US3910927A

US3910927A - 3-Hydroxyisoquinoline ethers

Info

Publication number: US3910927A
Application number: US423841A
Authority: US
Inventors: William Eugene Kreighbaum; William Timmey Comer
Original assignee: Mead Johnson and Co LLC
Current assignee: Mead Johnson and Co LLC
Priority date: 1971-09-27
Filing date: 1973-12-11
Publication date: 1975-10-07
Anticipated expiration: 1992-10-07

Abstract

New 2-substituted-3(2H)-isoquinolones and 2-substituted-3alkoxyisoquinolines are disclosed. They are orally active hypotensives and peripheral vasodilators with an extended duration of action. Representative embodiments of this invention are 6,7-dimethoxy-2-methyl-1-veratryl-3(2H)-isoquinolone hydrochloride, 2-allyl-6,7-dimethoxy-1-1-veratryl-3(2H)isoquinolone hydrochloride, 2-cyclopropyl-6,7-dimethoxy-1veratryl-3(2H)-isoquinolone hydrochloride, 2-amino-6,7-dimethoxy1-veratryl-3(2H)-isoquinolone hydrochloride, and 3-ethoxy-6,7dimethoxy-1-veratrylisoquinoline.

Description

United States Patent Kreighbaum et al.

[ 1 Oct. 7, 1975 l S-HYDROXYISOQUINOLINE ETHERS [75] Inventors: William Eugene Kreighhaum;

William 'Iimmey Comer, both of Evansville, Ind.

Related US. Application Data [62] Division of Ser. No. l84,l97, Sept. 27, I971, Pat.

[56] References Cited UNITED STATES PATENTS 7/1954 Shepard 260/289 R l2/l955 Shepard 260/289 R OTHER PU BLlCATlONS Evans et al., J. Chem. Soc. (B), pp. 590-595 (1967).

Henderson, J. Amer. Pharm. Assoc. Vol. 40, 207-210 (1951).

Primary Examiner-Donald G. Daus Assistant ExaminerD. B. Springer Attorney, Agent, or Firm-R. E. Carnahan; R. H. Uloth [57] ABSTRACT New 2-substituted-3(2HMsoquinolones and 2- substituted-3-alkoxyisoquinolines are disclosed. They are orally active hypotensives and peripheral vasodilators with an extended duration of action. Representative embodiments of this invention are 6,7- dimethoxyQ-methyl-l-veratryl-3(2H)-isoquinolone hydrochloride, 2-allyl-6,7-dimethoxy-l l -veratryl- 3(2H)-isoquinolone hydrochloride, 2-cyclopropyl-6,7- dimethoxy-l-veratryl-3(2H)-isoquinolone hydrochloride, 2-amino-6.7-dimethoxy-l-veratryl-3(2H)- isoquinolone hydrochloride, and 3-ethoxy-6,7- dimethoxy-l -veratrylisoquinoline.

6 Claims, No Drawings 3-I-IYDROXYISOQUINOLINE ETHERS CROSS-REFERENCE TO RELATED APPLICATION This application is a divisional application of US.

Pat. application Ser. No. l84,l97 filed Sept. 27, 1971,

now U.S. Pat. No. 3,798,225, issued Mar. I9, 1974.

BACKGROUND OF THE INVENTION This invention is concerned with certain heterocyclic carbon compounds having one hetero-N-atom. More particularly, it relates to 3(2H)-isoquinolones and 3- alkoxyisoquinolines which have hypotensive and peripheral vasodilating properties. Although the compounds of the present invention are of the same basic ring system as the isoquinoline, 6,7-dimethoxy-lveratryl-3isoquinolinol described by G. N. Dorofeenko and V. G. Korobkova, J. Gen. Chem., USSR, 40, 230 I970), they differ substantially in biological activity. Thus, for example, the compounds of the present invention are active orally as hypotensive and peripheral vasodilating agents whereas the prior art isoquinolinol is essentially inactive.

SUMMARY OF THE INVENTION The present invention is concerned with novel 2- substituted-3(2Hl-isoquinolones of Formula I and 3- alkoxyisoquinolines of Formula II and with non-toxic pharmaceutically acceptable acid addition salts thereof. These substances have utility as peripheral vasodilators and hypotensivc agents.

