IE83295B1 - Ring-substituted 2-amino-1, 2, 3, 4-tetra-hydronaphthalenes and 3-aminochromanes - Google Patents

Abstract

Abstract of theépisclosgre The present invention provides novel ring- substituted 2—amino-1,2,3,4—tetrahydronaphtha1enes and 5 3-aminochromanes which exhibit binding activity at the serotonin 1A receptor.

Description

PATENTS ACT, 1992 RING—SUBSTITUTED 2—AMINO—l,2,3,4—TETRA—HYDRONAPHTHALENES AND 3- AMINOCHROMANES ELI LILLY AND COMPANY RING-SUBSTITUTED 2-AMINO-1,2,3,4-TETRA- HYDRONAPHTHALENES AND 3-AMINOCEROMANES Over the last several years it has become apparent that the neurotransmitter serotonin (5-hydroxy- tryptamine -- 5-HT) is associated directly or indirectly with a number of physiological phenomena, including appetite, memory, thermoregulation, sleep, sexual be- havior, anxiety, depression, and hallucogenic behavior [G1ennon, R. A., Q; fled; ghgm; 39, 1 (1987)].

It has been recognized that there are multiple types of 5-HT receptors. These receptors have been classified as 5-HT1, S-HT2, and 5-HT3 receptors, with the former being further divided into the sub—classes -HT HTIB, S-HTIC, and 5-ET1D.

Selected 2-amino-1,2,3,4-tetrahydronaphthalenes (2-aminotetralins) and 3-aminochromanes have been shown to exhibit binding affinity at the 5-HT1A receptor.

European Patent Application No. 385,658 published September 9, 1990 describes 2-aminotetralins substituted in the 8-position and 3-aminochromanes substituted in the 5-position by sulfides, sulfoxides, and sulfones.

These compounds, as well, are described as having binding affinity at the S-HTIA receptor. Another class of 2—aminotetralins are described in European Patent Application No. 343,830, published November 29, 1989.

These compounds have a piperazinyl or homopiperazinyl moiety in the 2-position and, distinct from the foregoing tetralins, exhibit serotonin re-uptake A’ 5‘ inhibition as opposed to serotonin receptor binding affinity. European Patent Application No. 399,982 published November 28, 1990, describes 2-aminotetralins having in the 8-position, among others, a 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S. PCT Application W090/15047 published December 13, 1990, describes 2-aminotetralins substituted in any of the 5-, 6-, 7-, or 8-positions by, "bet". Het is described as a five atom heterocyclic ring containing nitrogen, carbon, and in among others, some cases oxygen. we have now discovered a class of compounds which, by reason of their exceptional 5-BTIA activity, are highly useful in the treatment, for example, of sexual dysfunction, anxiety, depression, and eating disorders, such as anorexia.

The compounds are novel ring—substituted 2- amino—l,2,3,4-tetrahydronaphthalenes having in the 8- -position of the tetrahydronaphthalene a defined isoxazol—3—yl or isoxazol—S-yl substituent. The compounds have partial agonist and antagonist activity at the 5—HTlA receptor.

More specifically they are selected from the group consisting of: -di-n—propy1amino—8-(isoxazol-5—y1)-1,2,3,4- tetrahydronaphthalene, -di-n-propy1amino(4-methylisoxazol-S-yl)-1,2,3,4- tetrahydronaphthalene, -di-n-propylamino(3-methylisoxazol-S-yl)-1,2,3,4- tetrahydronaphthalene, -di-n-propy1amino(isoxazolyl)-1,2,3,4- tetrahydronaphthalene, -di-n-propy1amino(3-methylthioisoxazol)-S-y1)- 1,2,3,4-tetrahydronaphthalene, -di—n-propy1amino—8-(4—methoxyisoxazo1yl)-1,2,3,4- tetrahydronaphthalene; and pharmaceutical1y-acceptable acid addition salts and solvates thereof.

The preferred compound is: -di-n-propylamino(isoxazo1—S-yl)-1.2.3.4- tetrahydronaphthalene.

These compounds possess an asymmetric carbon represented by the carbon atom labeled with an asterisk in the following formula: * NRR1 X As such, each of the compounds exists as its individual d- and 1-stereoisomers and also as the racemic mixture of such isomers. Accordingly, the compounds include not only the dl—racemates but also their respective optically active d- and l—isomers.

Pharmaceutically acceptable acid addition salts of the compounds defined by the above formula exist. Since the compounds are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceu- tically acceptable acid addition salts. Since the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their corresponding pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phos- room temperature. phoric acid, and the like, and organic acids such as 2-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, y-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalenesulfonate, naphthalene-2—sulfonate, mandelate, and the like.

Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

In addition, some of these salts may form sol- vates with water or organic solvents such as ethanol.

