KR100284462B1 - Isoxazole derivatives for the treatment of irritable bowel syndrome - Google Patents

Abstract

Methods of treating irritable bowel syndrome (IBS) using a series of isoxazole derivatives (1) having both 5-HT1A agonist and M1 muscarinic activity, and formulations suitable therefor, have been provided.

Wherein R is hydrogen, C ₁ -C ₃ alkyl, allyl, or ego; R ¹ is hydrogen, C ₁ -C ₃ alkyl, allyl, Or-(CH ₂ ) _n -X wherein n is 1 to 5; X is optionally substituted phenyl, C ₁ -C ₃ alkoxy, or C ₁ -C ₃ alkylthio; R ² and R ³ are independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, halo, CH or phenyl; Together are-(CH ₂ ) _p- , where p is 3 to 6; Y is -CH _2- , -O- or -SO _m- , where m is 0, 1 or 2.

Description

Isoxazole derivatives for the treatment of irritable bowel syndrome

The present invention relates to a pharmaceutical formulation suitable for the treatment and treatment of irritable bowel syndrome (IBS) in mammals.

Irritable visceral syndrome (IBS) is a motility disorder consisting of altered bowel habits, abdominal pain and the absence of detectable lesions. IBS is recognized by its symptoms, which are significantly affected by psychological factors and stressful living conditions.

IBS is one of the most commonly occurring gastrointestinal disorders. 20% to 50% of patients seeking a gastrointestinal clinic suffer from IBS. On the other hand, symptoms of IBS occur in about 14% of apparently healthy people. This is one of the least known disorders, in part because it is not a disease but a syndrome consisting of many abnormalities with similar signs.

The main symptoms of IBS (changed bowel habits, abdominal pain and dysfunction) are manifestations of increased intestinal motility and gastric acid secretion.

The activity of the gastrointestinal tract is neurologically regulated by the central nervous system (CNS) through parasympathetic and sympathetic nerve domination and by the peripherally located intestinal nervous system (ENS) present in the gastrointestinal tract itself.

ENS is also very well organized and consists of all the elements necessary to regulate organ activity in the absence of a central input signal (Goyal, RK, “Neurology of the Gut”, Gastrointestinal Disorders, Ed., Sleisenger and Fordtran, Saunders (1983), pp 97-114).

Serotonin (5-hydroxytryptamine, 5-HT) is directly or indirectly associated with many physiological phenomena, including appetite, anxiety and depression (RA Glennon, J. Med. Chem. 30, 1 (1987). )). 5-HT receptors have been identified in the CNS and in peripheral tissues including the gastrointestinal tract, lungs, heart, blood vessels and various other smooth muscle tissues.

It has been recognized that there are many types of 5-HT receptors. The receptors have been classified as 5-HT1, 5-HT2, 5-HT3 and 5-HT4, and at least the 5-HT1 receptor is further subclassed to be identified as 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D. Are classified.

In the CNS, 5-HT receptors are located on neurons that receive serotonergic input after synapse and on 5-HT releasing neurons before synapse. It is believed that presynaptic receptors function to sense 5-HT concentrations in the synaptic gap and thus regulate further release of 5-HT.

In general, “agonists” are chemical compounds that mimic the action of endogenous neurotransmitters at the receptor.

Direct-acting serotonin agonists are chemicals that bind to serotonin receptors and mimic the action of serotonin.

Indirect-acting serotonin agonists are chemicals that increase the concentration of serotonin in the synaptic gap. Indirect serotonin agonists include inhibitors of serotonin specific absorption carriers, agents that release serotonin from storage granules, agents that increase serotonin formation (serotonin precursors), and monoamines that increase the amount of serotonin available by blocking serotonin degradation. Oxidase (MAO).

Serotonin is known to have a number of actions in the gastrointestinal tract. Intravenous infusion of 5-HT or 5-HTP (5-hydroxytryptophan) into humans is known to increase the production of mucus while inhibiting the amount and acidity of spontaneous and histamine-induced gastric secretion (Handbook of Experimental Pharmacology, Val.XIX, “5-Hydroxy-tryptamine and Related Indolealkylamines”, Erspamer, V., sub-ed., Springer-Verlog, New York, 1966, pp 329-335). It is not known whether it is necessary to bind to one or several combinations of 5-HT receptor sites or which receptor (s) are involved to achieve this inhibitory response.

It is known that 5-HT receptors on smooth muscle of the gastrointestinal tract regulate the contraction of such tissues. Rat fundus and guinea pig ileum are widely used for the study of 5-HT agonists and antagonists in vivo. Intestinal chromaffin cells of the gastrointestinal tract are the major sites for 5-HT production in the intestine.

Intestinal motility is also greatly influenced by choline functional receptors. It is known that acetylcholine increases gastrointestinal motility by acting on muscarinic receptors. However, at least five different muscarinic receptors (M1-M5) are known (see Barry B. Wolfe: In the Muscarinic Receptors. Ed. By J. H. Brown, The Humana Press, N. J. 1989, pp 125-150). The relative role of these receptors in regulating gastrointestinal motility is not known because no selective agonists and antagonists of these receptors have been identified. IBS compounds that act as muscarinic antagonists, such as bentyl, are useful therapeutics but have serious side effects.

Current treatments for IBS are limited to drugs that treat only a small percentage of patients. For example, anticholinergic drugs alleviate some abdominal pain by reducing spasticity. On the other hand, histamine H ₂ receptor antagonists inhibit gastric acid secretion and thus alleviate indigestion symptoms. Therapies that alleviate most IBS symptoms are not currently available.

It has been found that 5HT1A agonists act directly on 5HT-receptors to inhibit gastric acid secretion and thus alleviate dyspepsia symptoms. The inventors have found a series of such agonist compounds, and they have also been shown to have affinity for M1-cholinergic receptors in binding studies and to have anticonvulsive activity in vivo. Thus, the compounds of the present invention will be particularly useful for the treatment of IBS and most of the symptoms associated therewith.

It is an object of the present invention to provide a group of compounds which are directly acting 5-HT1A agonists and are M1-cholinergic receptor selective agents. Since these two features are important for normalizing the intestinal tract and reducing the abdominal pain and abdominal distension of IBS, the agents with the combination activity thus act to normalize gastrointestinal motility and are associated with IBS and its associated It will be useful for the treatment of a wide range of abnormalities.

It is a further object of the present invention to simultaneously provide novel formulations suitable for the claimed method.

Other objects, features and advantages of the invention will be apparent to those skilled in the art from the following detailed description and the appended claims.