Formula I In Formulas I and II above, R represents lower alkyl. The R N-substituent" identifies a member of the group consisting of hydroxy, lower alkoxy, amino, lower alkylamino, lower dialkylamino, lower alkyl, alkenyl, cycloalkyl of from 3 to 5 carbon atoms inclusive, and phenylalkyl having up to 10 carbon atoms. Said phenylalkyl may have substituents attached to the phenyl ring which are selected from halogen, lower alkyl, methylenedioxy, and up to 3 lower alkoxy groups. R, in Formula II, represents lower alkyl, alkenyl, cy- Cloalkyl of from 3 to 5 carbon atoms inclusive, and benzyl.

It is to be understood that the terms lower alkyl and lower alkoxy" when used herein contemplates both straight and branched chain groups, containing from I to about 4 carbon atoms. Illustrative of such groups are methyl, ethyl, propyl, isopropyl, l-butyl, l-

CH iCH,.

It is to be understood that the term non-toxic pharmaceutically acceptable acid addition salts" used herein and in the appended claims denotes a combination of the 3(2H)-isoquinolones and isoquinolines of Formulas l and II with suitable non-toxic inorganic or Formula II organic acids to provide salts having physical properties including requisite stability adaptable for pharmaceutical formulations. Examples of non-toxic pharmaceutically acceptable acid addition salts of the compounds of Formulas l and II are those formed with sulfuric, hydrochloric, phsophoric, hydrobromic, hydrolodic, sulfamic, methanesulfonic, benzenesulfonic, para-toluenesulfonic, acetic, lactic, succinic, malic, maleic, mucic. tartaric, citric, gluconic, benzoic, cinnamic, isethionic, fumaric, and related acids.

The 3(2H)-isoquinolones of Formula I and acid addi tion salts thereof have a distinctive light to deep yellow color in the solid state. This color is attributed to the ortho-quinoid structure as represented by Formula I. The orthoquinoid structure is consistent with ultraviolet, nuclear magnetic resonance, and infrared spectra for the 3(2HJ-isoquinolones of Formula I rather than other tautomeric forms such as those represented by chloric acid, this intermediate converts rapidly to 6.7- Formula la and Formula lb. Formula la in which R and dimethoxy-Z-methyll -veratryl-3(2H)isoquinol0ne R are methyl groups has been reported by I. W. Elliott, hydrochloride. J. Heterocycl. Chem. 7, l229-l 230 I970). Lactones identified by general Formula II] above are R -R R m CH OR ca R Formula Ia Formula Ib A variety of methods may be employed to produce obtained by dehydrating keto acids of Formula IV the novel isoquinolones of this invention. One particuwherein R has the above meaning in a mixture of larly preferred method is the condensation of an acetic anhydride, glacial acetic acid and concentrated R'-NH intermediate with a lactone corresponding to sulfuric acid. This method is essentially that described Formula [II wherein R and R have the meaning given by l. W. Elliott, supra, for the preparation of l-(3.4- above. dimethoxybcnzylidene )-6,7-dimethoxy- 3- isochromanone from the keto acid 2-( 3,4- 1 0 dimethoxyphenylacetyl )-4,S-dimethoxyphenylacetic R 0 acid.

CH o 1 R 0 002}! R R10 C 0 on CH 0R Formula III 1 The condensation is carried out in an inert organic solvent as a reaction medium. Tetrahydrofuran is a prew ferred solvent but other solvents such as benzene. toluene. dioxane. acetonitrile, chloroform and the like are KQIO a id n rmediates of Formula IV are provided also useful. Preferably, the reaction is conducted at by in rm lecular acylation of pp p i lk0xabout 25C.. although this temperature is not critical yphenylacetic acid in polyphosphoric cid at moderand reaction temperatures appreciably above and temperatures of from about 25040011 This below are also operable. After the condensation is method is know" and is described y Dorofeenko complete. the solvent is evaporated and the residue and KOrObkOt/H. J. Cheflt, R. 40. 230 treated with hydrochloric acid to provide a hydrochlo- 1970) for the preparation 0f 4 ride salt of the isoquinolones of Formula I. Other nondimethoxyphenylacetyl)- t yph nylucetic toxic pharmaceutically acceptable acid addition salts acid from 3Adimethoxyphenylacetic acid- Illustrative may be prepared by treating the residue with other suitof kem acids P y this Procedure ill'ei able organic or inorganic acids.

