DERIVATIVES OF 2-AMINO-6,7-DIHYDROXYTETRAHYDRONAPHTHALENE(ADTN)

Abstract: Derivatives of 2-amino-6,7-dihydroxytetrahydronaphthalene (ADTN) represented by the formula (FORMULA) wherein R is OH, alkyloxy, hydroxyalkyl or acyloxy, and R' is an arylalkyl where the aryl group is benzyl, substituted benzyl, phenyl or substituted phenyl and the alkyl group is a straight or branched chain alkyl having one to twenty carbon atoms; and the pharmaceutically acceptable salts thereof. These derivatives of 2-amino-6,7-dihydroxytetrahydronaphthalene are useful as inotropes.

Description: DERIVATIVES OF 2-AMIN0-6 ,7-DIHYDR0XYTETRAHYDR0- NAPHTHALENE (ADTN) DETAILED DESCRIPTION OF THE INVENTION Thi s i nventi on rel ates to deri vati ves of 2-amino-6 , 7-di hy- droxytetrahydronaphthal ene (ADTN) and, more parti cul arly, to N-aryl al kyl deri vati ves of 2-amino-6 ,7-dihydroxytetrahydro- naphthal ene (ADTN) characteri zed by formul a ( I) wherein R is OH, alkyloxy, hydroxyalkyl or acyloxy, and R 1 is an arylalkyl where the aryl group is benzyl, substituted benzyl, phenyl or substituted phenyl and the alkyl group is a straight or branched chain alkyl having one to twenty carbon atoms; and the pharmaceutically acceptable salts thereof. The term "alkyloxy" as used herein refers to oxygenated straight or branched chain radicals containing one to ten carbon atoms, as illustrated by, but not limited to, methoxy, ethoxy, butoxy and the like. The term "hydroxyalkyl" as used herein refers to hydroxyl- ated straight or branched chain radicals containing one to ten carbon atoms, as illustrated by, but not limited to 2-propanol, 3-propanol and the like. The term "aryl" as used herein refers to benzyl, substituted benzyl, phenyl and substituted phenyl where the substituents of benzyl and phenyl include loweralkyl, hydroxy, alkoxy, acyloxy and the like. The term "alkyl" refers to straight and branched chain alkyl radicals having from one to twenty carbon atoms such as methyl, n-amyl, 3-methyl-2-octyl, 2-nonyl and 2-tetradecyl. -gfREA OMPI /., IPO KNATI The term "acyloxy" as used herein refers to acetoxy, pro- pionyloxy, butyrylojcy and the like. The term "pharmaceutically acceptable salts" r p fers to acid addition salts prepared by reactiny the basic amines of this in¬ vention with an organic or inorganic acid, or by reacting the amine salts with the salt of an appropriate acid. Representative salts which are so formed include the hydrochloride, hydrobromide, sul¬ fate, bisulfate, acetate, oleate, laurate, benzoate, phosphate, citrate, maleate, succinate, tartrate and napsylate salts of the amines. The present compounds, i.e., N-arylalkyl derivatives of 2-amino-6,7-dihydroxytetrahydronaphthalene (ADTN), may be pre¬ pared by reductive aminations of the protected (ADTN) which may be prepared by a modification of the preparation reported by J. 6. Cannon et al. (J. Med. Chem., 20, p. 1111 (1977)) and as il¬ lustrated in Scheme I below. O Sλr- W The preparation of the present derivatives by reductive ami- nations of the protected (ADTN) is carried out with the appro¬ priate ketones and aldehydes. Generally, in the preparation of the present derivatives, there is, initially, a solution of 2-amino-6,7-dimethoxy -1,2,3,4- tetrahydronaphthalene (VI) in dry