (1957), in order to assess central and peripheral analgesia in compounds of the present invention, PBQ (phenyl-p -Benzoquinone). C between 18 and 22 g in weight
The test was performed on male D # 1 mice. The mice were weighed, marked, and
A 2% phenylbenzoquinone (PBQ) solution was intraperitoneally administered at 0.3 ml / 20 g body weight. Twisting that appeared 15 minutes after injection was counted and the ED ₅₀ value (the dose of compound that induced a 50% reduction in the number of writhing observed compared to controls) was calculated. After subcutaneous or oral administration of compound (or culture solution or standard solution), PBQ was injected at time intervals of 5, 20, or 60 minutes. A PBQ solution was prepared by dissolving 20 mg of PBQ in 5 ml of 90% ethanol (Sigma, reagent, alcohol). PBQ dissolved in 95 ml of distilled water, previously warmed (not boiled) and shaking continuously, was added slowly. 2 hours before use, P
The BQ solution was allowed to stand and always shielded from light. Fresh solutions were prepared daily for each test.

C. Central analgesia-tail splash assay D'Amour et al., J. Pharmacol., 72: 7, incorporated herein by reference.
Compounds of the invention were evaluated for central analgesia as described in 4-79 (1941).

Although the invention has been described in connection with specific embodiments thereof, it is capable of further modification, and its application generally follows the principles of the invention and includes such departures from the present description. Is intended to cover any alterations, uses, or adaptations of the invention as it is known or practiced within the skill of the art to which the invention pertains and as to the essential features mentioned above. It will be understood that it is applicable and within the scope of the claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 101 A61P 43/00 101 C07C 53/18 C07C 53/18 217/52 217/52 // C07B 53/00 C07B 53/00 A C07M 7:00 C07M 7:00 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, A , AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN , MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Teachao Lee, Indiana, United States 46038. Fishers. Turnham Drive 12853 (72) Inventor Edward Roberts Ze Ha-4112 Flew, Switzerland. Heenweg12 (72) Inventor Richard Stoller Quebec H9 X2 N3 Canada 3. Bedulf. Oak Ridge 215 (72) Inventor Woo Wang Quebec H. Canada 4 R 1 M 3. Ville Saint Laurent. Frenet 2297 F term (reference) 4C206 AA01 AA02 AA03 AA04 FA41 MA01 MA04 NA14 ZA08 ZC41 4H006 AA01 AA03 AB21 BJ50 BM10 BM71 BN20 BP20 BS10 BU42

Claims (28)

[Claims] 1. A compound of the formula (I) And a pharmaceutically acceptable derivative thereof. In the above formula, X represents: (i) a bond (ii) —CR ₇ R ₈ — wherein R ₇ and R ₈ are independently H, OH, halogen, CN
, COOH, CONH _2, an amino, nitro, SH, 1 or more carbon atoms is O, optionally substituted with one or more heteroatoms selected from S, and N C _{1- 6} alkyl, C _2-6 alkenyl, 1 or more of which 1 or more carbon atoms may be optionally substituted with one or more heteroatoms selected from O, S, and N C _2-6 alkynyl optionally having many carbon atoms optionally substituted with one or more heteroatoms selected from O, S and N, and COOR _c , wherein R _c is C _{1 -6} alkyl, C _2-6 alkenyl, or C _2-6 alkynyl); and R ₇ and R ₈ are linked to form a C _3-8 cycloalkyl, _3-8 cycloalkenyl, or a saturated heterocyclic 3-8 atom Is selected from any of the bets could]; R ₁ is, H, 1 or more carbon atoms is O, optionally substituted with one or more heteroatoms selected from S, and N A C _1-12 alkyl,
C _2-12 alkenyl, optionally having one or more carbon atoms optionally substituted with one or more heteroatoms selected from O, S, and N, one or more carbon atoms Is optionally substituted with one or more heteroatoms selected from O, S, and N, C _2-12 alkynyl, C _6-12 aryl, C _6-12 aralkyl, C _{6 -12} aryloxy, acyl of C _1-12, heteroaryl, and it is selected from the group consisting of phosphoryl having 6 to 12 atoms; R ₂ and R ₃ are independently 1 or more carbon atoms Is a C _1-6 alkyl optionally substituted with one or more heteroatoms selected from O, S, and N, wherein one or more carbon atoms are from O, S, and N Optionally substituted with one or more selected heteroatoms Alkenyl which may C _2-6 is, 1