The compounds are available by a number of general reactions. General schemes are provided_in the following; in each, the groups Ra and RC are as follows: Ra - hydrogen, C1-C4 alkyl, o(c1—c4 alkyl), or S(C1-C4 alkyl); RC — hydrogen or C1-C3 alkyl.

Isoxazote O R. R: }~:_ 0 1. base 0 H NOH O \|,/\R1 R. 2 / R‘ A, 2. a,cooa._ NMBI N HC(NMa,)3, A I I -' —————- o HZNOH 0 / _ R, Hz Ar Mes SMe N 5M‘ 3. Mel | I O H NOH 0 R, 2 / R.

Ar Ar Fla 9" 94 H NQH 1. base Ar 2- RICOOH: A! (or HCONMe2) 3. H30’ SM‘ SMe e,P=cHsMe our-‘ NH 0“ °‘“ mono / ._-.... OHC / 2 \\ pocx, Ra Ra Ar Ar Ar The aforementioned methods of synthesis provide compounds in which the heteroaromatic ring may or may not bear a substituent. The following general reactions provide methodology for incorporating, interconverting, and removing substituents on the heteroaromatic ring. Additional methods for performing these transformations are cited in Comprehensive Organic Transformations by Richard C. Larocke, VCH Publishers, Inc., New York (1989). In the following, Ar‘ refers to the heteroaromatic system attached to the 2-aminotetralin ring system at C-8 or to the 3-aminochromane ring system at C-5.

A. 0(C,-C. a1ky1): Ar'X + Ar'0R' R'0-, CuI, (DME, or DMAC, or NMP), A Ar'OH + Ar'OR' Base, R'x'; or CH2N2 B. Hydroxy substituent: Ar'NHg + Ar'OH Ar'OMe + Ar'0H . EONO; 2. 830+, A 48% HBI, A: or BBI3 C. Cyano substituent: Ar'NEg + Ar'CN Ar'X' 9 Ar'CN . HON0; 2. CuCN CuCN, (DME, or DMAC, or NM), A or CN-, A D. S(C1-C, alkyl): Ar'NH2 + Ar'SR‘ Ar‘X' + Ar'SR' E. Amino substituent: Ar'NO2 + Ar'NH2 F. Hydrogen substituent: Ar'X' + Ar'H Ar'OH + Ar'H Ar'NH2 + Ar'E Ar‘-CH2Ph + Ar'H Ar'SR' + Ar'H . HONO; 2. R'SH, base R'5-. CHI: (DMF, or DMAC, or NMT), A B2, catalyst (i.e. Pt or Pd) H2, catalyst; or R'3SnH, 2,2'-azobis(2-methyl—pro- pionitrile) A . 5—chlorophenyltetrazole, 2. H2, catalyst . HONO, 2. H3PO2 H2, catalyst (i.e. Pd) (This applies if the benzyl group is attached to a nitrogen in the heterocyclic ring.) Raney Ni Optically active isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures.

This resolution can be carried out in the presence of a resolving agent, by chromatography or by Particularly useful resolving repeated crystallization. agents are d- and 1-tartaric acids, d- and l-ditoluoyl- tartaric acids, and the like. one particularly useful method for producing optically active isomers of the compounds of this inven- tion is via an 8-substitutedtetralone or a 5- substitutedchromanone. may be reductively alkylated with an optically active a- phenethylamine after which the resulting mixture of Either of these intermediates diastereomers is separated by recognized methodology, such as chromatography. Cleavage of the a-phenethyl moiety produces a correspondingly substituted, optically active 2-amino-1,2,3,4-tetrahydronaphthalene or 3-aminochromane.

The conditions necessary for removing the phenethyl moiety are relatively severe and can tend to disrupt the integrity of the core tetralin or chromane molecule; It has been discovered that the cleavage can be carried out in a much more facile and efficient manner requiring only mild cleavage conditions when the particular a-phenethylamine which is used is 2-nitro-a-phenethylamine.

Cleavage of the p-nitro-a-phenethyl moiety is achieved by reduction of the p-nitro group followed by acid-catalyzed solvolysis of the resulting p-amino-a- phenethyl moiety._ Reduction of the nitro group can be accomplished by a wide range of reducing agents includ- ing, for example, titanium trichloride, lithium aluminum hydride, or zinc/acetic acid, or by catalytic hydrogena- solvolytic cleavage takes place when the monohydrochloride (or other monobasic salt) of the tion. reduction product is treated with water or an alcohol at room temperature or, in some instances, at elevated temperatures. A particularly convenient condition for removing the p-nitro-a-phenethyl moiety is hydrogenation of the amine monohydrochloride in methanol over a platinum catalyst.

