IL44636A - N substituted alkanesulfinamido-and alkanesulfonamido-alkanoic and 3-oxa-alkanoic acid derivatives their preparation and pharmaceutical compositions containing them - Google Patents

Description

N-Supstituted alkanesulfinamido- and alkanesulfonamiido- alkanoic and 3-oxa-alkanoic acid derivatives, their preparation and pharmaceutical compositions containing them MERCK & CO., INC.

C: 42517 This invention relates to N-substituted alkanesulfinamido- and alkanesulfonamido-alkanoic and ' -3-oxa-alkanoic acid derivatives and processes for their manufacture. These compounds have prostaglandin-like biological activity and are particularly useful as renal vasodilators, for the prevention of thrombus formation, to induce growth hormone release and for the treatment of certain autoimmune diseases. The invention also relates to pharmaceutical compositions comprising these novel compounds. The novel compounds provided by this invention can be represented by the following structural formula: wherein R s selected from the group consisting of carboxy and a carboxy salt which incorporates a pharmaceutically acceptable cation, such as metal cation derived from alkali metals, alkaline earth metals and amines such as ammonia, primary and secondary amines and quaternary ammonium hydroxides. Especially preferred metal cations are those derived from alkali metals, e.g., sodium, potassium, lithium, and- the like and alkaline earth metals, e.g., calcium, magnesium, and the like and other metals, i.e., aluminum, iron and zinc.

Pharmaceutically acceptable cations derived from primary, secondary, or tertiary amines, or quaternary ammonium hydroxides are methylamine, dimethylamine , trimethylamine , ethylamine, N-methylhexylamine , benzyl-amine, a-phenethylamine , ethylenediamine , piperidine, morpholine, pyrrolidine, 1 , -dimethylpiperazine , ethanol-amine, diethanolamine , triethanolamine , tris (hydroxymethyl) -aminomethane , -methylglucamine , N-methylglucosamine , ephedrine, procaine, tetramethylammonium hydroxide, tetra-ethylammonium hydroxide, benzyltrimethylammonium and the like .

R is also selected from alkoxycarbonyl (-COOY) wherein Y is alkyl having 1-10 carbon atoms, carbamoyl ( -COM^ ) and substituted carbamoyl 6 6 ( -COiJHR ) wherein R is dilower- alkylaminoalkyl having 4-7 carbon atoms.

A is selected from the group consisting of ethylene (-CH2CH2~) , trimethylene (-CH2CH2CH2-) , a-methyl-ethylene (-CH2-CH (CH..) -) , β-methylethylene (-CH (CH^) CH2~) , a ,a-dimethylethylene (-CH2~C (CH^) 2~) , β , β-dimethylethylene (-C(CH3) 2CH2~) and oxy ethylene (-O-CHj-) . (Note that when A consists of a two' carbon bridge, the term "a" refers to the carbon adjacent to R, while "β" refers to the other carbon atom. ) R^" is selected from the group consisting of methyl, ethyl, propyl and isopropyl.

Z is selected from the group consisting of ethylene (-CH2-CH2-) , vinylene (-CH=CH-) and ethynylene 2 (-OC-) . R is independently selected from the group consisting of hydrogen, methyl, ethyl or propyl.

R^ is selected from the group consisting of hydrogen and lower alkanoyl of 1-5 carbon atoms, e.g., for yl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, and the like. each R is independently selected from the group consisting of hydrogen and methyl. is selected from the group consisting of hydrogen, lower alkyl of 1-4 carbon atoms either straight or branched chain (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl) , vinyl and 2,2,2-trifluoroethyl.

In addition, R5 and R2 can form together an unbranched chain of the formula -(CH2)n wherein n is an integer from 1 to 5. y is 1 or 2.

A preferred embodiment of this invention relates to the N-substituted alkanesulfonamido-alkanoic and 3-oxa- alkanoic acids having the following general formula: R1-S02-N- (CH2 ) 4-A-COOH II H OH 1 4 9 wherein R , A, and R are as defined in formula I and R is lower alkyl of 1-4 carbon atoms. An even more preferred embodiment encompasses compounds of formula II, wherein R is methyl or ethyl; A is ethylene or oxymethylene; and R9 ferred embodiment includes compounds of formula II, wherein q R is joined to the carbon bearing Η,ΟΗ to form a carbocyclic ring with from 6 to 9 members.

It is to be noted that the carbon atom bearing 3 the OR group in formula I and the one bearing one hydroxyl group in formula II is asymmetric. This invention also covers stereoisomers in which the asymmetric center is exclusively in either one or the other of the two possible configurations, R and S.

BACKGROUND OF THE INVENTION; The compounds of formula I can be described as 8-aza-9-oxo(and dioxo) thia-(and 9-aza-10-oxo(and dioxo) thia)-ll, 12-secoprostaglondins because of their structural relationship to the naturally occurring prostaglandins.

The prostaglandins constitute a biologically prominent class of naturally occuring, highly functionalized" C2Q fatty acids which are anabolized readily in a diverse array of mammalian tissues from three essential fatty acids; namely, 8 , 11 , 14-eicosatrienoic acid, 5 , 8 , 11 , 14-eicosatetrae-noic acid and 5 , 8 , 11 ,14 , 17-eicosapentaenoic acid. Each known prostaglandin is a formal derivative of the parent compound, termed "prostanoic acid"; the latter is a C^Q fatty acid covalently bridged between carbons 8 and 12 such as to form a trans, vicinally-substituted cyclopentane in which the carboxy-bearing side chain is "alpha" or below the plane of the ring and the other side chain is "beta" or above the plane of the ring as depicted in formula III: 13 15 17 19 The six known primary prostaglandins, PGE PGE„, PGFia' PGF2a' and PGF3a' result;i-n9 directly from anabolism of the above cited essential fatty acids via the action of prostaglandin synthetase, as well as the tree prostaglandins resulting from in vivo dehydration of the PGE's, i.e., PGA.^, PGA2 , and PGA3 , are divided into three groups; namely, the PGE, PGF, and PGA series on the basis of three distinct cyclopentane nuclear sub-stitution patterns as illustrated as follows: PGE nucleus PGF nucleus PGA nucleus a It should be noted that the Arabic subscripts designate the number of carbon-carbon double bonds in the j designated compound and that the Greek subscript used in the PGF series designates the stereochemistry of the C-9 hydroxy1 group.

Although the prostaglandins were discovered y independently in the mid-1930' s by Goldblatt [J. Chem.

Soc. Chem. Ind. Lond. , 2_, 1056 (1933)] in England and Von Euler [Arch. Exp. Path. Pharmark. , 175, 78 (1934)] in Sweden, these complex natural products received little attention from the scientific community until the early 1960's which coincides with the advent of modern instru-mentation (e.g., mass spectrometry) which, in turn, was requisite for their successful isolation and structural elucidation by Bergstrom and colleagues [see Angew. Chem. Int. Ed. , 4_, 410 (1965) and references cited therein for an account of this work]. Within the last decade, a massive international scientific effort has been expended in developing both biosynthetic and chemical routes to the prostaglandins and, subsequently, in investigating of their biological activities. During this period, prostaglandins have been shown to occur extensively in low concentrations in a myriad of mammalian tissues where they are both rapidly anabolized and catabolized and to exhibit a vast spectrum of pharmacological activities including prominent roles in (a) functional hyperemia, (b) the inflammatory response, (c) the central nervous system, (d) transport of water and electrolytes, and (e) regulation of cyclic AMP. Further details concerning the prostaglandins can be found in recent reviews of their chemistry [J.E. Pike, Fortschr. .-am Chem. Org. Naturst. , 2_8, (1970) and G.F. Bundy, A. Rep. in Med. Chem., 7, 157 (1972)], biochemistry [J.W. Hinman, A. Rev. Biochem. , 4_1, 161 (1972)], physiological signficance [E.W. Horton, Physiol. Rev., £9, 122 (1969)] and general clinical application [J.W. Hinman, Postgrad. Med. J., 46, 562 (1970) ] .

The potential application of natural prostaglan-dins as medicinally useful therapeutic agents in various mammalian disease states is obvious but suffers from three formidable major disadvantages; namely, (a) prostaglandins are known to be rapidly metabolized in vivo in various mammalian tissues to a variety of metabolites which are devoid of the desired original biological activities, (b) the natural prostaglandins are inherently devoid of bio-logical specificity which is requisite for a successful drug, and (c) although limited quantities of prostaglandins are presently produced by both chemical and biochemical processes, their production cost is extremely high; and, consequently, their availability is quite restricted.

Our interest has, therefore, been to synthesize novel compounds structurally related to the natural prostaglandins but with the following unique advantages; (a) simplicity of synthesis leading to low cost of pro-duction; (b) specificity of biological activity which may be either of a prostaglandin-mimicking or prostaglandin-antagonizing type; (c) enhanced metabolic stability. The combination of these advantages serves to provide effective, orally and parenterally active therapeutic agents for the treatment of a variety of human and animal diseases. Inclu-ded are applications in renal, cardiovascular, gastrointes-^ tinal, respiratory, immune, and reproductive systems, and in the control of lipid metabolism, inflammation, blood clotting, skin diseases, and certain cancers.

More specifically, in the clinic, prostaglandin agonists can function as agents for improving renal function (e.g., renal vasodilation), anti-ulcer agents, agents for fertility control, antithrombotics, antiasthmatics, anti-lipolytics, antineoplastic agents, agents for the treatment of certain skin diseases, dwarfism (by inducing growth hormone release) and certain autoimmune diseases.

Prostaglandin antagonists can function as anti-inflammatory agents, anti-diarrheal agents, antipyretics, agents for prevention of premature labor, and agents for the treatment of headache.

The compounds of this invention are particularly useful for improving renal function, for the treatment of ulcers, and prevention of thrombus formation. It is emphasized that not all of these compounds possess each utility; however, each compound has been tested in a variety of assays and has shown activity in at least one area of activity.

The compounds of this invention can be adminis-tered either topically or systemically , i.e. , intravenously, subcutaneously, intramuscularly, orally, rectally, or by aerosolization in the form of sterile implants for long action. They can be formulated in any of a number of pharmaceutical compositions and non-toxic carriers to this end.

The pharmaceutical compositions can be sterile injectable suspensions or solutions, or solid orally administrable pharmaceutically acceptable tablets or capsules; the compositions can also be intended for sub-lingual administration, topical application, or for suppository use. It is especially advantageous to formu-late compositions in dosage unit forms for ease and economy of administration uniformity of dosage. "Dosage unit form" as a term used herein refers to physically discrete units suitable as unitary dosages for animal and human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired biological effect in association with the required pharmaceutical means.

Illustratively, a sterile injectable composition can be in the form of aqueous or oleagenous suspensions or solutions.

The sterile injectable composition can be aqueous or oleagenous suspension or solution. Suspensions contai dispersing and wetting agents and suspending agents. Solu-tions are similarly prepared from the salt form of the compound. For the laboratory animals, we prefer to use incomplete Freund's adjuvant or sterile saline (9%) as carrier. For human parenteral use, such as intramuscularly, intravenously, or by regional perfusion, the diluent can be a sterile aqueous vehicle containing a preservative; for example, methylparaben , propylparaben, phenol, and chloro-butanol. The aqueous vehicle can also contain sodium chlo-ride, preferably in an amount to be isotonic; as well as a suspending agent, for example, gum arabic, polyvinylpyrroli-done, methylcellulose , acetylated monglyceride (available commercially as Myvacet from Distillation Products Industry, a division of Eastman Kodak Company), monomethyl glyceride , -. dimethyl glyceride, Emulphor (available from Badische or a moderately high molecular weight polysorbitan (commercially available under the tradenames Tween or Span from Atlas Powder Company, Wilmington, Delaware) . Other materials employed in the preparation of chemotherapeutic compositions containing the compound may include glutathione, 1,2-propanediol, glycerol and glucose. Additionally, the pH of the composition is adjusted by use of an aqueous solution such as tris (hydroxy-methyl) aminomethane (tris buffer).