The present invention is directed to treating a mammalian irritable bowel syndrome (IBS) comprising administering to a mammal in need thereof an effective amount of a compound of formula (1) or a pharmaceutically acceptable acid addition salt or solvate thereof: Provide a way:

In the above formula,

R is hydrogen, C ₁ -C ₃ alkyl, allyl, or ego; R ¹ is hydrogen, C ₁ -C ₃ alkyl, allyl, Or-(CH ₂ ) _n -X wherein n is 1 to 5; X is optionally substituted phenyl, C ₁ -C ₃ alkoxy, or C ₁ -C ₃ alkylthio; R ² and R ³ are independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, halo, CN or phenyl; Together is-(CH ₂ ) _p- , where p is 3 to 6; Y is -CH _2- , -O- or -SO _m- , where m is 0, 1 or 2.

The compound of formula 1 has never been used to treat IBS. Accordingly, another aspect of the present invention provides a pharmaceutical suitable for the treatment of IBS containing a compound of Formula 1, or a pharmaceutically acceptable acid addition salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients. Formulation.

General chemical terms used in Equation 1 have their usual meanings. For example, the term “alkyl” refers to straight or branched chain alkyl having the specified number of carbons. C ₁ -C ₃ alkyl groups are methyl, ethyl, n-propyl and isopropyl; Is cyclopropylmethyl.

Halo refers to bromine, chlorine, flute or iodine. Optionally substituted phenyl refers to a phenyl ring which may include one or two substituents selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, halo, NO ₂ and CN.

Irritable bowel syndrome is the most suitable and accurate term currently available for the disease that can be treated by the method of the present invention.

The term IBS emphasizes that an abnormality is a motility disease that exhibits hypersensitivity, that it is not a single disease but a syndrome, and that many areas of the intestine are involved. Many of the other commonly used terms for the disease, for example, neurological, labile or convulsive colon or colitis, are inappropriate, inaccurate, or both.

The international working team report reports IBS (1) abdominal pain and / or (2) symptoms of disturbed bowel movements (emergency, strain, incomplete bowel movements, altered bowel pattern [density] and altered bowel frequency / time) or (3) It is defined as a functional gastrointestinal disorder caused by hyperplasia.

Recent revisions suggest the following standards: abdominal pain or discomfort associated with changes in the frequency or density of feces reduced by defecation, and (1) altered frequency of stool; (2) altered stools (such as firm or soft / watery); (3) altered stool passage (tension or urgency, incomplete defecation); (4) passage of mucus; And (5) three or more of hyperplasia or abdominal bloating (Schuster, M.M., Gastroenterology Clinics of Health America, 20, 269-278 (1991)).

Thus, it is apparent that the compounds of the present invention treat irritable bowel syndrome as indicated by the symptom or population of symptoms, whatever is defined now or later.

Symptoms that help distinguish IBS from organic disease include (1) visible abdominal distension, (2) relief of abdominal pain due to bowel movements, (3) more frequent bowel movements with onset of pain, and (4) onset of pain With softer stools (Schuster, MM, Gastrointestinal Diseases, Ed., Sleisenger and Fordtran, Saunders (1983), 870-895).

As mentioned above, compounds useful for carrying out the methods of the present invention include pharmaceutically acceptable acid addition salts of the compounds defined by Formula 1 above. Since these compounds are amines, they are essentially basic and therefore react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since the free amines of these compounds are typically oils at room temperature, it is desirable 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 room temperature. Because it is. Acids commonly used to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and P-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, stony Organic acids such as nitric acid, citric acid, benzoic acid and acetic acid. Thus, examples of such pharmaceutically acceptable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydro Iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heltanoate, propiolate, oxalate, malonate, succinate, suverate, Sevagate, fumarate, maleate, 2-butyne-1, 4-dioate, 3-hexyne-2,5-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzo Ate, methoxy benzoate, phthalate, sulfonate, xylene sulfonate, phenyl acetate, phenyl Lopionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc. to be. Preferred pharmaceutically acceptable acid addition salts are those formed using inorganic acids such as hydrochloric acid and hydrobromic acid and those formed using organic acids such as maleic acid.

In addition, some of the salts may form solvates with water or organic solvents such as ethanol. Such solvates are also within the scope of the present invention.

The compounds of the present invention are useful for treating IBS due to their unique ability to modulate the function of both 5-HT1A and muscarinic (M1) receptors in mammals. The preferred class of equation 1

(a) R is C ₁ -C ₃ alkyl or ego;

(b) R ¹ is C ₁ -C ₃ alkyl or ego;

(c) R ₁ is propyl;

(d) R ² and R ³ are independently hydrogen or C ₁ -C ₃ alkyl;

(e) R ² and R ³ together are — (CH ₂ ) _p —;

(f) Y is 0 or-(CH ₂ )-.

Especially preferred

(a) R is propyl;

(b) Formula 1 class wherein R ² and R ³ are independently hydrogen or methyl.

Particularly preferred Formula 1 compounds are:

(a) 8- (isoxazol-5-yl) -2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene;

(b) 8- (4-methylisoxazol-5-yl) -2-dipropylamino-1,2,3,4-tetrahydronaphthalene; And

(c) 8- (3-methylisoxazol-5-yl) -2-dipropylamino-1,2,3,4-tetrahydronaphthalene.

It goes without saying that the classes can be combined to form another preferred class.

The compounds of the present invention have asymmetric carbons represented by carbon atoms labeled with an asterisk (*) in the formula:

Based on the above fact, each compound also exists as its respective d- and 1-stereoisomers and also as racemic mixtures of such isomers. Thus, the compounds of the present invention include not only d1-racemic compounds but also their respective optically active d- and 1-isomers.