The invention particularly provides a novel intermediate compound employed in the above processes, of the formula in which R is C1‘C4 a1kYl. al1Y1 Or Cyclopropylmethyl; R1 is hydrogen, C1-C4 alkyl, allyl, cyclopropylmethyl or aryl(C1—C4 alkyl); X is -CH3- 5 Q is CH - = - or c CHN< 3 I Ra CH3 $2 -CH-CR,; and each Ra is independently hydrogen, c1—c4 alkyl C1-C4 alkoxy or C1-C4 alkylthio.

The compounds employed as initial starting materials in the synthesis of the compounds of this invention are well known and readily synthesized by standard procedures commonly employed by those of ordinary skill in the art.

The pharmaceutically acceptable acid addition salts of this invention are typically formed by reacting a l,2,3,4—tetrahydronaphthalene of this invention with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or benzene, and the salt normally precipitates out of solution within about one hour to days, and can be isolated by filtration.

The following Examples 1 to 5 illustrate the use of the above novel intermediates.

Preparation 1 -Di-n-propy1amino(1-methylpyrazo1-3—y1)- 1,2,3,4-tetrahydronaphthalene, maleate salt and -Di-n-propylamino(1-methy1pyrazo1—S-y1)- 1,2,3,4-tetrahydronaphthalene, hydrobromide salt.

A solution of n-butyllithium (1.6 M in hexane, .1 ml, 24.2 mmol) was added to a solution of -bromodi-n-propylamino-1,2,3,4-tetrahydronaphthalene (5.0 g, 16.1 mmol) in THF (50 ml) at -78° and the reaction stirred at -78° for one hour. Gaseous carbon dioxide was bubbled through the reaction at -78° until the deep violet color which forms dissipates.

Methyllithium (1.4 M in ether, 23 ml) was added. The reaction was stirred at -78° for 30 minutes and warmed to room temperature. The reaction was stirred for an additional ten minutes at room temperature at which time the pink color had been lost. An additional 10 ml of the methyllithium solution was added and the reaction became pink once again. After 15 minutes, the pink color was lost and an additional 10 ml of the methyllithium solution added. onto ice, made acidic with hydrochloric acid and The reaction was poured extracted with ether. The aqueous layer was made basic and extracted with methylenechloride. extracts were dried (Na2SO4) and concentrated to give The basic 3.8 g of crude product. Purification by flash silica gel chromatography using 2:1 hexane:ether containing trace ammonium hydroxide provided 2-di-n-propylamino- 8-acetyl-1,2,3,4-tetrahydronaphthalene as a yellow oil (2.7 g, 61%).

-Di—n-propylaminoacetyl-l,2,3,4—tetra- hydronaphthalene (3.0 g; 11.0 mmol) was dissolved in 125 ml of toluene after which 4.6 ml (27.5 mmol) of tris(dimethylamino)methane were added. The mixture was heated to 80°C overnight after which it was evaporated, and the residue was dissolved in 100 ml of methanol.

Methylhydrazine (2.9 ml; 54.9 mmol) was added. The mixture was refluxed for six hours and then stirred at room temperature overnight. The mixture was then poured into water, and the aqueous mixture was extracted with methylene chloride. The methylene chloride extract was dried over sodium sulfate and evaporated to give 3.7 g of a residue which contained both of the title compounds.

The residue was placed on a silica gel column and was eluted with a mixture of 2% methanol in methylene chloride containing a trace of ammonium hydroxide. give 2.1 g of the major isomer, 2-di-n-propy1amino The appropriate fractions were combined to -(1-methylpyrazolyl)-1,2,3,4-tetrahydronaphthalene (Rf=O.31 in 2% methanol in methylene chloride containing a trace of ammonium hydroxide). This material was converted to the maleate salt, and the salt was recrystallized from a mixture of ethanol and ether to give 2.3 g of white crystals, m.p. 139.5-140.5°C.

MS(FD): 3ll(lO0) Analysis: Theory: C, 67.42; H, 7.78; N, 9.83; Found: C, 67.62; H, 7.81; N, 9.80.

The appropriate fractions were combined to give 165 mg of the minor isomer, 2-di-n-propylamine(1-methylpyrazolyl)-1,2,3,4- tetrahydronaphthalene. (Rf=0.27 in 2% methanol in methylene chloride containing a trace of ammonium hydroxide) recrystallized from a mixture of methanol and ethyl The Hr salt of this material was formed and acetate to give 30 mg of a solid, m.p. 203-204°C.

MS(FD): 311(100) Analysis: Theory: C, 50.76; H, 6.60; N, 8.88 Found: C, 50.09; H, 6.61; N, 8.65.

Preparation 2 Preparation of 2-Di-n-propylamino—8- (5-hydroxypyrazolyl)-1,2,3,4- tetrahydronaphthalene.