Or from a number of carbon atoms O, S, and one or more optionally substituted also good C _2-6 and alkynyl with heteroatoms selected from N, aryl C _6-12, C ₆ Selected from the group consisting of _-12 aralkyl, heteroaryl having 6-12 atoms, and H: or R ₂ and R ₃ together form a saturated heterocyclic ring having 3-8 atoms may; be R ₄ and R ₅ are independently, 1 or more carbon atoms is O, S, and optionally substituted in many heteroatom than 1 or are selected from N C _{1 -6} alkyl, one or more number of carbon atoms O, S, and one or more optionally substituted alkenyl which may C _2-6 with a heteroatom selected from N, 1
Or selected from the group consisting of C _2-6 alkynyl, and H wherein or more carbon atoms are optionally substituted with one or more heteroatoms selected from O, S, and N; Further, R ₄ and R ₅ are attached, cycloalkyl, can also form a saturated heterocyclic ring cycloalkenyl, or 3-8 atoms of C _3-8 of C _3-8; R ₆ is hydrogen OH, one or more carbon atoms optionally substituted with one or more heteroatoms selected from O, S and N, C _1-6 alkyl, one or more Is a C _2-6 alkenyl, wherein one or more carbon atoms are optionally substituted with one or more heteroatoms selected from O, S, and N, and one or more carbon atoms are O, S, And optionally substituted with one or more heteroatoms selected from N It is alkynyl which may C _2-6, the one or more number of carbon atoms O, S, and one or more of good O-C ₁ be optionally substituted with hetero atoms selected from N _-6 alkyl, O-C _2-6 alkenyl, one or more carbon atoms of which are optionally substituted with one or more heteroatoms selected from O, S, and N; Or more carbon atoms are O,
S, and one or more optionally substituted also good O-C _2-6 and alkynyl with heteroatoms selected from N, halogen, CN, COOH, CONH _2, an amino, nitro, or a SH Wherein 1) R ₄ and R ₅ are not both H, and 2) at least one of R ₂ and R ₃ is H or C _1-6 alkyl. 2. The compound according to claim 1, wherein X is —CH ₂ —. 3. The compound of claim 2, wherein the geometric relationship between the substituents on the carbon marked with * is trans. 4. The compound according to claim _{3, wherein} R ₂ and R ₃ are H. 5. The compound according to claim 3, wherein R ₆ is H. 6. The compound of claim 5, wherein R ₄ and R ₅ are C _1-4 alkyl. 7. The compound of claim 5, wherein R ₄ and R ₅ are independently selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl, and isobutyl. 8. The compound of claim _{5, wherein} R ₄ and R ₅ are ethyl. 9. The compound of claim _{5, wherein} R ₄ and R ₅ are methyl. 10. R ₁ is H, alkyl of C _1-12, compound of Claim 5 selected aryl C _6-12, and from the group consisting of aralkyl of C _{6 -12.} 11. The compound of claim 5, wherein R ₁ is selected from the group consisting of C _1-6 alkyl, C _6-12 aryl, and C _6-12 aralkyl. 12. The compound of claim 5, wherein R ₁ is C _1-6 alkyl. 13. R ₁ is CH ₃ , — (CH ₂ ) _n —CH ₃ and — (CH ₂ ) _n —O—
CH ₃ (wherein, n is an integer selected from 1 to 5) A compound of claim 5 which is selected from the group consisting of. 14. The compound of claim 5, wherein R ₁ is C _6-12 aryl. 15. R ₁ is embedded image Is selected from the group consisting of, wherein A is wherein alkyl C _1-6, alkyl of C _1-6, alkenyl C _1-6, alkynyl of C _1-6, alkyl O-C _1-6, O alkenyl of -C _2-6, alkynyl O-C _2-6, alkyl of S-C _1-6, alkenyl of S-C _2-6, alkynyl of _{S-C 2-6, N-C} 1-6 Alkyl, N-C _2-6 alkenyl, N
-C _2-6 alkynyl, CF ₃ , fluoro, chloro, bromo, iodo, OH, SH
, CN, nitro, amino, Aminoamijino, amidino, guanido, from COOH, and COOR _z (wherein, R _z is an alkynyl alkyl, alkenyl or C _2-6 of C _2-6 of C _1-6) 15. The compound of claim 14, wherein the compound is selected from the group consisting of: 16. The compound according to claim 5, wherein R ₁ is C _6-12 aralkyl. 17. R₁IsSelected from the group consisting of: wherein A is C_1-6Alkyl, C_1-6Alkyl, C _2-6 Alkenyl, C_2-6Alkynyl, OC_1-6Alkyl, OC_2-6Al