The following compounds further illustrate compounds contemplated within the scope of the present invention:

8- (isoxazol-5-yl) -2- (di-n-propylamino) tetrahydronaphthalene

8- (isoxazol-5-yl) -2- (propylamino) tetrahydronaphthalene

8- (isoxazol-5-yl) -2- (dimethylamino) tetrahydronaphthalene

8- (isoxazol-5-yl) -2- [di (cyclopropylmethyl) amino] tetrahydronaphthalene

8- (isoxazol-5-yl) -2- (di-allylamino) tetrahydronaphthalene

8- (3-methylisoxazol-5-yl) -2- (dipropylamino) tetrahydronaphthalene

8- (3-methylisoxazol-5-yl) -2- (propylamino) tetrahydronaphthalene

8- (3-methylisoxazol-5-yl) -2- (dimethylamino) tetrahydronaphthalene

8- (3-methylisoxazol-5-yl) -2- [di (cyclopropylmethyl) amino] tetrahydronaphthalene

8- (3-methylisoxazol-5-yl-2- (diallyl) amino) tetrahydronaphthalene

8- (4-methylisoxazol-5-yl) -2- (dipropylamino) tetrahydronaphthalene

8- (4-methylisoxazol-5-yl) -2- (propylamino) tetrahydronaphthalene

8- (4-methylisoxazol-5-yl) -2- (dimethylamino) tetrahydronaphthalene

8- (4-methylisoxazol-5-yl) -2- [di (cyclopropylmethyl) amino] tetrahydronaphthalene

8- (4-methylisoxazol-5-yl) -2- (diallylamino) tetrahydronaphthalene

8- (3,4-dimethylisoxazol-5-yl) -2- (dipropylamino) tetrahydronaphthalene

8- (3,4-dimethylisoxazol-5-yl) -2- (propylamino) tetrahydronaphthalene

8- (3,4-dimethylisoxazol-5-yl) -2- (dimethylamino) tetrahydronaphthalene

8- (3,4-dimethylisoxazol-5-yl) -2- [di (cyclopropylmethyl) amino] tetrahydronaphthalene

8- (3,4-dimethylisoxazol-5-yl) -2- (diallylamino) tetrahydronaphthalene

8- (4, 5, 6, 7-tetrahydrobenz [c] isoxazol-1-yl) -2- (dipropylamino) tetrahydronaphthalene

8- (4, 5, 6, 7-tetrahydrobenz (diisoxazol-1-yl) -2- (propylamino) tetrahydronaphthalene

8- (4, 5, 6, 7-tetrahydrobenz [c] isoxazol-1-yl) -2- (dimethylamino) tetrahydronaphthalene

8- (4, 5, 6,

5- (4, 5, 6, 7-tetrahydrobenz (c] isoxazol-1-yl) -3- (dipropylamino) chroman

5- (isoxazol-5-yl) -3- (dipropylamino) chroman

5- (3-methylisoxazol-5-yl) -3- (dipropylamino) chroman

5- (4-methylisoxazol-5-yl) -3- (dipropylamino) chroman

5- (3,4-dimethylisoxazol-5-yl) -3- (dipropylamino) chroman

5- (isoxazol-5-yl) -3- (dipropylamino) thiochroman

5- (3-methylisoxazol-5-yl) -3- (dipropylamino) thiochroman

5- (4-methylisoxazol-5-yl) -3- (dipropylamino) thiochroman

5- (3,4-dimethylisoxazol-5-yl) -3- (dipropylamino) thiochroman

The compounds of the present invention can be prepared by methods well known to those skilled in the art. The compounds of the present invention can be utilized by a number of general reactions. General reaction schemes are provided below; The groups in each are as follows:

R ² , R ³ : hydrogen, C ₁ -C ₃ alkyl, halo, OH, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, NH ₂ , CN, phenyl or (—CH ₂ —) _p ;

Rc: hydrogen or C ₁ -C ₃ alkyl;

X: halo, SRc, ORc, or N (Rc) ₂ ;

Ar: the remainder of the compound of formula 1, i.e.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

The synthetic methods described above provide compounds in which the heteroaromatic ring may or may not have a substituent. General reactions that provide a methodology for incorporating, interconverting, and removing substituents on heteroaromatic rings are mentioned in Comprehensive Organic Transformations by Richard C. Larocke, VCH Publishers, Inc., New York (1989). .

Optically active isomers of the compound of formula l are also considered part of the present invention. Such optically active isomers can be prepared from their respective optically active precursors or by decomposing the racemic mixture by the method described above. The procedure is described in European patent application 498,590.

Compounds used as initial starting materials for the synthesis of the compounds of the present invention are well known or can be readily synthesized by standard methods commonly used by those skilled in the art.

Pharmaceutically acceptable acid addition salts of the present invention are conventionally formed by reacting Formula 1 base of the present invention with equimolar or excess acid. The reactants are generally compounded in a solvent in which they can be dissolved, such as diethyl ether or benzene, and salts are normally precipitated in solution within about 1 hour to 10 days and can be isolated by filtration.

The following preparations are provided to describe representative methods for preparing the compound of formula 1. Other methods for their preparation are apparent to those skilled in the art. They are therefore provided for the purpose of illustration only and should not be construed as limiting the scope of the invention in any way.

[Production Example 1]

[Preparation of 2- (di-n-propylamino) -8- (isoxazol-5-yl) -1, 2, 3, 4-tetrahydronaphthalene maleate]

2- (di-n-propylamino) -8-acetyl-1, 2, 3, 4-tetrahydronaphthalene (0.3 g, 1.1 mmol) and tris (dimethylamino) methane (0.32 g, 2.2 mmol) in toluene The solution of was heated to reflux for 5 hours and heated at 60 ° C. for 18 hours. An aliquot of Tris (dimethylamino) methane (0.16 g, 1.1 mmol) was added and the reaction was further stirred at 60 ° C. for 2 hours. The reaction was concentrated to give 2- (di-n-propylamino) -8- [1-oxo-3- (dimethylamino) -prop-2-en-1-yl] -1, 2, 3, 4- tetra Hydronaphthalene (0.39 g) was obtained as a viscous orange oil.

Hydroxylamine hydrochloride (0.32 g, 4.6 mmol) was added 2- (di-n-propylamino) -8- [1-oxo-3- (dimethylamino) -prop-2-ene in acetic acid (5 mL). -1-yl] -1, 2, 3, 4-tetrahydronaphthalene (0.75 g, 2.29 mmol) was added and the reaction stirred at room temperature. The reaction was concentrated and the residue dissolved in water. The solution was made basic by addition of concentrated ammonium hydroxide solution and extracted with ether. The extract was washed with brine, dried over Na ₂ S0 ₄ and concentrated to give a viscous light orange oil. The maleate salt was formed according to standard methods. Crystallization from ethanol / ether gave the title compound as yellowish white crystals (0.24 g). Melting point 136-138 ° C. The crystals were recrystallized from ethanol to give colorless crystals (155 mg), melting point 139-141 ° C.

Elemental Analysis:

Theoretical: C, 66.65; H, 7. 29; N, 6.76;

Found: C, 66.86; H, 7. 33; H, 6.79.