To a solution of 8-bromodi-n—propy1amino- l,2,3,4-tetrahydronaphthalene (1.0 g, 3.22 mmol) in THF (50 ml) at -78°C was added a solution of n-butyllithium in hexane (1.1 M, 4.4 ml, 1.5 eq). allowed to stir at -78° for one hour and carbon dioxide gas was bubbled through the reaction. mixture was warmed to room temperature.

The reaction was The resulting After removal of the volatiles from the reaction, the brown oil was poured into H20 and washed with ether. The organic phase was discarded and the aqueous layer was concentrated and taken up in methanol. Hcl gas was bubbled through the solution and the reaction heated to reflux for 3 hours. After cooling, the reaction was poured into H20 (50 ml), made basic using NaHC03 (aq), and extracted with ether. The ether extract was dried over MgSO4 and concentrated to give 1 g of a black oil.

Purification by flash column chromatography eluting with 4:1 Hex:EtOAc yielded 440 mg of 2-di-n-propylamino (methoxycarboxyl)-1,2,3,4-tetrahydronaphthalene.

A LDA solution was formed from 17 mmol of 2.42 ml diisopropylamine and 17 mmol (17 ml, 1 M) nBuli at -78°C. The LDA solution was warmed to -20°C for 30 minutes and cooled back to -78°C before adding 2.83 ml (20.96 mmol) of t-butyl acetate. After 10 minutes, 440 mg (1.47 mmol) of 2-di-n—propylaminomethoxycarbonyl- 1,2,3,4-tetrahydronaphthalene was added in 20 ml of dry THF. This reaction was warmed to room temperature and allowed to stir for 3 days.

. The resulting mixture was poured into H20 (50 ml) and extracted with CH2C12 (3 x 50 ml). The extract was dried (MgS0,) and concentrated to give 1.8 g of an oil. Purification by flash column chromatography, eluting with 10% methanol in dichloromethane, gave 160 mg of 2-di-n-propylamino-8f(E-butoxycarbonylacetyl)- ,2,3,4-tetrahydronaphthalene as a yellow oil.

Example 1 Preparation of 2-Di-n-propylamino(isoxazo1- -yl)-1,2,3,4-tetrahydronaphthalene, maleic acid salt.

A solution of 2-di-n-propylaminoacety1- 1,2,3,4-tetrahydronaphthalene (0.3 g, 1.1 mmol), prepared as in Preparation 1, and tris(dimethylamino)— methane (0.32 g, 2.2 mmol) in toluene was heated to reflux for 5 hours and at 60° for 18 hours. An additional aliquot of tris(dimethy1amino)methane (0.16 g, 1.1. mmol) was added and the reaction stirred at 60° for an additional 2 hours. The reaction was concentrated to give 2-di-n-propylamino(1-oxo (dimethylamino)-propenyl)-1,2,3,4-tetrahydronaphthalene (0.39 9) us a viscous, orange oil.

Hydroxylamine hydrochloride (0.32 g, 4.6 mmol) was added to a solution of 2-di-n—propylamino(1- oxo(dimethylamino)-propenyl)-1,2,3,4-tetrahydro- naphthalene (0.75 g, 2.29 mmol) in acetic acid (5 ml) and the reaction stirred at room temperature. The reaction was concentrated and the residue dissolved in water. This solution was made basic by the addition of concentrated ammonium hydroxide solution and extracted with ether. The extract was washed with brine, dried with Na2SO., and concentrated to give a viscous, light orange oil. The maleate salt was formed.

Crystallization from ethanol/ether gave the title compound as off-white crystals (0.24 g). mp 136-138°.

Recrystallization of this salt from ethanol gave colorless crystals (155 mg). m.p. 139-141° Analysis: Theory: C, 66.65; H, 7.29; N, 6.76; Found: C, 66.86; H, 7.33; N, 6.79.

PO ¢-- Preparation 3 -Di-n-propylamino(S-hydroxyisoxazol- 3-yl)-1,2,3,4—tetrahydronaphtha1ene. (1.0 g, 3.3 mmol) was taken up in 25 ml methanol. Ten equivalents of hydroxylamine hydrochloride (8.3 g, 33 mmol) were added and the reaction stirred at room temperature for 48 hours. The solution was filtered to remove unused hydroxylamine hydrochloride. The mixture was then concentrated and three crystalliza-tions were performed from methanol/ethylacetate. The title compound (30 mg) was recovered.

FD mass spectroscopy shows correct mass of .

Example 2 Preparation of 2-Di-n-propylamino(4-methyl- isoxazolyl)-1,2,3,4-tetrahydronaphthalene, maleate salt.

