FR2460944A1 - PROSTACYCLINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THE SAME - Google Patents

Abstract

THE PRESENT INVENTION RELATES TO PROSTACYCLINE DERIVATIVES, TO PROCESSES FOR THEIR PREPARATION AND TO SUITABLE INTERMEDIATE PRODUCTS. FOLLOWING THE INVENTION, PROSTACYCLINE COMPOUNDS OF THE 19-HYDROXY TYPE OR OF THE 19-HYDROXY-19-METHYLIC TYPE ARE PROVIDED, A CHARACTERISTIC EXAMPLE OF 19-HYDROXY COMPOUNDS BEING THE (5Z) -9-DESOXY-6 METHYL ESTER , 9A-EPOXY-D-19E-HYDROXY-PGF.

Description

246O0944

  "Derivatives of prostacyclins and their preparation"

  The present invention relates to derivatives

  prostacyclins and processes for their pre-

  repair. Prostacyclines are a group of organic compounds, including, for example, prostacyclin itself, also called prostaglandin 12 (PGI2), represented by formula 1:

<% OOH

16 1 20

t 13 17 19

OH 6H

  Prostacyclin is (5Z) -9-deoxy-6,9a-epoxide

  xy-A5-PGF1 = (using the prostitution nomenclature

  glandins) or (5Z, 9a, 11a, 13E, 15S) -6,9-epoxy

  xy-11,15-dihydroxyprost-5,13-dien-l-oic. The number of carbon atoms of the carbon skeleton is represented in this formula. Also defined by this structure are the absolute configurations (5Z, 8R, 9S, 11R, 12R, 13E and 15S) for potential centers

isomers of this molecule.

  With regard to generalities relating to prostacyclin and its pharmacological activity, it is

  For example, R.A. Johnson et al.

  Prostaglandins 12, 915-928 (1976) and R.A.

  Johnson et al., J.Am.Chem.Soc. 100.7690 to 7704

  (1978). With regard to prostacycline analogues

  see, for example, J. Friend et al., Proc. Natl. Acad.Sci. U.S.A.74,2199-2203, K.C.Nicolaou et al.

  J.C.S.Chem.Comm. 1977, 331-332-, N.A.Nelson, J.Am.Chem.

  Soc. 99, 7362-7363 (1977), and K. Kojima et al., Tetra.

  Letter, 1978, 3743-3746. With regard to nomenclature

  clature PGI2 analogs, see R.A. Johnson and

  Collaborates, Prostaglandins 15, 737-740 (1978).

  Prostacyclines are related to prostaglandins

  which are in turn related to prostatic acid

  which has the structure and the number of atoms of formula 2:

> / 7 COOH2

  There is a detailed literature relating to prostaglandins, and for basic knowledge reference will be made, for example, to Bergstrom et al., Pharmacol. Rev. 20.1 (1968). PGF2a is represented by formula 3: H0

> C OOH 3

H OH

  As they are represented, the

  represent an optically active isomer, specifically

  that has the same absolute configuration as the PGE1 ob-

  held from mammalian tissue.

  In formulas, the links in

  the cyclopentane nucleus indicate substitutions

  killing in alpha configuration, that is, lying

  below the plane of the cyclopentane nucleus. The links

  Thick solid lines at the cyclopentane ring denote substituents in the beta configuration, that is, above the plane. With regard to the use of the abbreviations "R" and "S",

  see R.S.Cahn, J.Chem.Ed.41,116 (1964). With regard to

  the "Z" and "E" nomenclature for stereo-

  somery around a double bond, we refer to

  will be J.E.Blackwood et al., J.Am.Chem.Soc.

90, 509 (1968).

  An object of the present invention is to provide

  new products with pharmacological activity.

  Another object is to provide a process for preparing these products and their intermediates. More specifically, cpaâcitdiffétns derived from prostacyclines

  having the characteristic of presenting a grouping 19-

hydroxy or 19-hydroxy-19-methyl.

  Compounds of the 19-hydroxy type of formula 4 are therefore provided: ## STR2 ## wherein Q is a radical represented by the loss

  C19 and C20 from a prostacy-

  cline belonging to one of the following groups of compounds comprising respectively: (I) compounds of formula 5:

__M1-L1-R1

Rs

1920

A5X-C - C- (CII2) 2 CH2Ct1

I!

R2 Q R6

  (II) compounds of the formula 6: s, 2 to R5

{X-0C-- (CH 2) 2 -CH 2 CH 3

2 Q R6

  (III) compounds of formula 7: M1-L 1-Ri

A2 \

X Rs 7 I

X-C --- C- (CH) 2-CH2CH3

  R 6 (IV) compounds of formula 8:

C-CH-L3-R,

EJ! A <I

, 8

R5

X-C --- C- (CH 2) 2 -CH 2 CH 3.

R2 Q 6

(V) the compounds of formula 9:

H H

<\ ', L2-R

C--, C = C.

, X - C - C - (Cf: 2) 2-CHRCH3 / 11H

R2 Q R5

246094 '

  (VI) compounds of formula 10:

/ C CH2-L14-R1

o \

1

l CH2 l R5

X-C-C- (CH2) 2-CH2CH3

  R6 (VII) compounds of formula 11:

0

  C₁ CH-CH₂-C₁-L5-R₁₁H₂ R R₁A₁ a-C --- (CH₂-CH₂CH3)

R2 Q R6

  (VIII) The compounds of formula 12:

C / -CH2-L4-R1

CH

R5 12

X-C - C- (CH2) 2-CH2CH3

  R6 (IX) the compounds of formula 13:

- / C-CH 2 -L 6-R,

  C13 R5-X-C-C- (CH2) 2-ClH2CH3, and

R2 Q R6

(X) compounds of formula 14:

MH / -L3-R1

CH2

<R514

X-C ---- (CH.2) 2 -CH2CH3

R9 Q R6

  With regard to formulas 5 to 14, the symbols

  boles A, E1, L1lM1, etc., are defined in the table of

  definition of symbols of the formulas given below, from

  very symbols or terms are also denied in this

board.

Board

  Definition of the symbols of the formulas A1 represents:

oxa (-o-).

A2 represents:

-CH20-.

Ac represents:

acetyl (CH3C (O) -).

E1 represents:

methylene (-CH2-).

E2 represents: -

ethylene (-CH 2 CH 2 -).

G represents:

  nitrato, iodo, chloro, bromo, acetato, trifluoro-

acetato, or benzoato.

Hal represents:

chloro, bromo or iodo.

  L1 represents: (1) - (CH2) n- where n is 1 to 5 inclusive, or

ú460944

  (2) - (CH2) p-CF2- o p is 2.3, or 4, with the proviso that when M1 is H

- C-CH2-,

  L1 also represents -CH2-CH = CH-. L 2 represents: (1) - (CH 2) j - where j is 1 to 4 inclusive, (2) - (CH 2) q-CF 2 -O q is equal to 1.2, or 3, or

(3) -CH = CH.

  L3 represents: (1) - (CH2) n- where n is 1 to 5 inclusive, (2) - (CH2) pCF2- where p is 2.3, or 4, or

(3) -CH 2 -CH = CH-.

  L4 represents: (1) - (CH2) n- where n is 1 to 5 inclusive, or

  (2) - (CH2) p-CF2-o p is 2.3 or 4.

  L5 represents: (1) - (CH2) p- o p is equal to 2.3, or 4, or

(2) -CH2-CF2-

  L6 represents: (1) - (CH2) n- where n is 1 to 5, or

(2) -CH 2 CH = CH-.

  L7 represents: (1) - (CH2) j- where j is 1 to 4 inclusive, or

  (2) - (CH2) q-CF2-o-q is 1,2, or 3.

  M1 represents: (1) C f'L) (A) -c = c (2):

(A) -, 1 = C

(L)

(3) H

-C-1 CH2- or i 2 (4) oH

? CH2,

  with the links to A1 and L as shown, and o the sign -_indicates the link in the configuration

alpha or buta.

} represents: L (1) -_ = or H

H

(2) -V - C /

(L)

  with the links to L as indicated.

Ms represents you:

mesyl (CH3-SO2-).

Q represents:

0, H H R4 OH or R4 OH.

  o R4 is hydrogen or an alkyl of 1 to

4 carbon atoms inclusive.

  Q1 represents: H H, R4 OR25 or R4 OR25 where R4 represents hydrogen or alkyl

  from 1 to 4 carbon atoms inclusive, and R25

  a blocking group as defined below.