Oily pharmaceutical carriers can also be used, since they dissolve the compound and permit high doses.

Many oily carriers are commonly employed in pharmaceutical use, such as, for example, mineral oil, lard, cottonseed oil, peanut oil, sesame oil, or the like.

It is preferred to prepare the compositions, whether aqueous or oils , in a concentration in the range of from 2-50 mg./ml. Lower concentrations require need-less qualities of liquid. Higher concentrations than 50 mg./mg. are difficult to maintain and are preferably avoided.

Oral administration forms of the drug can also be prepared for laboratory animals or human patients provided that they are encapsulated for delivery in the gut. The drug is subject to enzymatic breakdown in the acid environment of the stomach. The same dosage levels can be used as for injectable forms; however, even higher levels can be used to compensate for biodegradation in the transport. Generally, a solid unit dosage form can be prepared containing from 0.5 mg. to 25 mg. active ingre-dient.

Whatever the mode of administration, doses in the range of about 0.10 to 20 mg./kg. of body weight administered one to four times per day are used. The exact dose depending on the age, weight, and condition of the patient, and the frequency and route of administra-tion.

The low cost and ready accessibility of the compounds of this invention make them particularly promis-ing for applications in veterinary medicine in which field their utilities are comparable to those in human medicine. PROCESSES TO PREPARE THE COMPOUNDS OF THIS INVENTION: The new chemical compounds with which this invention is concerned are prepared by the following two processes. The first process involves the reaction of a compound such as III with a compound such as IV, wherein A, 1 2 4 5 y, Z, R , R , R and R are as defined: R1-SOy-NH- (CH2) 4-A-COOR8 III IV g as in formula I above and R is loweralky1 having 1-5 carbon atoms, preferably ethyl; and X is halogen, e.g., chloro, bromo, or iodo. The reaction is carried out by preparing the alkali metal salt of III by reaction of III with sodium hydride in a solvent, such as a 1:1 mixture of benzene and dimethylformamide , adding compound IV at ambient temperature, then heating the reaction mixture at 50-100°Cy for from one to twenty hours. This reaction scheme affords intermediates represented by formula V: Mild basic hydrolysis (NaOH in aqueous methanol or ethanol) of the ester functions of compound V affords compounds of formula I, e.g., VI: VI In the second process a compound such as VII is caused to react with a compound of formula VIII, wherein 1 4 8 A, X, y, Z, R , R , and R are as defined as in formulas III and IV above, and THP is the 2-tetrahydropyranyl group. The reaction is carried R1-SOy-NH-CH2-Z-CH-C(R4)2CH2CH2R9 VII OTHP X- (CH2) 4-A-COOR8 VIII Q out by preparing the alkali metal salt of VII (wherein R is hydrogen, loweralky1 of 1-4 carbon atoms, or 2,2,2-trifluoroethyl) by reaction of VII with sodium hydride in a solvent such as 1:1 mixture of benzene and dimethylforma-mide, adding compound VIII at ambient temperature then heating the reaction at 50-100?C. for from 1-20 hours.

This reaction scheme affords intermediates represented by formula I OTHP Mild acid hydrolysis (aqueous HC1 in methanol or ethanol) removes the tetrahydropyranyl protecting group, then mild basic hydrolysis (NaOH in aqueous methanol or ethanol) of the ester function affords compounds of formula I, e.g., X: R-^SO -N- (CH_) „ -A-COOH X y - 2 4 4 a CH2-Z-CH-C(R )2CH2CH2R OH It is frequently advantageous from a therapeutic standpoint to prepare compounds of this invention (formula I) in which 3 the asymmetric carbon atom which bears OR is exclusively in the R or S configuration. It will be recalled that the corresponding center in the natural prostaglandins is in the S configuration; inversion of this center may or may not produce a reduction in biological activity, although a marked increase in biological specificity is often realized.

In the series of compounds of formula I according to the invention, compounds which are exclusively R or S at this center can be produced by employing preresolved compounds IV or VII and carrying out the steps of process 1 or 2. An example of the use of such a preresolved compound IV is given under the section "Preparation of Intermediates (Examples J and K) " .

DERIVATI ATION OF PRODUCTS: The directly obtained products of the processes described supra can be derivatized to yield the other products of formula I. 1. The fundamental processes yield compounds where R is carboxy. To obtain carboxy salts the acid products are dissolved in a solvent such as ethanol, methanol, glyme and the like and the solution treated with an appropriate alkali or alkaline earth hydroxide or alkoxide to yield the metal salt, or with an equivalent quantity of ammonia, amine or quaternary ammonium hydroxide to yield the amine salt. In each instance, the salt either separates from the solution and may be separated by filtra-tion or, when the salt is soluble it may be recovered by evaporation of the solvent. Aqueous solutions of the carboxylic acid salts can be prepared by treating an aqueous suspension of the carboxylic acid with an equivalent amount of an alkaline earth hydroxide or oxide, alkali metal hydroxide, carbonate or bicarbonate, ammonia, an amine or a quaternary ammonium hydroxide.

To obtain carboxy esters (i.e. , compounds where R is alkoxycarbonyl) the acid products are treated in ether with an ethereal solution of the appropriate diazoalkane.

For example, methyl esters are produced by reaction of the acid products with diazomethane . To obtain products where R is carbamoyl or substituted carbamoyl, the acid product is first converted to an active Woodward ester. For example, the acid product can be made to react with N-tert-butyl-5-methylisoxazolium perchlorate in acetonitrile in the presence 1 of a base such as triethylamine to yield an active ester 2 which R is 3 -C-0-C(CH3)=CH-NH-C-(CH3) 3· Active esters of this type 4 can be reacted with ammonia to yield products of formula I 5 where R is carbamoyl, with primary or secondary amines or 6 di-lower-alkylaminoalkylamines to yield products where 6 7 7 R is substituted carbamoyl, i.e., -CONR R , and with 8 hydrazine to yield products wherein R is carbazoyl. 9 2. The fundamental process yields products 3 10 where R is hydrogen. In compounds of formulas VI and X, 11 reaction with formic acid, acetic anhydride, propionic 12 anhydride, butyric anhydride, isobutyric anhydride, valeric 13 anhydride, pivalic anhydride, and the like, without solvent 14 and at temperatures from 25 to 60°C. , gives compounds 3 15 wherein R is formyl, acetyl, propionyl, butyryl , isobutyryl, 16 valeryl , and pivaloyl, respectively. 17 PREPARATION OF STARTING MATERIALS; 18 1. The reagent III which has the general formula 1 8 19 shown, wherein A, Y, R , and R are as defined previously, 20 is prepared in the following manner. The sodium salt of the 21 corresponding alkanesulfonamide or alkanesulfinamide is 22 treated with the appropriate halo compound (i.e., 23 X- (CH„) ,-A-COOR8) to give reagent III: The reagent IV A which has the following general /2? formula wherein X is halogen and R5 and R4 are as previously defined as prepared in the following manner. A Grignard reagent R5CH2CH2 (R4) 2C-MgI or R5CH2CH2 (R4) 2C-MgBr is allowed to react, in ether, with a nitrile X(CH2)3C . The resulting imine is hydrolyzed in aqueous acidic solution to give ketones of the formula XI: X(CH2)3C(=0)C(R4)2CH2CH2R5 XI The ketones (XI) are reduced to the corresponding alcohols 4 5 X(CH2) 3CH(OH)-C(R ) 2CH2CH2R with sodium or potassium borohydride in a suitable solvent such as methanol, ethanol, or diglyme. Acetylation of these alcohols, preferably with acetic anhydride, yields the reagents IV A.

By treatment of ketone XI with Grignard reagents 2 2 R MgBr(or I) where R is methyl, ethyl or propyl, compounds of formula X (CH2 ) 3C (R2) (OH) C (R4) 2CH2CH2R5 are obtained which upon acetylation with acetic anhydride in pyridine give compounds of formula IV B: IV B The reagents IV C which have the following general formula 2 4 wherein X, R and R are as defined previously and hydrogen, loweralkyl of 1-4 carbon atoms or 2 , 2 , 2-trifluoro-ethyl are prepared in the following manner. Acetylenic " " alcohols HC^C-C (R2) (OH) C (R4) 2CH2CH2R9 are treated with acetic anhydride to give the acetylated alcohols HC C-C(R2) (OCOCH3)C(R4) 2CH2CH2R9. Those compounds are treated with paraformaldehyde and diethylamine to afford the tertiary amines (C2H5) 2 -CH2C=C-C (R2) (OCOCH3) C (R4) 2CH2CH2R9 which when treated with cyanogen halide, e.g, bromide yield 2 the reagents IV C. The acetylenic alcohols HC=C-C (R )- 4 9 (OH)-C(R ) 2CH2CH2R intermediates for compounds of formula IV C are prepared by reaction of ethynylmagnesium bromide or lithium acetylide with aldehydes or ketones of the formula R9CH2CH2C(R4) 2C(R2)=0.

By using the resolved R and S forms of the HCHC-CH(OII)C(R4) 2CH2CH2R9 in the above scheme, the corres-ponding R and S forms of the reagent IV C can be obtained.

It should be noted here that the use of the R or S enantiomers of reagent IV C produce the R and S enantiomers, respectively, of compounds of formula VI A 1 2 4 9 wherein R , R , R , R , and Y are as defined previously and Z1 is -C-C-.

R1-SOy-N-(CH2) 4-A-COOH VI A CH _CH CH R9 These optically active products VI A can be hydrogenated over a platinum catalyst to give the R and S enantiomers of compounds of formula VI A where Z is ethylene -CH -CH - The reagent IV D which has the following general formula: X-CH2-CH=CH-CH-C(R4)2CH2CH2R9 IV D OCOCH3 4 9 wherein X, R and R are as defined above and are prepared 9 4 in the following manner. A Grignard reagent R CH2CH2C(R ) 2~ 9 4 MgBr or R CH2CH2C(R ) 2 gI is allowed to react with crotonaldehyde to give, after hydrolysis, the alcohol . 4 9 CH3CH=CH-CH(OH)-C(R ) 2CH2CH2R . This alcohol is acetyl-ated, preferably with acetic anhydride without solvent at 30-100°C. for 2-12 hours, to give the intermediate 4 9 CH3CH=CH-CH (OCOCH3) -C (R ) 2CH2CH2R . This intermediate is allowed to react with N-bromosuccinimide in carbon tetrachloride at 50-70°C. for 2.5 to 5 hours to effect allylic bromination and give the reagent of formula IV D. 3. The reagent VII which has the formula R1-SOy-NH-(CH2)3-CH-C(R4)2CH2CH2R5 VII OTHP is prepared by the following reactions. The alcohol prepared in Section 2 above with the formula X (CH2) 3CH-C (R4) 2CH2CH2 5 OH is treated with dihydropyran and a catalytic amount of acid to give X (CH2) 3-CH-C (R4) 2CH2CH2R5. Treatment of this OTHP halo compound with the sodium salt of phthalimide in dimethylformamide affords the corresponding phthalimido compound. Cleavage of this compound with hydrazine in ethanol yields the amine H2~ (CH2) 3-CH-C (R4) 2CH2CH2R5 OTHP v/hich upon treatment with the appropriate alkanesulfonyl chloride or alkanesulfinyl chloride in pyridine affords the reagent VII. 4. The preparation of reagents of formula VIII X-(CH2)4-A-COOR8 VIII has been described in the scientific and patent literature in instances where A is ethylene, trimethylene, ct-methylethylene, β- methylethylene , a ,a-dimethylethylene , β , β-dimethylethylene.

