FI58327C - FRAMEWORK FOR THE PROCESSING OF THERAPEUTIC ANALYTICAL N-SUBSTITUTE PROSTAGLAND-CARBOXAMIDER - Google Patents

Description

r, ANNOUNCEMENT C 07 -) - 7 -w <11) uTLÄG6NINGSSKIIIFT / W) fa tent ne id e 1a1 '(si) Kv.ik.3 / int.a.3 c 07 C 177/00 FINLAND —FIN LAND ( 21) P * t * n «tW» «k * mu * - PactnaMdknlnf 1762/73 (22) Htfcemltpiivi - Ameknlngad ·! 30.05 · 73 (23) STARTUP · —G (M | h «tsdt | 30.05.73 (41) Tulhit julklMkil - Blivlt cffmtllg 0 8.12.7 3

Patent / a rakirterlhallltuf (44s Nihti »iiaip« »ioo jt kuLjuiiuiiun date -

Patent and Regulatory Authorities Published by the United States 30.09.80 (32) (33) (31) «ueik * M * —BagftH prtorim 07.06.72 USA (US) 260518 (71) Pfizer Inc., 235 East U2nd Street, New York 17, NY, USA (72) Thomas Ken Schaaf, Old Lyme, Connecticut, Hans-Jiirgen Ernst Hess,

Old Lyme, Connecticut, USA, Leonard Joseph Czuba, Canterbury,

This invention relates to a process for the preparation of N-substituted prostaglandin carboxamides. In particular, it relates to a process for the preparation of new N-substituted prostaglandin carboxamides, wherein the substituent in these new compounds is alkanoyl having 2 to 5 carbon atoms, cyclopropionyl, benzoyl, methanesulfonyl, thiophenesulfonyl, benzenesulfonyl or toluenesulfonyl.

Prostaglandins are C-20 unsaturated fatty acids with various physiological effects. For example, E- and A-series prostaglandins are potent vasodilators (Bergstrom, et al., Acta Physiol. Scand. 6U: 332-33, 1965 and Bergstrom, et al., Life Sci. 6: 449-445, 1967). and lower systemic blood pressure when administered intravenously (Weeks and King, Federation Proc. 23: 327, 1964; Bergstrom, et al., 1965, op. cit .; Carlson, et al., Acta Med.

2 58327

Scand. 183: ^ 23- ^ 30, 1968; and Carlson, et al., Acta Physiol. Scand. 75: 161-169> 1969) · Another well-known physiological effect in the context of PGE2 and PGE2 is bronchodilation (Cuthbert, Brit. Med. J. 1+: 723-726, 1969).

Yet another important physiological role in the context of naturally occurring Prosta glandins is in the context of the reproductive cycle. PGE2 is known to have the ability to induce labor (Karim, et al., J. Obstet Gynaec. Brit. Cwlth. 77: 200-210, 197Ο), to induce therapeutic miscarriage (Bygdeman, et al., Contraception, 1+, 293 ( 1971) and is useful in regulating fertility (Karim, Contraception, 3, 173 (1971)) · Patents have been granted for various prostaglandins of the E and F series as pathogens in mammals (Belgian patent T? B 158 and German patent 2 03 ^ 6U1 ) and PGFβ, -F 2 and -F 2+ to control the reproductive cycle (South African Patent 69/6089).

Still other known physiological effects of PGE2 include inhibition of gastric acid secretion (Shaw and Ramvell, In: Worcester Symp. On Prostaglandins,

Nev York, Wiley, 1968, pp. 55-61 +) and also inhibition of platelet aggregation (Emmons, et al., Brit. Med. J. 2: U68-i + 72, 1967) ·

It is now known that such physiological effects occur in vivo only shortly after prostaglandin administration. A substantial body of evidence indicates that this rapid cessation of activity is due to the rapid and efficient metabolic inactivation of naturally occurring prostaglandins due to carboxylic acid side chain β-oxidation and oxidation of the 15α-hydroxyl group (Anggard, et al., Acta. Physiol. Scand. 81, 396 (1971) and its papers).

Thus, it was, of course, highly desirable to provide analogs of prostaglandins that have the same physiological activities as naturally occurring compounds, but with greater selectivity and duration of action. The greater selectivity of action is expected to eliminate a number of side effects, especially intestinal side effects often observed with systemic administration of naturally occurring prostaglandins (see Lancet, 536, 1971) ·

The novel compounds according to the invention, the N-substituted prostaglandin carboxamides in which the carboxylic acid moiety has been replaced by an N-substituted carboxamide and in which the 15 / i-hydrogen can be replaced by a 15 / methyl group if desired, satisfactorily satisfy the above requirements. They have a highly selective activity compared to basic prostaglandins and in many cases have a longer duration of action. A good example of the therapeutic significance of these Prosta-glandin analogs is the effect of N-acetyl-prostaglandin-N-carboxamide as a selective aerosol bronchodilator.

The present invention relates to a process for the preparation of a novel therapeutically useful Prostaglandin compound of formula W 0

j / M "-y C-NHR

/ ^ y ^ \ / R2 I

H ° R

R1 OH

wherein R is alkanoyl of 2 to 5 carbon atoms, cyclopropionyl, benzoyl, methanesulfonyl; thiophenesulfonyl, benzenesulfonyl or toluenesulfonyl, is hydrogen or methyl; R 2 is -C (CH 2) or -C (CH 2) 2; W is a single bond or a cis double bond, Z is a single bond or a trans double bond; M is = O or -C, iiOH, characterized in that the compound of formula W 0

^ M '"y"' '"".' ^^ '- C-NHR

THP 0 R 1 wherein R, R, R, W, M and Z are as defined above and THP is 2-tetrahydropyranyl is reacted with aqueous acetic acid.