  Q2 represents: II H, R4 OSi (R17) 3 or I4f'Si (R17) 3 where R4 represents hydrogen or an alkyl of 1 to 4 carbon atoms inclusive, and R17 represents a

  alkyl of 1 to 4 carbon atoms inclusive,

  nyl, a phenyl substituted with 1 to 2 fluoro radicals,

  chloro or alkyl of 1 to 4 carbon atoms inclusive

  or an aralkyl of 7 to 12 carbon atoms

  inclusively, the R17 groups being identical or different

  ent. Q3 represents: ## STR2 ## wherein R4 represents an alkyl radical of 1 to 7 carbon atoms;

carbon inclusively.

Q4 represents:

H and R4 OR24 or R4 0R24.

  R 24 represents a carboxyacyl as defined above

after. Q5 represents:

H1H, R4 OH or R4 011.

R1 represents:

(1) -COOR3

(2) -CH 2 OH

(3) -CH2N (R7) (RB)

(4) 0

-C-N (R7) (R8)

(5) 0

= b-NH-SO2-R15 -

(6) NH-N

-C / 1

  R3 represents (a) hydrogen, (b) alkyl of 1 to 12 carbon atoms inclusive, (c) cycloalkyl

  from 3 to 10 carbon atoms inclusive, - (d) an aralkyl

  from 7 to 12 carbon atoms inclusive, (e) phenyl, (f) phenyl substituted with 1,2 or 3 chloro or alkyl radicals of 4 to 3 carbon atoms inclusive; (g) -C3 o o (hi) - -NH-C-H-C-C3, 10 o Nil-C

(J) -O3-NH-C-CH3,

  (k) - -NO-C-N-H 2 o It 1) -CH-N-Ni-C-N 4 2 1, 11 (i)) n

0

(n) -CHl2-c-Ri6

  R16 represents a phenyl radical, p-bromophenyl, p-

  biphenyl, p-nitrophenyl, p-benzamidophenyl or 2-naphthyl

  the, or (o) a pharmacologically acceptable cation,

  o R and R8, in identical or different

  hydrogen, an alkyl of 1 to 12 carbon atoms

  inclusively, benzyl, or phenyl, and R15 is hydrogen, alkyl of 1 to 12 atoms

  inclusive of carbon, phenyl, a substituted phenyl

  killed by 1,2 or 3 chloro or alkyl radicals of 1 to 3 atoms

  carbon inclusively, or a substituted phenyl

  killed by a hydroxycarbonyl or alkoxycarbonyl radical

  from 1 to 4 carbon atoms inclusive.

  R2 represents hydrogen, hydroxyl

or hydromethyl.

  R3 is as defined above for R1.

  R4 represents hydrogen or an alkyl of

  1 to 4 carbon atoms inclusive.

  R5 and R6, being identical or different, represent hydrogen, an alkyl of 1 to 4 atoms

  including carbon, or fluoro,

  that one of R5 and R6 represents:

  when the other is hydrogen or

fluoro.

  R7 and R8, being the same or different, are hydrogen, alkyl of 1 to 12 carbon atoms inclusive, benzyl, or phenyl, and R15 is hydrogen, alkyl of 1 to 12 carbon atoms, carbon inclusive, phenyl, phenyl substituted with 1,2 or 3 chloro or alkyl radicals of 1 to 3 carbon atoms inclusive, or phenyl substituted by a hydroxycarbonyl radical or an alkoxycarbonyl radical;

  bonyle of 1 to 4 carbon atoms inclusive.

  R9 represents hydrogen or hydroxyl.

  R10 represents a straight chain alkyl of 1 to

6 carbon atoms inclusive.

  R11 represents hydrogen or a group -OR25

  or -CH20R25, where R25 is a blocking group as defined

2 25 25

finished below.

  R12 represents a chloro, bromo or iodo radical.

  R13 represents hydrogen or methyl.

  R14 represents hydrogen, -O-Si (R17) 3, or

  -CH2OSi (R17) 3, where R17 is as defined above

  after. R15 is hydrogen, alkyl of 1 to 12 carbon atoms inclusive, aralkyl of 7 to 12 carbon atoms inclusive, phenyl, phenyl substituted with 1,2 or 3 chloro or alkyl radicals

  from 1 to 3 carbon atoms inclusive, or

  nyl substituted with a hydroxycarbonyl or alkoxy radical

  carbonyl in which the alkoxy group has from 1 to 4 carbon atoms inclusive R16 represents phenyl, p-bromophenyl, biphenylyl, p-nitrophenyl, p-benzaminophenyl

or 2-naphthyl.

  R17 represents an alkyl of 1 to 4 carbon atoms;

  inclusively, phenyl, phenyl substituted with 1 to 2 fluoro, chloro or alkyl radicals of 1 to 4 carbon atoms inclusive, or aralkyl of 7 to 12 carbon atoms inclusive, the R 17 groups being

identical or different.

  R18 has the same meaning as R1, to the exclusion

Radica / COOH.

  R19 represents hydrogen, -O- -R20, or -CH20-CR20, where R20 is as defined below.

  R20 represents an alkyl of 1 to 7 carbon atoms;

bone inclusively.

  R21 has the same meaning as R1, but in replacement

  placing -COOR3 by -COOR26, where R26 represents a cation

of alkali metal.

  R22 represents hydrogen or a group -OSi

* (R17) 3, wherein R17 is as defined below.

  R23 represents hydrogen or a group -OR24, where R24 represents a carboxyacyl as defined

below.

  R24 represents a carboxyacyl group comprising: (a) O (T) 1 (T) e wherein "T" represents alkyl of 1 to 4 carbon atoms inclusive, bromo, phenylalkyl of 7 to 10 carbon atoms. inclusive, or ritro, and "e" has the value of 0 to 5 inclusively, provided that not more than two T's are different from an alkyl, and the total number of carbon atoms in the T's does not exceed 10 carbon atoms; p p COORC_

  R35 represents an alkyl of 1 to 4 carbon atoms

sively; (C) o

(C (T)

  _ - o "T" and "e" are as defined above, or (d)

-ë-R36

  R 36 represents hydrogen, an alkyl of 1 to 19 carbon atoms inclusive, or an aralkyl of 7 to 12 carbon atoms inclusive, where the alkyl or

  aralkyl are substituted with 0 to 3 halogen atoms.

  R25 represents a blocking group comprising

  Tetrahydropyranyl, tetrahydrofuranyl, or a group of the formula: ## STR1 ##

R32 R33

  wherein R 31 is alkyl of 1 to 18 carbon atoms inclusive, cycloalkyl of 3 to 10 carbon atoms inclusive, aralkyl of 7 to 12 carbon atoms inclusive, phenyl, or phenyl substituted with 1, 2 or 3 alkyls of 1 to 4 carbon atoms

  inclusive, R32 and R33, being identical or different

  are hydrogen, alkyl of 1 to 4

  including carbon atoms, phenyl or phenyl-

  substituted with 1,2 or 3 alkyls of 1 to 4 carbon atoms

  inclusively, or when R32 and R33 are taken together, they represent - (CH2) a- or - (CH2) b0- (CH2) c-, where o is 3,4 or 5, b is 1 , 2 or 3, and c is equal to 1.2 or 3, provided that b + c is equal to

  2,3 or 4, and R34 represents hydrogen or phenyl.

  R 26 represents an alkali metal cation R 27 represents hydrogen, OR 24 or -CH 2 CR 24, where R 24 represents a carboxyacyl group such as

as defined above.

  R28 represents hydrogen or methyl. R29 represents a straight chain alkyl of

3 to 7 carbon atoms.

  R 30 represents an alkyl of 1 to 4 carbon atoms;

bone inclusively.

  R31, R32, R33 and R34 have the same definition as

for R25 above.

  R35 and R36 have the same definition as for R24 above.

  R37 represents an alkyl of 1 to 4 carbon atoms;

bone inclusively.

  R38 represents a hydrocarbyl of 1 to 18 atoms

of carbon inclusively.

SePh represents a group

phenylselenidyl (-Se-C6H5).

  (T) e is alkyl of 1 to 4 carbon atoms inclusive, phenylalkyl of 7 to 10 carbon atoms inclusive, or nitro, and is 0 to 5 inclusive, with the proviso that two T at madmum are different from an alkyl, and that the total number of carbon atoms in the T does not exceed

carbon atoms.

THP is tetrahydropyranyl.

