US3892730A - 1{40 -({62 -hydroxyethyl)-1{40 -demethyl clindamycin 2-acylates - Google Patents

Abstract

1''-( Beta -Hydroxyethyl)-1''-demethylclindamycin 2-acylate compounds of the formula:

OR THE ACID ADDITION SALTS THEREOF WHEREIN Halo is chlorine, bromine, or iodine, X is an acyl radical of an aliphatic carboxylic acid having from 2 to 18 carbon atoms, inclusive; R is alkyl of not more than 4 carbon atoms; and R1 is alkyl of not more than 8 carbon atoms. The compounds have clindamycin-like antibacterial activity and provide particularly high concentrations of compound in the urinary tract thereby being particularly useful in treating bacterial infections of the upper and lower urinary tract as well as L-forms in the kidney.

Description

United States Patent [191 Birkenmeyer 1'-( B-HYDROXYETHYL)-l -DEMETHYL CLINDAMYCIN Z-ACYLATES [75] Inventor: Robert D. Birkenmeyer, Galesburg,

Mich.

[63] Continuation-in-part of Ser. No. l56,099, June 23,

1971, Pat. No. 3,787,390.

[52] US. Cl. 260/210 R; 424/180 [51] Int. Cl C08b 19/00 [58] Field of Search 260/210 R [56] References Cited UNITED STATES PATENTS 3,580,904 5/1971 Morozowich et al. 260/210 R Primary Examiner.lohnnie R. Brown Attorney, Agent, or FirmJohn J. Killinger; Roman Saliwanchik [57] ABSTRACT I '-(B-Hydroxyethyl )-l -demethylclindamycin 2- acylate compounds of the formula:

[ July 1,1975

(IIH CH OH a N H Hal 0 I CN R1 ll 0 or the acid addition salts thereof wherein Halo is chlorine, bromine, or iodine, X is an acyl radical of an ali phatic carboxylic acid having from 2 to 18 carbon atoms, inclusive; R is alkyl of not more than 4 carbon atoms; and R is alkyl of not more than 8 carbon atoms.

The compounds have clindamycin-like antibacterial activity and provide particularly high concentrations of compound in the urinary tract thereby being particularly useful in treating bacterial infections of the upper and lower urinary tract as well as L-forms in the kidney.

3 Claims, No Drawings 1 -(B-HYDROXYETHYL)-l -DEMETHYL CLINDAMYCIN Z-ACYLATES CROSS REFERENCE TO RELATED APPLICATIONS BRIEF SUMMARY OF THE INVENTION This invention relates to novel compounds and is particularly directed to l'-(Bhydroxyethyl)-l -demethylclindamycin Z-acylates. wherein the acylates are the acyl moiety of an aliphatic carboxylic acid having from 2 to 18 carbon atoms. inclusive. These compounds in addition to having the antibacterial spectrum of clindamycin have been found to provide extremely high concentrations of the compound in the urinary tract subsequent to oral or parenteral administration. The compounds are useful in treating infections in the upper and lower urinary tract as well as for treating L-forms in the kidneyv The novel compounds of the invention can-be represented by the following structural formula:

or the acid addition salts thereof wherein Halo is chlorine. bromine. or iodine; X is an acyl radical of an aliphatic acid having from 2 to 18 carbon atoms. inclusive; R is alkyl of not more than 4 carbon atoms; and R, is alkyl of not more than 8 carbon atoms.

Examples of alkyl of not more than 8 carbon atoms (R1) are methyl. ethyl. propyl. butyl. pentyl. hexyl. heptyl. octyl and the isomeric forms thereof.

Examples of aliphatic carboxylic acids providing the acyl moiety are the saturated and unsaturated. straight or branched chain aliphatic carboxylic acids. for example. acetic. propionic. butyric. isobutyric. tertbutylacetic. valeric. isovaleric. caproic. caprylic. decanoic. dodecanoic. lauric. tridecoic. myristic. pen tadecanoic, palmitic. margaric. stearic. undecylenic. oleic. hexynoic. heptynoic. and octynoic acids and the like.