To prepare reagents where A is oxymethylene , an ester of g glycolic acid, HOCH2COOR is treated with a strong base, preferably sodium hydride, in a non-protic solvent (dimethylformamide , glyme, and the like) and the resulting anion caused to react with a 1 , 4-dihalobutane , preferably 1 , 4-dibromobutane . The glycolic ester and base are employed in approximately equimolar quantities; a 1.5 to 2 molar excess of the dihalobutane is advantageously used. 5. Methods for obtaining optical antipodes of some compounds of this invention have been described supra whereby one of the compounds of the molecule is preresolved prior to its assembly into the whole molecule. Other methods also can be employed; for example, mixtures of racemates may be separated by taking advantage of the physiochemical difference between the components using chromatography and/or fractional crystallization. The racemic products and intermediates of this invention can be resolved into their -optically active components by any one of a number of methods of resolution which are well described in the chemical literature.

Those compounds which are carboxylic acids can be converted to the diastereoisomeric salts by treatment with an optically active base such as + or - a-methylbenzyl-amine, + or - a- (1-naphthyl) -ethylamine , brucine, cincho-nine, cinchonidine , or quinine. These diastereoisomeric salts can be separated by fractional crystallization.

The carboxylic acids of this invention also can be converted to esters using an optically active alcohol, such as, estradiol-3-acetate , or d- or 1-menthol and the diastereoisomeric esters resolved by crystallization or by chromatographic separation.

Racemic carboxylic acids also may be resolved by reverse phase and absorption chromatography using an optically active support and absorbent.

Compounds of this invention which contain free hydroxyl groups can be esterified with acid chlorides or anhydrides derived from optically active acids, such as, (—) -10-camphorsulfonic acid, (—0 -a-bromocamphor-^7"-sulfonic acid, or d- or 1-6 , 61 -dinitrodiphenic acid to form esters which can be resolved by crystallization.

Another method of obtaining pure optical isomers involves incubation of the racemic mixture with certain microorganisms such as fungi, by processes well estab-lished in the art, and recovering the product formed by the enzymatic transformation.

The methods described supra are especially effective if one applies the process to a compound where one asymmetric center has been preresolved by the techniques already described.

This invention is further described in the follow-ing examples.

PREPARATION OF INTERMEDIATES A. Preparation of l-Chloro-4-acetoxynonane Step 1. Preparation of l-Chloro-4-nonanone To the Grignard reagent prepared from a mixture of amyl bromide (226.59 g. ; 1.5 moles) and magnesium (36.48 g. 1.5 moles) in ether (1000 ml.) is added, dropwise, during one hour, 4-chlorobutyronitrile (155.34 g. ; 1.5 moles). Stirring is continued for an additional one hour. The reaction mixture is poured into a mixture of finely crushed ice (1000 g.) and concentrated hydrochloric acid (750 ml.). The ether layer is separated quickly and discarded. The aqueous layer is heated on a steam bath for one hour to hydrolyze the intermediate imine and cause the separation of the ketone as an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum and the residual oil is distilled to give 69.0 g. (26%) of colorless oil, b.p. 115-117°/14 mm.; pmr (CDC13) cf °·90 (3H,t), 3.56 (2H,t ,CH2C1) .

Step 2. Preparation of l-Chloro-4-nonanol A suspension of sodium borohydride (6.62 g.; 0.175 mole) and sodium hydroxide (1.3 g.) in ethanol (310 ml.) is treated, dropwise, over 1 hour with 1-chloro-4-nonanone (61.40 g.; 0.349 mole) while the temperature is maintained at 45-50°C. Stirring is continued for one hour^ longer without external cooling.

The reaction mixture is acidified with con-centrated hydrochloric acid to the Congo red endpoint and then the ethanol is removed under reduced pressure. The residue is treated with water (200 ml.) and the resulting oil is extracted with ether. The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum to give the title compound as a light yellow residual oil, yield- 58.85 g.j ir (neat) 3400 cm-1.

Step 3. Preparation of l-Chloro-4-acetoxy- nonane A mixture of l-chloro-4-nonanol (111.99 g.; Ο.627 mole) and acetic anhydride (128.0 g.; 1.254 moles) is heated on a steam bath for 1-1/2 hours.

The volatile materials are removed under reduced pressure and the residual oil is distilled to give 88.6 g. (64%) of colorless oil, b.p. 130-133°/l4 mm.; pmr 3-53 (2H,t CH2C1), 4.8 (lH,m). Anal. Calcd. for C-j^H^ClC^: C, 59.85; H, 9.59 Pound: C, 59.87; H, 9-67.

B . Preparation of l-Chloro-4-acetoxy-8-methylnonane Step 1. Preparation of l-Chloro-8-methyl-4- nonanone To the Grignard reagent prepared from a mixture of l-bromo-4-methylpentane (200.00 g.j 1.21 mole) and magnesium (29.43 g.; 1.21 mole) in ether (800 ml.) is added, dropwise during one hour, 4-chlorobutyronitrile (125.30 g.; 1.21 mole). Stirring is continued for an additional one hour.

The reaction mixture is poured into a mixture of finely crushed ice (800 g.) and concentrated hydro-chloric acid (600 ml.). The. ether layer is separated quickly and discarded. The aqueous layer is heated on a steam bath for one hour to hydrolyze the intermediate imine and cause the separation of the ketone as an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum and the residual oil is distilled to give 23-3 g. (10$) of colorless oil, b.p. 121-122°/15 mm.; pmr (CDCl-)cfΟ.89 (6H,d), 3.57 (2H,t CH2C1).

Anal. Calcd. for C,oH,nC10: C, 62.98; H, 10.04 Found: C, 62.86; H, 10.20 Step 2. Preparation of l-Chloro-8-methyl-4- nonanol A suspension of sodium borohydride (2.3 g-> 0.06I mole) and sodium hydroxide (0.5 g.) in ethanol (110 ml.) is treated dropwlse during one hour with l-chloro-8-methyl-4-nonanone ( 23 · 0. g . , 0.121 mole) while the temperature is maintained at 45-50°C. Stirring is continued for one hour longer without external cooling.

The reaction mixture is acidified with con-centrated hydrochloric acid to the Congo Red endpoint and then the ethanol is removed under reduced pressure.

The residue Is treated with water (70 ml.) and the resulting oil Is extracted with ether. The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum to give the title compound as a light yellow residual oil, yield 22.73 g.; ir (neat) 3400 cm-1.

Step 3· Preparation of l-Chloro-4-acetoxy-8- methylnonane A mixture of l-chloro-8-methyl-4-nonanol (22.73 g.; 0.118 mole) and acetic anhydride (24.07 g.j Ο.236 mole) is heated on a steam bath for 1-1/2 hours.

The volatile materials are removed under reduced pressure and the residual oil is distilled to give 14.58 g. ( 58% ) of colorless oil, b.p. 138-139V15 mm.; pmr (CDC13) , 3-53 (2H,t CH2C1), 4.92 (lH,m).

C. Preparation of l-Chloro-4-acetoxyundecane Step 1. Preparation of l-Chloro-4-undecanone This compound is prepared essentially by the same procedure as described for l-chloro-4-nonanone (Example A, Step 1) using the following reagents: 1-Bromoheptane 214.94 g. (1.2 mole) Magnesium 29. l8 g. (1.2 mole) Ether . 800 ml. 4-Chlorobutyronitrile . . . 124.27 g. (1.2 mole) The title compound is obtained as a colorless oil, yield 60.4 g. (15%), b.p. 135-l40°/15 mm.; pmr (CDC13X/" 0.93, (3H,t), 3.57 (2H,t CH2C1).

Step 2. Preparation of l-Chloro-4-undecanol This compound is prepared essentially by the same procedure as described for l-chloro-4-nonanol (Example A, Step 2) using the following reagents: Sodium borohydride 5.56 g. (0.147 mole) Sodium hydroxide 1.12 g.

Ethanol 265 ml. l-Chloro-4-undecanone . . . 60.00 g. (0.294 mole) The title compound is obtained as a yellow residual oil, yield 60.02 g.

Step 3. Preparation of l-Chloro-4-acetoxy- undecane This compound is prepared essentially by the same procedure as described for l-chloro-4-acetoxy-nonane (Example A, Step 3), using the following reagents: l-Chloro-4-undecanol . . . . 60.02 g. (0.29 mole) Acetic anhydride 59-16 g. (Ο.58 mole) The title compound is obtained as a colorless oil, yield 44.6 g. (62%), b.p. 155-158°/15 mm.; pmr 0.88 (3H,t), 2.02 (3H,s CH3C00), 3-53 (2H,t CH2C1) , 4.92 (lH,m) .

Anal. Calcd. for C13H2,-C102: C, 62.76; H, 10.13 Pound: C, 63.03; H, 10.40 Dj_ Preparation of l-Chloro-4-acetoxy-8 , 8-dimethyl-nonane By following the procedure described for l-chloro-4-acetoxynonane (Example A) but substituting l-bromo- , 4-dimethylpentane for amyl bromide, there Is obtained In succession: l-chloro-8 , 8-dimethyl-4-nonanone , l-chloro-8, 8-dimethyl-4-nonanol, and l-chloro-4-acetoxy-8 , 8-dimethylnonane .

Preparation of l-Chloro-4-acetoxy-9 ,9 , 9-trifluoro- nonane By following the procedure described for l-chloro-4-acetoxynonane (Example A) but substituting l-bromo-5,5,5-trifluoropentane for amyl bromide, there is obtained in succession: l-chloro- , 9 , 9-trifluoro-4-nonanone, l-chloro-9 , 9 , 9-trifluoro-4-nonanol , and 1-chloro-it-acetoxy-9 , 9 > 9-trifluoronane .

P^. Preparation of l-Chloro- -acetoxy-8-nonene By following the procedure described for l-chloro-4-acetoxynonane (Example A) but substituting l-bromo-4-pentene for amyl bromide, there is obtained in succession: l-chloro-8-nonen-4-one , l-chloro-8-nonen-4-ol, and l-chloro-4-acetoxy-8-nonene .

Preparation of l-Chloro-4-acetoxy- , 5-dimethyl- nonane Step 1. Preparation of l-Chloro-5 , -dimethyl- 4-nonanone Four hundred ml. of a solution in ether of 1,1-dlmethylpentylmagneslum chloride prepared from mag-nesium (24.3 g., 1.0 mole) and 1-chloro-l ,1-dimethyl-pentane (134.5 g., 1.0 mole) according to the procedure of Whitmore and Badertscher [J. Am. Chem. Soc . , 5_5, 1559 (1933)] is added dropwise with stirring to 4-chloro-butyryl chloride (197 g., 1.4 moles) in ether (400 ml.) during 6 hours. The reaction mixture is stirred for an additional 12 hours. It is then poured into a mixture of ice and dilute hydrochloric acid. The ether layer is separated, washed with water and brine and dried over sodium sulfate. The ether is evaporated and the residue distilled at aspirator vacuum through a Vigreaux column to yield the product as a colorless oil.

Step 2. Preparation of l-Chloro-5 , -dimethyl- 4-nonanol By following the procedure described for 1-chloro-4-nonanol (Example A, Step B) but substituting l-chloro-5 > -dimethyl-4-nonanone for l-chloro-4-nonanone and continuing stirring and heating at 50° for 6 hours, there is obtained l-chloro-5 , -dimethyl-4-nonanol .

Step 3 · Preparation of l-Chloro-4-acetoxy- , 5- dimethylnonane By following the procedure described for l-chloro-4-acetoxynonane (Example A, Step 3) but substitut-ing l-chloro-5 , -dimethyl-4-nonanol for l-chloro-4-nonanol and continuing the steam bath heating for 4 hours, there is obtained l-chloro-4-acetoxy-5 , 5-dimethylnonane . H_;_ Preparation of l-Bromo-4-acetoxy-2-nonene A mixture of 4-acetoxy-2-nonene (73-5 g 0.4 mole), N-bromosuccinimide (80.0 g., 0.45 mole), and carbon tetrachloride (500 ml.) is boiled under reflux for 3 hours. The mixture is then cooled and the suspended succinimide^ removed by filtration. The carbon tetrachloride solution is washed with dilute sodium bicarbonate solution and water, and is dried over sodium sulfate. The carbon tetrachloride is evaporated in vacuo and the residual oil is distilled to yield 62 g. (59%) of l-bromo-4-acetoxy-2-nonene as a light yellow oil, b.p. 110-112°/0.1 mm.