[Production Example 2]

[Preparation of 2- (di-n-propylamino) -8- (3-bromoisoxazol-5-yl) -1, 2, 3, 4-tetrahydronaphthalene maleate]

Copper iodide (1) in a solution of 2- (di-n-propylamino) -8-iodo-1, 2, 3, 4-tetrahydronaphthalene (4.3 g, 12.1 mmol) and triethylamine (100 mL) (228 mg), bis (triphenylphosphine) -palladium (11) chloride (841 mg) and trimethylsilylacetylene (1.7 mL) were added. The mixture was stirred at room temperature overnight. The reaction was poured into water and extracted with ether. The extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 5 g of crude product. 4.33 g of 2- (di-n-propylamino) -8- (2-trimethylsilylethynyl) -1, 2, 3, 4- by flash chromatography using 20: 1 methylene chloride: methanol as solvent Tetrahydronaphthalene was obtained and used for the next reaction.

2- (di-n-propylamino) -8- (2-trimethylsilylethynyl) -1, 2, 3, 4- tetrahydronaphthalene (4.3 g) and tetraethylammonium fluorine in tetrahydrofuran (150 mL) The solution of lide (12.1 mmol) was stirred at room temperature for 18 hours and under reflux for 6 hours. The reaction mixture was concentrated and the residue was dissolved in methylene chloride. The solution was washed with water, dried (Na ₂ SO ₄ ) and concentrated to give 3.6 g of brown oil. Purification by flash chromatography using 20: 1 methylene chloride: methanol as a solvent to give 2- (di-n-propylamino) -8-ethynyl-1, 2, 3, 4-tetrahydronaphthalene (1.1 g, 36% total yield).

2- (di-n-propylamino) -8-ethynyl-1, 2, 3, 4-tetrahydronaphthalene (900 mg; 3.5 mmol) was stirred at room temperature in 90 ml of ethyl acetate containing 1 ml of water It was. Br ₂ CNOH (715.8 mg) in 10 ml of ethyl acetate was added and the mixture was stirred at room temperature for 2 days, followed by 150 mg potassium carbonate and 250 mg Br ₂ CNOH. The mixture was further stirred for 4 hours, then poured into water and washed with ethyl acetate. Ethyl acetate washes were combined, dried and concentrated to give 1.0 g of residue. The residue was purified by flash column chromatography using 20: 1 CH ₂ Cl ₂ : MeOH. Appropriate fractions were collected to yield about 120 mg of material. Ether was added and removed by filtration once a solid formed. The filtrate contains the desired product which is then converted to the maleate salt. Crystallization from a mixture of ethyl acetate and hexanes gave the title compound (84 mg). Melting point 113-114 ° C.

Elemental Analysis:

Theoretical: C, 55.99; H, 5.92; N, 5.68;

Found: C, 55.77; H, 5. 90; N, 5.48

[Manufacture example 3]

[Preparation of 2- (di-n-propylamino) -8- (4-methylisoxazol-5-yl) -1, 2, 3, 4-tetrahydronaphthalene maleate]

2- (di-n-propylamino) -8-bromo-1, 2, 3, 4-tetrahydronaphthalene (8.5 g; 27.4 mmol) was dissolved in 80 ml of tetrahydrofuran (THF) and -78 ° C. After cooling with 25.7 ml of n-butyllithium (1.6 M in hexane) was added. The mixture was stirred at -78 [deg.] C. for 1 hour and then 2.4 mL (32.9 mmol) propionaldehyde was 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 yield 9.1 g of yellow oil.

The oil was placed on a silica gel column and eluted with a mixture of 3% methanol in methylene chloride containing traces of ammonium hydroxide. Appropriate fractions were collected to give 6.5 g (82.0%) of 2- (di-n-propylamino) -8- (1-hydroxyprop-1-yl) -1, 2, 3, 4-tetrahydronaphthalene as a clear Obtained as an oil.

The above product was dissolved in 250 ml methylene chloride and 17.0 g (78.7 mmol) pyridinium chlorochromate (PCC) was added along with 30 g of 4A molecular sieve. The mixture was stirred at room temperature for 3 hours and then 250 ml of ether and celite were added. The mixture was poured onto a silica gel column and eluted with ether. Methanol was added to dissolve the brown precipitate that precipitated when ether was added to the reaction. This material was added to the column and eluted with 10% methanol in methylene chloride.

The eluate was concentrated to give a brown oil which was further purified by silica gel column chromatography using 2: 1 hexanes: ether followed by 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-propylamino) -8-propionyl-1, 2, 3, 4-tetrahydronaphthalene (1.5 g; 5.2 mmol) is dissolved in 50 ml of 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 stirred at room temperature overnight. The mixture was poured into water, the pH was adjusted to 11 with ammonium hydroxide and the resulting mixture was extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to yield 1.5 g of orange oil.

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

50 mg of free base was converted to the maleate salt according to standard methods and recrystallized from a mixture of ethanol and ether to give 55 mg of white crystals. Melting point 118 ° C.

Elemental Analysis for C ₂₄ H ₃₂ N ₂ O ₅ :

Theoretical: C, 67.27; H, 7.53; N, 6.54;

Found: C, 66.99; H, 7. 60; N, 6.35.

[Production Example 4]

[Preparation of 2- (di-n-propylamino) -8- (4-ethylisoxazol-5-yl) -1, 2, 3, 4-tetrahydronaphthalene]

2- (di-n-propylamino) -8-bromo-1, 2, 3, 4-tetrahydronaphthalene (5.0 g; 16.1 mmol) was dissolved in 50 mL of THF and the mixture cooled to -78 ° C. 21.0 mL of n-butyllithium (0.92 M in hexane) was added. The mixture was stirred for 30 minutes and 1.85 mL (21.0 mmol) butylaldehyde was added. The mixture was allowed to warm to room temperature and stirred overnight, then 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 residue. The residue was placed on a silica gel column and eluted with a mixture of 2% methanol in methylene chloride containing traces of ammonium hydroxide. Appropriate fractions were collected to yield 4.8 g of 2- (di-n-propylamino) -8- (1-hydroxybut-1-yl) -1, 2, 3, 4-tetrahydronaphthalene as a thick oil.

Oil (4.0 g; 13.2 mmol) was dissolved in 200 mL methylene chloride and 4A molecular sieve (30 g) was added. The mixture was stirred and 10.0 g (46.2 mmol) PCC was added. After stirring was continued for 3 hours at room temperature, the mixture was poured into a pad of silica gel and eluted sequentially with 3% methanol in methylene chloride containing ether and a trace amount of ammonium hydroxide to recover the product as a brown oil.