The starting materials for the preparation of the novel compounds of the present invention are compounds of the formula I wherein X is hydrogen. The compounds are disclosed and can be prepared by methods set forth in U.S. Pat. application Ser. No. 156.099. filed June 23, 1971. now allowed.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are prepared by the following steps starting with a compound of the Formula I wherein X is hydrogen:

1. Protecting the 3- and 4-hydroxy groups by forma tion of a 3.4-alkylidene or arylidene.

II. Protecting the primary hydroxy by (A) tritylation or (B) silylation or (C) formation of a tetrahydropyranyl ether.

Ill. Acylation. and

IV. Removal of the protection groups put on in steps I and II.

STEP I To protect the 3.4-hydroxy groups. a compound of the Formula I wherein X is hydrogen. advantageously as the hydrochloride salt. is first condensed with an alkyl or aryl aldehyde or ketone. with the aid of mild heat. to form the 3.4-0-alkylidene or 3.4-0-arylidene. Acid catalysis of-the reaction is unnecessary if the hydrochloride salt is used as this provides sufficient catalysis of the reaction. The reaction can be forced to completion through azeotropic removal of water by an organic solvent. for example. benzene. toluene. chloroform. ethylene chloride. and the like. The azeotropeforming solvent can be eliminated if water is removed by some other means. such as by evacuation. vaporization with an inert gas. or merely by co-distillation with a solvent which has a higher boiling point than water. The azeotrope-forming solvent is used in admixture with a highly polar solvent. such as N.N-dimethylformamide. N.N-dimethylacetamide. dimethylsulfoxide. N-methyl pyrrolidone. and the like. in order to solubilize the starting compound hydrochloride and thus pro duce a homogeneous solution.

The condensation reaction can be conducted between temperatures of about 15 to 180C; the preferred temperatures being about l55() for alkylidene and l 10C. for arylidene. The optimum temperature depends on the ratio of polar to non-polar solvent. and on the specific properties of the non-polar solvent. such as the boiling temperature of the azeotrope formed with water as well as the boiling point of the non-polar solvent itself according to the art. The nonpolar solvent containing moisture can be continuously removed by distillation and replaced periodically with fresh. dry solvent. The water also can be removed by condensation and separation with a water trap. or a dessicant can be used. thus permitting the dried solvent to return to the reaction vessel.

The time for complete condensation as disclosed. above. varies with the solvent composition and the efficiency of removal of the water. When azeotropeforming solvents are used. as described above. the course of the reaction can be followed by measuring the amount of water liberated. Alternatively. the reaction vessel can be sampled periodically and chromatographed. With solvent combinations of benzene and dimethylformamide. reaction times of about I-l 6 hours can be used. with 23 hours usually being optimum. Typical alkyl ketones useful in the process are acetone. diethyl ketone. methylbutyl ketone. and the like. A variety of aromatic aldehydes can also be used in the process of the invention. for example. furfural. 5- methylfurfural. benzaldehyde. salicylaldehyde. mtolualdehyde. o-tolualdehyde. p-tolualdehyde. o-

3 chlorobenzaldehyde. m-chlorobenzaldehyde. mbromobenzaldehyde. p-bromobenzaldehyde. pmethoxybenzaldehyde, m-methoxybenzaldehyde. o-

methoxybenzaldehyde. 3.4-dimethoxybenzaldehyde (veratric aldehyde). p-isopropylbenzaldehyde. salicy- Ialdehyde. p-hydroxybenzaldehyde. 3.4.5-trimethoxybenzaldehyde. piperonal. o-nitrobenzaldehyde. pchlorobenzaldehyde. phthaldehyde. mnitrobenzaldehyde. p-nitrobenzaldehyde. B-naphthaldehyde. p-bromobenzaldehyde. o-

bromobenzaldehyde. 2.4-dichlorobenzaldehyde. vanillin. terephthaldehyde. protocatechualdehyde. and cinnamaldehyde.

Also useful are aldehydes in which the carbonyl group is separated from the aromatic moiety by one or more double bonds giving a conjugated structure of:

wherein n can be an integer of from l-4. and Z can be one of the following substituents on the aromatic moiety:

The acetals formed by the above-disclosed process are initially isolated as crystalline hydrochloride salts. With stable acetals. for example. the 3.4benzylidene derivatives. and 3.4-p-chlorobenzylidene derivatives. recrystallization of the hydrochlorides can be brought about with hot Methyl Cellosolve. dimethylformamide. chloroform. and the like. The less stable acetals. for example. 3.4-p-anisylidene derivative. 3.4- cinnamylidene. and 3.4-toluylidene derivative must be converted to the free base form before isolation of the acetal.