Acid addition salts of the present invention can be xyph ny y im h xyconverted to the corresponding free bases by reaction ph nyl e acid, with a basic reagent such as aqueous ammonia. Al- 2-(3.4-diethoxyphenylacetyl)-4,5-diethoxyphcnylathough both the free base and salt forms of the com- CeliC acid,

pounds of the present invention are useful for the pur- 2-(3,4-diisopropoxyphenylacetyl)-4.5-diisopropoxyposes of the invention. salts are generally preferred as phcnylacetic acid.

they are relatively more stable than free base forms. 2-(3,4-di-n-butoxyphenylacetyl)-4,S-di-n-butoxy- The lactone condensation probably involves formaphenylacetic acid, tion of 1-hydroxy-3(2H)-isoquinolone intemiediates which in presence of acid undergo dehydration to form which are obtained from intermolecular acylation of 3(2H)-isoquinolones of Formula I. Illustrative of such the 3,4-dialkoxyphenylacetic acids: an intermediate is 1,4-dihydrol -hydroxy-6.7- dimethoxy-Z-methyll -veratryl-3(2H)-isoquinolone 3,4-dimethoxyphenylacetic acid. which is obtained by the condensation of methylamine 3.4-diethoxyphenylacetic acid, with the lactone. l-(3,4-dimethoxybenzylidene)-6,7- 3.4-diisopropoxyphenylacetic acid. dimethoxy-3-isochromanone. In the presence of hydro- 3.4-di-n-butoxyphcnylacetic acid.

Some of the isoquinolones of Formula I may also be produced by cyclization of keto acids of Formula IV with R NH intermediates in acetic acid.

An alternate method of preparing isoquinolones of general Formula I wherein R is methyl is by alkylation of a 6,7dialk0xyl 3,4-dialkoxybenzyl )-3- isoquinolinol with methyl iodide in the presence of a base such as sodium methoxide. The predominate product is the N-alkylated isoquinolone with a minor amount of a 3-methoxyisoquinoline of Formula II.

Another method of preparing 3- methoxyisoquinolines of Formula ll is by alkylation of the silver salt of 6,7-dialkoxy-l-(3,4-dialkoxybenzyl)- 3-isoquinolinols with methyl iodide.

lsoquinolines of Formula ll are preferably obtained from corresponding 6,7-dialkoxyl 3 ,4-dialkoxybenzyl )-3-isoquinolinols by reaction with a RX-alkylating agent in a reaction inert organic solvent such as, e.g., benzene, toluene, dioxane and preferably acetone, at moderately high temperatures, e.g., between about 60 and lC. in the presence of bases, e.g., alkali metal carbonates such potassium carbonate. R" is as defined above and the symbol X refers to the acid residue of a reactive ester grouping such as e.g., a bromide, iodide, chloride, sulfate, tosylate or mesylate.

An alternate method of preparing isoquinolines of Formula ll is by alkylation of corresponding 6,7- dialkoxyl 3,4-dialkoxybenzyl )3-isoquinolinols with a trialkyloxonium fluoroborate as described in L. F. Fieser and M. Fieser, Reagents for Organic Synthesis," page l2l0 (Wiley, 1967).

The compounds of the present invention identified by Formulas l and ll have hypotensive and peripheral vasodilating properties and are, therefore, useful in treating conditions in mammals responsive to administration of such agents. They are orally active and when compared to papaverine in the dog have a considerably longer duration of action.

These valuable pharmacological properties can be demonstrated by standard pharmacological methods. For example. hypotensive and peripheral vasodilating activity are measured in anesthetized dogs according to the following procedure. A tracheotomy is performed and the animal is ventilated mechanically and arranged for recording arterial blood pressure, aortic blood flow, right ventricular contractile force and heart rate. The test agent is administered by a rubber catheter inserted into the duodenum through the pyloric sphincter via a small incision in the stomach wall (duodenal administration is considered to be equivalent to oral administration by mouth or by stomach tube).

Illustrative of the cardiovascular activity exhibited by the compounds of the present invention in this test is that obtained with a preferred compound, 6,7-

dimethoxy-Z-methyll -veratryl-3( 2H )-isoquinolone hydrochloride, which at a dose of 5 mg./kg. body weight produced a percent decrease in diastolic blood pressure and a 19 percent decrease in total pe ripheral resistance. Mean systemic blood pressure divided by mean aortic blood flow is taken as a measure of total peripheral resistance. At a similar dose, both papaverine. which is a well known peripheral vasodilator and 6,7-dimethoxy'l-veratryl-3-isoquinolinol, a prior art isoquinoline, are devoid of significant cardiovascular activity.