The oil was placed on a silica gel column and eluted with a mixture of 3% methanol and methylene chloride containing traces of ammonium hydroxide. The appropriate fractions were combined to give an oil which formed a brown precipitate upon dissolution in ether. The precipitate was removed by filtration and the filtrate was evaporated to yield 3.0 g of 2- (di-n-propylamino) -8-butyryl-1, 2, 3, 4- tetrahydronaphthalene as 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-propylimino) -8-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 solids. The resulting mixture of pH 6 was stirred at room temperature for 20 hours and then poured into water and the pH was adjusted to 12 using 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 mg toluene and 100 mg p-toluenesulfonic acid was added. The mixture was then refluxed for 1.5 h, then poured into water and extracted with methylene chloride. The methylene chloride extract was dried over sodium sulfate and evaporated.

The residue was placed on a silica gel column and eluted with a 2: 1 mixture of hexanes: ether containing traces of ammonium hydroxide. Appropriate fractions were collected to yield 0.9 g of the title compound. MS (FD): 327 (100).

Production Example 5

[Preparation of 2- (di-n-propylamino) -8- (3-methylisoxazol-5-yl) -1, 2, 3, 4-tetrahydronaphthalene maleate]

Potassium t-butoxide (450 mg; 4.0 mmol) is suspended in THF, 0.7 mL (7.3 mmol) ethyl acetate and 0.5 g (1.8 mmol) 2- (di-n-propylamino) -3-acetyl in THF -1, 2, 3, 4-tetrahydronaphthalene was added. The total amount of THF used was 30 ml. The mixture was then stirred at room temperature overnight and then 640 mg (9.2 mmol) of hydroxylamine hydrochloride was added. The reaction mixture was then stirred at room temperature for 64 hours. The mixture was poured into water and the pH was adjusted to 6-12 with ammonium hydroxide. The mixture was then extracted with a 3: 1 mixture of chloroform: isopropyl alcohol. The extract was dried over sodium sulfate and evaporated to give 450 mg of solid. The solid is dissolved in toluene; A small amount of p-toluenesulfonic acid is added; The mixture was refluxed for 2 hours. Then the mixture is poured into water; PH was adjusted to 12 with ammonium hydroxide; The mixture was extracted with methylene chloride. The methylene chloride extract was dried over sodium sulfate and evaporated to give 390 mg of brown oil.

The oil was placed on a silica column and eluted with methylene chloride containing 2% methanol and traces of ammonium hydroxide. Appropriate fractions were collected to give 210 mg (35%) of the free base of the title compound.

According to standard methods, the compound was converted to the maleate salt and recrystallized from a mixture of ethanol and ether to give 200 mg of the title compound. Melting point 125.5-127.5 ° C., MS (FD): 313 (100).

Elemental Analysis for C ₂₄ H ₃₁ N ₂ O ₅

Theoretical: C, 67.27; H, 7.53; N, 6,54;

Found: C, 67.52; H, 7. 29; N, 6.48.

[Manufacture example 6]

[Preparation of 2- (di-n-propylamino) -8- (3-phenylisoxazol-5-yl) -1, 2, 3, 4-tetrahydronaphthalene hydrobromide]

Acetophenone oxime (750 mg; 5.5 mmol) was dissolved in THF and the mixture was cooled to -5 ° C. n-butyllithium (12.0 mL; 11.1 mmol) was added and the mixture was stirred at -5 ° C for 1 h. 2- (di-n-propylamino) -8-methoxycarbonyl-1, 2, 3, 4-tetrahydronaphthalene (0.8 g; 2.8 mmol) dissolved in THF was added (total THF in the mixture was 100 Ml), and the mixture was allowed to warm to room temperature. The mixture was then poured into water and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 1.4 g of residue.

The residue was placed on a silica gel column and eluted with a 2: 1 mixture of hexanes: ether containing traces of ammonium hydroxide. Appropriate fractions were collected to give 220 mg of the free base of the title compound.

According to standard methods, the free base was converted to a hydrobromide salt and recrystallized from a mixture of methanol and ethyl acetate to give 150 mg of white powder. Melting point 171.5-173 ° C., MS (FD): 374 (100).

Elemental Analysis for C ₂₅ H ₃₀ N ₂ Br

Theoretic value: C, 65.93; H, 6. 86; N, 6. 15;

Found: C, 65.74; H, 6. 86; N, 5.92.

[Manufacture example 7]

[Preparation of 2- (di-n-propylamino) -8- (3-methylpyioxazol-5-yl) -1, 2, 3, 4-tetrahydronaphthalene maleate]

2-di-n-propylamino) -8- [3,3-di (methylthio) -1-oxoprop-2-en-1-yl] -1, 2, 3, 4-tetrahydronaphthalene ( 0.64 g; 1.7 mmol) was dissolved in a mixture of toluene and acetic acid. Hydroxylamine hydrochloride (1.2 g; 17 mmol) and sodium acetate (1.2 g; 14 mmol) in 10 mL water were added. Ethanol (10 mL) was then added to make the mixture uniform. The mixture was heated to 100 ° C. for 18 h and then 0.6 g of hydroxylamine hydrochloride was added. The mixture was further stirred at 100 ° C. for 4 hours and further 0.6 g of hydroxylamine hydrochloride was added. The mixture was then stirred at 100 ° C. for 7 hours and then at room temperature overnight. The mixture was poured into water and the aqueous mixture was washed twice with ether and then extracted with 10% hydrochloric acid. The aqueous layers were combined and made basic (pH 12). The mixture was then extracted with methylene chloride and the extract was dried over sodium sulfate and evaporated to yield 560 mg of dark yellow oil.

The oil was placed on a silica gel column and eluted with a gradient of 1.5-2% methanol in methylene chloride containing traces of ammonium hydroxide. Appropriate fractions were collected to give 230 mg of product. The product was converted to maleate salt and recrystallized from a mixture of ethyl acetate and hexanes to yield 210 mg of the title compound. Melting point 118-119.5 ° C. MS (FD): 344 (100).

Elemental Analysis:

Theoretical: C, 62.59; H, 7.00; N, 6.08;

Found: C, 62.84; H, 7.04; H, 6.07.

[Manufacture example 8]

[Preparation of 2- (di-n-propylamino) -8- (4-methoxyisoxazol-5-yl) -1, 2, 3, 4-tetrahydronaphthalene hydrobromide]

2- (di-n-propylamino) -8-bromo-1, 2, 3, 4-tetrahydronaphthalene (5.0 g: 16.1 mmol) was dissolved in 25 mL THF and cooled to -78 ° C, followed by 3.22 ML of n-butyllithium (1M in hexane) was added. The mixture was kept at -70 ° C for 1.5 h. At -78 ° C the solution was transferred via cannula to a solution of methyl methoxyacetate (7.5 mL, 160 mmol) in THF. The reaction mixture was stirred at room temperature overnight, poured into NaHCO ₃ solution and extracted with CH ₂ Cl ₂ . The extract was dried (Na ₂ SO ₄ ) and concentrated to give 6.8 g of crude product.