Numerous in vivo and in vitro experiments have shown that prostaglandin N-substituted carboxamide analogs have the same physiological activities as naturally occurring prostaglandins. These experiments included experiments to investigate the effects on isolated guinea pig uterine smooth muscle, dachshund colon, guinea pig ileum, and rat uterus, to prevent histamine-induced bronchospasm in guinea pigs, to determine effects on canine blood pressure, and to prevent fertility in hamsters.

The physiological reactions observed in these experiments are useful in assessing the potential utility of these agents for the treatment of various natural and * 58327 pathological conditions. Potential utility has been identified when the test substance has a selective activity profile comparable to naturally occurring prostaglandins E1 and F1 (see Table I below).

For example, N-acetyl-13,11-dihydroprostaglandin-E.] Carboxamide has as strong a hypotensive effect when studied in dogs as PGE2, but with a longer duration of action. In addition, the anticonvulsant effects on various smooth muscle preparations were significantly less with N-acetyl-13,1β-dihydroprostaglandin-Eβ-carboxyamides than with PGE4. Thus, N-acetyl-13,1U-dihydroprostaglandin-N-carboxamide is more preferred than PGE2 as a selective hypotensive agent.

Table I

Threshold doses for antispasmodic effects Test compound in isolated smooth muscle ng / ml

Rat Guinea Pig Guinea Pig

Prostaglandin R uterus uterus ileum colon 1. PGE2 - 10-30 0.1-1.0 10-30 10-30 2. PGF2 - 10-30 1-10 10-30 25 ~ 50 3. PGEg acetyl 500-1000 3 100-500> 1000 ^. 13,1U-dihydro-PGE1 acetyl> 1000 -> 1000> 1000 5-PGF2e (_acetyl - 30-100 600-1000 6. PGE2 propionyl 1000 1 10 7 · PGE2 cyclopropylcarbon-250-500-500 nyl 8. PGF0. cyclopropylcarbonyl 1000-1000 nyl 9. PGE2 pivaloyl 50-100 1-3 500 10. PGE2 methanesulfonyl 10-30 3-6 30-60 30-60 11. PGF2et methanesulfonyl £ 1000 1000 21000> 1000 12. PGE2 p-toluenesulfonyl 100 -500 -> 1000 13. PGF2e ^ p-toluenesulfonyl 100 -> 1000 1 ^ PGE2 benzenesulfonyl 100-300 - 100 15. PGF2eC benzenesulfonyl 100 - 100 16. PGEq methanesulfonyl - 100-300 30-100 17 · 15_methylmethanesulfonyl 100 -300 0.3-1 30 pge2 18. PGEg 2-thiophenesulfonyl - 600-1000 60-100 19 · PGFg 2-thiophenesulfonyl - 600-1000 600-1000 20. PGFg, 2-methanesulfonyl 1000 3-10 1000 21. 16 , 16-dimethylmethanesulfonyl 30 0.3 li-PGE2 22. 16,16-dimethylacetyl 300-1000 0.3-li-PGE2 (continued) 5 58327.

Histamine ai- Threshold dose affected- Relative force-: obtained lung anesthetized dog taste (PGE ^ = 100) tube spasm to blood pressure pressure ·, · ·, ^ «//, · diarrhea in guinea pig protective- £ g / kg l.v. administration to a mouse at 100 g / ml (-) - lowers the pressure hd 't 11 aerosol dose (+) - raises the pressure * 50 ^ 1S ee e j

Test compound 2 »00 j

Prostaglandin___ ____i _ j 1, 75-85 0.16 (-) 100: 2. - 1.2, ¾ (+), 10 (-) 10! 3. 65-75 0.16 (-) 150; U. 30-35 0.08 (-) -! 5. - - 80 j

6. 7U J

7- 59 10 (+) '8. - 10 (+) 9 · 0 no reaction at doses; £ 20 10-20; 10. 0 10 (-) 33 11. - no reaction at doses of £ 20 12. 19 no reaction at doses of £ 20 13. - no reaction at doses of £ 20 1J +. 0 no response at doses of £ 20 15. - no response at doses of £ 20 16. 0 - 17. 1 + 3 - 900 18. 0 - 19. - - 20. 0 no response at doses no reaction at £ 1 »0 at 1 mg.

21. 28 - 2 700 22. 2k - 1 100 X · · ♦

The numbers and R-substituents of the compounds correspond to the information given at the beginning of the table.

• s 6 58327 N-acetyl-prostaglandin-Eg-carboxamide, N-propionyl-prostaglandin-Eg-Eg and N-cyclopropylcarbonyl-prostaglandin-Eg-carboxamide have similar activity to PGEg (TO and 59, respectively 80%) in protecting guinea pigs from histamine. against bronchospasm. However, as carboxyamide analogs, they have significantly less spasmogenic effects on various smooth muscle preparations than PGEgt. In addition, N-acetyl-prostaglandin-Eg-carboxamide and N-cyclopropylcarbonyl-prostaglandin-Eg-carboxamide were significantly less potent than PGEg in lowering blood pressure in guinea pig and dog. Thus, the compounds are more selective bronchodilators and cause fewer unwanted side effects than naturally occurring prostaglandins.

N-trimethylacetyl-prostaglandin-Eg-carboxamide, N-methanesulfonyl-prostaglandin-Eg-carboxamide and N-p-toluenesulfonyl-prostaglandin-Fgl-carboxamide11a all had a spasmogenic effect on the rat uterus, an effect comparable to that of PGEg. In comparison, these carboxamide analogues had a significantly lower effect than PGEg on other smooth muscle preparations, canine blood pressure and histamine-induced bronchospasm in guinea pigs · The biological profiles observed with Eg-carboxamide 11a, N-methanesulfonyl-Prostaglandin-Eg-carboxamide and Np-toluenesulfonyl-prostaglandin-Fg 2 -carboxamide show better activity compared to PGEgie in that they produce fewer unwanted side effects than PGE.