X represents:

(1) trans-CH-CH-

(2) cis-CH = CH-

(3) -CsC- or

(4) -CH2CH2-,

X1 represents:

(1) trans-CH = CH-

(2) cis-CH = CH-

(3) -CH 2 CH 2- or (4) -CH = C (Hal) -,

  Hal represents a chloro, bromo or iodo radical.

  e has the value from zero to 5 inclusive

  j is 1 to 4 inclusive.

  m is 2 to 5 inclusive.

  n is 1 to 5 inclusive.

pest equal to 2.3 or 4.

q is 1, 2 or 3.

  The sign ---- (wavy line) represents the bond or attachment in the cis or trans configuration

(or alpha or beta).

  19-hydroxy-19 compounds are also provided.

  methyl of formula 15, wherein has the meaning

  cation given above for formula 4 (hereinafter formulated).

  Among the compounds of formulas 4 and 15, with respect to the itel group represented by formula 5, they are PGI 2 compounds when M 1 is / (L 1)

(A) <- = C L H

H

  these are PGI1 compounds when M1 represents H

-t --- CH2-, and -

  they are 6-hydroxy-PGI compounds (in equilibrium with 6-oxoPGF1a compounds) when M1 represents OH

-C --- CH-.

  With regard to group II, represented by formula 6, they are 5,9-hydroxy analogs of

  PGI2 or PGI1. For generalities, refer to the

  United States of America No. 4,123,441.

  With regard to Group III, represents

  by formula 7 they are 6,9-epoxymethal analogs

  PGI2 or PGI1. For generalities, refer to

  in U.S. Patent No. 4,124,499.

  With regard to group IV, represented by formula 8, they are 5-hydroxy-PGI compounds. For generalities, see US Pat.

of America No. 4.110.532.

  With regard to group V, represented

  by the formula 9, they are 4-didhydro compounds ("a4") -

  PGI1. For generalities, see the United States patent.

United States of America No. 4.109.082.

  Ee6e concerning Group VI, represented by

  Formula 10 are 6-alkoxy-PGI1 compounds.

  As regards group VII, represented by formula 11, they are 4-oxo-PGI1 compounds. For

  generalities, see the United States Patent of America.

that n 4.126.744.

  With regard to group VIII, represented by formula 12, these are compounds - PGI1. For generalities, refer to the US patent

of America No. 4,128,713.

  With regard to group IX, represented by formula 13, they are 2-PGI compounds. For generalities, refer to the United States of America.

n 4.151.351.

  For group X, represented by formula XIV,

  they are analogues of 6a-carba prostacyclin.

  Of these, there are 11-deoxy compounds when R2 is hydrogen, and 11-desoxy-11-hydroxymethyl compounds when R2 is

hydroxymethyl radical.

  Also incorporated are acids,

  ters and salts when R represents -COOR3.

  There are C1 alcohols, that is to say

  2-decarboxy-2-hydroxymethyl type

  that R1 represents -CH20H, there are amines at C-1,

  that is, 2-decarboxy-2-aminomeric derivatives

  when R1 represents -CH2N (R7) (R8), there are amides at C-1, when R1 represents

--N (R7) (R8),

  there are sulfonyamides, when R1 represents -C-NH-SO 2 -R15, and

  there are tetrazole derivatives at C-1 when R1 represents

IlH-N

No.

  With regard to the compounds of formulas 4 and 15 in which Q represents:

R4 OH

  that is, the hydroxyl group at C-15 is attached

  in the alpha side, the confi-

  e-15 is identical to that of prostaglandins

  of natural origin, such as PGE1, obtained

  from mammalian tissue. The 15-epimetric compounds

  res are represented by formulas 4 (see below) and 15:

24609.4

CH3

C-C3 15

OH when Q represents a group:

R4 OH

  and are identified as appropriate by the corresponding name.

  preceded by the prefix "15-epi", "15-beta" or "15R".

  As is known in the art. the designations "R" and "S" depend on the neighboring substituents. See

  R.S.Cahn, J.Chem. Ed. 41, 116 (1964).

  Prostaglandin cis-13 derivatives are generally represented here by a lower side chain shown partially as follows: I IR5 Q R6

-

  X represents cis-CH = CH- and, for the S configuration, Q represents a group of the formula:

R4 OH.

  That equals the R4 OH representation

C = / I6

H H

  for configuratizon S with hydroxy at C-1 = fans configuration 153 as shown (see patent)

  United States of America No. 4,026,909, column 13).

  A typical example of the compounds of formula 4 is represented by formula 228:

(CH2) 3-COOCH3

lo

CC / H228

C: C 6 H H - (CH 2) a-CH-C 6 H 3

  and this compound is referred to as "methyl ester of (19P, S) -19-

  The full chemical identity is (5Z, 9a, 11a, 13E, 15S, 19R, S) -6,9-epoxy-11, 15,19-trihydroxyprosta-5, 13 The compound of Formula 228 is a type of compound of Formula 4 wherein P is Group I represented by Formula 5 wherein L1 is - (CH2) 3-, M1 is

(O) -C = C- [(CH2) 3-]

H Q represents

H OH,

  R1 represents -COOCH3, R2 represents hydroxyl, R5 and

  R6 represent hydrogen, and X represents trans-

CH = CH-.

  The composition of these compounds follows that of prostacyclines. For example, compounds having

  Lateral catches longer or shorter are

  peeled respectively compounds "homo" or "nor".

  The products of the present invention entering

  in the context of formulas 4 and 15 are extremely

  to induce various biogical activities. For this reason, these compounds are therefore useful for pharmacological purposes. Some of these biological activities are: inhibition of aggregation, platelets, inhibition of

  gastric secretion and reduction of gastrointestinal

  intestinal tract resulting from administration of prostaglandin synthetase inhibitors, spasmolytic effect and improvement of respiration in

  asthmatic conditions, and degeneration of the nasal passages.

  In view of these biological activities, the

  -new compounds are interesting to use for

  to prevent, combat or alleviate a wide variety of diseases and physiological conditions

  mammals, including humans, animals,

  useful domestic ailments, pets and zoological specimens, as well as

  laboratory, for example mice, rats, milk

pines and monkeys.

  These compounds are useful when it is desirable to inhibit platelet aggregation,

  reduce the adhesive nature of platelets, and remove

  to prevent thrombi formation in mammals.

  males, including humans, in rabbits and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarction,

  to treat and prevent postoperative surgical conditions

  as well as to treat conditions, such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, other conditions

  clinics whose etiology is associated with an imbalance

  lipids or hyperlipidemia. Other applications

  In vivo studies are in geriatric patients to prevent cerebral icsemic attacks and long-term prophylaxis after myocardial infarction and heart attacks. For these applications, these compounds are administered to the body, for example, intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for action.

  extended. For a quick answer, especially

  in emergency situations, the way of administra-

  Intravenous use is the preferred route. Doses of

  0.01 to about 10 mg per kg of body weight per day are used, the exact dose depending on the age, weight and condition of the patient or animal, as well as

  than frequency and route of administration.

  The addition of these compounds to whole blood

  constitutes inwvitro applications such as

  eitier blood for use in heart-lung devices. In addition, whole blood containing these compounds can be circulated through the limbs and organs, for example the heart and lungs, which are connected to the original body, detached and

  preserved or prepared for transplants, or

  stained to a new body. The blocking of aggregated platelets is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in the form of single or multiple portions to the circulating blood, to the blood of the donor person or animal, to the perfused body part, attached or detached, to the container, or two or more than two

  of these at a constant total erygimetric dose of approximately

  0.001 to 1.0 microgram / ml of whole blood. These com

  posed are also of interest in the preparation

  platelet-rich concentrates obtained from blood for use in the treatment of thrombocytopenia.

topology or chemotherapy.

  These compounds are also interesting

  in mammals, including man and certain animals

  useful ailments, such as dogs and pigs, to

  to control and combat gastric hypersecretion with a view to resorbing a gastro-intestinal ulcer or to preventing its formation, and to accelerate the healing of such an ulcer already existing in the gastrointestinal tract. For this purpose, these compounds are used by intravenous, subcutaneous or intramuscular injection or infusion, in an infusion dosage range of from about 0.01 to about 10 mg per kg of body weight per day, the dose

  depending on the age, weight and condition of the

  animal control, as well as frequency and pathway

of Directors.

  These compounds are also interesting to

  use to reduce the gastrointestinal effects inde-

  resulting from the administration to the body of

  anti-inflammatory prostaglan synthetase hibitors

  dine, and they are used for this purpose by

  of the compound of the formula 4 or 15 and the inhibition of

  anti-inflammatory prostaglandin synthetase inhibitor.