The 3.4-protected. e.g.. arylidene. hydrochloride salts can be converted to the free base by mixing the salts with a basic material. for example. aqueous sodium hydroxide. a quaternary ammonium hydroxide. ammonium hydroxide, or a strong amine base. Basic ion exchange resin can be used. The insoluble arylidene base can be removed by filtration. or it can be extracted with water-immiscible solvents. for example. chloroform. methylene chloride. ethylene dichloride. ether and the like. Alternatively. the 3.4-protected hydrochloride salts can be converted to the free bases by first neutralizing the salt with a base after placing the salt in solution in a solvent such as dimethylformamide. dimethylacetamide. propylene glycol. and the like. The base can be an alkoxide. an amine. ammonia. or a solid inorganic base. for example. sodium hydroxide. potassium hydroxide. and the like. The resulting solutions of the base can be recovered from water-miscible solvents by dilution with water to the cloud point resulting in slow crystallization of the acetals. The solutions of the base in water-immiscible solvents can be recovered by dilution of the solution with a nonpolar solvent, for example. hexane. isomeric hexanes. and the like. or by simply evaporating the solvent. The latter procedure for forming the free base from the 3.4-protected hydrochloride salts is suitable for isolating the very labile acetals since a nonaqueous procedure can be employed. Most of the 3.4-p rotected bases can be purifed by solution of the compound in acetone, diluting the solution with ether. and then adding hexane to the cloud point to induce spontaneous crystallization.

STEP IlA' Trityl ethers of the 3.4-O-protected derivatives are prepared by reacting an excess of trityl halide or substituted trityl halide with the 3.4-arylidene or alkylidene derivatives from Step I in the presence of a strong base and a suitable solvent. The preferred mole ratio of trityl halide or substituted trityl halide to the 3.4-arylidene or alkylidene compound is 4: 1. Higher ratios of tritylating agent to 3.4-protected compound can be used (up to about 10: l although increasing amounts of ditritylated byproducts are formed with a large excess of tritylating agent. Lower mole ratios of tritylating agent to 3.4-protected compound (below l:l result in an incomplete reaction. as well as formation of additional unidentified by-products.

The preferred trityl halide in the above reaction is trityl chloride. However. other trityl halides and substituted trityl halides of the following formula can be used:

wherein Y is selected from the group consisting of Cl and Br and X X and X;; are selected from the group consisting of hydrogen. halogen. and OCH The compounds of the type in which the substituents X X and X: are mono. di-. or tri-para-chloro may be made by the methods reported by Gomberg [Ber. 37. I633 (1904)]. The corresponding compounds in which X X and X1. are para-methoxy may be prepared by the methods described by Smith. ct al.. and references therein [1. Am. Chem. Soc.. 84. 430 1962). see page 436]. i

The preferred solvent for the tritylation is acetone.

Other solvents which can be used'are Z-butanone, 2-

pentanone, 3-pentanone, ether, benzene. N,N-dimethylformamide, N.N-dimethylacetamide, dimethylsulfoxide, methyl acetate. ethyl acetate. pyridine. and the like. Use of the higher boiling polar solvents, however, tends to result in the production of additional byproducts from the reaction. whereas the lower boiling solvents do not permit a complete reaction. 7

The preferred base is triethylamine. Other strongly basic trialkyl amines can be used, for example. triethylenediamine. N-alkylmorpholine derivatives. tripropylamine, tributylamine. and the like. Tertiary bases having a pKa greater than 8 permit a more rapid reaction since better solubility of the 3,4-protected starting compounds is' maintained. Weaker bases, such as pyridine. require longer reaction times since 3,4-protected starting compounds are largely insolubilized as the hydrochloride salt in the presence of such a base.

The r'eaction'time is determined by several factors, for example. the boiling point of the solvent. the strength of the base, the concentration and ratio of trityl halide to 3,4-p'rotected compound. and the polarity of the solvent. For example, with the following mole ratio-oftrityl chloride to anisyliden'e derivative to triethylamin'e to acetone of 72:15:16i34, the preferred reaction time at reflux temperature is 24 hours. Reaction times up to 48 hours can be used although increasing amounts of di-tritylated derivatives are formed. Reaction times less than six hours result in appreciable amounts of unchanged anisylidene derivatives. With other mole ratios. the operating reaction time can range from 1 to 100 hours. The course of the reaction can be monitored by paper chromatography or thin layer chromatography (tlc) according to the art.

Upon completion of the tritylation reaction. the l- (trityloxyethyl)-3,4-protected derivative is precipitated by the addition of a non-polar solvent such as hexane, heptane, pentane, cyclohexane, benzene, and the like. The crude reaction product is recrystallized repeatedly from hot acetonitrile and finally from. hot acetonewater (1:1) mixture to provide a pure preparation of the derivative. Other organic solvents can be used for recrystallization. for example. Z-butanone, 3- pentanone, n-propanol, Z-propanol, butyl acetate, benzene, butyronitrile, N.N-dimethylformamide water, N.N-dimethylacetamide-water, methanol-water, ethanolwater, and the like.