I_ Preparation of l-Bromo-4-acetoxy-2-nonyne Step 1. Preparation of 3-Acetoxy-l-octyne l-0ctyn-3-ol (100 g., 0.79^ mole) is dissolved in pyridine (79 g., 1.0 mole) and acetic anhydride (81.6 g., 0.80 mole) is added dropwise with stirring during one hour. The temperature rises to 45°. The solution is heated at 55° for one hour and is then cooled and poured into 200 ml.^ ice-cold 5% hydrochloric acid. The oily product is taken up in ether, washed with water and brine and dried over sodium sulfate. The ether is evaporated and the residual oil distilled to yield 106.4 g. (80%) of 3-acetoxy-l-octyne, b.p. 91-92°/15 mm.

Step 2. Preparation of l-Dlethylamino-4-acetoxy- 2-nonyne A mixture of 3-acetoxy-l-octyne (58.8 g., 0.35 mole), diethylamine (28.5 g., 0.39 mole), paraformal-dehyde (13-8 g., 0.46 mole) and p-dioxane (60 ml.) is heated on the steam bath under a reflux condenser for 17 hours. The resulting solution is cooled and diluted with 250 ml. of ether. The solution is extracted with 300 ml. of 5% hydrochloric acid. The acidic aqueous extract is made basic with 10% sodium hydroxide solution. The liberated amine is taken up in ether, washed with water and brine and dried over sodium sulfate. The ether is evaporated and the residual oil distilled to yield 73.1 g. (89%) of l-diethylamino-4-acetoxy-2-nonyne , b.p. 103-109°/0.3 mm.

Anal, calcd. for C±,-.H„-(7N0o: C, 71.10; H, 10.74; N, 5-33 Found: C, 70.73; H, 11.03; N, 5-55 Step 3 · Preparation of l-Bromo-4-acetoxy-2- nonyne A solution of l-diethylamino-4-acetoxy-2-nonyne (50.6 g., 0.20 mole) and cyanogen bromide (21.2 g., 0.20 mole) in ether (250 ml.) is allowed to stand at 25-27° for 18 hours. The ether solution is washed with 53» hydrochloric acid solution, water, and brine and dried over sodium sulfate. The ether is evaporated and the residual oil distilled. After a forerun of diethyl-cyanamide, there is collected 34.1 g. (65$) of l-bromo-4-acetoxy-2-nonyne , b.p. 97-105°/0.2 mm.

Anal, calcd. for C- -, H, ^BrO^ : C, 50.59; H, 6.56 Found: C, 50.54; H, 6.49 Preparation of l-Bromo- (R)-acetoxy-2-nonyne By following the procedure described in Example H but substituting (R) -l-octyn-3-ol [a] + 6.1° [C 3-1, CHCl^] for the racemic l-octyn-3-ol , there is obtained ?6 successively: 3 (R) -acetoxy-l-octyne , [a]D + 70° [C 3.1, CHC13], l-dlethylamino-4(R)-acetoxy-2-nonyne, O]^6 + 74° [C 3.2, CHCl^], and l-bromo-4 (R)-acetoxy-2-nonyne , [α]ρβ + 75° [C 3.2, CHC13].

Preparation of l-Bromo-4 (S)-acetoxy-2-nonyne By following the procedure described in Example H but substituting (S)-l-octyn-3-ol , [a]^6 - 6.4° [C 3.3,CHC13], for the racemic l-octyn-3-ol , there are obtained succes-sively: 3(S)-acetoxy-l-octyne, - 79° [C 3.0, CHClg], l-diethylamino-iJ(S)-acetoxy-2-nonyne, [a]" - 80° (C 3.3, CHCl^], and l-bromo-4(S)-acetoxy-2-nonyne , [ ]^6 - 83° [3.7, CHClg].

L . Preparation of Methyl 7-bromo-2-methylheptanoate Step 1. Preparation of 5-Acetoxypentyl chloride Acetic anhydride (102 g., 1 mole) is added dropwise with stirring to pentamethylene chlorohydrin (90 g., 0.7^ mole). The resulting solution is heated on the steam bath for one hour and allowed to stand overnight at room temperature. The reaction mixture is distilled to yield 83-6 g. (69%) of 5-acetoxypentyl chloride, b.p. 101-10l°/20 mm.

Step 2. Preparation of Diethyl (5-Acetoxy- pentyl)methylmalonate Sodium hydride (4.8 g., 0.2 mole) as a 50% suspension in mineral oil is washed with petroleum ether under nitrogen to remove the mineral oil, suspended in dry benzene (150 ml.), and the suspension cooled in an ice bath. Diethyl methylmalonate (3^.8 g., 0.2 mole) dissolved in molecular sieve-dried DMF (150 ml.) is added to the suspension of sodium hydride dropwise.

The mixture is allowed to stand overnight at room temperature. Potassium iodide (0.4 g. ) and 5-acetoxypentyl chloride (32.9 g., 0.2 mole) are then added, and the mixture is heated for 21* hours at 125° in an oil bath.

The reaction mixture is concentrated in_ vacuo, diluted with ether (200 ml.), a'nd filtered to remove sodium chloride. The filtrate is washed with brine, dried over anhydrous magnesium sulfate and concentrated to yield 39-6 g. (66$) of oily product.

Step 3. Preparation of 7-Bromo-2-methyl- heptanolc acid A mixture of the crude diethyl (5-acetoxy-pentyl)methylmalonate (68 g., 0.23 mole) and 48% aqueous hydrobromlc acid (100 ml.) Is refluxed for 20 hours.

The mixture is then concentrated by distillation until the internal temperature rises to 120°; 96 ml. of distillate (2 layers) is collected. The residual liquid is cooled, dissolved in ether, washed with brine, dried over magnesium sulfate, and the solution concentrated in vacuo to yield 4 g. of crude 7-bromo-2-methyl-heptanoic acid as a dark viscous liquid.

Step 4. Preparation of Methyl 7-Bromo-2- methylheptanoate A solution of crude 7-bromo-2-methylheptanoic acid (54 g., 0.24 mole) and concentrated sulfuric acid (2 drops) in absolute methanol (300 ml.) is refluxed for 5 hours. After standing overnight at room temperature, the solution is concentrated in vacuo and diluted with water. The mixture is made basic by the addition of saturated sodium carbonate solution and the product taken up in ether. The ether extract is washed with water, dried over anhydrous magnesium sulfate and distilled to yield 11.8 g. (16%) of methyl 7-bromo-2-methylheptanoate, b.p. 67-70°/0.05mm. ; pmr 1.13 (3H,d 2-CH3), 2.42 (lH,m CHCOOCHg), 3.38 (2H,t CH2Br), 3. (3H,s Ci^O) . 1 Preparation of Ethyl 4-Bromobutoxyacetate 2 Sodium hydride (9.0 g., 0.375 mole) Is sus- 3 pended in 1, 2-dimethoxyethane . The mixture is stirred 4 and cooled in an ice bath while ethyl glycollate 5 (39.0 g., 0.375 mole) is added dropwise during one hour. 6 1, 4-Dibromobutane (108 g., 0.5 mole) is added all at 7 once to the resulting thick suspension. The mixture is 8 warmed gently to initiate a strongly exothermic reaction; 9 then the mixture is heated 3 hours on the steam bath. 10 The mixture is poured into cold water. The heavy oil 11 layer is taken up in ether, washed with three portions 12 of water, and dried over sodium sulfate. 13 Evaporation of the ether and distillation of l^t the residual oil yields 21.3 g. (24$) of ethyl 4- 15 bromobutoxyacetate , a colorless oil, b.p. 99-103°/0.2 mm. 16 N_;_ Preparation of N-[4-(2-Tetrahydropyranyloxy)nonyl]- 17 methanesulfonamide 18 Step 1. Preparation of l-Chloro-4-( 2-tetra- 19 hydropyranyloxy )nonane 20 To a stirred solution of l-chloro-4-hydroxy- 21 nonane (Example A, Step 2) (11.0 g., 0.062 mole) and di- 22 hydropyran^ (5.2 g., 0.062 mole) cooled in an ice bath is 23 added 5 drops of hydrochloric acid (cone.). A slight 24 exothermic reaction is noted and when this is complete the 25 reaction is allowed to come to room temperature, then 26 stand for 2 hours. At the end of this period several 27 pellets of sodium hydroxide are added and the reaction is 28 distilled in vacuo. The yield of l-chloro-4-( 2-tetra- 29 hydropyranyloxy )nonane is 12.5 g. (77%), boiling 96-102V0.1 mm. Upon redistillation a boiling point of 90-92°/0.1 mm. is obtained.

Step 2. Preparation of N-[4-( 2-Tetrahydro- pyranyloxy )nonyl]phthalimide Sodium hydride (53%) (1.5 g. excess) is washed with benzene three times by decantation, then dimethyl— formamide (100 ml.) is added. To this stirred suspension is added a solution of phthalimide (4.3 g., 0.03 mole) in dimethyl^formamide (50 ml-.) at such a rate as to keep the temperature below 35°C. A clear solution is obtained and to it is added l-chloro-4-(2-tetrahydropyranyloxy)nonane (7.8 g. 0.03 mole) and the resulting solution is stirred and heated at 95°C. for 20 hours. The reaction is then concentrated to one-half its volume in vacuo , poured into ice water (200 ml.) and extracted with ether (2 x 150 ml.). The ether is washed with 5% sodium hydroxide (2 x 50 ml.), saturated sodium chloride solution (2 x 50 ml.), then dried over sodium sulfate. Evaporation of the ether affords 1.5 g. (4 % yield) of N-[4-( 2-tetrahydropyranyl-oxy)nonyl]phthalimide melting 59-6l°C. After crystalll-zation from cyclohexane the product melts at 62-63°C.

Anal. Calcd. for C-H,,- NO,, : C, 70.75; H, 8.36; N, 3.75 Found: C, 71.03; H, 8.28; N, 3.81 Step 3. Preparation of 4-( 2-tetrahydropyranyl- oxy )nonylamine To a solution of N-[4-(2-tetrahydropyranyloxy )- nonyl]-phthalimide (33.0 g., 0.88 mole) In absolute ethanol (300 ml.), Is added hydrazine (64%) (10 ml. excess) and the reaction Is heated at reflux for 1.5 hours. An additional 5 ml. of hydrazine (64%) is added and reflux continued for 1.5 hours. The reaction is cooled to room temperature and the white solid that is present is removed by filtration. The filtrate is con-centrated In vacuo to 75 ml., then poured into water (200 ml.). The solution is made basic with 5% sodium hydroxide and then extracted with ether (3 x 100 ml.).

The ether layer is washed with saturated sodium chloride solution, then dried over sodium sulfate. The ether is removed In vacuo and the resulting oil is distilled.

The yield of 4-(2-tetrahydropyranyloxy)nonylamine is 16.0 g. (75%), boiling 100-102°/0.1 mm.

Anal. Calcd. for C-„H^ N0o: C, 69.08; H, 12.01; N, 5-75 Found: C, 68.58; H, 12.42; N, 5.66 Step 4. Preparation of N-[4-(2-Tetrahydro- pyranyloxy )nonyl]methanesulfonamide To a stirred, ice cold solution of 4-(2-tetra-hydropyranyloxy )nonylamine (7.29 g., 0.03 mole) in pyridine (40 ml.) is added methanesulfonyljchloride (3.42 g., 0.03 mole) at such a rate as to maintain the reaction temperature at 5-10°C. The reaction is then allowed to stand at room temperature for six hours, poured into ice water (200 ml.) and extracted with ether (2 x 100 ml.). The ether is washed with ice cold 5% hydrochloric acid (2 x 20 ml.), with brine (2 x 25 ml.), and then dried over sodium sulfate. Evaporation in vacuo affords N-[4-( 2-tetrahydropyranyloxy )nonyl]methanesulfon-amide as a pale yellow liquid.

