IL40183A

IL40183A - Tetrazolyl derivatives of naturally occurring prostaglandins

Info

Publication number: IL40183A
Application number: IL40183A
Authority: IL
Original assignee: Pfizer
Priority date: 1971-09-01
Filing date: 1972-08-22
Publication date: 1977-06-30
Also published as: DK144730C; ATA51974A; ES417558A1; CA978939A; SE7606690L; FI55497C; PH10416A; IL48544A; PH10443A; ATA743472A; FR2283136A1; SE7606691L; FR2283147B1; AT327219B; SE409032B; FR2283147A1; SE421526B; ES406250A1; IL40183A0; IL48544A0

Abstract

Title compds. are of formula (I): where R = or ; A = alpha-OR3 where R3 = H or THP or B=H or A and B form a single bond; Y = a single or trans-double bond; X and Z = single or cis-double bonds, and if Z = cis-double Y is trans-double and X is cis-double; R' = H or l.alkyl, R2 = H or THP, and THP = tetrahydropyranyl. I have prostaglandin-like actions with prolonged activity. I are prepd. by reacting the novel reagent. II (prepd. from Ph3P(CH2)4CN with NaN3/NH4Cl/LiCl/DMF, followed by NaH), with 2- 5 alpha-hydroxy-3 alpha(OTHP)-2 beta-(3 alpha(OTHP)-trans-oct-1-ene 1-yl) cyclopent-1 alpha-yl aldehyde gamma-hemiacetal the oct-1-yl analogue, or the corresp. l.alkyl derivs. as required for I, and transforming the subsequent intermediate, by methods usual to prostaglandin chemistry. [FR2283134A1]