STEP lIB Alternatively. the primary hydroxyl of the hydroxyethyl group on the pyrrolidine nitrogen atom may be protected before acylation (STEP III) by silylation, for instance with a trimethylsilyl group, according to the art. The silylation is carried out by reacting the 3.4- protected compound with a silylating agent in a suit able solvent. A typical procedure is to react the 3,4- protected compound with excess hexamethylsilazane (a bifunctional silylating agent) with trimethylchlorosilane as a catalyst, in pyridine solution. The reaction .occurs readily at ambient temperature and results in the formation of a trimethylsilyl-protected derivative. Other operable silylating agents, according to the art. include for example diorganomonochlorosilanes such as diphenylmonochlorosilane. dibenzylmonochlorosi lane and methylphenylmonochlorosilane as in British Patent 822,970, referred to in Chemical Abstracts 44,

658 1950); and other trisubstituted chlorsilanes [Cram and Hammond, Organic Chemistry page 257 (I959); Sneed and Brasted. Comprehensive Inorg. Chem. 7, Ill (1958); Roberts and Caserio. Basic Principles ofOrg. Chem, page 1,182 1964)] from trimethylto tribenzylchlorosilanes. An alternative suitable solvent is piperidine/For purification of the silyl ethers the reaction mixture is evaporated to dryness under vacuum, taken up in chloroform, washed with water. filtered through silica gel and evaporated. Other purification according to the art is also possible. and upon completion of 2-acylation according to Step Ill. the l-protective silyl group is removed simultaneously with the 3,4 -protective group by acid hydrolysis. for example by treatment with acetic acid-water as given below.

STEP "C A third method for protecting the primary hydroxyl of the hydroxyethyl group on the pyrrolidine nitrogen atom is by reacting with dihydropyran to form a tetrahydropyranyl ether.

The reaction is carried out at room temperature in an inert solvent such as diethyl ether with a few drops of concentrated hydrochloric acid as a catalyst. After stirring for several hours the acid is neutralized with sodium hydroxide and the solvent evaporated under vacuum. The solid residue may be purified by crystallization or chromatography but is usually pure enough to use in the following step without further treatment.

The 3.4-protected clindamycin compounds can be acylated by processes already well known in the art. for example. by reacting with an acylating agent in the presence of an acid-binding agent. for example. a tertiary amine. to produce a 3,4-protected Z-acylate. Suitable acylating agents include acid halides and acid anhydrides. Suitable tertiary amines include heterocyclic amines such as pyridine. quinoline. and isoquinoline; trialkylamines such as trimethylamine, triethylamine. triisopropylamine. and the like; N.N-dialkylanilines such as dimethylaniline. diethylaniline. and the like; and N-alkylpiperidines such as N-ethylpiperidine. N- methylpiperidine. and the like. The preferred base is pyridine.

The acylation is advantageously conducted by treating a solution of a 3.4-protected clindamycin compound or a suspension of the hydrochloride in a mixture of an inert solvent and a tertiary amine, for example, pyridine, with an acylating agent. for example, acyl chloride, and cooling the reaction mixture to prevent side reactions. Advantageously, the reaction is conducted in pyridine at low temperature, preferably 20 to C., however higher or lower temperatures can be used. Suitable inert solvents include chloroform. dimethylformamide, dimethylacetamide, acetonitrile. methylene chloride. acetone, and dioxane.

STEP IV The protective groups can be removed by hydrolysis. preferably, a mild acid hydrolysis. For example, protected Z-acylates on being heated with 80 percent acetic acid at C. for 10 to 15 min. yield the corresponding l '-(,B-hydroxyethyl)-l -demethylclindamycin 2-acylate compounds. Acids such as formic, propionic. dilute hydrochloric and dilute sulfuric can also be used.

The desired Z-acylate can be isolated from the reaction mixture by various techniques well known in the art. The 2-acylates so prepared are easily isolated as the hydrochloride salt by precipitation with anon-solvent such as acetone or ether. The compounds are usually isolated in a pure state by this method although if necessary recrystallization may be achieved from water or acetone plus a small amount of water.

The following examples are illustrative ofthe process and products of the present invention but are not to be construed as limiting.