The material was then chromatographed on silica gel and the product eluted using 4% methanol in methylene chloride containing traces of ammonium hydroxide. Appropriate fractions were combined to obtain 1.4 g of 2- (di-n-propylamino) -8-methoxyacetyl-1, 2, 3, 4-tetrahydronaphthalene.

2- (di-n-propylamino) -8-methoxyacetyl-1, 2, 3, 4-tetrahydronaphthalene (1.0 g) and tris (dimethylamino) methane (1.5 mL) in toluene (25 mL) Heated to reflux for 1.5 hours. The reaction was concentrated to give crude 2- (di-n-propylamino) -8- (1-oxo-2-methoxy-3- (dimethylamino) -prop-2-enyl) -1, 2, 3, 4 Tetrahydronaphthalene (1.2 g) was obtained.

Hydroxylamine hydrochloride (1.2 g) was added 2- (di-n-propylamino) -8- (1-oxo-2-methoxy-3-dimethylamino) -prop-2-enyl)-in methanol To a solution of 1, 2, 3, 4- tetrahydronaphthalene (1.1 g) was added and the reaction was 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 was heated to reflux for 2 hours. The reaction was concentrated and the residue was dissolved in a mixture of water and methylene chloride. The mixture was poured into sodium bicarbonate solution and the resulting mixture was extracted with methylene chloride. The extract was dried over MgSO ₄ and concentrated to give an oil (600 mg). Purification by flash chromatography using 1: 1 ether: hexane as solvent gave 160 mg of the free base of the title compound. Hydrobromide salts were formed. Two recrystallizations from methanol / ether gave the title compound hydrobromide as white crystals (86 mg). Melting point 178 ℃

Elemental Analysis:

Theoretic value: C, 58.68; H, 7.14; N, 6.84;

Found: C, 58.88; H, 7. 23; N, 6.60.

[Manufacture example 9]

[Preparation of S-(-)-8- (isoxazol-5-yl) -2-dipropylamino-1, 2, 3, 4-tetrahydronaphthalene maleate]

S-(-)-8-acetyl-2-dipropyl-1, 2, 3, 4-tetrahydronaphthalene maleate (5.0 g, 18.3 mmol) and tris (dimethylamino) methane (7.6) in toluene (200 mL) ML, 45.8 mmol) was heated to 80 ° C. for 20 h. The solvent was removed and the residue was dissolved in acetic acid (50 mL). Hydroxylamine hydrochloride (2.5 g, 36.6 mmol) was added and the reaction stirred at room temperature for 20 hours. The reaction was poured into water. The resulting mixture was made basic with NaOH solution and extracted with methylene chloride. The extract was dried (Na ₂ SO ₄ ) and concentrated to give a dark red oil. Purification by flash chromatography (1: 2, ether: hexane (NH ₄ OH)) afforded 4.3 g (79%) of the desired product. Salt was formed using maleic acid and crystallized from ethanol / ether to give pale yellow crystals (5.3 g, melting point 127-128.5 ° C.). MS (FD): 298 (100).

OR: [a] _D = -33.04 ° (c = 1.0, H ₂ O); [a] ₃₆₅ = -57.34 ° (c = 1.0, H ₂ O).

Elemental Analysis for C ₁₉ H ₂₆ N ₂ O · C ₄ H ₄ O ₄ · 0.2H ₂ O:

Theoretic value: C, 66.07; H, 7. 33; N, 6.70;

Found: C, 65.95; H, 6.92, N, 7.08.

[Production Example 10]

[Preparation of R-(+)-8- (isoxazol-5-yl) -2-dipropylamino-1, 2, 3, 4-tetrahydronaphthalene maleate]

R-(+)-8-acetyl-2-dipropyl-1, 2, 3, 4-tetrahydronaphthalene maleate (5.0 g, 18.3 mmol) and tris (dimethylamino) methane (7.6) in toluene (200 mL) ML, 45.8 mmol) was heated to 80 ° C. for 20 h. The solvent was removed and the residue was dissolved in acetic acid (25 mL). Hydroxylamine hydrochloride (2.5 g, 36.6 mmol) was added and the reaction mixture was stirred at room temperature for 20 hours. The reaction was poured into water and washed with ether. The resulting aqueous layer was made basic with NaOH solution and extracted with methylene chloride. The extract was dried (Na ₂ SO ₄ ) and concentrated to give 5.1 g of crude product. Purification by flash chromatography (1: 2, ether: hexane (NH ₄ OH)) afforded 4.6 g (83%) of the desired base. Salts were formed with maleic acid and crystallized from ethanol / ether to give a white solid (5.4 g, melting point 127-128.5 ° C.). MS (FD): 298 (100).

Elemental Analysis for C ₁₉ H ₂₆ N ₂ O · C ₄ H ₄ O ₄ · 0.2H ₂ O

Theoretic value: C, 66.07, H, 7.33; N, 6.70;

Found: C, 65.71; H, 6.93; N, 7.14.

[Production Example 11]

[Preparation of R-(+)-8- (4-methyl-5-isoxazolyl) -2- (dipropylamino) -1, 2, 3, 4-tetrahydronaphthalene hydrobromide]

R-(+)-8-propionyl-2-dipropylamino-1, 2, 3, 4-tetrahydronaphthalene (2.0 g, 7.0 mmol) and tris (dimethylamino) methane (2.54) in toluene (65 mL) g, 2.9 mL, 17.4 mmol) was heated to reflux for 3 hours. The solvent was removed and the residue was dissolved in 20 ml acetic acid (hydroxylamine hydrochloride (0.97 g, 14 mmol) was added and the reaction stirred for 3 days at room temperature. The reaction was poured into water. Basic with NaOH solution and extracted with 1: 3 mixture of isopropanol and chloroform The extract was dried (Na ₂ SO ₄ ) and concentrated to give a yellow / orange oil Flash chromatography (1: 1, ether: hexane (NH ₄ OH)) to give 1.46 g (67%) of a colorless oil, which formed a hydrobromide salt and crystallized twice from THF / hexane to give white crystals (1.32 g, melting point 167-169 ° C.)

OR: [a] _D = + 27.26 ° (c = 1.0, H ₂ O); [a] ₃₆₅ = + 40.90 ° (c = 1.0, H ₂ O).

Elemental Analysis for C ₂₀ H ₂₈ N ₂ O · HBr:

Theoretic value: C, 61.07; H, 7. 43; N, 7. 12;

Found: C, 61.21; H, 7. 50; N, 6.97.