-Di-n-propylaminobromo—1,2,3,4-tetrahydro- naphthalene (8.5 g.; 27.4 mmol) was dissolved in 80 ml of THF and cooled to -78°C after which 25.7 ml of n-butyllithium (1.6 M in hexane) were added. The mixture was stirred at -78°C for one hour after which 2.4 ml (32.9 mmol) of propionaldehyde were added. The mixture was warmed to room temperature and then poured into water, and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 9.1 g of a yellow oil.

The oil was placed on a silica gel column and was eluted with a mixture of 3% methanol in methylene chloride containing a trace of ammonium hydroxide. The approriate fractions were combined to give 6.5 g (82.0%) of 2-di-n-propylamino(1'-hydroxypropyl)-1,2,3,4- tetrahydronaphthalene as a clear oil.

The foregoing product was dissolved in 250 ml of methylene chloride, and 17.0 g (78.7 mmol) of pyridinium chlorochromate (PCC) were added along with 30 g 4A molecular sieves. The mixture was stirred for three hours at room temperature after which 250 ml of ether and Celite were added. The mixture was poured onto a short silica gel column and eluted with ether.

Methanol was added to dissolve the brown sludge which had precipitated upon addition of ether to the reaction.

This material was added to the column and eluted with % methanol in methylene chloride. The eluent was concentrated to give a brown oil which was further purified by column chromatography employing 2:1 hexanes:ether and then pure ether as solvent. Fractions containing the product were combined and concentrated to give 4.7 g of 2-di-n-propylamino—8-propionyl-1,2,3,4- tetrahydronaphthalene. 2-Di-n-propylaminopropionyl-1,2,3,4-tetra- hydronaphthalene, (1.5 g; 5.2 mmol) was dissolved in 50 ml toluene, and 2.2 ml of tris(dimethylamino)methane was added: The mixture was heated to 80°C overnight. The mixture was then evaporated and the residue was taken up in 15 ml of acetic acid. Hydroxylamine hydrochloride (730 mg; 10.4 mmol) was added, and the mixture was The mixture was poured onto water, the pH was adjusted to 11 with ammonium hydroxide, and the resulting mixture was stirred at room temperature overnight. extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 1.5 g of an orange oil.

The oil was placed on a silica gel column and was eluted with a 2:1 mixture of hexane and ether containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 1.0 g (61.3%) of the free base of the title compound.

Fifty mg of the free base were converted to the maleate salt and recrystallized from a mixture of ethanol and ether to give 55 mg of white crystals, m.p. 118°C.

Analysis, for C24H32N2O5: C, 67.27; H, 7.53; N, 6.54; C, 66.99; H, 7.60; N, 6.35.

Theory: Found: Example 3 "Preparation of 2-Di-n-propylamino(4-ethy1- isoxazolyl)-1,2,3,4-tetrahydronaphthalene.

-Di-n-propylaminobromo-1,2,3,4-tetrahydro- naphthalene (5.0 g; 16.1 mmol) was dissolved in 50 ml of THF, and the mixture was cooled to -78°C after which 21.0 ml of n-butyllithium (0.92 M in hexane) were added.

The mixture was stirred for 30 minutes, and 1.85 ml (21.0 mmol) of butyraldehyde were added. was allowed to warm to room temperature and was stirred The mixture overnight after which it was poured into water and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 6.4 g of a residue. The residue was placed on a silica gel column and was eluted with a mixture of 2% methanol in methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 4.8 g of 2-di—n-propylamino(1'-hydroxybutyl)- 1,2,3,4-tetrahydronaphthalene as a thick oil.

The oil (4.0 g; 13.2 mmol) was dissolved in ml of methylene chloride and 4A molecular sieves (30 g) were added. The mixture was stirred, and 10.0 g (46.2 mmol) PCC were added. three hours at room temperature after which the mixture Stirring was continued for was poured onto a pad of silica gel and eluted sequentially with ether and 3% methanol in methylene chloride containing a trace of ammonium hydroxide to recover the product as a brown oil.

The oil was placed on a silica gel column and was eluted with a mixture of 3% methanol and methylene _ chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined to obtain an oil which, when dissolved in ether, caused a brown precipitate to form. The precipitate was removed by filtration, and the filtrate was evaporated to give 3.0 g of 2-di-n-propylaminobutyryl-1,2,3,4-tetra- hydronaphthalene as a light brown oil.

Potassium t-butoxide (0.82 g; 7.3 mmol) was suspended in 100 ml of tetrahydrofuran (THF). Ethyl formate (1.0 g; 13.3 mmol) and 2-di—n-propylamino butyryl-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.3 mmol) in THF was added to the mixture. The resulting mixture was stirred at room temperature overnight.

Hydroxylamine (1.2 g; 16.6 mmol) was added followed by sufficient water to dissolve the solid. The resulting mixture, having pH 6, was stirred at room temperature for 20 hours after which it was poured into water, and the pH was adjusted to 12 with ammonium hydroxide. The mixture was then extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated.