Inhibitory activity of the same order of magnitude in vivo in rats was observed with both N-methanesulfonyl-prostaglandin-Eg-carboxamide and N-methanesulfonyl-prostaglandin-Fg ^ -carboxamide as with PGEg and PGFgβ. The fact that the latter compound prepared according to the invention showed an insignificant stimulatory effect on the uterus at the doses studied (Table I) means that its inhibitory effects on fertility are due to the luteolytic mechanism of action, which is not involved in smooth muscle stimulation.

The novel compounds prepared by the method of the invention can be used as various pharmaceutical preparations containing the compound or a salt thereof, and can be administered in various ways, such as intravenously, orally and topically, including as an aerosol, vaginally, intranasally, etc.

Naturally occurring prostaglandins are well known agents for inducing miscarriage, and the E- and F-series N-substituted-prostaglandin-carbox-siamides have this utility. For such treatment, an aqueous suspension of N-substituted PGE carboxamide is administered at about 0.2-5.0 mg / dose or an aqueous suspension of N-substituted PGF carboxamide at 30-50 mg / dose using 1-7 oral doses per day in each case.

If intravaginal treatment is desired to induce miscarriage, a sterile ethanolic solution of one of said N-substituted prostaglandin carboxamides or lactose tablets of these substances. Suitable doses for such treatments are 15-200 mg / dose with N-substituted PGE carboxamide or about 35-500 mg / dose with N-substituted PGF carboxamide one or two doses per day.

In cases where a median miscarriage is required, an ethanol / dextrose solution of N-substituted-PGEg-carboxamide administered intravenously is effective. A suitable dose is about 5 to 500 yug / min administered over about 1-1 + 8 hours. Alternatively, for median miscarriage, an effective dose is an ethanol / dextrose solution of N-substituted-PGF 4 -carboxamide administered by water-membrane injection. A suitable dose is about 1-50 mg / injection using 1-12 doses at intervals of 3 ~ 2l + hours. For parenteral, intrauterine administration, 0.1 to 5 mg of N-substituted-PGEg carboxamide is injected at intervals of 2 hours for up to 12 hours.

Another use of N-substituted-prostaglandin carboxamides is to induce labor. For this purpose, ethanol / saline of the PGE 2 analog is used for intravenous administration in an amount of about 3-100 μg / kg / min. about 1-2l per hour.

Other uses of N-substituted-prostaglandin carboxamides are fertility control. For this purpose, lactose tablets impregnated with a sterile 95% solution of PGE2 or PGFβ for intravaginal administration in an amount of 5 ~ 500 mg / dose using 1-2 doses per day for 2-7 days after the expected day of the menstrual cycle are used. gone past.

Another known use of naturally occurring prostaglandins is to regulate heart rate. Prostaglandin carboxamides, especially E-series carboxamides, have this property.

Perhaps the most important use of N-substituted prostaglandin carboxamides, based on the known use of naturally occurring prostaglandins, is to cause bronchodilation or increase nasal palpation. A suitable dosage for this use is an aqueous ethanolic solution of N-acetyl-PGE2-carboxamide for use as an aerosol using fluorocarbons as a propellant, about 10-500 .mu.g / dose.

The 9-, 11- and 15-alkanoates, formates and benzoates of PGE and F-carboxamides have the same use as the non-esterified compounds. They often have fewer unwanted side effects.

15-Niethyl-substituted-PGE- and -F-carboxamides have the same utility as unsubstituted prostaglandins, but have a longer duration of action.

Novel prostaglandins with a / ®-OH group in the 15-position are generally less potent, although often more selective than the corresponding? -Hydroxyl epimers. In addition, prostaglandins having an β-hydroxyl group at the C-15 »position are valuable intermediates for the preparation of prostaglandins having a ® * hydroxyl group at the C-15» position by a process comprising oxidation and reduction at the C-15 * position.

Various inert diluents, additives or carriers may be used to prepare any of the dosage forms described above or otherwise. Such substances include, for example, water, ethanol, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, resins, polyalkylene glycols, petrolatum, cholesterol and other known drug carriers. If desired, these pharmaceutical compositions may contain other excipients such as preservatives, wetting agents, stabilizers, or other therapeutic agents such as antibiotics.

Table 2 compares the novel compounds according to the invention with the carboxyamide disclosed in DE-A-2 150 361 (e.g. 18).

9 58327 b "1 ^ 'd on ö K uv on i; cd n! Hm vo on K * -h 3 υ K o td vo o> s o O O O O ftj Ai C 11) C \ JOJ O O O O O O 09. ··

w W tu O 3 O CJ CO '' MC

S3 3 3 3 3 3 3 · g 0> OO O, 3 O 3 3 3 |> U5 O \ O \ O \ O \ 0 \ O, o O cd · uv · Η <H <,] (] o. nnn! iii s \> -§ \ V§ \> “§ \ V § \> S \, \, a \ \ = \ n == S .3.” s} {) 1 J1 () l J (, i ° Ji> ° li r ° ao <? § • s {) 4 y /; O /) IS (S / S s ϊ “s K) f * / I H J— | m) —1 k) - / V · - / a m ra c "o b bD 'b b ^' O ^ ~ ^ 0 d ^ ö 33 3 3 3 3 3 K p-h ^" 5 "

3 C en O

09 P

• en + j | 3 .3 "

C <3 · Η CM

3 P CÖ Pl

3 3> U

O -H 3 3 cd: cö 2!> "C: aö cd P C 3 3 en cd tn -h

Sh> ai cd cd td O

S 3 cd 3 <Vh C · h tn <O O OO CU C 09 S 09 vo ov - = t · -> i 3 p 3 · - · - S ai cd