  See, for this purpose, US Pat. No. 3,781,429 to Partridge for the administration of certain E and A series prostaglandins.

2460944

  The anti-inflammatory synthetase inhibitor, for example

  indomethacin, aspirin or phenylbutazone.

  administered according to any of the various

  known in the art to relieve an inflammatory condition, for example in any dosage

  that by any of the known routes of administration

  administration to the organization. The compound of

  formula 4 or 15 together with the anti-inflammatory

  inflammatory prostaglandin synthetase by the

  same route of administration or by a different route.

  The dosage for the compound of formula 4 or 15, in accordance with such treatment, depends on various factors, such as

  species, age, weight, sex and condition

  of the mammal, the nature and dosage of the animal

  anti-inflammatory synthetase hibitor which is administered

  the mammal, and sensitivity to the

  do not have the compound of formula 4 or 15 to administer. For example, all human beings whose condition requires an anti-inflammatory substance do not suffer the same harmful gastrointestinal effects when they absorb the substance. The gastrointestinal effects often vary to a large extent in nature and intensity. However, the attending physician or veterinarian is able to determine whether the administration of the anti-inflammatory substance produces undesirable gastrointestinal effects in humans or

  the animal, and to prescribe an effective quantity of the

  formula 4 or 15 to reduce and then eliminate

  substantially reduce these adverse effects.

  These compounds are also of interest in the treatment of asthma. For example, they can

  be used as bronchodilators or as inhibitors

  of mediating substances, such as the substance

2450944

  SRS-A, and histamine which are released from cells excited by an antigen-antibody complex. So, these

  compounds fight spasms and facilitate breathing

  in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema.

  me. For these purposes, the compounds are administered under various conditions.

  its dosage forms, for example orally in the form of tablets, capsules or liquids, rectally in the form of suppositories, by

  parenteral route, subcutaneously or indiscriminately

  tramuscular, intravenous administration

  being preferred in emergency cases, these compounds can

  also be administered by inhalation under the

  aerosols or solutions for nebulizers, or by insufflation in the form of a powder. Doses in the range of about 0.01 to 5 mg per kg of body weight

  are used 1 to 4 times a day, the exact dose depends on

  age, weight and condition of the patient, as well as

  than frequency and route of administration.

  For the application indicated above, we can combine

  advantageously the compound with other anti-

  asthmatics, such as sympathomimetics (isopro-

  terenol, phenylephrine, ephedrine, etc.), xanthine derivatives (theophylline and aminophylline), and

  corticosteroids (ACTH and prednisolone).

  These compounds are administered in a manner

  effective for humans suffering from asthma

  oral or inhalation halation in the form of aerosol

  soils. For administration by the oral inhalation route with ordinary nebulizers or in the form of aerosols with oxygen, it is appropriate to bring the ingredient of formula 4 or formula 15 in a diluted form, preferably at concentrations

246-0944

  from about 1 part of drug up to about 100 to

* parts by weight of the total solution. We can use

  use ordinary additives to stabilize

  these solutions or to form isotonic media, for example sodium chloride,

  sodium citrate, citric acid, etc. For the ad-

  administration as a self-propelling dosage unit for the administration of the active ingredient under a

  aerosol form suitable for therapeutic therapy

  the composition may comprise the active ingredient suspended in an inert propellant (such as

  mixture of dichlorodifluoromethane and dichlorotetra-

  fluoroethane), together with a cosolvent, such as

  ethanol, flavoring materials and stabilizers.

  In place of a cosolvent, it is also possible to use a dispensing agent, such as oleyl alcohol. of the

  appropriate means for using the therapeutic technique

  that by inhalation in the form of aerosols are, by

  example, described in detail in the US Pat.

United States of America No. 2,868,691.

  These compounds are of interest to mammals

  fears, including in humans, as decongestion-

  and are used for this purpose in a dosage range of from about 10 μg to about 10 mg per ml of a

  a liquid vehicle acceptable from the pharmacological point of view

  or in the form of a sprayable composition

  aerosols, in both cases for local application.

  down. These compounds are also interesting

  in the treatment of peripheral vascular diseases

  in humans. Peripheral vascular disease means the diseases of any of the blood vessels outside the heart

24609P44

  and diseases of the lymphatic vessels, for example

  frostbite, ischemic cerebrovascular disease

  arteriovenous fistulas, ulcers

  ischemic legs, phlebitis, venous insufficiency

  se, gangrene, hepatorenal syndrome, arteriosclerosis of small ducts, mesenteric ischemia

  obstructive, arteritis, lymphangitis, etc. These examples

  ples are given for illustrative purposes and do not constitute

  in no case a limitation to the expression

  Peripheral cues. For these conditions, the compounds are administered orally or parenterally by injection or infusion directly into a vein or artery. The dosages of these compounds are in the range of 0.01 to 1.0 g administered by infusions at an hourly rate or by injection on a daily basis,

  that is, 1 to 4 times a day, the exact dose depends on

  age, weight, and condition of the patient and the frequency and route of administration. The treatment is continued for 1 to 5 days, although 3 days are usually enough to ensure action

  long-term therapeutic. In the case where

  serve effects due to the organism or secondary, the

  dosage is lowered below the threshold at which

  ve these effects due to the body or secondary. These

  compounds are therefore of interest for the treatment

  peripheral vascular diseases in the extremities or limbs of etreshumains which have circulatory insufficiency in them, this treatment

  relieving pain at rest and provoking

  to cure ulcers. With regard to one

  A full description of the nature and clinical manifestations of peripheral vascular diseases in humans, and methods of treatment with prostaglandins, previously known, will be referred to South African Patent No. 74/0149 listed under No.

  58400V from Derwent Farmdoc. See Elliott et al., Lan-

  this, January 18, 1975, pages 140-142.

  These compounds are also interesting

  hypotensive agents to reduce arterial pressure

  in mammals, including humans.

  For this purpose, the compounds are administered by intravenous infusion at a rate of from about 0.01 to about 50 μg per kg of body weight per minute or in the form of isolated or multiple doses of about 25 to 500 μg per kg.

  body weight per day. The exact dosages depend on

  for that purpose, the age, weight and condition of the

patient or animal.

  Various methods are also provided for preparing the compounds of formulas 4 and 15. Thus, for compounds of Group I corresponding to the formulas

  4 and 15 (that is, respectively the compounds of the ty-

  19-hydroxy and 19-hydroxy-19-methyl), the method illustrated in Scheme 1 below is used: ## STR1 ##

_ 17

R2 Q "s

Q 5R6 OH

29 2460944

  Diagram 1 (continued) c L-Ri i step (b) 1 8

R5 R13

RR6

Q5 OH11

  As can be seen from Scheme 1, this process consists of a PGF2a compound of Formula 16 and (a) converting the starting compound to a halo compound of Formula 17 (b) to be submitted. the product of step "a" at a dehalogenhydration with a tertiary amine or a reagent selected from the group consisting of superoxides or hyperoxides of sodium and potassium, sodium and potassium carbonates, hydroxides of sodium and potassium, sodium and potassium benzoates, sodium acetates and

  potassium, trifluoroacetates of sodium and potassium

  sium, sodium and potassium bicarbonates, acetic acid

  silver and tetraalkylammonium superoxides of the formula (R37) 4NO2, wherein R37 represents

  an alkyl radical of 1 to 4 carbon atoms inclusive

  in order to form an enol ether of the formula

  18, and (c) to separate the products.

  The C-1 and C-2 conversions into ester, alcohol, amine, amide, sulfonamide or tetrazolyl groups falling within the scope of R 1 are carried out by means of

  methods well known in practice

  here. Likewise, the transformations or substitutions with respect to L4, Q2, R2, R5, R6 and X are performed by methods well known in the art or described in the context of the present invention. The schemes discussed below

  will provide a better understanding of the prepa-

  of the compounds of the present invention. Scheme 2 OH R2 R2H OH Hg-G

O X H-L4-R4

step (a) step (b) H -

H., CH2-L4-R1

I

R2 R5 ROH

RE YR--

  ## STR2 ## wherein: ## STR2 ## Scheme ## STR2 ##

CH2- COOR1 0

  Rs R13 H step (b) o COO, Qs OH é / step (c)

O CH2 R,

 k R R3 RRR

32 2460944

Schema 4

R2

H i12 Q- - L3-Ri

R) H 25

Rs R1

AT

R2 Q 5 OH

| / step (a)

CH2-L3-R,

: L Rs. Ria

R2

Figure 5 Il1 CH S COO Rio

R5 R3

  R2 "step (a) H R12 SePh 0 CH> -1l OCOORR R. Rs $ axR1

I R6

d2 OH step (b)

H R12

HO

^ - CH --CH COOR10

> R5

R2 5 6 OH

H R12R

  o H - RI step (c) R13 R2 R2 Diagram 6 H Rl2

C-L3-R1

H

R5 R, 3

R2 URG OH

10.j |, step (a)} H

_CH2-L3-R1 X

k 2-L3-R1

32 12 R33 OH

32 33

-Z

(Bu> (.U) N _: (._ H :: _ 3 "- ..