Preparation of Ethyl 7-(methanesulfonamido)heptanoate A stirred suspension of sodium hydride (57%) (2.33 .j 0.055 mole) in a solvent mixture of benzene (50 ml.) and dimethylformamide (50 ml.) is treated, over 30 minutes with methanesulfonamide (4-75 g.j 0.055 mole). This mixture is heated on the steam bath for 1.5 hours, then cooled to room temperature. At this temperature is added ethyl 7-bromoheptanoate (13 g., 0.055 mole) and the reaction is heated at 90°C. for twenty hours. The reaction is poured into water (200 ml.), neutralized with hydro-chloric acid and extracted with ethyl acetate (2 x 100 ml.). The ethyl acetate layer is washed with brine, dried over sodium sulfate, then concentrated in vacuo. The yield of ethyl 7-(methanesulfonamido )heptanoate is 7.1 g. (51%) boiling l65-l68°/0.1 mm.

Anal. Calcd. for C^H^NO^S: C, 47.78; H, 8.42; N, 5-57 Pound: C, 47.05; H, 8. 1; N, 5.4l Pj_ Preparation of Ethyl 7-(ethanesulfonamido )heptanoate The synthesis of this compound is carried out as described in Example 0 except that the methanesulfon-amide is replaced by an equimolar amount of ethanesulfon-amide. Ethyl 7- ( ethanesulfonamido ) heptanoate is obtained as a pale yellow oil upon evaporation of the ethyl acetate extracts.

Preparation of Ethyl 7-{Propanesulfonamido )heptano- ' Example 0 but substituting propanesulfonamlde for methanesulfonamlde there Is obtained ethyl 7-(propane-sulfonamido)heptanoate .

Preparation of Ethyl 7-[ ( 1-methylethane ) sulfon- amido]heptanoate By following the procedure described in Example 0 but substituting 1-methylethanesulfonamlde for methanesulfonamlde there is obtained ethyl 7-[ ( 1-methylethane ) sulfonamido]heptanoate .

Preparation of l-Chloro-4-acetoxy-4-methylnonane The Grlgnard reagent prepared from iodo-methane (14.2 g., 0.1 mole) and magnesium (2.4 g., 0.1 mole) in ether solution is added, dropwise to an ether solution of l-chloro-4-nonanone (Example A, Step 1) (17.6 g.s 0.1 mole). The reaction is refluxed gently for three hours then cooled and poured carefully into ice water (300 ml.). The ether layer is separated, washed with brine, and dried over sodium sulfate. Re-moval of the ether In vacuo gives l-chloro-4-hydroxy-4-methylnonane as an oil. The tertiary alcohol is dis-solved in pyridine and treated with one molar equivalent of acetic anhydride at 60-80° for 8-16 hours to give l-chloro-4-acetoxy-4-methylnonane as a colorless oil. T^ Preparation of Ethyl 7-(methanesulfinamido)heptano- ate The synthesis of this compound is carried out as described in Example 0 except that the methanesulfon-amide is replaced by an equimolar amount of methane-sulflnamide. The ethyl 7-(methanesulfinamido)heptanoate is obtained as a yellow liquid upon evaporation of the ethyl acetate extracts .

U. Preparation of 1-Acetoxy-l- (3-bromo-l-propynyl) - cyclohexane Step 1. Preparation of 1-Acetoxy-l-ethynylcyclo- hexane 1-Ethynylcyclohexan-l-ol (100 g 0.8 mole) is added dropwise with stirring to a mixture of acetic anhydride (86.7 g., 0.85 mole) and sulfuric acid (0.25 ml.). The temperature of the reaction -mixture is kept at 10-12°C. during the addition by means of an ice bath. The mixture is then stirred without cooling for 1.5 hours. It is then poured into 300 ml. of ice water. The oily product is taken up in ether, washed with water, dilute sodium bicarbonate solution and brine and dried over sodium sulfate. Distillation affords 107 g. (80%) of 1-acetoxy-l-ethynylcyclohexane , b.p. 95-97°C./15 mm.

Step 2. Preparation of 1-Acetoxy-l- (3-diethyl- amino-l-propynyl) cyclohexane A mixture of 1-acetoxy-l-ethynylcyclohexane (64.00 g. , 0.385 mole), diethylamine (30.95 g. , 0.424 mole), paraformaldehyde, (15.00 g. 0.500 mole), cuprous chloride (1.5 g.) and dioxane (60 ml.) is stirred well. An exo-thermic reaction gradually results which may require external cooling to prevent spillage. After this initial reaction, the mixture is heated on a steam bath for 1-1/2 hours.

The cooled reaction mixture is treated with ether and the product is extracted into ice-cold 5% hydrochloric acid. This cold aqueous acidic solution is then basified with ice-cold 10% sodium hydroxide. The oily amine is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent is removed under ^ vacuum and the residual oil is distilled to give 72.7 g. (75%) of light yellow oil, b.p. 113-115°C./0.15 mm.; pmr (CDC13) 1.07 (6H,t), 2.02 (3H,s CH..COO) , 2.60 (4H,q CH3CH2 ) , 3.52 (2H,s CH20) .

Step 3. Preparation of 1-Acetoxy-l- (3-bromo- 1-propynyl) cyclohexane Cyanogen bromide (31.8 g. , 0.3 mole) is added to a solution of 1-acetoxy-l- ( 3-diethylamino-l-propynyl) -cyclohexane (61 g. , 0.24 mole) in ether (250 ml.) and the resulting solution is allowed to stand at 25-27°C. for 18 hours. The ether solution is washed with 5% hydro-chloric acid solution, water and brine and dried over sodium sulfate. The ether is evaporated and the residual oil distilled. There is obtained 34.8 g. (55%) of 1-acetoxy-1- ( 3-bromo-1-propynyl) cyclohexane , a slightly yellowish oil, b.p. 114°-120°C./0.2 mm.

V. Preparation of 1-Acetoxy-l- (3-bromo-l-propynyl) cyclo- octane By the following the procedure described in Example U but substituting in Step 1 1-ethynylcyclooctan-l-ol for 1-ethynylcyclohexan-l-ol there are obtained success-ively 1-acetoxy-l- (3-diethylamino-l-propynyl) cyclooctane (Step 2), and 1-acetoxy-l- ( 3-bromo;-l-propynyl) cyclooctane (Step 3) .

W. Preparation of l-Bromo-4-acetoxy-4-propyl-2-heptyne Step 1. Preparation of S-Acetoxy-S-propyl-l^hexyne 3-Propyl-l-hexyn-3-ol (98.0 g., 0.7 mole) is added dropwise with stirring to a mixture of acetic anhydride (79.5 g. , 0.78 mole) and sulfuric acid (0.25 ml.) during 50 min. the temperature rises to 50°C. The mixture is allowed to stand 18 hours and is then poured into 300: ml. y"4†"^ of ice water. The oily product is taken up in ether, washed with water, dilute sodium bicarbonate solution and brine and dried over sodium sulfate. Distillation yields 108.5 g. (86%) of 3-acetoxy-3-propyl-l-hexyne , b.p. 93-95°C./17 mm.

Step 2. Preparation of l-Diethylamino-4-acetoxy- 4-prop l-2-he tyne A mixture of 3-acetoxy-3-propyl-l-hexyne (115.2 g. , 0.634 mole), diethylamine (51 g. , 0.7 mole), paraformaldehyde (24.9 g. , 0.83 mole) and dioxane (120 ml.) is stirred and heated on the steam bath for 2 hours. The reaction mixture is cooled, treated with ether and the product extracted into ice-cold 5% hydrochloric acid. The cold acidic solution is then basified with ice-cold 10% sodium hydroxide. The oily amine is taken up in ether, washed with water and brine and dried over sodium sulfate.

Distillation yields 99.5 g. (59%) of the amine product, b.p. 101-110°C./0.1 mm.

Step 3. Preparation of l-Bromo-4-acetoxy-4- propyl-2-heptyne Cyanogen bromide (46.6 g.; 0.44 mole) is added to a solution of l-diethylamino-4-acetoxy-4-propyl-2-heptyne (99.0 g. , 0.371 mole) in ether (400 ml.) and the resulting solution is allowed to stand at 25-27°C. for 16 hours. The ether solution is washed with 5% hydrochloric acid solution, water and brine and dried over sodium sulfate. The ether is evaporated and the residual oil distilled.

There is obtained 70.0 g. (69%) of l-bromo-4-acetoxy-4-propyl-2-heptyne , a colorless oil, b.p. 106-107°C./0.1 mm.

Anal. Calcd. for C12HigBr02: C, 52.88; H, 6.96; Found: C , 52.00 ; H , 6.91.

EXAMPLE 1 Preparation of 7- [ij- ( 4-Hydroxynonyl) methanesulfonamido] - heptanoic Acid STEP A: Preparation of Ethyl 7- [N- (4-Acetoxynonyl) - methanesulfonamido] heptanoate Sodium hydride (0.715 g., 0.0298 mole) is sus-pended in benzene (30 ml.) and dimethylformamide (30 ml.). Ethyl 7- (methanesulfonamido) heptanoate (6.8 g., 0.0271 mole) (Example 0, Step 1) is added and the suspension heated on the steam bath for 15 minutes. After cooling to room temperature, l-chloro-4-acetoxynonane (6.55 g., 0.0298 mole) (Example A, Step 3) is added over 15 minutes and the resulting solution heated on the steam bath for 20 hours. Then the reaction is poured into water (300 ml.) and extracted with ethyl acetate (3 x 100 ml.). The organic layer is washed with brine (2.x 50 ml.), dried over sodium sulfate then concentrated in vacuo to an oil which is purified by chromatography on silica gel. The silica gel is eluted with 3% methanol in chloroform and evapora-tion of the appropriate fraction affords ethyl 7-[N-(4-acetoxynonyl) methanesulfonamido] heptanoate. The yield is 6.0 g. (51%) .

Analysis calculated for C, 57.90; H, 9.49; N, 3.22 Found: C, 58.08; H, 9.99; N, 2.99 STEP B : Preparation of 7- [N- (4-;Hydroxynonyl)methane- sulfonamido] heptanoic Acid A solution composed of ethyl 7- [N- (4-acetoxy-nonyl) methanesulfonamido] heptanoate (6.0 g., 0.0134 mole), sodium hydroxide (1.66 g., 0.0414 mole), water (9 ml.), hours. Most of the solvent is removed in vacuo, water (150 ml.) is added and the solution extracted with ethyl acetate (100 ml.). Then the aqueous layer is acidified (hydrochloric acid) and extracted again with ethyl acetate (2 x 75 ml.). The organic layer is dried over sodium sulfate then concentrated in vacuo to yield 7-[N-(4-hydroxynonyl)methanesulfonamido] heptanoic acid. The yield is 4.3 g. (88%) .

Analysis calculated for C^^-H^gNO^S: C, 55.86; H, 9.65; N, 3.83 Found: C, 56.07; H, 9.77; N, 3.65 EXAMPLE 2 Preparation of 7- [N- (4-Hydroxy-2-nonynyl)methanesul- fonamido] heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the l-chloro-4-acetoxynonane is replaced by an equimolar amount of l-bromo-4-acetoxy-2-nonyne (Example I, Step 3) .

The product of Step A is thus ethyl 7- [N- (4-acetoxy-2-nonynyl) methanesulfonamido] heptanoate.