3> X

m -P cd cd

M <19 H M H 09 3 cd O

3 -P 3 3 oo uv ltv uv en o> 09 3. ·> ·> ·> -H C --- 3 3 <O O OShtHO) '- 3 <19 cd

H Ph · O

• h p ~ - 3Ö3 d Ό O <19 09 09

Eh O Sh 09 3 OO O O is O O uv · 09 Sh

. h- h- O CO CO · - «-> · Η C

S 'i * -' i H. -h o C 3 C ö cd · h

O OJ Sh * H i — I

. J- O 3 -rn en H

PL, ·> «O O 3 09 • O O O H- O O 0330909

m - CU OJ CM * - '' H to -P

. Λ CM - · Η 3 p w o e ρ o 3 co

Ph. aj 3 - tn ‘Τ’ • a e ^ 3 O P cd • co on -ett— t— 3 U cd ·

P CM VO en- CO j- 09 P 3 'S

• 3 -H e

O 3 ai JJ

cd S

td e ω -h>

• <- · η P ^ i — 1 * P

p VO O 3 P 'P

• Λ - 3 O p -P

PO O UV UV f- O OV t ~ - 09 O · Η 3 • VO C— VO is 09 <-pro O 3 fi

3 H—- '-H * H

p o in cd o II

O H ^ • • h- cm is - = 1- uv vo e— co e 3 3

S 09 09 II

o tn en **

O O CC 3 CM C

O O OV <- O3OW09

•> 5> 5 CO f- o >> «- UV 3 P O P

P, -r-5 TO 0O UV H— Ό I I »P C P 'Γ4 • H h I I I H OV cOCOCCaJ' -?»

CQ CO: 0 C— OV CO: 0 O <- · - · Η -H ’P

CO -3- O H- «-> - (d H O -H

- i> O 3 -P

• H P 7J i tn oi CC

T) WP I. CM> j I fi O 3 ai • PII Ci W Ti P kp 09 Sh ö · Η PPO CM O Ctntnoipll 3 tn W ip P p occ-pcd09. · • pH 3 O · Η · Η · Η I · γΗ O -HI · Η Oh O a C <cd (I d O P3 H3 · Η Td ΡηΌ · η3 H3 0) <Ö-Pv —'en 3 3 3 I * H 1 >> * P p HI · Η 3 · Η PP QJPP tn tno Sh · ηΒ Ι> ιΒ S d · ρ d S d tncd 60Ρ3® · Ρ • h 3 3 ι-led a3 tnS i — I 3> s3 · Η3 οο) 09γΗ3 3P 3 ίη · ρ O · Η O · Η> ϊ · Η O · Η PI dtnOlHo 3cd I> itn -rHtn m to> 5ω tn tn cdCMtn-H3 "Pp S3 3 33 P 3 33 33 33 täW PP3« I XrH 090 OO CO 090 CO 3 U * H p, td P 3: td P CMÖ t03 Sh 3 0) 3 W3 093 09P3COtdtOOcn WP * p td Sh PhSh 3 Sh 3Sh 3Sh dl'P H Pen O Od id ltd led to led Ι · ηΒ '^ 0 '^ Ρ >> p p3 S3 33 33 33 33 SHcdcdd'C'iitn 10 58327

The following examples illustrate the invention. All temperatures are in degrees Celsius and all melting and boiling points are uncorrected.

Example I

To a solution of 5.82 g (12.0 mmol) of N- (acetylaminocarbonyl) butyl / triphenylphosphonium bromide in 6.0 mL of dry dimethyl sulfoxide was added dropwise 9.8 mL (23.5 mmol) of a 2.1 M solution of sodium methylsulfinylmethide in dimethyl sulfide. . To this red ylide solution was added dropwise a solution of 1.32 g (3.00 moles) of 2- [5et-hydroxy-3α- (tetrahydropyran-2-yloxy) -2fr- (3ot- (tetrahydropyran-2- yloxy) -trans-1-octen-1-yl) -cyclopent-1-yl / acetaldehyde N-hemiacetal in 3.0 ml of dry dimethyl sulfoxide, over 0.5 hours. After the reaction mixture was stirred for 20 hours at room temperature, the reaction mixture was poured into ice water. The aqueous solution was covered with ether and the vigorously stirred mixture was acidified to pH 3 by the addition of 10% hydrochloric acid. The acidic aqueous layer was then extracted with ether (twice). The combined ether extracts were dried (anhydrous magnesium sulfate) and concentrated to give a semi-solid weighing 1.0 g. It was purified by column chromatography using silica gel (Baker "Analyzed" Reagent 60-200 mesh) and chloroform followed by ethyl acetate as eluent. Removal of high R 2 impurities gave 1.15 g (67.8% yield) of N-acetyl-9α-hydroxy-11β, 15β: bis- (tetrahydropyran-2-yloxy) -cis-5-trans-13- prostadienamide as a viscous colorless oil.

The IR spectrum of the product (CHCl 3) showed strong absorption at 5.8θ £ (carbonyl). The NMR spectrum (CDCl 3) showed a polyline at 5> 27 ~ 5.68 £ for oleic protons, a broad single line at 1.60-1.80 for S OH and NH, multiline at 3.25-1, 30 for -CHO and -CH2O, single line at 2.37 for -COCH2, and polylines at 0.68-2.37 £ for the remaining protons.

A solution of 108 mg (0.192 mmol) of the product obtained above in 2 ml of a 65:35 mixture of acetic acid and water was stirred under nitrogen at 12 ° for 3 hours. The solvent was removed under reduced pressure, and the resulting oil was purified by column chromatography (Mallinckrodt CC-1) using chloroform, ethyl acetate and then a 9: 1 mixture of methyl chloride and methanol as the eluent.

After removal of less polar impurities, 12 mg (89% yield) of N-acetyl-9β, 11β, 15α-hydroxy-5-cis-13-trans-prostadienamide were obtained as a viscous colorless oil.

11 58327

NMR of the product (CDCl 3 showed a multi-line at 5.65-5.22 <f (Ϊ + Η) for olefins, a multi-line at 1 +, 31-3.80 δ (3H) for CHOt, a broad single line at 3.20- 2.73 for 6 (1 + H) OH and NH 4, single line at 2.1 + 1 d (3H) COCH 3, and polylines at 2.60-0.71 <5 (23H) for the remaining protons.