OH HO

He i

0 O HO

CLu su pna (A eeAi

he -.

  ST (u>) (<Lu) Nw-3 -. '1-.3-X L (ej aH s u! CLu tc

HOOJ _C1 -H3O

  In this case, FIG. 8 R1 2 L2-R. P \

R5 R13

OH 2:, QsR 0 / I1op, L 2 -R 1

C / c <.

1 2 t =, A HR, t <2H "* Q5

CH2-L2-R1 TO

/ -I 6 "'I step (a) step (b) R13

R / R R6 OH

dR '= ST

(the) all around Z; W.

  HO 98 eO Ir 0 HOX HO 6 emuIqDS Figure 10 H CIL N, COOR10 <sff 43

CL R 'R13

R2 OH

  i, step (a) R12, eh 12 SePh H CHe, s ,, - COORo% g \ 44

QR5 1

R13

OH s R. 45

R2 R6

step (c) R12

"> H OR

at X-t 46

R2 QR6 OH

  Scheme II R13 R2 R2 $ step (a) i2 OH

0C2-L2-R1

"CH2-L2-RI

9q

24609 44

  Figure 12 R12 o> H t \ step (a)

OH O

- - ,. '- CHL2-L2-R1

Y-sR i R6 H

R2 Q

2 Q5

  ## STR1 ## ELAj S T

OS 9

Z H

+ 01

() e) do; a Q HO

); "7l -

0H 61? 0

HOI-I5

  Fig. 14 R2 J stage (a) -._, L4-COOR1o

R5 R13

  R 1- R1 R14. $ step (b) CH2 - L4-COOR

R14 Q5 R6 OH

  Step (c) 5-COORRo R13 i (R1,7) Step (d) Continued L4-COOR0 Diagram 14 (Continued) + Step (d) CH2OH

/ L-, -. L, -COOR10

  R5 R14 Q OS i. (R-7) 3 Q2 step CH20H _L, -COOR1o

P5 lR-1R3 -

  ## STR2 ## ## STR2 ##

H R12 -

R5 R13

  I R2 step (a) vy Ra SePh CH "COORIo H qH2 z l e Rs step (b)

H R12

"O -CH COO-'ORO CH \,

- R R 3

J X <RR

  step (c) H R, 2 o-CH-R.R CH Q Rfi5 R, 3 Qs

246O944

Figure 16H R12 1.0 CH-L3-R1 CH2 \

% 62

</ R R13

 R5 1R13 R2 ROQs step (a)

 H_

/ -Y R.D _63

"13 R2I Scheme 17 H R, 2

/ O -L3-R,

/ R

R2 Q! 4

4, OH

: 0 CH2-L3-R1

QR k2 yH 3 OH Q5 CH20H

N 0

The at C-C * L 2 -L3-R,

Z R R, 3X

  4. ' Figure 18 OH 4step (a) H Hg-OAc

? _ CH-L4-COOR30

I X $% Rs R13

R OH

  Step (b) H g -Hlal CHi-L4-COOR30 OILRsX R5

R X

R2 4th step (C) H OH

0 CH-L.-COOR3

  I> R <Rts t step (d) (continued) é Diagram 18 (continued, e step, d)

R5 R3

t 13 RW2 H OH

/ OCH-L4-RI

I-1 -

--- 1: z-

  First ..-. Scheme 19 OH j tape (a) H H C00R0SePh O - (CH 'CO ORLO R2 step (b) HOH

- CH COOR10

R, 3 / |, step (c) OH O $ CH R Rt

/% R5

% 43R13

R2 Qs OH

2460944

Figure 20 OH

\ CH2-L7-COOII

R13 R! R R25 I step (a) H Se-C6H5

CH-CH2-L7-COOH

> R5 75

RR

R1 OR25

$ tape (b) H Se-C6H5

1

  0 '+ CH-CH2-L? -COOH <I {4X Rs. R13 76 Q

2 10 Re OH

  step (c) ## STR2 ## wherein: (a) SePh step (b) H r COORio R13 AH

0 R1

  I / step (C) Q5 R2 Ir, 1 c 52 Scattering 22 OH oOH1 C112-L-R1 tR5 R: o o.5 OH \ 0

S1- - C-CH2-L-R,

  \ 1 Bs OR13! ## STR1 ## wherein step (a) is OReoO₂-CH₂-L4-R₁ R R5 R₁ RiH₂H₂, O.

C ,, - R,

O step (b) R.RsR, R .:

R2 Q5R

53 2460944

* Scema 23 OH o '

R R R13 85

R6 R25

  R1, step (a) CH2-C-L5-CH2OSi (R17) 3

86

oR mQ15 R13

R11 Q OR25

  step (b) II 0 A CH2-C-L5-CH20Si (R17) 3

0RA5

RI OR2! 5

step (c) 4, (continued)

54 2460944

  Scheme 23 (Cont'd) i step (c) o0 It CH2-C-Ls-CH2OH KTIIIR% R5 R13 88 Ri t, R 5 step (d) o0 Il-CH2-C-Ls-COOH-t) 89 / R Rt 25

RR2

stage (e)

0

p.5CH2-C-L5-COOH

(, .R, 3, 90

R! 1 (e.T ns) (P) @ 'ct; aT (p) acle49

 = 1: 3-0

He OLO

E6 I

   c 1-3- 0 eh l 0 oC l, iD0 'ú6 CLU g II HO u eu azuLUDS V 01 Oi t / Schbéea 24 (cont.)} éitae step 1 1 d

R5 R13

R2 R 2 Q5 1tape (e) CH2-L4-Ri L #

f - ---.

r. - -.

CH, -L, -R 2,

  Figure 25 R13 Step (a) o Pi Q.I o 0! S \ / - SePh} etapEb) R1 Ri, i1 1 step (c) A1 "step (d) (continued) R R2 Diagram 25 (continued) 0 K step (d) step (e) step (f) step (g) ) step (h): (continued) HO has ot ST (! ja of; - 9 Ili CLU SOL o S (e-ns) ad -meqo (GCons) -Sz- eujqqDF,

Ottt -u (= HD) - "-

  p}) adcZ t =) O [(e) cT (eOT oll4 BSSHO 4deS--, t (e) adeq OT <r "'bL0E 1 <- 4d aS110 FLJ- * to

66 8 5L

ydaS -

Q oe,

9,609,

  Figure 27 CH2- (CH2) n-CH2OH R13 Step (a) 3tap (b) - (CH2) n -CH2OH R1 R1: CH2- (CH2) n -COOH jet (C) R11 R1R5 Rs d2 Diagram 28 (OR, OR22 <SOtt | step (a) OR24 Rs,

I 1,13

  step (b) R5 step (c) r ^^^ S ^ OR24, step (d)

(after) -

  11-8 I% R22 R22 p1 J R22 Figure 28 (continued) step (d) 0R24 R12 "2 R, 3 R6 1 -OR25.s step (e) OR24 r-A i zça

64 2460944

Figure 29 A /

C-CH2

I / /

<2 O-CH2 .. CCH3

0-, CH1.C

O-chF? CH3 r .. 0

CH2 C /

/ CH2 i step (a) I

X CH, .O-CH2'.CH3

CH ,,.% / C \

O-CH2 TO CH3

  step (b) 0, wherein R 1 -CH 2 x L "CH 3 HC" O-CH 1 / "CH 3 -R 2 -R 1, step (c) a step (d) O-R 24

<, _, CHO

  step (e) ::. (continued) 122L f-O-CH2 1%,., Clia Ch <- (- CH2 .. "c -CH3

2460944

Sehema 29 (s ite) OH} step (e)

CH = CH-R29

step (f), y,

10.128

<C H = CH-R29

| Step (9)

<129

S.CH CH-R29

OH OH

step (h)

> 25,130

X 9

OH

I step (i) ..