Analysis calculated for C -H__N0(-S: C, 58.44; H, 8.64; N, 3.25 Found: C, 57.92; H, 9.15; N, 3.20 The subsequent step yields 7- [N- (4-hydroxy-2-nonynyl)methanesulfonamido] heptanoic acid (B) .

Analysis calculated for C^^H^^ OgS: C, 56.48; H, 8.64; N, 3.88 Found : / EXAMPLE 3 Preparation of 7- [N- (4 (R) -Hydroxynonyl)methanesulfonamido] - heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the l-chloro-4-acetoxynonane is replaced by an equimolar amount of l-bromo-4 (R) -acetoxy-2-nonyne (Example J) .

The product of Step A is thus ethyl 7- [N- (4 (R) -acetoxy-2- 3 3(6 nonynyl) methanesulfonamido] heptanoate, [a] _ + 46° D [C 2.95, CHC13] .

Analysis calculated for C2^H.-,-j OgS : C, 58.44; H, 8.64; N, 3.25 Found: C, 58.77; H, 8.98; N, 3.13 The subsequent step yields 7- [N- (4 (R) -hydroxy-2-nonynyDmethanesulfonamido] heptanoic acid (B) , - Ct - D + 0.93° [C 3.3 , CHC13] .

Analysis calculated for : C, 56.48; H, 8.64; N, 3.88 Found : C, 55.96; H, 9.13; N, 3.85 The product of Step B is hydrogenated over a platinum on charcoal catalyst to afford 7- [N- (4 (R) -hydroxynonyl) - 26 methanesulfonamido] heptanoic acid, [a] D - 3.0° [C 3.72, CHC13] .

Analysis calculated for : C, 55.86; H, 9.65; N. 3.83 Found : C, 55.62; H, 9.76; N, 3.70 rr EXAMPLE 4 Preparation of 7- [N- (4 (S) -Hydroxynonyl)methanesulfonamido] - heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of l-bromo-4 (S) -acetoxy-2-nonyne (Example K) . The product of Step A is thus ethyl 7- [N- (4 (S) -acetoxy-2-nonynyl) - 2( methanesulfonamido] heptanoate, [a] Dn - 48.8° [C 2.865, CHC13] .

Analysis calculated for C21H37 OgS: C, 58.44; H, 8.64; N, 3.25 Found: C, 58.72; H, 9.15; N, 3.13 The subsequent step yields 7- [N- (4 (S) -hydroxy- 26 c 2-nonynyl) methanesulfonamido] heptanoic acid (B) , [a] D - (153 [C 3.015, CHC13] .

Analysis calculated for C^^H^-^ O^S : C, 56.48; H, 8.64; N, 3.88 Found : C, 56.30; H, 8.61; N, 3.79 The product of Step B is hydrogenated over a platinum on charcoal catalyst to afford 7- [N- (4 (S) -hydroxynonyl) - 26 methanesulfonamido] heptanoic acid, [α] β + 3.92° [C 2.44, CHC13] .

Analysis calculated for C^H^NOcjS :.

C, 55.86; H, 9.65; N, 3.83 Found : C, 55.45; H, 9.40; N, 3.74 EXAMPLE 5 Preparation of 7- [N- (4-Hydroxynonyl) ethanesulfonamido] - heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7- (methanesulfonamido) heptanoate is replaced by an equimolar amount of ethyl 7-ethanesulfonamidoheptanoate (Example P) . The product of Step A is thus ethyl 7- [N-(4-acetoxynonyl) ethanesulfonamido] heptanoate. The subsequent step yields 7- [N- (4-hydroxynonyl) ethanesul-fonamido] heptanoic acid (B) .

EXAMPLE 6 Preparation of 7- [N- (4-Hydroxynonyl) propanesulfonamido] - heptanoic Acid · '' ■ The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7- (methanesulfonamido) heptanoate is replaced by an equimolar amount of ethyl 7- (propanesulfonamido) heptanoate (Example Q) . The product of Step A is thus ethyl 7-[N-(4-acetoxynonyl) propanesulfonamido] heptanoate . The subsequent hydrolysis step yields 7- [N- (4-hydroxynonyl) -propanesulfonamido] heptanoic acid (B) .

EXAMPLE 7 Preparation of 7- [N- (4-Hydroxynonyl) -1-methylethanesul- fonamido] heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7 - (methanesulfonamido) heptanoate is replaced by an equimolar amount of ethyl 7- [ (1-methylethane) sulfonamido] -heptanoate (Example R) . The product of Step A is thus ethyl 7- [N- (4-acetoxynonyl) -1-methylethanesulfonamido] - EXAMPLE 8 Preparation of 7- [N- (4-Hydroxynonyl)methanesulfonamido] - 2-methylheptanoic Acid STEP A; Preparation of Ethyl 7-{N- [4- (2-Tetrahydro- pyranyloxy) nonyl]methanesulfonamido^J-2-methyl- heptanoate A stirred suspension of sodium hydride (57%) (5.0 g., excess) in a solvent mixture of benzene (75 ml.) and dimethylformamide (75 ml.) is treated, over 30 minutes, with N- [4- (2-tetrahydropyranyloxy) nonyl.methanesulfonamide (Example N, Step 4) (32.1 g., 0.1 mole) dissolved in benzene (20 ml.). Stirring is continued for one hour.

Then ethyl 7-bromo-2-methylheptanoate (Example L, Step 4) (25.3 g., 0.1 mole) is added dropwise, and the reaction is heated on the steam bath for 6 hours. The cooled reaction mixture is poured into water (400 ml.) and extracted with ethyl acetate (2 x 200 ml.). The organic fractions are combined, washed with brine, then dried over sodium sulfate. The solvents are removed in vacuo to give 7-£N- [4- ( 2-tetrahydropyranyloxy) nonyl]methane-sulfonamido"^-2-methylheptanoate as a pale yellow liquid. STEP B; Preparation of 7- [N- (4-Hydroxynonyl)methanesul- fonamido] -2-methylheptanoic Acid A solution is prepared from ethyl 7-{N-[4-(2-tetrahydropyranyloxy) nonyl]methanesulfonamido"^-2-methyl-heptanoate (4.9 g., 0.01 mole), ethanol (50 ml.), and 4 drops of hydrochloric acid (cone), and kept at ambient temperature for 4.5 hours. Then to the reaction is added a solution of sodium hydroxide (0.72 g., 0.018 mole) in water (10 ml.) and the reaction is kept at ambient temperature for an additional 20 hours. Most of the ethanol is removed in vacuo and the residue dissolved in water (100 ml.). The solution is extracted once with ether (75 ml.) then acidified with hydrochloric acid (dil.). The oil that separates is extracted into ether, the ether is washed with brine, dried over sodium sulfate, then removed under vacuum to give 7- [N- (4-hydroxynonyl) -methanesulfonamido] -2-methylheptanoic acid as a yellow liquid.

EXAMPLE 9 Preparation of 7- [N- (4-Hydroxynonyl)methanesulfonamido] - 2 , 2-dimethylheptanoic Acid The synthesis of this compound is carried out as described in Example 8 except that, in Step A, the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of methyl 2 , 2-dimethyl-7-iodoheptanoate. The product of Step A is thus methyl 7-{N- [4- (2-tetra- , hydropyranyloxy) nonyl] methanesulfonamido ^-2 , 2-dimethyl-heptanoate. The subsequent step yields 7- [N- (4-hydroxy-nonyl) methanesulfonamido] -2 , 2-dimethylheptanoic acid (B) .

EXAMPLE 10 Preparation of 7- [N- (4-Hydroxynonyl) methanesulfonamido] - 3-methylheptanoic Acid The synthesis of this compound is carried out as described in Example 8 except that, in Step A, the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of methyl 3-methyl-7-iodoheptanoate .

The product of Step A is thus methyl 7-[N- [4- (2-tetra-hydropyranyloxy) nonyl] methanesulfonamido"j-3-methyl-heptanoate. The subsequent hydrolysis step yields 7- [N-(4-hydroxynonyl) methanesulfonamido] -3-methylheptanoic acid (B) .

EXAMPLE 11 Preparation of 7- [N- (4-Hydroxynonyl)methanesulfonamido] - 3 , 3-dimethylheptanoic Acid The synthesis of this compound is carried out as described in Example 8 except that, in Step A, the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of methyl 3 , 3-dimethyl-7-iodoheptanoate . The product of Step A is thus methyl 7- N- [4- (2-tetrahydropyranyloxy) -nonyl] methanesulfonamido -3 , 3-dimethylheptanoate . The subsequent step yields 7- [N- (4-hydroxynonyl)methanesulfona-mido] -3 , 3-dimethylheptanoanoic acid (B) .

EXAMPLE 12 Preparation of 4- [N- (4-Hydroxynonyl)methanesulfonamido] - butoxyacetic Acid The synthesis of this compound is carried out as described in Example 8 except that, in Step A, the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of ethyl 4-bromobutoxyacetate (Example M) . The product of Step A is thus ethyl 4-{N- [4- ( 2-tetrahydropyranyloxy) nonyl] methanesulfonamido^butoxyacetate . The subsequent step yields 4- [N- (4-hydroxynonyl) methanesulfonamido] butoxyacetic acid (B) .

Anal. Calcd. for C, 52.29; H, 9.05; N, 3.81; Found: C, 52.04; H, 8.90; N, 3.81 EXAMPLE 13 Preparation of 7- [N- (4-Hydroxy-8-methylnonyl)methane-sulfonamido] heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro- 4-acetoxynonane is replaced by an equimolar amount of 1-chloro 4-acetoxy-8-methylnonane (Example B, Step 3) . The product of Step A is thus ethyl 7- [N- ( 4-acetoxy-8-methylr.or.yl) -methanesulfonamido] heptanoate. The subsequent step yields 7- [N- (4-hydroxy-8-methylnonyl) methanesulfonamido] heptanoic acid (B) .

EXAMPLE 14 Preparation of 7- [N- (4-Hydroxyundecyl) methanesulfonamido] - heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar arount of 1-chloro-4-acetoxyundecane (Example C, Step 3). The product of Step A is thus ethyl 7- [N- ( 4-acetoxyundecanyl) methanesulfonamido] heptanoate . The subsequent step yields 7- [N- ( 4-hydroxyundecanyl) methanesulfonamido] heptanoic acid (B) .

EXAMPLE 15 Preparation of 7- [N- (4-Hydroxy-r8 , 8-dimethylnonyl) methane- sulfonamido] heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro- 4-acetoxynonane is replaced by an equimolar amount of l-chloro-4-acetoxy-8 , 8-dimethylnonane (Example D) . The product of Step A is thus ethyl 7- [N- (4-acetoxy-8 , 8-dimethyl-nonyl) methanesulfonamido] heptanoate . The subsequent step yields 7- [N- (4-hydroxy-8 , 8-dimethylnonyl) methanesulfonamido]-heptanoic acid (B) .

EXAMPLE 16 Preparation of 7- [N- (4-Hydroxy-9,9,9-trifluorononyl)methane- sulfonamido] heptanoic Acid The synthesis of this compound is carried out as described in Example 1, except that, in Step A, the 1-chloro- 4-acetoxynonane is replaced by an equimolar amount of 1-chloro- 4-acetoxy-9 , 9 , 9-trifluorononane (Example E) . The product of Step A is thus ethyl 7- [N- ( 4-acetoxy-9 , 9 , 9-trifluoro- / -_ nonyl)methanesulfonamido]heptanoate. The subsequent step yields 7- [N- (4-hydroxy-9 , 9 , 9-trifluorononyl) methanesulfo-na ido] heptanoic acid (B) .

EXAMPLE 17 Preparation of 7- [N- (4-Hydroxy-8-nonenyl) methanesulfo- namido] heptanoic Acid. ■ The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro- 4-acetoxynonane is replaced by an equimolar.. amount of 1- chloro-4-acetoxy-8-nonene (Preparation F). The product of Step A is thus ethyl 7-[N-(4-acetoxy-8-nonenyl)methanesulfonamido] heptanoate. The subsequent step yields 7-[N-(4-hydroxy-8-nonenyl)-methanesulfonamido] heptanoic acid (B) .

