IE870654L - Indole derivatives. - Google Patents

Description

b h !l O k.

The present invention is concerned with intermediates useful in syntheses of certain indole derivatives described and claimed in our Patent Specification No. 5(>$Ol . , hereinafter referred to as our "primary" 5 Application, from which the present Application has been divided. Our primary Application is concerned with certain heterocyclic carbon compounds of the indole series having an amino substituent, and with drug bio-affecting and body-treating processes employing 10 these compounds.

A rather large body of prior art exists relating to compounds of 3-(aryloxy)-2-hydroxypropylamine series which have beta-adrenergic receptor blocking activity and/or vasodilating properties and are useful in treat-15 ment of cardiovascular diseases. Much of this prior art concerns the beta-adrenergic blocking agent class of these series of compounds. The prototype for these structures is propranolol; chemically, 1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol. Propranolol and some re-20 lated naphthyloxy propanolamines are the subject of U.S. Patent No. 3,337,628 issued August 22, 1967. Numerous subsequent patents have been granted covering carbocyclic ethers in which other aromatic rings or heterocyclic systems replaced the naphthyloxy group of propranolol.

A series of patents has been granted to J. J. Baldwin disclosing the employment of the pyridinyloxy group in this fashion. These compounds and their salts are disclosed and claimed as useful antihypertensive agents. These patents, which are listed below, generally disclose the following gencric structure (1) R2^ H OR (1) 0 wherein R is alkyl, phenalkyl, phenoxyalkyl; R* is H, C-L, with L 0 being alkyl or aryl; is H, CN, CF^, OH, C-L, CI, NO^, F, pyrrolyl, oxadiazolyl.

The series of Baldwin patents, assigned to Merck & Co., Inc. comprise the following: 4,000,282, December 28, 1976; A,060,601, November 29, 1977; 4,091,104, May 23, 1978; 4,092,419, May 30, 1978; 4,144,343, March 13, 1979; 4,145,425, March 20, 1979; 4,151,284, April 24, 1979; 4,210,653, July 1, 1980; 4,259,327, March 31, 1981; 4,263,307, April 21, 1981; 4,279,913, July 21, 1981; and 4,329,351, May 11, 1982, A preferred compound of this series, 2-[3-(tert.-butylamino) 2-hydroxypropoxy]-3-cyanopyridine, also known as MK-761, has undergone considerable further study as described in: Sweet, et al., The Journal of Pharmacology and Experimental Therapeutics, 211/1, 195-296 (1979); Sweet., et al.. Clinical and Experimental Hypertension, 1(4), 449-471 (1979); and Vickers, et al., Drug Metabolism and Disposition, 8/3, 163-167 (1980). Acute studies in man were terminated, however, when MK-761 was found to be teratogenic in rabbits after chronic •] administration at high doses (cf: Journal of Medicinal Chemistry, 22/11, 1284-1290 (1979)).

CN MK-761 N'^0'X^]^s>JHC(CH3)3 "HC1 OH A series of indol-3-yl-tert.butylaminopropanols (2,3) with antihypertensive properties was described in: Kreighbaum, et al., U.S. Patenc No. 4,234,595 patented November 18, 1980; U.S. Patent No. 4,314,943 patented February 9, 1982; and Journal of Medicinal Chemistry, 23:3, 285-289 (1980). ■'-to o- Ar-Xn K1 \r2 OH (2) Vh r3 nr °-Ar-Het OH i1 (3) A preferred compound of the series represented by structure (2) is designated MJ 13105, also known as bucindolol, and is currently undergoing evaluation clinically as an antihypertensive agent.

CN Xs-— T " OH H mj 13105 Out primary Patent Concerns vasodilators having a range of beta-adrenergic blocking potency and possessing the general formula I and the pharmaceuticals acceptable acid addition salts thereof.

(I) In the foregoing structural formula, X is CHO, CH^OH, CN, CF^, CONR3^ or CO^R0 with Ra and R*5 being independently chosen from hydrogen or RC, and R° being lower alkyl, aryl, or arylalkyl; Y Is II,Oil, halogen, acyloxy, alkoxy, aralkyloxy, arylaxy, or COO(Cj_g alkyl); "o R is hydrogen or C-L with L being selected from alkyl, aryl, 1 2 substituted aryl, or arylalkyl; R , R , A and B are independently selected from hydrogen or alkyl; and C hydroxy, alkyl or alkoxy. is halogen, hydrogen, The number of carbon atoms signified herein by the word "lower" is 1 to 4.