The residue was dissolved in 100 of toluene, and 100 mg of p-toluenesulfonic acid was added. The mixture then was refluxed for 1.5 hours after which it was poured into water and extracted with methylene chloride. The methylene chloride extract was dried over sodium sulfate and evaporated. . title compound.

The residue was placed on a silica gel column and was eluted with a 2:1 mixture of hexane and ether containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 0.9 g of the MS(FD): 327(100).

Example 4 Preparation of 2-Di-n~propylamino(3-methyl- isoxazolyl)—1,2,3,4-tetrahydronaphthalene, maleate salt.

Potassium t-butoxide (450 mg; 4.0 mmol) was suspended in THF, and 0.7 ml (7.3 mmol) of ethyl acetate and 0.5 g (1.8 mmol) of 2-di-n-propylamino—8- V acetyl2,3,4-tetrahydronaphthalene (prepared as in in THF was added. which was used was 30 ml.

Preparation 1) The total amount of THF The mixture was then stirred overnight at room temperature after which 640 mg (9.2 mmol) of hydroxylamine hydrochloride were added. The reaction mixture was then stirred at room temperature for 64 hours. The mixture was poured into water and the pH adjusted from 6 to 12 with ammonium hydroxide. The mixture then was extracted with a 3:1 mixture of chloroform and isopropyl alcohol. The extract was dried over sodium sulfate and evaporated to give 450 mg of a solid. amount of p-toluenesulfonic acid was added, and the The solid was dissolved in toluene, a small mixture was refluxed for two hours. The mixture then was poured into water, the pH adjusted to 12 with ammonium hydroxide, and the mixture extracted with methylene chloride. The methylene chloride extract was dried over sodium sulfate and evaporated to give 390 mg of a brown oil. ' The oil was placed on a silica column and eluted with a mixture of 2% methanol in methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 210 mg (35%) of the free base of the title compound.

The compound was converted to the maleate salt which was recrystallized from a mixture of ethanol and ether to give 200 mg of the title compound, m.p. 125.5-l27.5°C. MS(FD): 3l3(100).

Analysis, for C2,H31N2O5: C, 67.27; H, 7.53; N, 6.54; C, 67.52; H, 7.29; N, 6.48.

Theory: Found: Example 5 Preparation of 2-Di-n-propylamino (4-methoxyisoxazolyl)-1,2,3,4-tetra- hydronaphthalene hydrobromide.

-Di-n-propylamino—8-bromo-1,2,3,4-tetrahydro- naphthalene (5.0 g; 16.1 mmole) was dissolved in 25 ml of TH? and cooled to -78°C after which 3.22 ml of n—butyllithium (1 M in hexane) was added. was maintained at -78°C for 1.5 hours.

The mixture This solution was transferred via cannula to a solution of methyl methoxyacetate (7.5 ml, 160 mmol) in THF at -78°C. The reaction mixture was stirred at room temperature overnight, poured into NaHCO3 solution and extracted with CB2C12. ‘The extract was dried (Na2S0.) and concentrated to give 6.8 g of crude product.

The material then was placed on a chromato- graphic column, and the product was eluted using 4% methanol in methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 1.4 g of 2—di-n-propylamino—8- methoxyacetyl-1,2,3,4-tetrahydronaphthalene.

A solution of 2-di-n-propylamino-8—methoxyacety1— 1,2,3,4-tetrahydronaphthalene (1.0 g) and tris(dimethyl- amino)methane (1.5 ml) in toluene (25 ml) was heated to reflux for 1.5 hours. The reaction was concentrated to . give crude 2-di-n-propylamino(1-oxomethoxy (dimethylamino)—propenyl)-1,2,3,4-tetrahydronaphthalene (1.2 g).

Hydroxylamine hydrochloride (1.2 g) was added to a.solution of 2-di-n-propylamino(l-oxomethoxy (dimethylamino)-propenyl)-1,2,3,4-tetrahydronaphthalene (1.1 g) in methanol and the reaction stirred at room temperature overnight. The reaction was concentrated and the residue dissolved in toluene. p-Toluenesulfonic acid (660 mg) was added to the solution and the reaction heated to reflux for 2 hours. The reaction was concentrated and the residue dissolved in a mixture of water and methylene chloride. This mixture was poured into a sodium bicarbonate solution and the resulting mixture extracted with methylene chloride.. The extract was dried with MgSO4 and concentrated to give an oil (600 mg). :1 ether:hexanes as solvent provided 160 mg of the free Purification by flash chromatography using base of the title compound. The hydrobromide salt was formed. Two recrystallizations from methanol/ether gave the title compound as white crystals (86 mg). m.p.