methanol is treated with the appropriate ketone or aldehyde and NaCNBH, under a nitrogen at¬ mosphere. The mixture is then stirred for 72 hours whereupon concentrated HCl is added dropwise until the mixture becomes acidic. The methanol is removed on a rotary evaporator and the mixture is extracted with ether. The aqueous mixture is made basic to a pH greater than 12.0 with solid OH and the mixture is ex¬ tracted with ether. The combined extracts are dried (MgSO.) and the solvent is removed on a rotary evaporator. The products are dissolved in CHC and hydrogen chloride is bubbled in and the solvent removed on a rotary evaporator. The products are crystal¬ lized in isopropanol and then isolated. The compounds of the present invention that can be prepared by the reductive aminations of the protected (ADTN) and repre¬ sented by formula (I) include: (I) a) 2(3-p-hydroxyphenyl-l-methylpropyl) amino-6,7-dihy- droxy-l,2,3,4-tetrahydronaphthalene where R is OH and R' is represented by the formula ' Lπ h OH O Λ. WI b) 2-(3-p-hydroxyphenyl-l-methylpropyl) amino-6,7-dime- thoxy-1,2,3,4-tetrahydronaphthalene where R is 0CH-. and R' is represented by the formula c) 2-diacetoxy- -methy1 dopaminimino-6,7-diacetoxy-1,2, 3,4-tetrahydronaphthalene where R is CH 3 0- and R' is represented by the formula d) 2-α-methy1 dopamiπimino-6,7-dihydroxy-1,2,3,4-tet a- hydronaphthalene where R is OH and R' is represented by the formula e) 2-Dopaminimino-6,7-dihydroxy-l,2,3,4-tetrahydronaph¬ thalene where R is OH and R' is represented by the formula f) 2-dimethoxy-α-methyl dopaminimino-6,7-dimethoxy-l,2, 3,4-tetrahydronaphthalene where R is OCH., and R' is represented by the formula The compounds of the present invention exhibit inotropic activity in warm-blooded animals at a dosage ranging from about 10.0 ug/kg to about 60.0 ug/kg of the body weight daily. The following examples will further illustrate the present invention. O /., WI EXAMPLE I Preparation of 6,7-dimethoxy-2-methoxyimino-l,2,3,4- tetrahydronaphthalene (V) A mixture of 0.56 g (5.7 mmol) of methoxylamine hydrochlo¬ ride and 6.5 ml (6.5 rrrmol) of a 1M aqueous solution of NaOH was added to 0.689 g (3.34 mmol) of 6,7-dimethoxy-2-tetralone (TV). While under a nitrogen atmosphere the mixture was warmed to c_a_. 100° for 15 minutes and then kept at 40° using an infrared lamp for 18 hours. Water was added to the mixture which was then extracted with ether. The combined extracts were dried (MgSO * ) and the solvent was removed on a rotary evaporator, affording 0.700 g (89.2%) of brown oil: nmr (CDC1 3 ) δ 2.3-2.9 (m, 4H), 3.32 (S, IH), 3.57 (S, IH), 3.73 (S, 6H), 3.78 (S, 3H), 6.4-6.6 (m, 2H). The compound was used without further purification. EXAMPLE II Preparation of 2-amino-δ,7-dimethoxy-l,2,3,4- tetrahydronaphthalene (VI) 2-amino-6,7-dimethoxy-l,2,3,4-tetrahydronaphthalene (VI). A solution of 0.7.00 g (2.98 mmol) of _V in 20 ml of dry THF was treated with 5.0 ml (5.0 mmol) of a l_[ borane/THF solution while under a nitrogen atmosphere. The solution was heated to reflux for 6 hours and was then quenched with water. The aqueous mixture was extracted with CHCl.,, the combined extracts were dried and hydrogen chloride was bubbled into the solution. The solvent was removed on a rotary evaporator, leaving 