For medicinal use, the pharmaceutical^ acceptable acid addition salts, those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, are preferred. The acid addition salts are obtained either by reaction of an organic base of structure I with an organic or inorganic acid, preferrably by contact in solution, or by any of the standard methods detailed in the literature and available to any practitioner skilled in the art. Examples of useful organic acids are carboxylic acids such as, for example, maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionlc acid, succinic acid, pamoic acid, cyclamic acid and pivalic acid; useful inorganic acids are for example, hydrohalide acids such as HCl, HBr, HI; sulfuric acid and phosphoric acid.

The compounds of the primary Patent include all the optical isomer forms, that Is, mixtures of enanticsners, e.g., racemic modifications as well as the 7 individual enantiomers. These individual enantiomers are commonly designated according to the optical rotation they effect, by (+) and (-), (1) and (d), or combinations of these symbols. The symbols (L) and (D) and the symbols 5 (S) and (R), which stand for sinister and rectus res pectively, designate an absolute spatial configuration of the enantiomcr. Where no isomer designation is given for a compound, the compound is the racemic modification.

The compounds of the primary Patent are preferably 10 prepared by coupling a Z-substituted pyridine (IV) with a suitable W-substituted propanol intermediate (II), as follows (IV) In the foregoing scheme, roxyl and is hydroxyl when Z is halogen. Generally, the hydroxyl-bcaring reactant is initially converted to the oxide anion with a strong base prior to reaction with the halogen-bearing intermediate. 8 The present invention, in a first aspect thereof, consists in the provision of compounds having the above-mentioned formula IIB. The structure of a compound of formula IIB having w = OH will be more 5 readily appreciated from the following scheme for a "Reaction 1", which also shows more fully the utilization of this compound of formula IIB for the nrcixiration of a compound of formula I.

Reaction 1 12 c ^ B B (IIB) (I) 1 2 In the foregoing scheme, X, Y, R, R , R , A, B, and C are as defined in Formula I. Essentially this process Involves heating the selected substituted halopyridine with the appropriate indolylalkylasnino-propanol intermediate (IIB) in the presence of a base, all in an 15 inert organic liquid under mild conditions. Standard strong bases such as potassium t-butoxide, potassium hydroxide, or sodium hydride may be employed but the sodium hydride is preferred. Similarly, any of a number of inert organic liquids may be chosen as the reaction medium or the cyanopyvidine and indolylalkylaminopTopanol may be reacted neat in the presence of the base. Suitable solvents Include bat are not limited to, for example, benzene, toluene, tetrahydrofuran, di- butylether and dimethoxyethane. Suitable reaction tenperatures are frcai about -80°C. Addition of a suitable crown ether, such as 18-crown-b ether, aids the reaction process.

Formula I products in which Y and/or C are hydroxy, are prepared by cleavage of the corresponding methoxy precursor as shown in Reaction 2: Reaction 2 OR B , B Other synthetic methods resulting in conversion to hydroxylated products, e.g. such as hydrogenolysis of benzyloxy precursors, are well known to the chemical practitioner and may also he applied in these cases.

Requisite halopyridines are available commercially or may be prepared using standard methods for their preparation reported in the literature. Preparation of related trisubstituted pyridines is disclosed in U.S. 4,329,351, issued May 11, 1982 to Baldwin, et al.. Reference to U.S. 4,329,351 is particularly recommended.

According to a second aspect of the present invention, there is provided a process for preparing a compound having the above-mentioned formula IIB o H N - G wherein W is a hydroxyl group; wherein R is hydrogen; and wherein G is as defined earlier herein; said process comprising: reacting a compound of the formula III shown in the following "Reaction 3" scheme with 3-chloro-l,2-propanediol in refluxing alcohol and a base which is preferably sodium carbonate Reaction 3 Base Alcohol HO' (iii) (IIB) A, B, and C are as defined In reaction scheme 3, R , in Formula I.

The indolylalkylamines (III) are described in the aforementioned Kreighbaum, et al. patents and Journal of Medicinal Chemistry article, consultation of these texts being recommended, as also certain references cited therein. Although these referenced procedures are applicable to the preparation of other indolylalkylamine intermediates not specifically disclosed therein but which are required as intermediates for the present invention, renrcsent-:tive syntheses of Formula III compounds are given yereinbelow for further exemplification.