[Manufacture example 12]

[Preparation of 5- (5-isoxazolyl) -3- (dipropylamino) chroman hydrobromide]

A solution of 5-acetyl-3-dipropylaminochroman (500 mg, 1.81 mmol) and tris [dimethylamino] methane (540 mg, 5.4 mmol) in toluene (20 mL) was heated to reflux for 2 hours. TLC showed the presence of fresh low Rf product. The reaction was diluted with dilute NaOH solution and extracted with a 1: 3 mixture of isopropanol and chloroform. The extract was dried (Na ₂ SO ₄ ) and concentrated to give a dark yellow oil. This material was dissolved in acetic acid (10 mL) and solid hydroxylamine hydrochloride (480 mg, 6.9 mmol) was added. The reaction was stirred at room temperature for 17 hours, diluted with water, made basic with NaOH, and extracted with a 1: 3 mixture of isopropanol and chloroform. The extract was dried (Na ₂ SO ₄ ) and concentrated to give 534 mg of orange oil. Purification by flash chromatography (1: 1, ether: hexane (NH ₄ OH)) gave the product as a colorless oil (482 mg, 88%). This material was converted to its hydrobromide salt and crystallized from ethyl acetate / hexanes to give a white solid.

Melting point 171.5-173 ° C.

MS (FD): 300 (100)

_{C 18 H 24 N 2 O 2} · Elemental Analysis for HBr

Theoretical: C, 56.70; H, 6.61: N, 7.35;

Found: C, 56.71; H, 6.56: N, 7.54.

As mentioned above, the compounds of the present invention have binding affinity for both 5-HTIA and muscarinic (M1) receptors.

The following experiments were performed to demonstrate the ability of the compounds of the present invention to bind 5-HT1A receptors. The tritium-treated 8-hydroxy-2-dipropylamino-1, 2, 3, 4-tetrahydronaphthalene-by ^{(3 H-8-OH-} DPAT) specifically labeling region was found as the 5-HT1A receptors . Such general methods are disclosed in Wong et al., J. Neural Transm. 71, 207-218 (1988).

[In vivo Binding to 5HT1A Receptor]

Male Sprague-Dawley rats (110-150 g) from Harlan Industries, Cumberland, Ind. Were optionally fed Purina Chew for at least 3 days prior to use in the study. The rat was killed by a guillotine. The brain was removed quickly and the cerebral cortex was dissected at 4 ° C.

Brain tissue was homogenized in 0.32M sucrose. After centrifugation at 1000 xg for 10 minutes and then at 17000 xg for 20 minutes, a crude synaptosomal fraction precipitates. The pellet was suspended in 100-fold volume of 50 mM Tris-HCl, pH 7.4, incubated at 37 ° C. for 10 minutes and then centrifuged at 50000 × g for 10 minutes. This procedure was repeated and the final pellet was suspended in ice cold 50 mM Tris-HCl, pH 7.4. The method described above [Wong et al., J. Neural Transm. 64: 251-269 (1985)] for the binding of ³ H-8-OH-DPAT. Briefly, synaptosome membranes isolated from the cerebral cortex were treated with 2 ml of 50 mM Tris-HCl, pH 7.4; 10 mM Paglin; 0.6 mM ascorbic acid; 5 mM CaCl ₂ ; Incubated at 37 ° C. for 10 min in 2 nM ³ H-8-OH-DPAT and 0.1-1000 nm compound of interest. The bond was terminated by filtering the sample through glass fiber (GFB) filter paper under reduced pressure. The filtrate was washed twice with 5 ml of ice cold buffer and placed in scintillation vials with 10 ml of Amersham / Searle scintillation fluid. Radioactivity was measured using a liquid scintillation spectrometer. 10 mM unlabeled 8-OH-DPAT was also included in a separate sample to identify nonspecific defects. Specific binding of ³ H-8-OH-DPAT is defined as the difference in bound radioactivity in the absence and presence of 10 μM unlabeled 8-OH-DPAT. The results are reported in Tables 1 and 2 below.

[In vivo 5HT1A Activity]

The compounds of the present invention were also investigated for their in vivo effects on brain 5-H1AA and serum corticosterone levels. Male Sprague-Dawley rats, weighing 150-200 ° C., were administered subcutaneously or orally with an aqueous solution of the test compound. One hour after treatment, rats were gushed and main blood was collected. Blood was left to coagulate and centrifuged to separate serum. The concentration of corticosterone in serum is described by Solem, J.H. Brinck-Johnsen, T., Scand. J. Clin. Invest. [Suppl. 80], 17, 1 (1965)] 1.

Whole brains were quickly removed from the guillotine rats, frozen on dry ice and stored at -15 ° C. The concentration of 5-H1AA was determined by liquid chromatography using electrochemical detection as described in Fuller, R. W .; Snoddy H. D .; Perry, K W., Life Sci. 40, 1921 (1987). The results are reported in Table 1.

[In vivo [3H] -pyrenzepine binding]

To investigate 3H-pyrenzepine binding in vivo, male Sprague Dowley Indianapolis (IN) mice weighing 100-150 g were sacrificed by the head, the brain was quickly removed and the cerebral cortex was dissected from the brain. It was. Cortical membranes were obtained by fractional centrifugation, washed twice and frozen until used.

Inhibition of the binding of 3H-pyrenzepine to the receptor was determined by the study drug, 1 nM 3H-pyrenzepine (87.0 Ci / mmol, New England Nuclear, Boston, Mass.), And about 100 μg of cerebral cortical membranes in total containing 1 mM MnCl ₂ . Determined by addition to mL volume 20 mM Tris-Cl buffer, pH 7.4. After 1 hour of incubation at 25 ° C., the homogenate was vacuum filtered through glass filter paper (Whatman, GF / c), the filtrate was washed three times with 2 ml of cold buffer and then 10 ml of scintillation (Ready Protein). +, Beckman, Fullerton, Calif.) Into scintillation vials.

Radioactivity remaining in the filter paper was determined by a liquid scintillation spectrometer. Nonspecific binding was determined using 1 μM atropine.

The results are reported in Table 2.

[Suppression of stomach acid]

Gastric inhibition was determined in pyrolyzed mice according to Shay's method (Shay, H. Komarov, A.A. and Greenstein, M: Effects of vagotomy in the rat, Arch. Surg. 59, 210-226 (1949)). Male Sprague-Dawley rats weighing about 200 g were starved for 24 hours prior to use. Water was optionally supplied. The pylori was ligated under mild Her anesthesia, while the compound was administered intraperitoneally or subcutaneously to the rat and the rat awakened from anesthesia. Acid was accumulated for 2 hours. After this period the rats were killed. The contents of the stomach were removed, measured and titrated to the end point of pH 7.0. Each experiment included excipient treated controls to determine percent secretion inhibition.