EXAMPLE 18 Preparation of 7- [N- (4-Hydroxy-5 , 5-dimethylnonyl) methane- sulfonamido] heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-5 ,5-dimethylnonane (Example G) . The product of Step A is thus ethyl 7- [N- ( 4-acetoxy-5 , 5-dimethylnonyl) methanesulfonamido] heptanoate. The subsequent step yields 7- [N- ( 4-hydroxy-5 , 5-dimethylnonyl) methanesulfonamido] -heptanoic acid (B) .

EXAMPLE 19 Preparation of 7- [N- (4-Hydroxy- (E) -2-nonenyl) methanesulfo- namido] heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the* 1-chloro- 4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4-acetoxy-2-nonene (Example H). Die product of / Step A is thus ethyl 7-[N- (4-acetoxy-(E)-2-nonenyl)-methanesulfonamido ]heptanoate. Die subsequent step yields 7-[ - ( 4-hydroxy-(E ) -2-nonen 1 )methanesulfonamido]heptanoic acid (B).

EXAMPLE 20 Preparation of 7- [N- ( -Hydroxy-4-methylnonyl) methanesulfo- namido] heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro- 4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-4-methylnonane (Example S) . The product of Step A is thus ethyl 7- [N- (4-acetoxy-4-methylnonyl) -methanesulfonamido] heptanoate . The subsequent step yields 7- [N- (4-hydroxy-4-methylnonyl) methanesulfonamido] heptanoic acid (B) .

EXAMPLE 21 Preparation of 7- [N- (4-Hydroxynonyl) methanesulfinamido] - heptanoic Acid The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7- (methanesulfonamido) heptanoate. is replaced by an equimolar amount of ethyl 7- (methanesulfinamido.) heptanoate (Example T) . The product of Step A is thus ethyl 7- [N- (4-acetoxy-nonyl) methanesulfinamido] heptanoate. The subsequent step yields 7- [N- (4-hydroxynonyl) methanesulfinamido] heptanoic acid. (B) .

EXAMPLE 22 Preparation of Methyl 7- [N- (4-Hydroxynonyl) methanesul- onamido Iheptenoate A solution of diazomethane (approx. 2.5 g. » 7- [Ν- ( 4-hydroxynonyl) methanesulfonamido] heptanoic acid (10.8 g., 0.03 mole) (Example 1, Step B) in ether (50 ml.). The resulting solution is allowed to stand at room tem-perature for 4 hours. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-[N-(4-hydroxynonyl) methanesulfonamido] heptanoate as a viscous oil.

EXAMPLE 23 Preparation of Decyl 7- [N- (4-Hydroxynonyl) methanesulfona- mido] heptanoate Using the method of Example 22 but substituting an ether solution of 1-diazodecane for the ether solution of diazomethane, there is obtained decyl 7- [N- (4-hydroxy-nonyl) methanesulfonamido] heptanoate, as a viscous oil.

EXAMPLE 24 Preparation of N- [ (2-Dimethylamino) ethyl] -7- [N- (4-hydroxy- nonyl) methanesulfonamido] heptanamide A solution of 7- [N- (4-hydroxynonyl)methanesul-fonamido] heptanoic acid (3.65 g., 10 millimoles) (Example 1, Step B) , triethylamine (1.74 ml., 12.5 millimoles) and distilled water (18 ml.) in acetonitrile (100 ml.) is treated with N-t-butyl-5-methyl-isoxazolium perchlorate (3.0 g., 12.5 millimoles). The resulting solution is evaporated in vacuo at 20-25°C. over 4 hours providing a tacky residue which is triturated with water (150 ml.) at 0-5°C. for 15 minutes. After decanting the aqueous phase, the oily residue is dissolved in benzene-ether 'V-[(1:1), 200 ml.]. The organic extract is dried over sodium sulfate, then evaporated in vacuo providing the desired "active ester".

A solution of 2-dimethylaminoethylamine (0.88 g 10 millimoles) in acetonitrile (25 ml.) is added to a solution of the "active ester" in acetonitrile (25 ml.) and the solution is stirred at 25°C. for 17 hours. The solvent is removed in vacuo, the residual oil is partitioned between ether (200 ml.) and water (200 ml.). The ether layer is extracted with 5% hydrochloric acid (2 x 50 ml.). The aqueous acid phase is made basic with aqueous sodium carbonate then extracted with ether. The ether extract is washed with brine solution (100 ml.), dried over sodium sulfate, evaporated in vacuo leaving the N- [ (2-dimethyl-amino) ethyl] -7- [N- (4-hydroxynonyl)methanesulfonamido] -heptanamide as a viscous oil.

EXAMPLE 25 Preparation of 7- [N- (4-Hydroxynonyl)methanesulfonamido] - heptanamide Using the method, of Example 24 but substituting an acetonitrile solution of ammonia for the acetonitrile solution of 2-dimethylaminoethylamine, there is obtained 7- [N- (4-hydroxynonyl)methanesulfonamido] heptanamide.

EXAMPLE 26 Preparation of 7- [N- (4-Acetoxynonyl)methanesulfonamido] - heptanoic Acid A mixture of 7- [N- (4-hydroxynonyl)methanesul-fonamido] heptanoic acid (10.9 g., 0.03 mole) (Example 1, Step B) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60°C. for 18 hours. The mixture is cooled*.**.* and taken up in 80 ml. of ethyl ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The crude product that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent. There is obtained 7- [N- (4-acetoxynonyl)methanesulfonamido] heptanoic acid as a viscous oil.

By substituting for the acetic anhydride used in Example 26, an equivalent amount of acetic formic anhydride, propionic anyhydride , butyric anyhydride, isobutyric anhydride, valeric anhydride, or pivalic anhydride and conducting the reaction as described in Example 21, there is obtained 7- [N- (4-formyloxynonyl) -sulfonamido] heptanoic acid, 7- [N- (4-propionyloxynonyl) -sulfonamido] heptanoic acid, 7- [ ^- (4-butyryloxynonyl) -sulfonamido] heptanoic acid, 7- [N- (4-isobutyryloxynonyl) -sulfonamido] heptanoic acid, 7- [N- (4-valeryloxynonyl) -sulfonamido] heptanoic acid, and 7- [N- (4-pivaloyloxynonyl) -sulfonamido] heptanoic acid, respectively.

EXAMPLE 27 Preparation of 7- N- [3- (1-Hydroxycyclohexyl) propyl] methane- sulfonamido heptanoic Acid The synthesis of this compound is carried out as described in Example 3 except that, in Step A, the 1-bromo-4 (R) -acetoxy-2-nonyne is replaced by an equimolar amount of 1-acetoxy-l- ( 3-bromo-l-propynyl) cyclohexane (Example U) . The product of Step A is thus ethyl 7-^N- [3- (1-acetoxy-cyclohexyl) -2-propynyl]methanesulfonamido^ heptanoate.

Anal. Calcd. for C -H_c.N0_S: 21 35 6 C, 58.72; H, 8„21; , 3.26; Found: C, 59.05; H, 8.39; N, 3.05.

The subsequent step yields 7-¾N- [3- ( 1-hydroxycyclohexy1) -2-propynyl]methanesulfonamidojheptanoic acid (B) .

Anal. Calcd. for C, 56.80; H, 8.13; N, 3.90; Found: C, 56.24; H, 8.52; N, 3.51.

The hydrogenation step(c) yields 7-^N- [3- (1-hydroxycyclo-hexyl) propyl] methanesulfonamido fheptanoic acid (C) .

Anal. Calc. for 17H33 05S: C, 56.17; H, 9.15; , 3.85; Found: C, 56.01; H, 9.48; , 3.73.

EXAMPLE 28 Preparation of 7-^N- [3- (1-Hydroxycyclooctyl) propyl ]methane- sulfonamidoj heptanoic Acid The synthesis of this compound is carried out as described in Example 3, except that, in Step A, the 1-bromo-4 (4) -acetoxy-2-nonyne is replaced by an equimolar amount of 1-acetoxy-l- (3-bromo-l-propynyl) cyclooctane (Example V). The product of Step A is thus ethyl 7-^ [3- (1-acetoxycyclo-octyl) -2-propynyl]methanesulfonamidojheptanoate. The subsequent steps yield 7-^N- [3- (1-hydroxycyclooctyl) -2-propynyl]methanesulfonamidoJheptanoic acid (B) and 7-^N- [3 ( 1-hydroxycyclooctyl) propyl] methanesulfonamido^heptanoic acid (C) .

EXAMPLE 29 Preparation of 7- [N- (4-Hydroxy-4-propylheptyl) methane- sulfonamido] heptanoic Acid The synthesis of this compound is carried out as described in Example 3, except that, in Step A, the 1-bromo 4 (R) -acetoxy-2-nonyne is replaced by an equimolar amount of l-bromo-4-acetoxy-4-propyl-2-heptyne (Example W) . The product of Step A is thus ethyl 7- [N- (4-acetoxy-4-propyl-2-heptynyl) methanesulfonamido] heptanoate . The subsequent steps yield 7- [N- (4-hydroxy-4-propyl-2-heptynyl) methanesulfonamido] heptanoic acid (B) and 7- [N- (4-hydroxy-4- propylheptyl)methanesulfonamido Jheptanoic acid (C).

EXAMPLE 30 [ Capsule Formulation 7- [N- (4-hydroxynonyl) methanesulfonamido] - heptanoic acid , .50 gm.

Stearic Acid (U.S. P. triple pressed) 125 gm.

Pluronic F-68 7.5 gm.

Corn Starch 125 gm.

The stearic acid and Pluronic are united in a Vessel and melted using water bath at 60-65°C. The sulfonamido] eptanoic acid is dispersed into the mixture and the corn starch is added with stirring which is continued until the mixture cools to ambient temperature.

The mixture is reduced to granules by screening and placed in a number 0. hard gelatin containing 307.5 mg. of total solids and 50 mg. of 7- [N- (4-hydroxynonyl) methanesulfo- A-namido] heptanoic acid per capsule.

EXAMPLE 31 Parenteral Formulation of a Multidose Solution for Intramuscular and intravenous Use 7-^N- [3- (1-hydroxycyclohexyl) propyl] ethanesulfonamido? - heptanoic acid 1 gm.

Tris (hydroxymethyl) aminomethane (Reagent Grade Tha ) q.s. to adjust solution to pH 7.4 Sodium chloride (U.S. P.) q.s. to yield isotonic solution Methylparaben 10 mg.

Propylparaben 1 mg.

Distilled water (pyrogen-free) . . . q.s. to 10 ml.

The 7^N- [3- (1-hydroxycyclohexyl) ropyl] methanesulfonamido^heptanoic acid suspended in about 6 ml. of the water is treated with tris (hydroxymethyl) aminomethane with stirring until the pH reaches 7.4. The methylparaben and propylparaben are added with stirring and sufficient sodium chloride added to produce an isotonic solution. After water is added to bring the final volume to 10 ml., the solution is sterilized by membrane filtration and placed into a vial by an aseptic technique. The solution contains 'the Tham salt of 7-^N- [3- (1-hydroxycyclohexyl) propyl ]methanesul-fonamido^heptanoic acid equivalent to 100 mg./ml. of the free acid.

EXAMPLE 32 Preparation of Suppositories 7- [N- (4 (S) -hydroxynonyl)methanesulfonamido] heptanoic acid 200 gm.

Butylated hydroxyanisole 82 mg.

Butylated hydroxytoluene 82 mg.

Ethylenediamine tetraacetic acid 163 mg.

Glycerine, U.S.P 128 gm.

Sodium chloride, microfine 52.5 gm.