°C.

Analysis: Theory: C, 58.68; H, 7.14; N, 5.34; Found: C, 58.88; H, 7.23; N, 6.

As noted above, the compounds of this invention have binding affinity for the S—HTla Therefore, another embodiment of the present invention is a method of modulating the activity of the 5-HTla receptors which comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the invention.

The term "pharmaceutically effective amount", as used herein, represents an amount of a compound of the invention which is capable of binding to serotonin 1a receptors. The specific dose of compound I administered according to this invention will, of course, be determined by the particular circumstances receptor. surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated. A typical daily dose generally will contain from about 0.01 mg/kg to about 20 mg/kg of the active compound of this invention.

Preferred daily doses generally will be from about 0.05 to about 10 mg/kg, and ideally from about 0.1 to about 5 mg/kg.

The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutan- eous, intravenous, intramuscular, and intranasal.

A variety of physiologic functions have been shown to be subject to influence by brain serotonergic neural systems. As such, the compounds of this inven- tion are believed to have the ability to treat in mam- mals a variety of 5-HT mediated states and disorders such as sexual disorders, eating disorders, depression, alcoholism, pain, senile dementia, anxiety, gastrointestinal disorders, hypertension, and smoking.

Therefore, the present invention also provides methods of treating the above disorders at rates set forth above for action in mammals at 5-HT receptors.

The following experiment was conducted to demonstrate the ability of compounds of the present invention to bind to serotonin la receptors. Sites specifically labeled by tritiated 8-hydroxydipropyl- amino-1,2,3,4-tetrahydronaphthalene (3HOH-DPAT) have been identified as 5-HTIA receptors. This general procedure is set forth in Wong gt 31., Q; Neural Transm.

Zl:207-218 (1988).

Male Sprague-Dawley rats (110-150 g) from Harlan Industries (Cumberland, IN) were fed a Purina Chow ad libitum for at least 3 days before being used in the studies. brains were rapidly removed, and the cerebral cortices Rats were killed by decapitation. The were dissected out at 4°C.

Brain tissues were homogenized in 0.32 M sucrose. After centrifugation at 1000 x g for 10 min and then at 17000 x g for 20 min, a crude synaptosomal fraction was sedimented. The pellet was suspended in 100 vol of 50 mm Tris-Hcl, pH 7.4, incubated at 37°C for min, and centrifuged at 50000 x g for 10 min. The process was repeated and the final pellet was suspended in ice-chilled 50 mm Tris-Hcl, pH 7.4.

Binding was terminated by Briefly, synapto- compound of interest. filtering samples under reduced pressure through glass fiber (GFB) filters. ml of ice cold buffer and placed in scintillation vials with 10 ml of PCS (Amersham/Searle) scintillation fluid. scintillation spectrometer.

The filters were washed twice with Radioactivity was measured with a liquid Unlabeled 8—OH—DPAT at pM was also included in separate samples to establish non-specific binding. Specific binding of 3H-8—OH—DPAT is defined as the difference of radioactivity bound in the absence and in the presence of 10 pM unlabeled 8-OH-DPAT.

Compounds of this invention were also examined for their in yivg effects on brain 5-HIAA and serum corticosterone levels. Male Sprague-Dawley rats weighting 150-200 g were administered subcutaneously or orally with aqueous solutions of the test compound. One hour after treatment, the rats were decapitated and trunk blood collected. The blood was allowed to clot and then was centrifuged to separate the serum. The concentration of corticosterone in the serum was determined by the spectrofluorometric method of Salem, J.H.; Brinck-Johnsen, T., Scand. J. Clin. Invest.

[Suppl. 80], $1, 1 (1955). decapitated rats were quickly removed, frozen on dry The whole brains from the ice, and stored at -15°C. 5-HIAA concentrations were measured by liquid chromatography with electrochemical detection as described by Fuller, R.W.; Snoddy, H.D.; Perry, K.w., Life Sci. 39, 1921 (1987).

The results of the evaluation of various compounds of the present invention are set forth below in Table 1.

Example Number of the compound evaluated; the second In Table I, the first column provides the column provides the amount of the test compound expressed in nanomolar concentration required to inhibit the binding of 3H-8—OH—DPAT by 50%, indicated as IC5o; the third column provides the minimum effective dose (MED) of the test compound administered subcutaneously in lowering brain 5-HIAA levels; the fourth column provides the MD of the test compound administered subcutaneously in elevating serum corticosterone levels; and the fifth column provides the same information as the third column except that the test compound is administered orally. The results provided in columns -5 are indicative of 5-HT1A agonist activity. o...A OJ N4 ¢ 0.: o; m.~ m o2 o._ . m... as N m m.o To Ste H A2. .mw.\m.5 ems. an dxxuev ow: mum 4mwxu\m.5 8: 9,... .20: .oz ofiemxm. <<_:-m o:€3mou_tou <<:Tm mc_uc_n 82> .3 NFPIIM mmokmwuwm .r...:-m F< >.F_>_huU< .._.W_ZO0< O>_> Z. D2< Uz_oz.m O¢.P—> Z. _ M._m<._.