Selective hypotensive and peripheral vasodilating ef LII fects relative to the ventricular contractile force and heart rate are produced by the instant compounds when compared to papaverine. That is to say, desirable hypotensive and peripheral vasodilating responses are obtained with substantially less adverse cardiac effects, e.g., increased ventricular contractile force and heart rate, than is produced by an effective dose of papaverine.

There can be mentioned by way of example the following compounds as those particularly preferred for oral hypotensive and peripheral vasodilating activity:

6,7-dimethoxy-2-methyll-veratryl-3( 2H isoquinolone hydrochloride,

2-allyl-6,7-dimethoxyl-veratryl-3(2H )-isoquinolone hydrochloride,

2-cyclopropyl-6,7-dimethoxyl -veratryl-3( 2H isoquinolone hydrochloride,

2-amino-6,7-dimethoxyl -veratryl-3( 2H )-isoquinolone hydrochloride.

The process of the present invention for producing a hypotensive and peripheral vasodilating effect in a mammal is carried out by systemic administration of an effective non-toxic dose of the 3(2H )-isoquinolones of Formula I and 3-alkoxyisoquinolines of Formula II ranging from about 0.05 to 20 mg./kg. body weight of the mammal. It is intended by systemic administration to include both oral and parenteral routes. Oral administration is preferred, although parenteral routes, e.g., intramuscular, intravenous, intraperitoneal and subcutaneous administration may also be employed. The dosage will vary with the form of administration and the particular compound chosen. Generally, the compound is administered at a dosage substantially less than the dose of the compound which is thought to be effective. Thereafter. in conformity with accepted therapeutic methods, the dosage is increased by small increments until the desired hypotensive or vasodilating effect is reached.

The compounds which constitute this invention and their methods for preparation will appear more fully from the consideration of the following examples which are given for the purpose of illustration only and are not to be construed as limiting the invention in spirit or scope.

EXAMPLEl 3.6,7-Trimethoxyl -Veratrylisoquinoline Hydrochloride A suspension of 6,7-dimethoxy-l-veratryl-3- isoquinolinol (3.6 g., 0.01 mole) in a mixture of ml. of water and 20 ml. of IN sodium hydroxide is stirred at 25C. until the yellow isoquinolinol has turned white and the supernatent is colorless. The suspension is chilled, filtered, and the filter cake washed with 50 ml. of tetrahydrofuran. Air drying provides 4.0 g. (l007z) of 6,7-dimethoxy-l-veratryl-3-isoquinolinol sodium salt as a white solid monohydrate, sintering at 250-260C.

The sodium salt of 6,7-dimethoxy-l-veratryl-3- isoquinolinol (1.0 g. 0.0025 mole) is suspended in 20 ml. of absolute ethanol and 2% silver nitrate/ethanol is added dropwise thereto until further addition causes no more yellow-orange precipitate to form. The resulting suspension is stirred at 25C. for 1 hr. in the dark and filtered. The yellow filter cake is washed first with ml. of absolue ethanol then with ml. of ether and air dried to provide 1 g. of 6.7-dimethoxy-l-veratryl-3- isoquinolinol silver salt.

Methyl iodide (34 g.. 0.24 mole) is added to the silver salt in l5 ml. of ether and the mixture stirred for l6 hr. in the dark. Dilution of the mixture with 125 ml. of tetrahydrofuran, filtering and concentrating the filtrate provides a solid residue. Crystallization of the residue from ether-methylene chloride affords 0.5 g. (49%) of 3.6.7-trimethoxy-l-veratrylisoquinoline free base as pale yellow crystals. m.p. 135 l36C.

The hydrochloride salt prepared by acidifying the free base with ethanolic hydrogen chloride is crystallized from methanol-isopropano] to analytically pure 3,6.7-trimethoxyl -veratrylisoquinoline hydrochloride as a pale yellow solid, melting at l90.5l94.0C. (dec. )(corr.

Analysis. Calcd. for C H- NogHCl (percent): C. 62.14; H. 5.96; N, 3.45. Found (percent): C. 62.37; H. 6.00; N. 3.36.

Ultraviolet: A max (95% EtOH). 345 (6. 5700); 272

' e. 6900); 240 e, 60600) millimicrons.

NMR: 5 (DMSO-d tetramethylsilane reference). s. 3.8-4.1 (5s. l5. OCH-i); 4.5 (s. 2, ArH).