Example II

A solution of 1.12 g (0.20 mmol) of N-acetyl-9-oxo-11Cx, 15cx-his- (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienylamide 11 +, 0 ml: in a 65:35 mixture of acetic acid and water was stirred under nitrogen at room temperature for 18 hours and then concentrated by evaporation. The obtained crude oil was purified by column chromatography using silica gel (Mallinckrodt CC-7) and using mixtures of chloroform and ethyl acetate as eluent. After eluting the less polar impurities, crystalline N-acetyl-9-oxo-112,15a-dihydroxy-cis-5-trans-13-prostadienamide, N-acetyl-Prosta-flandin-Eg-carboxamide, weighing 1 + 07 mg (51.8% yield), m.p. 86-86.5 ° crystallized from ethyl acetate / hexane.

The IR spectrum of the product (CHCl 3) showed strong absorbances at 5.78 (ketone carbonyl) and 5.92 / 1 (imidicarbonyl). The NMR spectrum of the product (CDCl 3) showed two polylines at 5.26-5.72 S for olefinic protons, a multiline at 3.85-1 +, 28 6 -CHO, a single line at 2.35 6 -COCH 2 - They and the polyline at 0.68-2.82 pounds for the remaining protons.

Example III

A mixture of N-acetyl-9-oxo-11a, 15d-dihydroxy-cis-5-trans-13'-prostadienamide (38 mg, 0.097 mmol) prepared according to Example II was 5%. palladium on carbon (12 mg) and methanol (7 ml) were stirred at room temperature under one atmosphere of hydrogen for 90 minutes. The mixture was filtered to remove the catalyst and the filtrate was concentrated to give a thick, clear, colorless oil (38 mg). Chromatography of the oil using an acidic silica gel column (SilicAR CC-1 +) and eluting with chloroform followed by mixtures of chloroform and methanol separated the mixed fractions of less polar impurities (23 mg) from the pure product, N-acetyl-9-oxo-11y, 150f-dihydroxy From the N-acetyl-13,11 + -dihydroprostaglandin-N-carboxamide fraction as a crystalline solid (13 mg, 31%), m.p. 67_71 ° · The IR spectrum of the product (CHCl 3) showed precise absorption bands at 17 ^ 0 cm and 1705 cm (0 = 0), and broad bands at 3390 cm 1 and 3600 cm 1 (NH and OH). The absence of absorption at 965 cm -1 in the spectral range indicated the absence of a trans double bond. The mass spectrum of the product showed significant peaks at m / e 379 (M-H 2 O), 361 (M 2 O 2), 308 and 302, which can be compared to the corresponding peaks in the mass spectrum of the starting material at 12 58327 m / e 375, 357, 30a. and 298. Thin layer chromatography of the product using silica gel glass plates developed with chloroform / methanol 11a 5: 1 and visualized by heating with vanillin phosphoric acid showed a simple spot at Rf 0.62.

Example IV

A solution of Ηλβ mg of chromatographed N-propionyl-9-oxo-11a, 150t-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide and 5.0 ml of a 65/35 mixture of acetic acid and water , was stirred under nitrogen at room temperature overnight. Concentration of the mixture gave an oil which was purified by column chromatography using silica gel (Mallinckrodt CC-1 +) using mixtures of chloroform and ethyl acetate as eluent. Removal of less polar impurities gave crystalline N-propionyl-9-oxo-11y, 15 (* - dihydroxy-cis-5-trans-1,3-prostadienamide, N-propionyl-prostaglandin-E2-carboxamide weighing T6 mg, mp U9 ~ 51 ° crystallized from ethyl acetate / hexane.

The IR spectrum (CHCl 3) of the product showed strong absorptions at 11 * 1735 and 1695 cm due to carbonyl groups and moderate absorption at 970 cm 1 due to trans double bond. The NMR (CDCl 3) spectrum of the product showed a polyline at 5.70 ~ 5.6 3 6 for the trans double bond, a multiline at 5, δ 3, 5.10 6 for the cis double bond, a multiline at 1+, 30-369 (5 CHO for 3, * + 2-2.80 6 OH and NH, with the center of the four-line at 2.60 6 for COCH 2, the center of the triple line at 1.13 (for 5 -CH 2, and many lines at 2.72-0.60 0 for the remaining protons.

Example V

A solution of N-cyclopropanecarbonyl-9α-hydroxy-110,11β-bis-tetrahydropyran-2-yloxy) -cis-5 "trans-13-prostadienamide (90 mg) in 2.0 ml of acetic acid and water 65/35 mixture was stirred at 1 * 2 ° U for 5 hours under nitrogen gas, and the reaction mixture was concentrated to give an oil which was purified by column chromatography on silica gel (SilicAR CC-U) after elution of less polar impurities with ethyl acetate / benzene 2. : 1 eluting with a 9: 1 mixture of methylene chloride and methanol gave a colorless semi-solid N-cyclopropanecarbonyl 11-9, 11a, 15o-trihydroxy-cis-5-trans-13-prostadienamide, weighing 39 mg (60.7% yield) and melted at 99 ~ 102 ° (from ether).

The IR spectrum (CHCl 3) of the oily product showed strong absorptions at 1 -31 t 1 at 1680 and 1720 cm due to carbonyl groups and 970 cm due to trans double bond. The NMR spectrum (CDCl 3) showed a broad single line at 9.36 for the UH group, a polyline at 5.70 ~ 5.10 for the 6-olefinic protons, 58357 polylines at U, 27-3.00 for the 6 -CHO group, and polylines at 2.8U-0.5βό for the remaining protons.