The compounds of this invention are preferably formulated prior to administration. Therefore, another embodiment of the present invention is a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or exci- pient therefor.

The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. when the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.

Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.

Examples of suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl-hydroxybenzoates, propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations may additionally include lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavoring agents, and the like. formulated so as to provide quick, sustained or delayed The compositions of the invention may be release of the active ingredient after administration to the patient by employing procedures well known in the art.

The compositions are preferably formulated in a unit dosage form, each dosage generally containing from about 0.1 to about 500 mg, and preferably from about 1 to about 250 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.

The following formulation examples are illus- trative only and are not intended to limit the scope of the invention in any way.

Formulation 1 Hard gelatin capsules are prepared using the following ingredients: Quantity gmggcapsuleg 2-di—g—propylamino(isoxazol—3-yl) 1,2,3,4-tetrahydronaphthalene hydrochloride 250 starch, dried 200 magnesium stearate 10 Total 460 mg The aboye ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

Formulation 2 A tablet is prepared using the ingredients below: Quantity gmggtabletz 2-di-n—propylamino(4-methyl- isoxazolyl)-1,2,3,4-tetrahydro- naphthalene hydrochloride 250 cellulose, microcrystalline 400 silicon dioxide, fumed 10 stearic acid 5 Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg.

Formulation 3 An aerosol solution is prepared containing the following components: Weight Z -diisopropylamino(4—methoxyisoxazol- -yl)-1,2,3,4-tetrahydronaphthalene hydrochloride 0.25 ethanol ' 29.75 Propellant 22 (chlorodifluoromethane) 70.00 Total 100.00 The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C. and transferred to a filling device.

The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.

Formulation 4 Tablets, each containing 60 mg of active ingredient, are made as follows: -methylethylamino(3-methylthioisoxazol-5—yl)- ,2,3,4-tetrahydronaphthalene maleate 60 mg starch 45 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone (as 10% solution in water) 4 mg sodium carboxymethyl starch 4.5 mg magnesium stearate 0.5 mg talc 1 mg Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvinyl- pyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.s. sieve.

The granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. methyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

The sodium carboxy- Formulation 5 Capsules, each containing 80 mg of active ingredient, are made as follows: -propy1amino—8-(4-ethylisoxazolyl)-1,2,3,4- tetrahydronaphthalene hydrochloride 80 mg starch 59 mg microcrystalline cellulose 59 mg magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.

Formulation 6 Suppositories, each containing 225 mg of active ingredient, are made as follows: -di-Q-propylamino(5ehydroxyisoxazolyl)- 1,2,3,4—tetrahydronaphthalene hydrochloride 225 mg saturated fatty acid glycerides 2,000 mg Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7 Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are made as follows: -diallylamino(3-phenylisoxazol-Siyl)-1,2,3,4- tetrahydronaphthalene hydrochloride 50 mg sodium carboxymethyl cellulose 50 mg SYIUP 1.25 ml benzoic acid solution 0.10 ml flavor q.v. color q.v. purified water to total 5 ml The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxy- methyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Suffi- cient water is then added to produce the required volume.

Formulation 8 An intravenous formulation may be prepared as follows: -diethylamino(isoxazol-5—yl)-1,2,3,4- tetrahydronaphthalene hydrochloride isotonic saline mg 1000 ml The solution of the above ingredients gener- ally is administered intravenously at a rate of 1 ml per minute to a subject suffering from depression.

Claims (4)

1. A compound of the formula 0 Q in which R is C1-C4 alkyl, allyl or cyclopropylmethyl; R1 is hydrogen, C1-C4 alkyl, allyl, 5 cyclopropylmethyl or aryl(C1—C4 alkyl); X is -CH2-3 Q is CH - = - OI‘ C CH / 3 I N\CH Ra 3 $3 -(‘SH-CRa; and R3 10 each Ra is independently hydrogen, C1-C4 alkyl. Cl—C4 alkoxy or C1-C4 alkylthio. 45

2. Compound of Claim 1, in which R and R1 are both C1-C4 alkyl.

3. Compound of claim 1 or claim 2 in which Ra is hydrogen.

4. Compound of claim 3, which compound is 2-di-n- propylamino[1-oxo(dimethylamino)-prop-2—eny1]—l,2,3,4- tetrahydronaphthalene. F. R. KELLY & co., AGENTS FOR THE APPLICANTS.