0.775 g of off-white solid. Crystallization from isopropanol afforded 0.469 g (64.8%) of off-white product: mp. 83-86°C (lit. 85-87°C). EXAMPLE III Preparation of ADTN Derivatives by Reductive Amination of Protected ADTN In the preparation of the derivatives, the general procedure was as follows: A solution of 1 mmol of VI in 2 ml of dry methanol OMPI was treated with 1 mmol of the appropriate ketone or aldehyde and 1.05 mmol of NaCN8H 3 under a nitrogen atmosphere. The mixture was stirred for 72 hours whereupon concentrated HCl was added dropwise until the mixture became acidic. The methanol was removed on a rotary evaporator, the mixture was extracted with ether. The aqueous mixture was made basic (pH > 12) with solid KOH and the mixture was extracted with ether. The combined extracts were dried (MgSO,) and the solvent was removed on a rotary evaporator. The products were dissolved in CHC1 3 , hydrogen chloride was bub¬ bled in and the solvent was removed on a rotary evaporator. Crystallization of the products was carried out " in isopropanol and the compounds were isolated. The compounds produced and the date of their preparation are as follows: (a) 2-(3-p-hydroxyphenyl-l-methylpropyl) amino-6,7-dihy- droxy-1,2,3,4-tetrahydronaphthalene: The compound was isolated in 43% yield: mp. 236-237°C, nmr (CD 3 0D) δ 1.3-1.7 (m, 3H), 1.7-3.8 (m, 12H), 6.43 (S, 2H), 6.65 (d, J = 7Hz, 2H), 7.00 (d, J = 7 Hz, 2H). Calcd for C 2( -H 25 N0 3 Br; C, 58.63; H, 6.42; N, 3.43. Found: C, 58.54; H, 6.39; N, 3.37. (b) 2-(3-p-hydroxyphenyl-l-methylpropyl) amino-6,7-dime- thoxy-1,2,3,4-tetrahydronaphthalene: The compound was isolated in 91% yield: p. 230-232°C (d); nmr (CDC1 3 ) δ 1.13 (d, J = 6 Hz, 3H), 1.3-2.2 ( , 4H), 2.2-3.2 ( , 8H), 3.73 (S, 6H), 4.82 (S, 2H), 6.47 ( , 2H), 6.75 ( , 4H, J = 8 Hz). Calcd for C 22 H 30 N0 3 C1: C, 67.41; H, 7.46; N, 3.57. Found: C, 67.18; H, 7.72; N, 3.46. (c) 2- diacetoxy-α-methyl dopaminimino-δ,7-diacetoxy- 1, 2,3,4-tetrahydronaphthalene: A solution of 0.200 g of 2- -methyl dopaminimino-6,7-dihydroxy-l, ,3,4-tetrahydronaphthalene (d) in 1 ml of trifluoroacetic acid and 1 ml of acetyl chloride was warmed to c_a. 80° for 0.5 h. The solvent was evaporated and crystallization of the solid from ethanol afforded 0.140 g (50.4%) of product: mp. 192-194°C; nmr (CD 3 0D) δ 1.15 (d, J = 6 Hz, 3H), 2.10 (S, 12H), 2.6-3.9 (m, 10H), 6.8-6.9 (m, 2H), δ .03 (S, 3H). Calcd for C^H^ OgB : C, 56.06; H, 5.58; N, 2.42. Found: C, 56.19; H, 5.40; N, 2.26. (d) 2-α-methyl dopaminimino-6,7-dihydroxy-l,2,3,4-tetra- hydronaphthalene: The compound was isolated in 57% yield; nmr (CD 3 0D) δ (1.32, d, 0 = 6 Hz, 3H), 1.5 - 4.0 (m, 10H) 6.4-6.8 (m, 5H) . (e) 2-dimethoxy-α-methyl dopaminimino-6,7-dimethoxy-l, 2,3,4-tetrahydronaphthalene: The compound was isolated in 35% yield; mp. 224-229°C; ir ( Br) 3480, 3020-2650, 1612, 1590 cm "1 . EXAMPLE IV Inotropic, Chronotropic and Pressor/Depressor Activities The following tests were conducted: In anesthetized, open-chested dogs, instrumented with a Walton-Brodie strain gauge to measure cardiac contractile force, a ventricular catheter to measure left ventricular dP/dt and an aortic catheter to measure diastolic blood pressure and heart rate. Contractile force and L.V. dP/dt are indices