Example VI

A solution of 18U mg of N-cyclopropanecarbonyl-9-oxo-11c *, 150f-bis- (tetrahydropyran-2-yloxy) -cis-5 "trans-13" prostadienamide and U, 0 ml of acetic acid and water 65: 35 mixtures, heated in nitrogen gas at U 2 ° for 1.5 hours. Concentration of the mixture gave an oil which was purified by column chromatography using silica gel (SilicAR CC-U). After eluting the column with a 2: 1 mixture of ethyl acetate and benzene to remove less polar impurities, elution with ethyl acetate gave N-cyclopropanecarbonyl-9-oxo-11,150f-dihydroxy-cis-5-trans-13-prostadienylamide, N-cyclopropanecarbonyl prostaglandyl prostaglandyl prostaglandyl β-carboxamide as a colorless oily product, weighing 83 mg (63 * 5% yield).

The IR spectrum (CHCl 3) of the oily product showed strong absorptions - ί # 3 _ 1 at 1730 cm for ketone carbonyl, at 1680 and 1730 cm for imidicarbonyls and at 970 cm 1 for the trans double bond. The NMR spectrum (CDCl 3) of the oily product showed a single line at 9.17 ό for WH, a multi-line at 5.70-5 for U-96 trans-olefin, a multi-line at 5> U9 ~ 5.17 <3 cis- for olefin, polyline at U, 3Q “3.77 ό for CH-0, single line at 3.50 ci, and polyline at 3, OH-0.63 <5 for the remaining protons.

Example VII

A solution of 352 mg of crude N-trimethylacetyl-9-oxo-11c, 15β-bis-tetrahydropyran-2-yloxy) -cis-5-trans-13β-ostadienamide in h, 0 ml of acetic acid and water 65:35 mixture was stirred under nitrogen for 1.5 hours at 1 + 0 + 2 ° and then concentrated. The resulting oil was column chromatographed using silica gel (SilicAR CC-U) and benzene / ethyl acetate as eluent. After removal of the high R 2 impurities, U5 mg of the oily product N-trimethylacetyl-9-oxo-11 (?, 150-dihydroxy-cis-5-trans-13-prostadienamide, N-trimethylacetyl-prostaglandin-E ^ -carboxamide.

The IR spectrum (CHCl 3) of the product showed strong absorptions at _ 1 * _ ί 1680 and 1730 cm due to carbonyl groups and at 965 cm due to trans double bond. The NMR spectrum (CDCl 3) showed a single line at 1.22 for CCCH 2) * * a broad single line at 3.31 ό for OH, a polyline at 3.90-U, 23 ό for CHO, a multiline at 5.23-5, 52 6 for the cis-olefin, at 5.52-5.76 ό for the trans-olefin at the polyline, at 8.20 for the broad group at the broad single line at 8.20, and at 0.70-3.05 for the remaining protons. The UV spectrum (MeOH) after treatment with base (KOH) showed characteristic PGE absorption at 278 mu.

11+ 58327

Example VIII

A solution of 3.16 g of N-methanesulfonyl-90'-hydroxy-11 (>, 150 (-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide) and 32 ml of acetic acid and The solution was concentrated and the resulting oil was purified by column chromatography on silica gel (SilicAR CC-T) using mixtures of chloroform and ethyl acetate as eluent after removal of the less polar impurities. 1.1L g of crystalline N-methanesulfonyl-PösHO 2 -N-dihydroxy-cis-5-trans-13-prostadienamide, N-methanesulfonyl-prostaglandin F-carboxy-O-amide, mp 121-121.5 (from ethyl acetate / ether).

The IR spectrum (CHCl 3) showed strong absorptions at 1720 cm -1 for the carbonyl groups and 970 cm -1 for the trans double bond. The mass spectrum showed peaks for the loss of one, two and three molecules of water and one peak for the loss of H 2 O +.

Example IX

A solution of 2.1 g of N-methanesulfonyl-9-oxo-110 ', 150i-bis- (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide in 2k ml of acetic acid and water 65 : 35 mixture, heated to ^ 0 + 2 ° under nitrogen for 6 hours. The mixture was then concentrated, and the resulting oily product was purified by column chromatography on silica gel (SilicAR CC-k) using a mixture of chloroform and ethyl acetate as an eluent. Removal of less polar impurities gave 86 mg (U9.2% yield) of solid N-methanesulfonyl-prostaglandin-E2-carboxamide, m.p. 118.5-119 ° (from acetone / hexane).

The IR spectrum (CHCl 3) of the crystalline product showed absorbances at 1720 cm due to imidicarbonyl, at 1730 cm due to ketone carbonyl, and at 970 cm due to trans double bond. The NMR spectrum (CDCl 3) of the crystalline product showed a polyline at 5.70-5 ° C for the trans-olefin, a polyline at 5, + + - 5.18 for the cis-olefin, a multiline at U, 33 ~ 3.8o δ for CH -OH, single line at 3.23 δ for SO 2 CH 3 and polylines at 2.78-1.65 for the 6 remaining protons.

Anal: Calculated C 58.72; H 8.21; N 3.26; S 7, etty found C 59.01; H 8.12; N 3.19; S 7.5½

Example X

A heterogeneous mixture of 50 mg (0.116 mmol) of the product of Example IX and 10 mg of 5 # palladium on carbon in 5 mL of absolute methanol was stirred at room temperature under one atmosphere of hydrogen for 1.5 hours. The mixture was then filtered through a pad of Celite, and the filtrate was concentrated to give 38 mg of N-methanesulfonyl-9-oxo-110t, 15or-dihydroxyprostanamide as crystals, m.p. 58,327 m.p. 91-93 ° ·

The IR spectrum (film) of the product showed strong absorption at 1735 and 1720 cm -1 due to carbonyl groups and no absorption for the trans double bond. The NMR spectrum (CD 2 OD) showed no olefinic resonances, but showed polylines at 1 +, 31 + -3.90 δ and 3.80-3.1 + 8 ό for CHO, single line at 3.15 ό for SO ^ CH ^, and polylines for protons remaining at 2.97 “0.7δ ό.