The present invention will be understood more fully from 5 ; consideration of the following examples and appended claims which are f.iven for the purpose of Illustration only and are not to be construed as limiting the invention in sphere or scope. In the following examples, used to illustrate the foregoing synthetic processes, temperatures are expressed in degrees Celsius (°) and melting points are uncorrected. 10 The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (6 expressed as parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the H NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the 15 molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m), or doublet (d).

Abbreviations employed are DMSO-d^ (deuterodiroethylsulfoxide), (dcuterochloroform) and are otherwise conventional. The infrared (1R) spectra] descriptions include only absorption wave numbers (cm *) having functional group identification value. The IR determinations were employed using potassium bromide (KBr) as diluent. The elemental analyses are reported as percent by weight.

Synthesis of Intermediates A. Intermediates of Formula III EXAMPLE 1 3-(2-Amino-2-methylpropyl)-6-methoxyindole (R = R = Me, A and B - H, C - 6-MeO) To 15.2 mL of a chilled 25% aqueous solution of dimethyl-araine the following were added sequentially with stirring and continued cooling: 16.9 mL of acetic acid, 7.2 mL of 37% formaldehyde, 27 mL of 95% ethanol. The resulting stirred solution was kept at 0° to -5° with a cooling bath while 6-methoxyindole (10.0 g, 0.07 mole) was added in portions. This mixture was stirred and gradually warmed to 30° over a period of one-half hour and then held at 30° with stirring for 3 hrs. The reaction mixture was then chilled to 10-15° and acidified with 170 mL of 2N HCl. This acidic mixture was decolorized (Darco^G-SO), filtered and the filtrate made basic using 245 mL of 20% NaOH while being cooled and stirred. A resulting brown oily precipitate was ether extracted, and the extracts were water-washed, dried (MgSO^) and concentrated to a brown oily residue (14 g). The residue was recrystallized from isopropylether and hexane to yield 9 g (65%) of 6-methoxygramine as a tan solid, m.p. 88-90°.

* Trade Mark A mixture comprised of the 6-roethoxygramine (7.7 g, 0.04 mole), 2-nitropropane (26.5 g, 0.3 mole), and NaOH (1.7 g pellets, 0.04 mole) was refluxed under a nitrogen atmosphere for 3-5 hrs. The reaction mixture was cooled to room temperature, acidified with 10% acetic acid and extracted with ether. The ether extracts were water-washed, dried (MgSO^), and concentrated in vacuo to a residue. Recrystallization of the residue from isopropyl alcohol-water gave 7.6 g (80%) of 3-(2-methyl-2-nitropropyl)-6-methoxyindole as a tan solid,' m.p. 98-100°.

The nitropropylindole compound and activated Rancy nickel (4.2 g) were combined in 80 mL 95% ethanol and heated to reflux. Heating was halted as a solution comprised of 85% hydrazine hydrate (7.8 g) in 8 mL 95% ethanol was added dropwise. The reaction mixture was then heated at reflux for 2 hrs, cooled to room temperature and filtered. The filtrate was concentrated to a residual oil which slowly solidified and was recrystallized from ethyl acetate-isopropyl ether to give 4.2 g of product, m.p. 125-128°.

EXAMPLE 2 2-(2-Amino-2-methylpropyl)indole (R - R = Me, A, B, and C - H) A solution comprising indole-2-carboxylic acid (10.0 g, 0.06 mole) and thionyl chloride (20.0 g, 0.17 mole) in 130 mL of dry Et^O was stirred for 12-18 hrs at room temperature under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated to an oily residue which was taken up in 150 mL of dry Et^O. This ether solution was treated with 80 mL of dimethylamine in 90 mL of Et^O, The ethereal reaction mixture was concentrated to dryness and the Residue crystallized in isopropyl alcohol. The solid was isolated by filtration to give 4.0 g (34%) of the 2-indolylamide product, m.p. 181-183°.

The amide was dissolved in 100 mL THF and this solution was added dropwise to a stirred suspension comprised of 3 g lithium aluminum hydride in 50 mL of THF under a nitrogen atmosphere. After heat at reflux for 2 hr, the reaction mixture was cooled and decomposed with a small amount of water and dilute NaOH solution. This mixture was filtered and the filtrate concentrated to a residual oil which was taken up in absolute ethanol and treated with a slight excess of dimethyl sulfate. The resulting alcoholic solution was stirred at room temperature for 4 hrs and then concentrated Ijn vacuo to dryness giving as residue the trimethylamine quaternary salt.