EXAMPLE 1 l-Demethyl-l -(B-hydroxyethyl)-3.4-isopropylidineclindamycin One hundred grams of l-demethyl-l '-([3- hydroxyethyl)-clindamycin. 100 g. of p-toluenesulfonic acid hydrate and 6 L. of acetone are stirred at 25 for 60 hours. The unreacted starting material is removed by filtration and the filtrate adjusted to pH 7 with NaHCQ, solution. The acetone is removed under vacuum and the aqueous phase extracted with CHCL,. The CHCL; extracts are evaporated under vacuum to give a residue which is purified by chromatography over silica gel using a solvent system composed of CHCl,,:MeOH (6:1). The product fractions are identified by tlc. combined and evaporated to give 34 g. of l-demethyl-l (B-hydroxyethyl)-3.4-isopropylidineclindamycin in 31% yield.

EXAMPLE I 1 l'-Demethyl-l '-(trityloxyethyl )-3.4-isopropylidineclindamycin A mixture of 34 g. of l-demethyl-l'-(/3- hydroxyethyl)-3.4-isopropylidineclindamycin. l g. of chlorotriphenylmethane. l l. of acetone and 200 ml.

of triethylamine is heated at reflux for 4 hours. Skel- EXAMPLE III I -Demethyl-l '-(/3-hydroxyethyl)clindamycin-2- palmitate HCl Hydrate A solution of 6.0 g. of l-demethyl-l (trityloxyethyl )-3.4-isopropylidineclindamycin. l ml. of methylene chloride and 0.6 ml. of pyridine is stirred at 5 and 5.0 g. of palmitoyl chloride added. The reaction mixture is stirred at for 18 hours. Ethanol (50 ml.) is then added. the reaction mixture stirred for minutes and evaporated to dryness under vacuum. The residue is dissolved in a mixture of 60 ml. of HOAc and 10 ml. of H 0 and heated at 95 for 30 minutes. Water (60 ml.) is then added and the reaction mixture allowed to stand at 25 for l hour before filtering and discarding the solid material. The filtrate is evaporated to dryness under vacuum and the residue partitioned between dilute NaHCO=; and CHCl The CHCL, phase is evaporated to dryness under vacuum and the residue purified by chromatography over silica gel using a solvent system composed of CHCl;,:MeOH (6:1 The product fractions are identified by tlc. combined and evaporated to dryness under vacuum to give the desired product in the form of the free base. This material is converted to its HCl salt. decolorized with Darco 0-60 in MeOH. filtered and evaporated under vacuum to give 2.0 g. of the final product. l'-demethyl-l -(B- hydroxyethyl)clindamycin 2-palmitate HCl hydrate, as a waxy solid in 35 percent yield.

Analysis C. 57.59; H. 9.1]; N. 3.84; S. 4.39; Cl. 9.72. Found (Corrected for H O):

C. 57.97; H. 9.29; N, 3.79; S, 4.39; Cl, 9.70. [ah/ O +79(.c. 0.8890).

The compounds of the Formula I have clindamycinlikc antibacterial activity. i.e., similar spectrum, but unexpectedly show a high concentration in the urinary tract. i.e., the kidney and upper and lower urinary tract thereby providing an effective treatment for bacterial infections of the upper and lower urinary tract as well as treatment of L-forms or mycoplasma in the kidney.

The compounds can be admininstered both orally and parenterally and are particularly advantageous for oral administration for reasons of taste.

Urinary tract infections such as cystitis. pyelonephritis and pyelitis when due to causative organisms. such as E. (o/i. S. Aureus. enterococci and strains of Klebsiella. Aerobacter. Proteus and Pseudomanas.

The dosage in unesterified free base equivalents for such treatment can be from mg. to 300 mg. daily or calculated on a weight basis from 1 mg./kg. to 4 mg./kg. body weight daily.

I claim:

1. A compound of the formula:

or the acid addition salts thereof wherein Halo is chlorine. bromine. or iodine. X is an acyl radical of an aliphatic carboxylic acid having from 2 to 18 carbon atoms. inclusive; R is alkyl of not more than 4 carbon atoms; and R is alkyl of not more than 8 carbons.

2. A compound of claim 1 wherein R, is trans-propyl. R is methyl. Halo is chlorine and X is palmitate. or the acid addition salts thereof.

3. A compound of claim 2 wherein the acid addition salt is the hydrochloride.

Claims (3)

1. A COMPOUND OF THE FORMULA:

2. A compound of claim 1 wherein R1 is trans-propyl, R is methyl, Halo is chlorine and X is palmitate, or the acid addition salts thereof.

3. A compound of claim 2 wherein the acid addition salt is the hydrochloride.