Example XI

A solution of 523 mg (0.855 mmol) of N-methanesulfonyl-9-oxo-11 (1,15 (γ-bis- (tetrahydropyran-2-yloxy) -15 / 7-methyl-cis-5-trans-13-prostadiene) was added. amide and N-methanesulfonyl-9-oxo-11β, 15Cγ-bis (tetrahydropyran-2-yloxy) -150t-methyl-cis-5-trans-13-prostadienamide in 5.0 ml of a 65:35 mixture of acetic acid and water were stirred under nitrogen. The crude oily product was purified by silica gel column chromatography (Mallinckrodt CC-7) using mixtures of chloroform and ethyl acetate as eluent, and after eluting the less polar impurities, 159 mg (1 + 2) was collected. , 0% yield) colorless oily N-methanesulfonyl-9-oxo-11-ol, 15H-dihydroxy-15-methyl-5-cis-13-trans-prostadienamide and N-methanesulfonyl-9-oxo-11-ol, 15 / 3-dihydroxy-15C *-methyl-5-cis-13 "trans-prostadieeniamidia.

The NMR spectrum of the product (CDCl 3) showed many lines at 5.72-5.1 + 90 for the trans double bond, many lines at 5.1 + 9-5.12 ό for the cis double bond, many lines at U, 37 ~ 3.1 + 8 ό for CHO, single line at 3.26 for SO 2 CH 2, and polylines at 2.71 + -0.63 ό for the remaining protons.

The mass spectrum showed m / e at 1 + 1 + 3 due to per us molecule, m / e at 1 + 25 for MH + O, and m / e at 1 + 07 for m ~ 2E ^ 0 .

Example XII

A solution of 220 mg (0.36 mmol) of N-methanesulfonyl-9-oxo-110r, 150'-bis- (tetrahydropyran-2-yloxy) -16,16-dimethyl-cis-5-trans-13-prostadiene amide in 5 ml of a 65:35 mixture of acetic acid and water, stirred under nitrogen at room temperature overnight and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography using silica gel (Mallinckrodt CC-7) and mixtures of chloroform and ethyl acetate as eluent.

After elution of less polar impurities, 73 mp (1 + 1 +, 5% yield) of N-methanesulfonyl-9-oxo-11Jr, 150-dihydroxy-16,16-dimethyl-16 58327 cis-5-trans- 13_prostadienamide as a colorless oil.

The IR spectrum (CHCl 3) of the chromatographed product showed strong absorption -1. . . -1 at 1735 and 1720 cm for carbonyl groups and at 970 cm for the trans double bond. The NMR spectrum of the product (CDCl 3) showed a multiline at 5.78-5.50 ό for the trans double bond, a multiline at 5.50-5.20 for the 6 cis double bond, multiline at 1 +, 29-3.70 d for OHO, single line at 3.27 i for SO 2 CH 2, single line at 0.86 <5 gem-dimethyl groups, and polylines at 2.80-0.56 0 for the remaining protons.

Example XIII

A solution of 226 mg of N-acetyl-9-oxo-11β, 15 ([? -]) 18- (tetrahydropyran-2-yloxy) -16,16-dimethyl-cis-5-trans-13-prostadienamide 5 , 0 ml of a 65:35 mixture of acetic acid and water, was stirred under nitrogen at room temperature overnight and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography using silica gel (Mallinckrodt CC-7) and mixtures of chloroform and ethyl acetate as eluent. After eluting the less polar impurities, 57 mg of the desired N-acetyl-9-oxo-11,15 (7-dihydroxy-16,16-dimethyl-cis-5-trans-13-prostadienamide) were obtained as a viscous, colorless oil.

The IR spectrum (CHCl 3) of the product showed strong absorptions at 1117 ^ 5 and 1710 cm for the carbonyl groups and a moderate absorption at 975 cm for the trans double bond. The NMR spectrum (CHCl 3) showed a polyline at 5.75-5.1 + 8 ό for the trans double bond, a multiline at 5.1 + 8-5.20 ό for the cis double bond at U, 16-3 * 68 c5 * for CH0, single line at 2.2 6 <5 COCHyl, single line at 0.88 ό gemdimethyl, and polylines at 2.62-0.60 d for the remaining protons.

Example XIV

A solution of 10 U mg of N-benzenesulfonyl-9β-hydroxy-11,10a-bis- (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide and 5.0 ml of acetic acid and water 65 = 35 mixture, heated at 1 + 0 + 2 ° for 2.5 hours under nitrogen. The solution was then concentrated and the resulting oil was purified by column chromatography on silica gel (SilicAR CC-1 +), after removal of high Rj impurities with chloroform, eluting with 10% methanol in methylene chloride to give the desired N-benzenesulfonyl-9, -trihydroxy-cis-5-trans-13-prostadienamide as a white foam weighing 30 mg (38.0% yield).

The NMR spectrum (CDCl 3) of the chromatographed product showed polylines at 8.10-7.88 Å and 7.60-7.36 <6 for aromatic protons, polylines at 17 58327 5.60-5.37 δ and 5.37 ~ 5.08 ό for vinyl protons, dashes at 1 +, 21 + -3.73 0 for CHO, and dashes at 2.52-0.69 for the remaining protons.

The IR spectrum (CHCl 1) of the product showed strong absorptions at 1720 cm -1 for the carbonyl group and 965 cm for the trans double bond.

Example XV

A solution of 175 mg (0.266 mmol) of N-benzenesulfonyl-9-oxo-110r, 150'-bis- (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide in 3 ml of acetic acid and water 65 : 35 mixture, heated at 1 + 0 + 2 ° under nitrogen for 6 hours. The mixture was then concentrated and the resulting oily product was purified by column chromatography using silica gel (Mallinckrodt CC-U).

After removal of higher R 1 impurities with chloroform, elution with a 1: 1 mixture of chloroform and ethyl acetate gave the desired N-benzenesulfonyl-9-oxo-11U, 150t-dihydroxy-cis-5-trans-13-prostadienylamide as a foam weighing 35 mg. (26.8% yield).