Polyethylene glycol 6000 128 gm.

Polyethylene glycol 4000 1269 gm.

The polyethylene glycol 4000 and polyethylene glycol 6000 were placed into a vessel surrounded by a water bath at such a temperature as required to maintain the melted contents at 60-65°C. To the melt is added the butylated hydroxyanisole and butylated hydroxytoluene with stirring.

Then the ethylenediamine tetraacetic acid and microfine sodium chloride are added to and dispersed in the mixture. The 7- [N-4 (S) -hydroxynonyl) methanesulfonyl] heptanoic acid is then added and dispersed into the mixture. Finally, the temperature is lowered to 55-60°C. and the glycerine added and dispersed.

While maintaining the temperature of 55-60°C. and continuous mixing, the melt is dispersed into plastic suppository cavities of a conventional suppository cold-molding device. The suppositories thus prepared -..contain a total of 1.7778 gm. of contents of which 200 mg. are 7- [N- (4-hydroxy-8 , 8-dimethylnonyl)methanesulfonamido] -heptanoic acid. 44636/2

Claims (1)

1. CLAIMS 1. Compounds of the general formula: 2(CH2)2R wherein R is carboxy, a carboxy salt, or derivatized carboxy having the formula: -COOY, -CONHR wherein Y is alkyl having 1-10 carbon atoms; and R is diloweralkylaminoalkyl having 4-7 carbon atoms; A is ethylene, trimethylene , a-methylethylene , β-methylethylene , a ,a-dimethylethylene , β , β-dimethyl-ethylene, or oxymethylene ; Z is ethylene, vinylene, or ethynylene; R^ is methyl, ethyl, propyl or isopropyl; R2 i.s hydrogen, methyl, ethyl or propyl; 3 R is hydrogen or loweralkanoyl ; 4 each R is independently hydrogen or methyl; R^ is hydrogen, lower alkyl 1-4 carbon atoms either straight or branched, vinyl or 2 , 2 , 2-trifluoroethyl ; 5 2 or R and R can form together an unbranched chain of the formula ~(CH2)n~ wherein n is an integer from 1 to 5; and y is 1 or 2. 44636/2 2. Compounds according to Claim 1 wherein R carboxy or a carboxy salt having the formula: wherein Me® is a pharmaceutically acceptable cation derived from a metal or an amine. 3. Compounds according to Claim 2 which have the general formula: R1-S02-N- (CH2) 4-A-COOH CH2-Z-Q-C (R4)CH2CH2R5 H OH wherein R1 is methyl, ethyl, propyl or isopropyl; A is ethylene, trimethylene , a-methylethylene , β-methylethylene , a ,a-dimethylethylene , β , β-dimethyl-ethylene, or oxymethyene; Z is ethylene, vinylene , or ethynylene; 4 R is hydrogen or methyl; 5 and R is hydrogen, loweralkyl, vinyl, or 2 , 2 , 2-trifluoroethyl . 4. The compound of Claim 3 wherein A is ethylene or oxymethylene. 5. The compound of Claim 4 wherein R^" is methyl or ethyl. 6. The compound of Claim 5 wherein Z and A are ethylene, and R 4 is hydrogen and R5 is ethyl. r 7. 7-fN- (4-Hydroxynonyl)methanesulfonamido] -heptanoic acid, the compound of Claim 6 wherein R^" is methyl. 8. The compound of Claim 7 wherein ^" is methyl and the carbon atom bearing the hydroxy group is in the R configuration. 9. The compound of Claim 7 wherein R^" is methyl and the carbon atom bearing the hydroxy group is in the S configuration. 10. 7- [ - ( 4-Hydroxynonyl) ethanesulfona ido] -heptanoic acid, the compound of Claim 6 wherein ^ is ethyl. 'S 11. 4- [N- (4-Hydroxynonyl)methanesulfonamido] -butoxyacetic acid, the compound of Claim 5 wherein A is 1 4 oxymethylene, Z is ethylene, and R is methyl, R is hydrogen and R~* is ethyl. 12. 7- [N- (4-Hydroxy-2-nonynyl)methanesulfon-arnido] heptanoic acid, the compound of Claim 5 wherein A 1 4 is ethylene, Z is ethynylene, R is methyl, R i_3 5 hydrogen and R is ethyl. 13. 7- [N- ( 4-Hydroxy-9 , 9 , 9-trifluorononyl) -methanesulfonamido] heptanoic acid, the compound of Claim 5 ! 4 wherein A and Z are ethylene, R is methyl, R is hydrogen, and ^ is 2 ,2 ,2-trifluoroethyl. 14. 7- [N- (4-Hydroxy-8-nonenyl)methanesulfon-amido] heptanoic acid, the compound of Claim 5 wherein A 1 4 and Z are ethylene, R is methyl, R is hydrogen and 5 . R is vinyl. 4 15. .The compound of Claim 5 wherein R is 5 hydrogen and R is straight chain loweralkyl having 2-4 carbon atoms . 16. 7- [N- ( 4-Hydroxyundecyl) methanesulfonamido] -heptanoic acid, the compound of Claim 15 wherein A and Z 1 5 are ethylene, R is methyl, and R is butyl. 17. 7- [N- (4-Hydroxy-8 , 8-dimethylnonyl) methanesulfonamido] heptanoic acid, the compound of Claim 5 1 4 wherein A and Z are' ethylene , R is methyl, R is hydrogen and R5 is tert-butyl. The compound of Claim 3 which has the formula: R -S02- wherein A is ethylene, trimethylene , a-methylethylene , β-methylethylene , a ,a-dimethylethylene , β ,0-dimethyl-ethylene, or oxymethylejie; R^" is methyl, ethyl, propyl or isopropyl; 9 and R is hydrogen, loweralkyl of 1-4 carbon atoms, or 2 ,2 ,2-trifluoroethyl. [N- (4-Hydroxy- (E) -2-nonenyl) methanesulfon-a ido] heptanoic acid, the compound of Claim 18 wherein A 1 9 is ethylene, R is methyl and R is ethyl. The compound of Claim 2 which has the formula: R -S02-N-(CH2)4-A-COOH CH -Z-C-(CH_) _-R5 2 / \ 3 H OR in which R^" is methyl, ethyl, propyl, or isopropyl; A is ethylene, trimethylene , a-methylethylene , β-methylethylene , a ,a-dimethylethylene , β , β-dimethyl-ethylene, or oxymethylene; Z is ethylene, vinylene, or ethynylene; R^ is hydrogen, loweralkyl, vinyl or 2,2,2- 3 trifluoroethyl; and R is loweralkanoyl or hydrogen. 21. 7- [N- (4-Acetoxynonyl) methanesulfonamidp] -heptanoic acid, the compound of Claim 20 wherein A and Z 1 v 5 3 are ethylene, R is methyl, R is ethyl, and R is acetyl. A compound of Claim 3 which has the formula R1-S02-N- (CH2) 4-A-COOH CH2~Z-C^C (CH3) 2CH2CH2R5 H OH wherein R^" is methyl or ethyl; A is ethylene or oxymethylene; Z is ethylene or vinylene; and 5 R *is loweralkyl of 1-4 carbon atoms. 23. 7- [N- (4-Hydroxy-5 , 5-dimethylnonyl) methane-sulfonamido] heptanoic acid, the compound of Claim 22 wherein R^" is methyl, A and Z are ethylene and R^ is ethyl. 24. A compound of Claim 2 which has the formula: wherein R1 is methyl or ethyl; 2 R is' methyl, ethyl or propyl; A is ethylene or oxymethylene; Z is ethylene or vinylene; 3 R is hydrogen or loweralkanoyl; and 5 R is hydrogen and loweralkyl or 1-4 carbon atoms. 25. 7- [N- (4~Hydroxy-4-methylnonyl)methane-sulfonamido] heptanoic acid, the compound of Claim 24 wherein R1 is methyl, A and Z are ethylene, R^ is hydrogen, 5 2 R is ethyl and R Is methyl. 26. 7- [N- (4-Hydroxy-4-propylheptyl) methane-sulfonamido] heptanoic acid, the compound of Claim 24 1 2 wherein R is methyl, and Z are ethylene, R is propyl, 3 5 R * is hydrogen and R is hydrogen. 44636/2 27. The compound of Claim 2 which has the formula: R1-S02 n' wherein ,R is methyl, ethyl, propyl or isopropyl; A is ethylene, trimethylehe, a-methylethylene , β-methylethylene , a ,a-dimethylethylene , β , β-dimethylethylene or oxymethylene; Z is ethylene or ethynylene, and n' is an integer of 2 to 6. 28. 7-{N- [3- (1-Hydroxycyclohexyl) propyl] methane-sulfonamido^heptanoic acid, the compound of Claim 27 wherein A and Z are ethylene, R^" is methyl and n1 is 3. 29. 7- N- [3- (1-Kydroxycyclohexyl) -2-propynyl] -methanesulfonamido^heptanoic acid, the compound of Claim 27 v/herein A is ethylene, Z is ethynylene, is methyl and n' is 3. 30. [3- (1-Hydroxycyclooctyl) ropyl ] methane-sulfona idoj-heptanoic acid, the compound of Claim 27 wherein A and Z are ethylene, R1 is methyl and n' is 5. 44636/2 31. The process of preparing a compound having the formula I in Claim 1, which comprises reacting a compound of the formula: R1-SOy-NH-(CH2)4-A-COOR8 III Y is 1 o¾ 2 wherein R and Ά are as defined in Claim 1,/and R is loweralkyl of 1-5 carbon atoms; with about an equivalent of sodium hydride, and then reacting the sodium salt of the compound of formula III, thus obtained, with approximately afeoet an equivalent of the compound: 2CH2CH2R5 2 4 5 wherein X is halogen, Z, R , R and R are as defined in 3 Claim 1, and R is loweralkanoyl of 1-4 carbon atoms at a temperature of about 50-100°C for about 1 to 20 hours; 44636/2 recovering the intermediate product thereby produced, g subjecting it to mild basic hydrolysis to remove the R 3 and R blocking groups, and recovering the desired product of formula I in Claim 1. 32. The process of Claim 31 wherein A is ethylene. g 33. The process of Claim 32 wherein R is ethyl, and R2 is acetyl. : 34. The process of preparing the compound of the formula: wherein A is ethylene, trimethylene , a-methylethylene , β-methylethylene', a ,a-dimethylethylene , (3 ,β-dimethylethylene , or oxymethylene R1 is methyl, ethyl, propyl, or isopropyl; Z is ethylene, vinylene or ethynylene; R is hydrogen or methyl; ; g R is hydrogen, loweralkyl, or 2 , 2 , 2-trifluoro- ethyl; and y is 1 or 2; which comprises reacting a compound of the * formula: R1-SOy-NH-CH2-Z-CH-C (R4) 2„CH2CH2-R9 VvIxI OR10 1 wherein R is methyl, ethyl, isopropyl or propyl; y is 1 or 2; Z is ethylene, vinylene or ethynylene; 44636/2 ethyl; and R ° is tetrahydropyranyl; with about an equivalent of sodium hydride and then reacting the sodium salt of the compound of formula VII thus obtained, with approximately about an equivalent of the compound: X- (CH2) 4-A-C00R 8 wherein X is halogen, A is as defined, and R is loweralkyl of 1-5 carbon atoms) at a temperature of about 50-*100eC for about 1 to 20 hours; recovering the intermediate product thereby produced, subjecting the latter to mild hydrolysis to 8 10 remove the R and R blocking groups, and recovering the desired product of formula X above. 35. A composition comprising the compound of Claim 1 in a non-toxic pharmaceutically acceptable carrier. The composition of Claim 35 which is suitable for oral administration in tablet form. The composition of Claim 35 which is suitable for oral administration in capsule form. The composition of Claim 35 which is suitable for parenteral administration. The composition of Claim 35 which is suitable for use in suppository form.