Description

Tetrazolyl derivatives of naturally occurring prostaglandins ER INC This invention relates to certain novel analogs of the naturally occurring prostaglandins In it rela tes to novel and certain novel trahydropyranyl derivatives useful as intermediates in their The prostaglandins are unsaturated fatty acids which exhibit diverse physiological For the prostaglandins of the E and A series are potent vasodilators Acta 1 65 and et Life relaxant effect on small blood vessels probably accounts for the fall in systemic arterial blood pressure observed on intravenous injection of PGEi and and Federation Proc Bergstrom et et Acta and et Acta Scand 75 Another well known physiological action for and is as a bronchodilator Another important physiological role for the natural prostaglandins is in connection with the reproductive known to possess the ability to induce labor et 77 and also to induce therapeutic abortion et in Patents have obtained for several prostaglandins of the E and F series as inducers of labor in mammals Patent 75 and West German and on and for control of the reproductive cycle African Patent Still other known physiological activities for are in the inhibition of gastric acid secretion and Worcester on Prostaglandins New 55 and also of platelet aggregation et al It is now known that such physiological effects will be produced in vivo for only a short following the administration of a A substantial body of evidence indicates that the reason for this rapid cessation of activity is that the natural prostaglandins are quickly and efficiently metabolically deactivated by of the carboxylic acid and by oxidation of the group et references cited the It of considered desirable to create analogs of the prostaglandins which would have physiological activities equivalent to the natural but in which the selectivity of action and the duration il of the activity would be The novel of the in which the carbcxylic is vith the and in vhich the be replaced by a alkyl if satisfy the above they possess activity profiles comparable to the parent prosta and they exhibit a longer duration of action than the parent This invention comprises the tetrazolyl analogs of PGF and the alkyl derivatives of and This invention further useful for these as a of the structur vherein R is hydrosen or lover alkyl and is a of the vherein R is hydrosen or lover and is a of the 2 As shown in Reaction Scheme Hemiacetal I is caused to react with the novel ττ e novel reagent II to produce the tetrazolyl analog of the ether of Details of the preparation of novel ττ novel reagent II are gxven xn the appended example and copending Application To produce the alkyl derivatives of all of the above mentioned prostaglandin tetrazo one merely employs hemiacetal I or the hemiacetal VI with a lower alkyl moiety in the 15 position and proceeds as above to produce the desired To produce the alkyl derivatives of all of the above mentioned prostaglandin one merely employs hemiacetal I or the hemiacetal VI vith a lower alkyl moiety in the 15 position and proceeds as above to produce the desired To produce and hemiacetal VIII is employed as the starting material and all of the other reaction steps are identical to those given induced bronchospasm in guinea values of were obtained for both and In the test for effects on dog blood both PGEp j tetrazoyl were found to be depressors and values of and were obtained on the two compounds as the threshold dose for this In the case of rat blood the compounds were also depressors and the threshold dose for for was That the duration of the action of the tetrazoyl analogs i J is increased over that of the parent prostaglandin is clearly illustrated by the data in Table 1 This experiment demonstrates that a comparable drop in the blood pressure of anesthetized dogs was achieved with a comparable administered dose of the natural prostaglandin or tetrazoyl j In the case of the tetrazoyl while the size of the dose must be to achieve an equivalent drop in blood the length j of time that this reduced pressure is maintained is increased The new compounds of this invention can be used in a variety of pharmaceutical preparations which contain the compound or a salt and they may be administered by a variety of such as oral and topical including and intranasal among The natural prostaglandins are well known agents for the induction of and it can be reasonably predicted that the will share this For such an aqueous suspension of tetrazoyl or could appropriately be administered at a level of from about for or for with from oral doses per day being employed in either case If an intravaginal treatment for abortion induction is a suitable agent might be a sterile ethanolic solution of either of these two or lactose tablets of the same two In such suitable doses could be about 15 for or from about 55 for with 1 or 2 doses being In cases midterm abortion is an effective agent might be an solution of administered as an intravenous A suitable dosage could be from about administered for a period of from about Another proposed use for the is as an inducer of For this purpose an solution of might j j be employed as an intravenous infusion in the amount of from about 3 for from about 1 Still other applications which might be hypothesized for the prostaglandins on the basis of the uses of the natural prostaglandins are to produce bronchodilation or to increase nasal An appropriate dosage form for this use would be an aqueous ethanolic solution tetrazoyl employed as an aerosol using fluorinated hydrocarbons as propellant in the amount of from about A use for is as an ant For such a treatment an ethanol solution of the drug could appropriately be administered as an intravenous infusion at about for a total dose of from about t v c x other forms various excipients or carriers i may be Such for magnesium vegetable benzyl polyalkylene petroleum and other known carriers for If these pharmaceutical compositions may contain auxiliary substances such as preserving wetting stabilizing or other therapeutic agents such as The following examples are merely and in no way limit the scope of the appended EXAMPLE I A mixture of romovaleronitrile I phosphine and toluene was heated to reflux with was cooled with dimethylformamide and the combined filtrate and washings were concentrated The oily residue