The IR spectrum (CHCl 3) of the chromatographed product showed strong absorp-. . . . -1. .

at 1735 and 1720 cm for carbonyl groups and moderate absorption at 970 cm 1 for the trans double bond. The NMR spectrum of the product (CDCl 3) showed a polyline at 8.10-7.88 <j and 7.67 ~ 7, Uo ό for aromatic protons, a multiline at 5.72 ~ 5.50 d for the trans double bond and 5, 39 ~ 5.10 ά for the cis double bond, polyline at 1 +, 27-3.88 <5 for CHO, and multilines at 2.68-068 for the 6 remaining protons.

Example XVI

A solution of 222 mg (0.329 mmol) of Np-toluenesulfonyl-9CX-hydroxy-11 0 ·, 150f-bis- (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide in 2 ml of acetic acid and a 65:35 mixture of water, heated at 1 + 0 + 2 ° under nitrogen for 5 hours and then concentrated. The oily product was purified by column chromatography using silica gel (SilicAR CC-U). After removal of the less polar impurities with chloroform, elution with a 9: 1 mixture of methylene chloride and methanol gave the desired Np-toluenesulfonyl-9 (>, 11CV, 150f-trihydroxy-cis-5-trans-13-prostadienamide) as a colorless viscous oil which 50 mg (30% yield).

The NMR spectrum of the oily product showed two double lines at 7.85 and 7.23 6 (J = 7 cps) for aromatic protons, two overlapping polylines at 5.68-1 +, 91 + <$ no finin for those protons, multiline at 1+ , 68-2.90 c $ for the group -CHO- and OH, a single line at 2.32 <$ for the group -CH 2 -, and polylines at 2.50-0.1 + 3 for the remaining protons.

18 58327

Example XVII

A solution of 156 mg (0.232 mmol) of Np-toluenesulfonyl-9-oxo-1H-15C'-bis- (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide in 3.0 ml of acetic acid and a 65:35 mixture of water, heated at 1 + 0 + 2 ° under nitrogen for 1+ hours and then concentrated. The crude oily product was purified by silica gel column chromatography (Mallinckrodt CC-1 +). After removal of the less polar material with chloroform, elution with 2% methanol in chloroform gave a colorless viscous oily Np-toluenesulfonyl-9-oxo-11C *, 150f-dihydroxy-5-cis-13-trans-prostadienamide, which weighed 32 mg (7 »* + $ yield).

The NMR spectrum of the product showed two double lines at 7.81 and 7.20 (J = cps) for olefinic protons, many lines at 5.61 + -5.31 <5 for transolefin, many lines at 5.31 ~ 1 + »98 ό for cis-olefinic, multi-line at ^ »23 ~ 3.55 for -CH0-, single-line at 2.23 for -CH0-, and multiline at 2.57-0.37 for the remaining protons. IR spectrum (CDCl 3) .... -1. showed strong absorptions at 1720 and 1730 cm due to carbonyl groups and at 970 cm 1 due to trans double bond.

Example XVIII

A solution of 121 mg (0.178 mmol) of N- (2-thiophenesulfonyl) -9? -Hydroxy-10,15c-bis- (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide and 2.0 ml of a 65:35 mixture of acetic acid and water, heated at 1 + 0 + 2 ° under nitrogen for 5 hours. The solution was then concentrated and the resulting oil was purified by column chromatography using silica gel (Mallinckrodt CC-1 +). After removal of the higher R 1, impurities with chloroform, elution with methylene chloride in 3% ethanol gave N- (2-thiophene) sulfonyl-9α-110,15 Cγ-trihydroxy-cis-5-trans-13-prostadiene amide as a foam. pressing 61 mg.

The NMR spectrum of the product (CDCl 3) showed a polyline at 7.81 + -7.1 + 8 ό and 7.10-6.90 ά for thiophene protons, overlapping polylines at 5.60-5.100 for vinyl protons, multiline at 1 +, 28-3.75 ό for CH0, and polylines at 2.57-0, βθ <$ for the remaining protons.

Example XIX

A solution of 159 mg of N- (2-thiophenesulfonyl) -9-oxo-11β, 150β-bis-tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide in 3 ml of acetic acid and water 65:35 mixture, heated at 1 + 0 + 2 ° under nitrogen) + for 5 hours. The mixture was then concentrated and the resulting oily product was purified by column chromatography using silica gel (Mallinckrodt CC-1 +). After removal of higher Rf impurities with chloroform, elution with 2% methanol in methylene chloride gave 72 mg of the desired N- (2-thiophenesulfonyl) -9-oxo-11β, 15β-dihydroxy-5-cis -13-trans-prostadienamide as a viscous oil.

The NMR spectrum (CDCl 3) of the product showed a polyline at 7.90-7.55 ό and 7.16-6.9 ^ ό for thiophene protons, a multiline at 5.72-5.3 ^ όtrans double bond, at a multiline 5, ^ 3-5.10 ό for a cis double bond, a broad single line at 5.6θ-Π, 75 d for OH and NH, a multi-line at ^, 32-3.81 ^ for CHO, and a multi-line at 2, 75-0.63 <5 for the remaining protons.

Claims (1)

20 5 8 3 2 7 Patents: A process for the preparation of a novel therapeutically useful prostaglaxine compound of the formula O 1 M methanesulfonyl; thiophenesulfonyl, benzenesulfonyl or toluenesulfonyl, R 1 is hydrogen or methyl; R 2 is -C or -C (CH 2) 2 C 2 Hq; W is a single bond or a cis double bond, Z is a single bond or a trans double bond; M is' C = O or, characterized in that the compound of the formula? is 2-tetrahydropyranyl, is reacted with aqueous acetic acid; and when W and Z are double bonds, the product, if desired, is catalytically hydrogenated to obtain a product wherein W and Z are single bonds.