of cardiac contractility and provide information on the inotropic state of the heart. The experimental standard drugs are compared by nor¬ malizing prεssor/depressor and heart rate responses to a given inotropic effect. Cardioselective inotropic agents will produce minimal diastolic pressure changes for any given inotropic effect. Likewise, inotropic selective agents will produce minimal heart rate changes for any given inotropic effect. In the data summary below, compounds A-F are: Compound Name A 2-(3-p-hydroxyphenyl-l-methylpropyl) a ino- 6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene B 2-(3-p-hydroxyphenyl-l-methylpropyl) amino- 6,7-dihydroxy-l,2,3,4-tetrahydronaphthalene C 2-amino-6,7-dihydroxy-l,2,3,4-tetrahydro¬ naphthalene D (+)-4-(2(3-p-hydroxyphenyl-l-methylpropyl) amino) ethyl-l,2-benzenediol (Dobutamine ® : Lilly) E 4-(2-aminoethyl)-l,2-benzenediol (Dopamine) F 4-(1-hydroxy-2-((1-meth lethyl)-amino)ethyl)- 1,2- benzenediol (Isoproterenol) Inotropic Potency* (means + SEM) Compound _N CF 50 CF 100 dP/dt 75 dP/dt 15Q A 1 157.6 333.1 261.8 756.0 B 2 56.3 197.6 125.4 358.6 C 5 44, .9 + 3, .3 118 .8 + : 34. .7 40, .4 + 3.1 75.6 + 5. D 6 1, .4 ÷ 0. .2 4, A J - 0.2 4.0 + 0. E 6 9, .1 + 1. .0 19 .6 + 2. .7 9. .9 + 0.7 23.7 + 3. F 6 0, .04 + 0. .01 0. .09 + 0. .02 0. .04 + 0.01 0.14 + 0. *ug/kg required to produce 50 and 100% increase in cardiac contractile force (CF) and 75 and 150% increase in left ventricular dP/dt (dP/dt). Cardioselectivity* (means + SEM) Compound N CF 50 CF 100 dP/dt 75 dP/dt 150 A 1 -17 -27 -23 -40 B 2 -13 57 37 75 C 5 31 + 9 61 + 10 30 + 5 51 + 5 D 6 ' 3 + 1 4 + 3 4 + 1 3 + 3 E 6 -20 + 6 -12 + 9 -20 + 7 -10 + 8 r- Γ 6 -6 + 2 -15 + 2 -6 + 2 -16 + 2 *Change in diastolic blood pressure obtained at CF ςn . CF 100 : dP/dt75 ; dP/dt 15Q (mm Hg). OMPI , WWIIPPOO Inotropic Selectivity* (means +_ SEM) Compound dt 75 dP/dt 150 ϋ CF 50 CF 100 dP/ A 1 5 14 10 27 B 2 -17 15 0 32 C 5 -12 + 9 21 + 17 -12 + 10 5 + 8 D 6 3 + 1 17 + 5 3 + 1 13 + 2 E 6 5 + 5 12 + 5 5 + 6 13 + 6 F 6 14 + 2 34 + 3 14 + 1 41 + 5 *Change in heart rate obtained at CFr n . CF (BPM). bυ' 100 J dP/dt 75 , dP/dt 150 OMPI /». WIPO . «

Claims: WE CLAIM: 1 . A compound of the formul a wherein R is OH, an alkyloxy, hydroxyalkyl, or an acyloxy; and R' is an aryla.lkyl where the aryl group is benzyl, substituted benzyl, phenyl or substituted phenyl and the alkyl group is a straight or branched chain alkyl having one to twenty carbon atoms; and the pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, wherein R is OH, and R* is an arylalkyl of the formula 3. A compound according to claim 1, wherein tetrahydronaphtha¬ lene is 0CH 3 , and R 1 is an arylalkyl of the formula O Λ. WI 4. A compound according to claim 1, wherein R is acetyloxy and R' is an aryl lkyl of the formula 0 5. A compound according to claim 1, wherein R is OH and R' is an arylalkyl of the formula 6. A compound according to claim 1, wherein R is OH and R 1 is an arylalkyl of the formul 7. A compound according to claim 1, wherein R is 0CH 3 and R' is an arylalkyl of the formula OMPI /., WWIIPPOO

Inventors: STOUT D
Applicants: AMERICAN HOSPITAL SUPPLY CORP
Application year: 1979
Main classification: C07C93
IPC codes: A61K31, A61P9, C07C67, C07C213, C07C215, C07C217