(after)

66 2460944

  Figure 29 (continued) step (i) R29 4 / step (J) ro R29 R22, step (k) I /

/ R / 2 R29

R22 2

step (1)

A-- L \

  R24 | step (m) R22 CHO Scheme 30 OR24) 3Rs R13 135 i (R17) 2 Step (a)

OR 24

<XL R5 R3 136

JH QI1 R6 dR25

IQ

OR24 "Stage (b)

137

OMS QR6 OR25

  Step (C) 2 (I (step (d) (continued) where ST (a) ciedo I OT 6UL S (p) aej-x (a; Tfns) 0ElqtOS 1'f6G9l

- 1.1

-, 1 - z-- t

- - -: - 'y.

-: U--. -

- - Z 1- -

Figure 31 step (a)

(R17) 3

  d step (b) (R 17) 3 CH-L 3 -CH 2 -OR 25 J step (C) R 5 R 3 R 2 QS 2 1 (R 7) 3

R22 Q2

  * CH-L3-CH2-OR25 4, step (d) fi R5 R13

R9 JQ5

  step (e) (continued) Scheme 31 (next) CH-L3-CH2-OR2 '-step (e) r_. CH-L3CHl2-OR2s R13 step (f)

2 4R13

R23 RQ4

CH-L3-COOH

  step (g) R2 R23 v L3-COOH EH step (h) R13

H +

C C> L3-COOH

  Rg Q5 6 OH R3 R 23 Figure 32 - oO o

<- ,, OCH OH

<, CH CH

  step (a) <tH H = CH2 4 step (c) o I

W., O-C-C2HS

OCHO step (d) continued I step (b)

2460 44

  Scheme 32 (Continued% 41tape (d) O, -Co-1 <-1-O-c-C2H5H OH step (e) i 0

THPO O-C-C2H5

  THPO step (f) OH -THPO THPO 4, step (g)

* THPO- 0

m

- -f. _-

: - 1 - ,, - -

1. 1 -e- -, - ,. 4 to -

t-

-e, - -

Figure 33

<R25 CHO

o

OR 25 OR5

I multiple floors

I OR

OR2 Q 1 25

  OR25 H OM S O 5 ... R25 step (a) Scheme 34 o0 Clio C-0 I R R s OR2s5 step (a) steps (b). (c) and (d) to II (-taeOR2, step (e) continued f1 o <s4 Diagram 34 (continued) P-S Qi Ai step (e) OR25 step (f)

r k -

<R5

  ## STR2 ## wherein step (g) ## STR1 ## OH %

NL..L4-COOH

R5 O0R "several stages I J,

= _LLCOOH

R $ 5 OR

R. * I st I5 1: -

after-

- '- "- = - v * -C

, - -: - -, ..,

-, - - -: -, - ff-

.:. - * _-

R.11 OH t j Figure 35 (continued)

4-COOH

R5 CH2 /% L-COOH R

R 11 R6

  R ',, i 0R25% 4, R2 R = Scheme 36 Op d, -Lr 4-COOR28

R "I% R5 AH

R '11 JRH

tape (a) OH

/., .L4-CH2OH

1R 1 Q

Q. 1 OH

step (b) I.

The -.-- CH20H

  IR :, step (c) continued Diagram 36 (continued) step (c 1 / x "" -CH 2 -'-Si (R 17) 180 R 11 Of R 1, R OS 1 (R, 7) 3-step (d) ) R v ': <Xo>, 181 R. 1 s (R, 7) 3, step (e)

=, L4-L, -CH20H '

R5

R3 5OH

2-460944

Figure 37 OH

/) - 1. -1-- L4-COOH

I (aiARs 183

R2 Q OH

I - Step (ar) OH o0 0 CH3 i1 fi

>, =, L4-C-N (R,) (RH8)

<1CH3 184

  ## EQU1 ##

R2 HR

step (C) OH

- $ Y = L.-CH2-N (R7) (R8)

RH Diagram 38 OH

- "L.-COOH

R5 Mjetapea)

0 0 CH3

he i I

L4-C-O-C-O-CH2-.CH

CH3 step (b)

OH O

  <a.4-C-NH-SO2-Ri5 OH Scheme 39 OH o%

KIIIL2 S 190

X

Q OR25

stage (a) OH

- NNH-N

-

  ## STR2 ## wherein (b) 2 OH NH-N

1,192

  Q5 Scheme 40 OSi (R17) ## STR1 ## wherein L4-C-NH2

R5 193

R2 OH

(a) qsi (Ri7) 3, W An L4-C-N

<1XR5R 2 194

2

] step (b) OSi (R17) 3 NH-N

L4-Co He - -

<$ s 1N -N195 R5 It R

Q1 0R25

4tape (C)

OH NH-N

L4-C X L C lN-N 196

R11 R6

Qi- OR25 step (d)

OH NH-N

/ | - N-Nl

R '4- N' O

$ /> R5 197

R2 OH

  Scheme 41 R1 Ri11 (a) 1 <1 2i111 (% XR; 5 R1 R1 "step (b) 9 -R i R1 1 OH -i R 1 5 step (c) i" IRR II IlQ R continued Figure 41 (continued) 4step (d) OH

R, '% .--- L4- COOH

R 1 0 fNI R 'jROH

R.11 OH.

% step (e)

L4-COOR3

q! 5 R2 R2g step (f) J-- step (9)

U4- L-COOR3

  Rs R R2 Scheme 42 (R17) 3Si-O =, 4-COOR3o x 5

Q. OH

Step (a) (R.7) 3Si-O

---- 4-COOR30

  * 1 1 R 6il R1 Qi 6i I step (b) OH - '. x L4-COOR3

R. 5

% 2 Q

OH <> Ra L, -COOH

I R

R il - OH 1

after -

oC8oo3-

  - 0 r ST F1 I. I OZ OOo t? FN% S t. (qTdns) z5 -IlLDs L8 xi,., "C 5 9, LLz Scheme 43 (R17) 3Si-O / -t'L.-COOH 212 \ .1 RI Step (a) (A) 3Si-O - vs - L.-COOH Rs R 11 IQ step (b)

No> L L.-COOH

Rs 214

R 11 OH

(c) OH

L4-COOH

R2 OH

  step (d) Qs step (d) \ continued Figure 43 (continued) step C '"sX =, L4-'COOH O oH i R OH

R 11 6

teta- O

R, - L4-COOH

R

R6 OH

CR12

<- "N ===" L4-COOH

R1 OH

  step (f) step (g) CH2 It% - 4-COOH

R2 OH

* Q5 Figure 44 OR

): Y O R 30

<| R5 220

Oh he Retape (a) Se-C6H5

QR 2C 5

(| RS 221

RO H1 R O

[step (b>

OR25 C00R30

R5 222

Fold step (c) OH

COOR30-

0R | 5 R

OH 223

  Figure 45 OH -K> R6O Qi O25 step (a)

OH- J-V

> Q.R5HOR. 38

R "1.1 2

Oh he

$% R5 R-3

o..1 * Re OR2s

OH R

OH 4 /

step (b) to step (c)

'> -1 2COOH

R1 Q OH

R, 2 Q., OH

  ! Schemes 1 to 31 generally refer generally to compounds within the scope of Groups I-X as defined above, and are further illustrated in the examples hereinafter. Schemes 32 to 45 relate to intermediates or starting materials for these compounds, as illustrated in the following Preparations. The processes not illustrated in the Schemes are based on

  chemical processes generally known to specialists

  lists of the technique. The steps of the Schemes will be

discussed in detail below.

  With regard to Schemes 1 to 45, examples of alkyl groups of 1 to 4 carbon atoms inclusive are methyl, ethyl, propyl,

  butyl and their isomeric forms. Examples of radi-

  alkyl cations of 1 to 7 carbon atoms inclusive,

  are those given above, as well as pentyl,

  xyl, heptyl and their isomeric forms. Examples of alkyl of 1 to 19 carbon atoms inclusive are those given above as well as octyl, nonyl,

  decyl, undecyl, dodecyl, tridecyl,

  tradecyl, pentadecyl, hexadecyl, heptadecyl,

  octadecyl, nonadecyl and their isomeric forms.

  Examples of cycloalkyls of 3 to 10 carbon atoms, which also include alkyl-substituted cycloalkyls, are: cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, -30 -2,3-diethylcyclopropyl; 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl, 3-tertbutylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkyls of 7 to 12 carbon atoms inclusive are: benzyl, phenethyl 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2- (1-naphthylethyl), and

1- (2-naphthylmethyl).