was crystallized from water i at and air dried to give a white crystalline solid The product was recrystallized from to give white prisms j An analytical sample was prepared by recrystallizatic i from to give a white crystalline which was i for 5 35 Further details on the preparation of these novel mediates will be found in copending Application hy EXAMPLE The product of Example V stirred with formic acid for 2 The resulting mixture was diluted with i The aqueous mixture was with three portions of ethyl The extract was dried and concentrated j i to give a crude oil Chromatography of the j crude product on acidic silica gel using mixtures of chloroform and methanol as the eluent to separate the desired product as a colorless oil and an unidentified product Thin layer chromatography of the product on silica gel glass plates developed with acid 5 showed single spot acid with an The infrared of the showed a strong absorption band at 1710 cm in a and a moderately weak band at cm i i The uv spectrum of the product exhibited an absorption maximum at 222 This product is j After filtrat on of the resul an so s he ra e was extracted ί i with ethyl acetate The combined ethyl acetate extracts were washed with i water were dried magnesium and were concentrated to afford O of a oily This oil was purified by column chromatography on silica gel j i Reagent using a mixture of methylene ethyl acetate as After elution of higher impurities of the desired diol was collected Thin layer chromatography of the diol product on silica gel glass plates using a mixture of methylene methanol as eluent showed a single spot having an Rf The ir spectrum of the diol exhibited a strong absorption at cm for the lactone The nmr spectrum of the diol product exhibited a multiplet at 5 for the olefinic a multiplet at for the a multiplet at for the a j I singlet at for the and multiplets at for the remaining j To a cooled in of of the chromatographed of Example XI in of methylene chloride vras added of dihydropyran from lithium aliuninum and of acid The solution was stirred in the cold j for minutes then diluted with The organic solution was washed with saturated sodium bicarbonate was dried magnesium j and was concentrated to afford of the oily j ether 1 which was used without further Thin layer chromatography of the oily product on silica gel glass plates using 5 methanol in methylene i chloride as eluent showed a single spot having an The structure i of the product was substantiated by the virtual identity of its ir spectrum with that of the known compound reference for Example j EXAMPLE XIV To a solution of o the bromide of Example I in dimethyl sulfoxide was added dropwise of a M sodium methylsulfinylmethide To the resultant red solution was added dropwise over a 20 minute period a solution of of the chromatographed hemiacetal of Example XIII in of dimethyl The solution was stirred for an additional hours then was poured onto of ice The aqueous solution was acidified to pH 3 with 10 hydrochloric The aqueous layer was then extracted with ethyl acetate the combined organic extracts were dried magnesium and concentrated to afford an oil weighing This oil was purified column chromatography on o of silica gel Reagent using 10 ethyl acetate in chloroform as After elution of higher of starting hemiacetal were Further elution afforded yield based on unrecovered starting hemiacetal of the oily product pentane called compound Thin layer chromatography of the oily product on silica gel glass plates using methanol in methylene chloride as showed a single spot having an The structure of the product was confirmed by the virtual identity of its ir spectrum with that of the compound Example The above compound A may be converted by the process of Example VI to an intermediate which can be converted by the process of Example VII to dihydro or by the process of Example XIV above to another important This last named intermediate may be converted by the process of Example XVH to et l The l converted by the method of Example IX to The important intermediate compound A may also he converted by a modified process of Example VI the reaction temperature is i to called compound Compound B may be converted by the process of Example XV to Compound B above may be converted by the process of Example XIV to an another important which may be further converted by the process of Example XVII to I The tetrazoyl analog of may be converted by the process of Example IX to the I EXAMPLE XV A solution of of the bis ether of Example XIV in of a mixture of acetic water was stirred at for hours then was concentrated by rotary The crude oil was purified by column chromatography on silica gel using 5 methanol in j chloroform as A portion of the oily j 3 was j The structure of the oily was substantiated by the virtual identity i of its ir spectrum with that of the known compound Example This compound is the the Compound C above may also be converted by the processes of Examples i V to the j ί Compound C above may be converted by the process of Example IX to j the EXAMPLE XXII V Preparation of A heterogeneous mixture of 148 of a crude sample of 15 of absolute and 45 of was stirred at under one atmosphere of The catalyst was to insure accurate following of the hydrogen After about two 10 of hydrogen had been taken The mixture was filtered and concentrated to afford a colorless oil weighing 100 Thin layer chromatography indicated the presence of a spot having an Ef identical to that of in trace An nmr of the oil showed the presence of substantially more trans olefin than cis The 25 of and 10 of absolute methanol were again stirred at under one atmosphere of After 30 minutes of stirring an additional 5 of hydrogen had been taken The mixture was filtered and concentrated to afford a colorless oil weighing 96 The oil was purified by column chromatography on silica Fourteen fractions were eluted with ethyl Then 10 fractions were eluted with methanol in ethyl Concentration of fractions afforded a trace amount of an oil called Concentration of fractions afforded a colorless oil called weighing 20 Concentration of fractions afforded a colorless oil called weighing 22 Concentration of fractions afforded a colorless oil called in a trace amount nmr Studies revealed that oil was compound II because was present and was insufficientOCRQuality