The results are reported in Table 1.

[Cavacol-Induced Breakdown of Hypertone]

Male Sprague-Dawley rats weighing 300-350 g were starved for 24 hours. The rats were transferred to the laboratory, and the colons were removed immediately. The feces were washed and 4 cm long strips were placed in organ baths under 1 g tension using a Grass FTO3 transducer. The tissue was left to equilibrate and fed with 95% oxygen and 5% carbon dioxide. Subsequently, drug solution was added to observe relaxation. Percent relaxation was calculated from the pre-treatment control period. Many compounds were tested for more than one concentration of drug. In this situation, IC ₅₀ was calculated, an amount that inhibits carbacol induced responses by 50%. The results are reported in Table 2.

Tables 1 and 2 disclosed below show the results of the evaluation of the various compounds of the invention.

In Table 1, the first column shows Preparation Example No. of the evaluated compound; Columns 2 and 3 represent substituted groups of R ² and R ³ ; Column 4 shows the IC ₅₀ value (expressed in nm concentration) required to inhibit the binding of ³ H-8-OH-DPAT to the 5HT1A receptor; Column 5 shows gastric acid inhibition at dose or ED ₅₀ value expressed in μmol / kg in vivo; Column 6 represents the minimum effective amount (MED) of test compound administered subcutaneously in lowering brain 5-H1AA levels; Column 7 represents the MED of the test compound administered subcutaneously in raising serum corticosterone levels; Column 8 provides the same information as Column 5 except that the test compound is orally administered. Results in columns 6-8 are indicative of 5-HT1A agonist activity.

Table 2 summarizes the effects of representative Formula 1 compounds on muscarinic (M ₁ ) receptors. The first seran is shown in Table 1. Column 4 shows the IC ₅₀ value (expressed in nm concentration) required to inhibit the binding of 3H-pyrenzepine to the muscarinic (M ¹ ) receptor; The fifth column shows the IC ₅₀ value in μM for inhibiting carbacol induced induced failure in colon smooth muscle in vitro.

TABLE 1

TABLE 2

Thus, one aspect of the present invention provides an irritable bowel by modulating the activity of both 5-HT1A and muscarinic (M ₁ ) receptors comprising administering a pharmaceutically effective amount of a compound of formula 1 to a mammal in need of treatment of IBS. How to treat the syndrome.

As used herein, the term “pharmaceutically effective amount” refers to the amount of a compound of the invention capable of binding to both serotonin 1A and M ₁ receptors. The particular dosage of the compound administered according to the invention is, of course, determined by the particular situation around the patient, including, for example, the compound administered, the route of administration and the condition to be treated. Typical daily dosages generally comprise from about 0.01 mg / kg to about 20 mg / kg of the active compound of the present invention. Preferred daily dosages are generally about 0.05 to about 10 mg / kg, ideally about 0.1 to about 5 mg / kg.

The compound can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.

The compound of the present invention is preferably prepared before administration. Thus, another aspect of the present invention is a pharmaceutical formulation comprising a compound of formula 1 and a pharmaceutically acceptable carrier, diluent or excipient.

The pharmaceutical formulations can be prepared by known methods using well known and readily available ingredients. In making the compositions of the present invention, the active ingredient can usually be mixed with the carrier, diluted with the carrier, or enclosed in a carrier, which can be in the form of a capsule, sachet, paper or other container. When the carrier acts as a diluent, it may be a solid, semisolid or liquid substance which acts as a vehicle, excipient or medium for the active ingredient. Therefore, the composition contains tablets, pills, powders, sugar tablets, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example up to 10% by weight of the active compound. Ointments, 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, starch, acacia rubber, calcium phosphate, alginate, trigacanth, gelatin, calcium silicate, microcrystalline cellulose, poly Vinylpyrrolidone cellulose, water syrup, methyl cellulose, methylhydroxybenzoate, polyhydroxybenzoate, talc, magnesium stearate and mineral oil. The formulation may additionally include lubricants, wetting agents, emulsifiers, suspending agents, preservatives, sweeteners, fragrances and the like. The compositions of the present invention can be formulated to provide early, sustained or delayed release of the active ingredient after administration to a patient using methods well known in the art.

The composition may be preferably formulated in unit dosage form, which generally comprises from about 0.1 mg to about 500 mg, preferably from about 1 mg to 250 mg of active ingredient. The term “unit dosage form” refers to physically discrete units suited as unitary dosages for humans and other mammals, containing a predetermined amount of active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical carrier.

The following preparation examples are illustrative only and are not intended to limit the scope of the invention in any aspect.

Preparation Example 1

Hard gelatin capsules were prepared using the following ingredients:

Preparation Example 2

Tablets were prepared using the following ingredients:

The components were blended and pressed to form tablets weighing 665 mg each.

Preparation Example 3

A suspension containing 50 mg of each active ingredient per 5 ml dose was made as follows:

The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with sodium carboxy methyl cellulose and syrup to form a smooth dough. The benzoic acid solution, the fragrance and the coloring agent were added with some water and added with stirring. Sufficient water was then added to produce the desired volume.

Preparation Example 4

Intravenous preparations may be prepared as follows:

A solution of this component is usually administered intravenously to a patient suffering from depression at a rate of 1 ml per minute.

Claims (2)

A composition for treating irritable bowel syndrome in a mammal, comprising a compound of formula (I) or a pharmaceutically acceptable acid addition salt or solvate thereof and a pharmaceutically acceptable carrier, diluent or excipient. Wherein R is hydrogen, C ₁ -C ₃ alkyl, allyl or ego; R ¹ is hydrogen, C ₁ -C ₃ alkyl, allyl, Or-(CH ₂ ) _n -X wherein n is 1 to 5; X is phenyl which may be substituted, C ₁ -C ₃ alkoxy or C ₁ -C ₃ alkylthio; R ² and R ³ are independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, halo, CN or phenyl; Together are-(CH ₂ ) _p- , where p is 3 to 6; Y is -CH _2- . The compound of claim 1, wherein 8- (isoxazol-5-yl) -2-dipropylamino-1, 2, 3, 4-tetrahydronaphthalene, 8- (4-methylisoxazol-5-yl)- 2-dipropylamino-1, 2, 3, 4-tetrahydronaphthalene; And 8- (3-methylisoxazol-5-yl) -2-dipropylamino-1, 2, 3, 4-tetrahydronaphthalene.