  Examples of 1, 2-substituted phenyls

  or 3 chloro or alkyl radicals of 1 to 3 carbon atoms

  include: p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 4-chloro-2-methylphenyl, 2,4-dichloro-3-methylphenyl, (o- , m-, and p-) polyols, pethylphenyl, and 2,5-dimethylphenyl. Examples of phenyls substituted by hydroxycarbonyl or alkoxycarbonyl where the alkoxy group includes 1 to 4 carbon atoms inclusive are (o-, m- and p-) carboxyphenyls, methyl (o-, m-, and p -) - carboxyphenyls, and isopropyl (o-, m- and

p -) - Carboxyphenyl.

  Examples of hydrocarbyls of 1 to 18 atoms

  inclusive of carbon, are any of the examples

  from 1 to 18 carbon atoms, cycloalkyl

  kyles of 3 to 10 carbon atoms and aralkyls of 7 to

  12 carbon atoms given above.

  To combine in the optimal conditions, the specificity of the biological response, the activity and the duration of activity, certain compounds falling within the scope of formulas 4 and 15 are preferred. For example, it is preferable that Q represents:

R4 OH

  o it is particularly preferable that R4 represents

hydrogen or methyl.

When Q represents: R4

  it is preferable that R4 is methyl.

  Another preference for the compounds of the

  mules 4 and 15, as well as for R1, is that R3 in -COOR is either hydrogen or alkyl of 1 to 12

  including carbon atoms, or a salt of a

  from a pharmacological point of view. Moreover, when R 3 represents an alkyl, it is preferable that this alkyl contains from 1 to 4 carbon atoms, the

  methyl or ethyl proving particularly interesting.

  sants. Yet another preference for compounds

  19-hydroxy of formulas 4 and 15 is that the configuration

  19-hydroxy is an "R" configuration.

  Because of their relative instability, the enol ethers of formulas 18, 39, 51 and 96 are preferably not stored for prolonged periods in the form of their free acids in which R 1 represents -COOH, but preferably in the form of

  salts, esters or other C-1 derivatives.

  Compounds of Group I The scheme refers to Group I compounds as defined above, where M1 represents:

/ (L1)

(A1) -C = C H

  that is PGI2 type compounds. In the Sche-

  however, the starting materials of formula 16 are PGF 2 compounds having the 19-hydroxy group with or without the 19-methyl group. With respect to generalities on 19-hydroxy-PGF, reference will be made, for example, to J.C. Sih, Prostaglandins 13, 831-835 (1977), and references cited therein. These compounds of the

  formula 16 are not part of the scope of this

  vention, but they are available by

  written in the Preparations and by the Schemes of Accom-

  32-45 which will be discussed below.

  Continuing with Scheme 1, in step (a) the starting material 16 is subjected to halogenation and

  cyclization to obtain the halo compounds of the formula

  In the case of iodo compounds, an aqueous system containing iodine, potassium iodide and an alkaline carbonate or bicarbonate, or an organic solvent system such as dichloromethane containing iodine in the presence of an alkali metal carbonate. The reaction is carried out at temperatures below 25.degree.

  temperatures of about 0 -5 C for 10 to 20 hours. In-

  Then, the reaction is cooled with sodium sulphite and sodium carbonate, and the compound is separated off.

  Formula 17 of the reaction mixture.

  With regard to bromo compounds, it is

  read N-bromosuccinimide or N-bromoacetamide. See Fieser et al., Reagents for Organic Synthesis, vol. I, pages 74 and 78, vol. IV, page 51, John Wiley and Sons,

  Inc., N.Y. With respect to chloro compounds,

  methods are available, for example an exchange

  of the bromo radical with a chloro radical with

  chlorodifluoroacetic acid. See I.T. Harrison et al., Compendium of Organic Synthetic Methods, p.

346, 1971, Wiley Interscience, N.Y.

  The halo compounds of formula 17 are obtained as two isomers, one in small amounts

  and the other in large quantities, these two isomers differing in their chromatographic mobility. Normally, it is not

  necessary to separate these isomers because each one of them gives the desired products in

step "b" of Scheme 1.

  In step "b" of Scheme 1, compound 17 is converted to the enol ether compound of formula 18

  by putting it in contact with a dehalogenating reagent

  hydration. For these reagents, refer to

  example, in Fieser and Fieser, "Reagents for Organic Syn-

  Thesis, 1308, John Wiley and Sons, Inc., New York, N.Y. (1967).

  step "b" of the tertiary amines and the reagents

  in the group consisting of sodium superoxides

  and potassium, carbonates of sodium and potash-

  sium, sodium and potassium hydroxides, sodium and potassium benzoates, sodium and potassium acetates, sodium and potassium trifluoroacetates, sodium and potassium bicarbonates,

  silver acetate and superoxide tetraalkylamines

  monium of the formula (R37) 4N02, wherein R37 represents

  an alkyl radical of 1 to 4 carbon atoms,

  sively. Of the tertiary amines, it is preferred to use the following amines: 1,5-diazabicyclo [4.3.0] nonene-5 ("DBN"), 1,4-diazabicyclo [2.2.2] octane ("DABCO"),

  1,5-diazabicyclo [5.4.0] undecene-5 ("DBU").

  Other preferred reagents are sodium superoxides

  and potassium and tetramethylammonium superoxide.

  For further information on superoxides, see Johnson and Nidy, J. Org. Chem. 40, 1680 (1975). For larger scale preparation, it is recommended to use electrochemical superoxide production. See Dietz et al. J. Chem. Soc. (B), 1970,

pages 816-820.

  The dehydrohydration step is carried out in an inert organic medium, such as dimethylformamide, and this step is followed by layer chromatography.

  thin to show the disappearance of the starting material.

  The reaction is at 25 C and can be accelerated to

a temperature of 40-50C.

  When treating the reaction mixture, it is advantageous to maintain the basic conditions by

  example with triethylamine, to avoid decomposition

  acid position or structural modifications of the

  Duit. The purification is carried out by crystallization and subsequent separation from the impurities or starting material left in the mother liquor, or by means of column chromatography. With regard to the chromatographic separation, it is preferred to use a column of magnesium silicate ("Florisil

  R ") instead of silica gel.

  duit is avoided by pre-treating the column with

triethylamine.

  Compounds (5E) of group I in which M1 is H (A1) -c = C (L1) are prepared by substituting the corresponding 6-transPGF2 starting materials for the compounds of the formula

16 of Scheme 1.

  Ester groups such as the p-phenyl group

  phenolyl on the C-1 carboxyl are unchanged by the transformations of Scheme 1, and, if present on the starting material of formula 16, they are also

  in the product of formula 18. In so far as

  In the final products of formula 18, which are esters or amides, the preferred preparation process is made from halo compounds of formula 17 which

  are corresponding esters or amides.

  The other C-1 conversions are generally carried out either on the starting material, on the intermediate or intermediates, or on the final product by chemical methods which are well known to those skilled in the art. For example, if a lower alkyl ester is available or obtained according to Scheme 1, and subsequent Schemes 231, this

  ester is easily converted to the acid form by saponin

  fication. The acid is then used to prepare the various esters of formulas 4 and 15 in the range of R3 by methods well known in the art. By

  For example, the alkyl esters, cycloalkyl,

  and aralkyls by interaction of these acids with the appropriate diazohydrocarbide. For example, when

  diazomethane is used, the methyl esters are obtained

  thyliques. A similar use of diazoethane,

  diazobutane, 1-diazo-2-ethylhexane, diazocyclo-

  hexane and phenyldiazomethane, gives, for example,

  respectively the ethyl, butyl, 2-ethyl-

  hexyl, cyclohexyl and benzyl. Among these

  The methyl and ethyl esters are preferred.

  Esterification with diazohydrocarbons

  is carried out by mixing a solution of the diazohydro-

  carbide in a suitable inert solvent, preferably

  diethyl ether, with the acid reagent, advantageously

  in the same diluent or an inert diluent

  different. After realizing the esterification reaction

  The solvent is removed by evaporation and the ester is purified, if desired, by ordinary methods, preferably by chromatography. It is preferred that the contact of the acid reagents with the diazohydrocarbon is not longer than necessary to effect the desired esterification, preferably within about 1 to about 10 minutes, so as to avoid

  unwanted molecular changes. The diazohydro-

  carbides are known in the art or they can be prepared by methods known in the art. See, for example, Organic Reactions, John Wiley & Sons, Inc.,

  New York, N.Y., Vol. 8, pp. 389-394 (1954).