Claims

C L A I M S

1. Prostaglandin compounds of the formula: wherein H M is ^.C- -hydroxy or ^C=0, A is c-OR3 wherein R3 is hydrogen or tetrahydro-pyranyl and B is hydrogen, or A and B when taken together form an additional C-C bond, X is a single bond or a cis double bond; Y is a single bond or a trans double bond, with the proviso that when Y is a single bond X is a single bond, Rl is hydrogen or a lower alkyl group, and 2 is hydrogen or a tetrahydropyranyl . group.

2. A compound according to claim 1 of the formula: and th or X is a single bond or a cis double bond; Y is a single bond or a trans double bond with the proviso that when Y is a single bond, X is a single bond; A and B when taken together form a single bond or A is -o-hydroxy when B is hydrogen with the proviso that when A and B are taken together to form an additional C-C bond, M is^X!=0.

3. A compound according to claim 1 of the formula and the corresponding. C15-epimer, -wherein -THP is tetrahydro- pyran-2-yl and X and Y are as defined in claim 1.

4. A compound according to claim 1 of the formula: and the corresponding C^g. epimer, wherein X, Y and THP are as defined in claim 1.

5. The compound of claim 1, wherein said prostaglandin is PGE

6. The compound of claim 1, wherein said prostaglandin is 13 , 14-dihydro PG

7. The compound of claim 1, wherein said prostaglandin is 13 , 14-dihydro PGE-

8. The compound of claim 1, wherein said prostaglandin is PGF .

9. The compound of claim 1, wherein said prostaglandin is PGE2.

10. The compound* of claim 1, wherein said prostaglandin is PGA- .

11. 2-Descarboxy-2- (tetrazol-5-yl) -15-loweralkyl PGF2e<

12. 2-Descarboxy-2- (tetrazol-5-yl) -15-loweralkyl PGE,,.

13. A process for preparing a compound of the formula: wherein A . is <*-0R3 wherein R^ is hydrogen or tetrahydro- 'pyranyl and . B is hydrogen, or A and B when taken together form an additional C-C bond, X is a single bond or a cis double bond; Y is a single bond or is a trans double bond, with the proviso that when Y is a single bond X is a single bond, . , . RJI is hydrogen or a lower alkyl group, and R2 is hydrogen or a tetrahydropyranyl group; characterized by the fact that a) when A is wherein R3 is hydrogen and B is hydrogen M is ^C-°-hydroxy or . ~^:c=0 , R2 is hydrogen, and R-^, X and Y are as defined above, said compound is prepared by treating a compound of the Formula I, above, wherein B, M, R^, X and Y are as defined above, A is (^-OR^ wherein R3" is "tetrahydropyranyl and" R2 is tetrahydropyranyl, with dilute acetic acid; 40183/2 A is °-OR3 wherein is hydrogen and B is hydrogen, M is ^0=0 is hydrogen, and ...!-B^, X, and Y are as defined above said compound is prepared by treating a compound of Formula I above jwherein B, R, , X and Y are as defined above H 1 — » M is.^C-Ol-hydroxy , A. is -GRj wherein R^ is tetrahydropyranyl and ^ is tetrahydropyranyl with chromic acid in acetic acid; c ) when A and B when taken together form an additional C-G bond M is ^C=0 is o(-hydroxy and R^, X and Y are as defined above, said compound is prepared by reacting a compound of Formula wherein = A is c<-0R3 wherein R-j is hydrogen, B is hydrogen ' M is ^ =0 2 is -hydroxy and R^, X and Y are as defined above with formic acid A is oi-OR^ wherein R3 is tetrahydropyranyl and B is hydrogen , R-, is hydrogen or lower a kyl , \ ·' . j is tetrahydropyranyl, 40183/2 formula wherein and Y are as defined above, and Rj and R3 are tetrahydropyranyl , with an ylid of the formula: Na (+) e) when A is £~0R3 wherein R3 is tetrahydropyranyl and B is hydrogen M is ^?-<<-0H ^ is hydrogen or lower alkyl R2 is tetrahydropyranyl X is a cis double bond or a single bond when Y is a single bond or Y is a trans double bond when X is a single bond , said compound is prepared by selective reduction of the compound formed in step (d) , f) when A is £<-0R3 wherein R3 is tetrahydropyranyl and B is hydrogen, 40183/2 R2 is tetrahydropyranyl, X and Y are double bonds or single bonds, and said compound is prepared by treating the compound resulting from steps (d) and (e) with chromic acid in acetic acid. -42-