Kenyl, OC_2-6Alkynyl, SC_1-6Alkyl, S—C_2-6The alkene
Le, S-C_2-6Alkynyl, NC_2-6Alkyl, N-C_2-6Alkenyl,
N-C_2-6Alkynyl, CF_Three, Fluoro, chloro, bromo, iodo, OH, S
H, CN, nitro, amino, aminoamidino, amidino, guanide, COOH,
And COOR_z(Where R_zIs C_1-6Alkyl, C_2-6Alkenyl or C_2-6No
Y is-(CH_Two)_m-(Where m is 1 to
And n is an integer selected from 5). 18. The compound is trans-7-amino-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 1); trans-7-amino -6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 2); trans-7-amino-8,8-dimethyl-6-phenoxy-5, 6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 3); trans-7-amino-6-isopropoxy-8,8-dimethyl-5,6,7,8
Trans-7-amino-8,8-dimethyl-6-propoxy-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 5) Trans-7-amino-8,8-dimethyl-6- (2-phenoxy-ethoxy) -5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 6); trans-7-amino- 6-ethoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 7); trans-7-amino-8,8-diethyl-6- (2-methoxy- Ethoxy)
-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 8); trans-7-amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalene- 2-ol (Compound No. 9); trans-7-amino-8,8-diethyl-6- (2-hydroxy-ethoxy) -5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 10) )
Trans-7-amino-8,8-spiropentanyl-6-methoxy-5,6,7,
8-tetrahydro-naphthalen-2-ol (Compound No. 11); trans-7-amino-6-methoxy-8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 12) Trans-7-amino-6-ethoxy-8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 13); trans-7-amino-6- (2- Phenoxy-ethoxy) -8,8-dipropyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound No. 14
Trans-3-amino-4,4-diethyl-1,2,3,4-tetrahydro-naphthalene-2,6-diol (Compound No. 15); (−) trans-3-ethoxy-1,1 chloride -Diethyl-7-hydroxy-1,
2,3,4-tetrahydro-naphthalen-2-yl-ammonium (Compound No. 1
6); (+) chloride trans-3-ethoxy-1,1-diethyl-7-hydroxy-1,
2,3,4-tetrahydro-naphthalen-2-yl-ammonium (Compound No. 1
7); 1,1-diethyl-7-hydroxy-3-trans- (3-hydroxy-chloride)
Propoxy) -1,2,3,4-tetrahydro-naphthalen-2-yl-ammonium (Compound No. 18); 7-amino-6- (2-amino-ethoxy) -8,8-diethyl-5,6, 7,8
-Tetrahydro-naphthalen-2-ol bistrifluoroacetate (Compound No. 19); 3- (3-amino-4,4-diethyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yloxy ) -Propionic acid trifluoroacetate (
Compound No. 20); and the compound of Claim 1 selected from the group consisting of pharmaceutically acceptable derivatives thereof. 19. The compound according to claim 1, wherein the compound is Compound No. 1, Compound No. 2, Compound No. 3,
Compound No. 4, Compound No. 5, Compound No. 6, Compound No. 7, Compound No. 8, Compound No. 9, Compound No. 12, Compound No. 16, Compound No. 17, Compound No. 1
20. The compound of claim 18 selected from the group consisting of 8 and compound no. 20. The compound having the compound number 1, compound number 2, compound number 5,
20. The compound of claim 19, wherein the compound is selected from the group consisting of Compound No. 8, Compound No. 9, Compound No. 16 and Compound No. 17. 21. The compound of claim 19, wherein said compound is selected from the group consisting of Compound No. 16 and Compound No. 17. 22. The compound according to claim 1, wherein the compound is in the form of a mixture of (+) enantiomers, (−) enantiomers and mixtures of (+) and (−) enantiomers, including racemic mixtures.
21. The compound according to any one of 20. 23. The compound according to claim 1, wherein the compound is in the form of the (+) enantiomer.
The compound according to any one of the above. 24. The compound according to claim 1, wherein the compound is in the form of the (−) enantiomer.
The compound according to any one of the above. 25. A compound according to any one of claims 1 to 24 for use in therapy. 26. A method of treating pain in a mammal, comprising administering to the mammal an analgesic amount of a compound as defined in any one of claims 1 to 24. 27. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 24 and a pharmaceutically acceptable carrier, diluent or adjuvant. 28. Use of a compound according to any one of claims 1 to 24 for the manufacture of a medicament for treating pain.