EX AM PLF. 2

3-Ethoxy-6,7- Di methoxy l -Veratrylisoquinoline Triethyloxonium fluoroborate prepared from boron fluoride etherate (6.2M g.. 0.048 mole) and epichlorohydrin (3.33 g.. 0.036 mole) according to the method of H. Meerwin. Org. Syn. 46. 1 l3 1966) is taken up in I00 ml. of dry methylene chloride and 6,7 dimethoxy-l-veratryl-3-isoquinoliriol I08 g., 0.03 mole) in 200 ml. of methylene chloride added thereto. The mixture is stirred at C. for If) hr., chilled and washed first with aqueous potassium carbonate and then with three 200 ml. portions to water. After drying the washed methylene chloride solution over magnesium sulfate and treating with decolorizing charcoal. the solvent is evaporated. Crystallization of the residue first from methanol-isopropyl alcohol and then from acetonitrile and finally again from methanol-isopropyl alcohol affords 4.1 g. (439%) of analytically pure 3- ethoxy h.7-dimethoxyl -veratrylisoquinoline as a white solid. m.p. l l0.0l 110C. (corr.).

Analysis. Calcd. for C .H- ,,-,NO (percent): C. 68.92; H, (1.57; N. 3.65. Found (percent): C. 69.05; H. 6.53: N, 3.7l.

Ultraviolet: A max (CHCM). 348 (E. 5500); 273 7300): 243 55200) millimicrons.

NMR: 5 (deuterochloroform. tetramethylsilane referenee). l.3 (t. 3. CH 3.7'-1.0(4s. l2, OCHs); 4.4 N. 2. OCHQJ. 4.5 (s. 2, CH. .Ar); 6.77.4 (6. ArH).

EXAMPLE 3 3-Ben/.yloxy-6.7-Dimethoxyl -Veratrylisoquinolinc A mixture of 6.7-dimethoxylweratryl-3- isoquinolinol (3.6 g.. 0.0l mole). benzyl bromide l.7l g.. 0.0] mole, 1.2 ml.) powdered anhydrous potassium carbonate (2.8 g., 0.02 mole) in I00 ml. of acetone is refluxed for 72 hr. and filtered. The filtrate is conceit trated under reduced pressure and the resulting residue stirred with petroleum ether [b.p. 60C.) to provide a solid. Crystallization from a mixture of CH2); sans a,

methanol-acetone-isopropanol (with decolorizing charcoal) affords 3.2 g. of analytically pure 3- benzyloxy-6.7-dimethoxyl -veratrylisoquinolinc. m.p. ll4.0-l C. (corn).

Analysis. Calcd. for C H -NO (percent): C. 72.79; H. 6.1!; N. 314. Found (percent): C, 72.72; H. 6.04; N. 3. l4.

Ultraviolet: max (CHCM). 348 (E. 5500); 244 (e. 60600) millimicrons.

NMR: 6 (deuterochloroform. tetramethylsilane ref erence). 3.63.9 (4s, l2. OCH 4.4 (s, 2. CH 5.4 (s. 2. OCH 6.7-7.3 l l. ArH).

EXAMPLES 4ll Additional exemplification of the compounds of the present invention are provided in the following Table I. These compounds are obtained according to the procedures hereinabove described in Examples l3 from the indicated reactants.

ADDI'IlOTIAL ISOTDUINOLITITS No. R R Reactants CH3 t H, lu

7 C. .H,, cit..

It will be appreciated by those skilled in the art that specific embodiments disclosed in the foregoing specification are exemplary of other modifications which can be made without departing from the spirit and scope of the appended claims.

What is claimed is: l. A compound selected from the group consisting of those having the formula wherein R is lower alkyl having up to 4 carbon atoms; R is lower alkyl having up to 4 carbon atoms, alkenyl having from 3 to 6 carbon atoms, cycloalkyl having from 3 to carbon atoms, benzyl;

6. The compound of the group defined in claim I which is 3-benzyloxy-6,7-dimethoxyl veratrylisoquinoline.

Claims

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FOUMULA

2. The compound of the group defined in claim 1 which is 3,6,7-trimethoxy-1-veratrylisoquinoline.

3. The compound oF the group defined in claim 1 which is 3,6,7-trimethoxy-1-veratrylisoquinoline hydrochloride.

4. The compound of the group defined in claim 1 which is 3-ethoxy-6,7-dimethoxy-1-veratrylisoquinoline.

5. The compound of the group defined in claim 1 which is 3-ethoxy-6,7-dimethoxy-1-veratrylisoquinoline hydrochloride.

6. The compound of the group defined in claim 1 which is 3-benzyloxy-6,7-dimethoxy-1-veratrylisoquinoline.