The crude quaternary salt product (3.0 g, 0.01 mole) was combined with NaOH (2.0 g pellets, 0.05 mole) and 2-nitropropane (15 mL) and the mixture was heated at reflux under a nitrogen atmosphere for 1 hr. The resultant dark thick mixture was cooled, diluted with water, acidified with acetic acid to a pH of approximately 6 and then extracted with Et 0, These Et^O extracts were combined, washed with water, dried (MgSQ^) and concentrated to a dark residue which was chromatography on a silica column and diluted with methylene chloride. Removal of the methylene chloride and recrystallization of the crude material from isopropyl alcohol-water gave 0.4 g of 2-(2-methyl-2-nitropropyl)indole as a cream colored solid, m.p. 102-103°.

Reduction of this nitro product with Raney nickel and hydrazine according to the procedure used in Example 1 above yields the desired indolalkylamine as a white solid, m.p. 130-133°.

Additional examples of indolealkylamines are displayed in Table 1.

Table 1 1ndolea1kylamincs 1 0 Example 3 4 6 7 8 9 11 12 Me Me Me Me H H H Me Me Me h2N H Me Me Me Me Me Me Me H H SN' f B (111) 3-H 2-Me 2-H 2-H 2-H 2-Me 3-Me 2-H 2-Et 2-H Me H H H H Me Me n H H H H -Br -OMt H -OPr -Br 6-ONe h-CI 7-OMe B. Intermediates of Formula IIB EXAMPLE 13 3-[ [ 2-(3-IndoJ yl)-l, 1-dimet hyletliyl J amino]-!,2-propanedloI Hydrate (IIB) A mixture of a,a-dimethyl-f!-(3-indolyl)ethanamine (10.0 f>, 0.05 mole), Nn^CO^ (11.3 g, 0.11 mole), 3-chloro-l,2-propanediol (7.0 g, 0.06 mole) and EtOH (250 mL) was stirred overnight at reflux.

After cooling, the mixture was filtered and concentrated 2" vacuo.

The residue was dissolved in EtOAc, decolorized (Darco C-60), and evaporated to a volume of 100 mL. The solution deposited a white solid which was recrystallized from EtOAc to give 7.7 g (55%), m.p. 112-114°c. The material crystallized with one-fifth mole of water.

Using other intermediates of Formula III in this or a similar procedure readily gives a variety of Formula IIB intermediates.

The following abbreviations used herein have the following meanings: Ph stands for a phenyl group, Pr stands for a propyl group, Me stands for methyl group, and Et stands for an ethyl group.

Additionally, an accepted convention in modern organic chemistry has been used throughout. For alkyl structures, in a shorthand form, joined line sigments substitute for explicit notation of C and H groups. Thus, for example, formula I can also be written: CH. CH 2"s. / 2 OR 1 3

Claims (5)

CLAIMS:

1. A compound having the formula IIB IIB wherein W is a halogen or hydroxyl group; wherein R is hydrogen or ' with L being selected from alkyl, aryl, substituted aryl, or arylalkyl; and wherein G is the radical A 1 2 with R , R , A, and B being independently chosen from 10 hydrogen or alkyl and with C being hydrogen, halogen, alkyl, alkoxy, or hydroxy.

2. A process for preparing a compound having the formula IIB 15 wherein W is a hydroxyl group; wherein R is hydrogen; and wherein G is the radical ,2 „ ,C : ft 1 2 with R , R , A, and B being independently chosen from hydrogen or alkyl and with C being hydrogen, halogen, alkyl, alkoxy, or hydroxy; said process comprising: reacting a compound of formula III 1 2 wherein A, B, R , R , and C are as defined above, with 3-chloro-l,2-propanediol in refluxing alcohol and a base.

3. A process according to claim 2, wherein the base is sodium carbonate.

4. JO 4. A process as claimed in claim 2, substantially as described in Examples 1-13.

5. A compound as claimed in claim 1, prepared by a process as claimed in any one of claims 2-4. Dated this the12thday of March , 1957. F. R. KELLY & CO. BY = Q,iA/t e EXECUTIVE 27 Clyde Road, Ballsbridge, Dublin 4 AGENTS FOR THE APPLICANTS.