  Another method for esterifying the carboxyl moiety of the acid compounds of formulas 4 and 15 or their intermediates is to convert the free acid to the corresponding silver salt, followed by an interaction of this salt with a salt. Alkyl iodide. Examples of suitable iodides are methyl iodide,

  ethyl iodide, butyl iodide, iodide of isobutane

  tyl, tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, phenethyl iodide, and the like. The silver salts are prepared by ordinary methods, for example by dissolving the acid

  in dilute aqueous ammonia, evaporating the

  ammonia at reduced pressure, and then adding

  the stoichiometric amount of silver nitrate.

  The phenyl and substituted phenyl esters of the compounds of formulas 4 and 15 or their intermediates are prepared by silylating the acid to protect the hydroxy groups, for example by replacing each -OH group with a -o-si- group. (CH3) 3. Such a treatment also changes -COOH to -COO-Si- (CH3) 3. A

  rapid treatment of the silylated compound with water

  will run the -COO-Si (CH 3) 3 groups back to -COOH groups. Processes for this silylation are known in the art and are available. Then, treating the silylated compound with oxalyl chloride gives the acid chloride which is reacted with phenol or

  with phenol substituted appropriately to obtain

  a substituted phenyl or phenyl ester, silylated.

  Then, the silyl groups, for example -O-Si- (CH 3) 3 are again changed to -OH groups by treatment with dilute acetic acid. The processes for these

  transformations are known in practice.

  An interesting method for phenyl esters

  Substituted nylics are those described in US Pat. No. 3,890,372, wherein a mixed anhydride is reacted with a suitable phenol or naphthol. The anhydride is formed from the acid with isobutyl chloroformate in the presence of

of a tertiary amine.

  Phenacyl esters are prepared from the acid using a phenacyl bromide, for example p-phenylphenacyl bromide, in the presence of a tertiaceous amine. See, for example, U.S. Patent No. 3,984,454, German Patent Application Laid-Open No. 2,535,693 and Derwent

Farmdoc n 16828X.

  Figures 36 to 40 relate to trans-

  C-1 formations for these 19-hydroxy compounds of the

  4 and 15 or their intermediaries.

  When it is desired to obtain a 2-decarbox product

  boxy-2-hydroxymethyl, that is to say when R1 represents

  -CH 2 OH, the acid or lower alkyl ester form is reduced

  (see Scheme 36, Formula 177 and 178) using known reagents to reduce carboxylic acids

  in the corresponding primary alcohols. See, for example

  The United States Patent No. 4,028,419,

  lithium aluminum hydride or hyaluronate

  diisobutylaluminum fiber. Interesting solvents

  are diethyl ether, tetrahydrofuran and di-

  methoxyethane. The reaction can be carried out at times

  temperatures ranging from -78 C to 100 C, although we prefer

  use temperatures of about 0 C to 50 C.

  carbonyl groups in the molecule will also be reduced unless appropriately protected such as oximes, ketals or similar carbonyl derivatives that are reconstituted to carbonyls.

  after realizing the reduction.

  A 2-decarboxy-2-hydroxymethylPGE compound can also be prepared by blocking the C-1 alcohol groups as shown in Scheme 36, Formula 180. Thereafter, the C-9 hydroxy is oxidized to form the product of the formula 181 and we finally separate the

  blocking group -Si (R17) 3 by hydrolysis. It is pre-

  fable that the group -Si (R17) 3 be a group tert-

butyl-dimethylsilyl.

  The compounds in which R 1 represents: ## STR1 ## (R 7) (R 8) or -C-N (R 7) (R 8)

  are prepared in an appropriate way from the

  formulas 4 or 15 or intermediates that are

  acids, that is to say when R1 represents -COOH.

  For generalities, reference is made to the United States patent.

  United States of America No. 4,085,139. The compounds are simple-

  converted to a mixed anhydride using alkyl, aralkyl, phenyl chloroformate or

  substituted phenyl in the presence of a tertiary amine.

  An interesting reagent is isobutyl chloroformate.

  The anhydride is then reacted with ammonia or the appropriate amine (R7) (R8) NH to form the amide in which R1 represents:

-C-N (R7) (R8)

  The 2-decarboxy-2-amino compound is prepared

  from the amide by reducing the

  carbonyl using methods well known in the art for

  tick, for example by a reduction by means of hydride

  of lithium and aluminum. See Figure 37.

t. O9I4

  The compounds in which R1

present:

-2-NH-SO2-R15

  That is N-sulfonylamidE, from the compounds of formula 16 in the form of acid. In Scheme 38, the steps by which these compounds represented by Formula 183 are converted into the sulfonylamides of formula 189 are shown. In step (a), the mixed acid is converted. represented here by formula 188, by reaction with isobutyl chloroformate, in the presence of a tertiary amine such as triethylamine. Other mixed anhydrides can also be used. In step (b),

  react the anhydride with the sodium derivative of a sulfonyl

  amide of the formula Na-NH-SO2R15 obtained, for example, by the reaction of methanolic sodium methoxide with an equimolar amount of the sulfenylamide. The reaction of step (b) is favored by the addition of a small

  amount of hexamethylphosphoramide to ensure homo-

geneity.

  The compounds in which R1 is

feel

NOT

  either by the method of Scheme 39 or by the method of Scheme 40. In Scheme 39, the starting lactone 190 is available above, for example by a reduction of the product of formula 170. By applying the Wittig reaction and using the ylide prepared from a phosphonium compound of formula 139, the compound of formula 19 is obtained. See U.S. Patent No. 3,928,391. Replacement of groups of

  blocking R25 then gives the products of formula 192.

  Compounds 191 are transformed by methods

  cut here or well known in practice, in the compounds

  Tetrazolyl is within the scope of formula 4.

  In Scheme 40, the method makes it possible to obtain graduatively from an amide, a nitrile and then a

  Tetrazolyl compound. Starting materials 193 are dis-

  available, for example from a blocked acid pre-

  with R25 at C-11 and C-15, and converted to an amide via a mixed anhydride, which

  is then blocked with C-9 silyl groups.

  In step (a), the nitrile of formula 194 is prepared by dehydration of amide 193 with a

  carbodiimide. See C.Ressler et al., J.org.

  Chem.26,3354 (1961). For example, N, N'-dicyclo

  hexylcarbodiimide (DCC) proves to be interesting in pyrolysis

  dine around room temperature.

  In step (b), the tetrazolyl group is formed in the compound of formula 195 from the foregoing nitrile by reaction with sodium azide and ammonium chloride, such as dimethylformamide. See "Heterocyclic Compounds", R.C.Elderfield, John Edition

  Wiley and Sons, Inc., N.Y., Vol. 8, pages 11-12.

  In steps (c) and (d), the blocking groups -Si (R17) 3 and R25 are replaced by desilylation and mild acid hydrolysis in the usual manner to give the compound of formula 196 and then the compound of the formub 197. The compound 196 is interesting

  as an intermediate for the preparation of

  trazolylates falling within the scope of formula 4.

  Compounds are incorporated into formulas

  4 and 15, the salts when R3 represents an acceptable cation

  table from a pharmacological point of view. These salts are acceptable

  pharmacologically interesting for the above applications, are those obtained with metal cations, ammonium cations,

  amine cations or ammonium cations quater-

  are acceptable from a pharmacological point of view.

  Especially interesting metal cations are those derived from alkali metals, for example lithium, sodium and potassium, and those from alkaline earth metals, for example magnesium and calcium, although the cationic forms of other metals, for example aluminum, zinc and

  iron, also fall within the scope of this

  vention. Pharmacologically acceptable amine cations are those derived from primary amines,

* secondary and tertiary.

  Examples of suitable amines are: methylamine, dimethylamine, trimethylamine, ethylamine,

  dibutylamine, triisopropylamine, N-methylhexylamine,

  cylamine, dodecylamine, allylamine, crotylamine, cyclohexylamine,

  pentylamine, dicyclohexylamine, benzylamine, dibenzylamine

  N, α-phenylethylamine, A-phenylethylamine, ethylenediamine

  mine, diethylenetriamine, etc., as well as amines

  phasic, cycloaliphatic and araliphatic

  up to and including about 18 carbon atoms, and

  if the heterocyclic amines, for example the

  ridine, morpholine, pyrrolidine, piperazine,

  and their lower alkyl derivatives, for example 1-

  methylpiperidine, 4-ethylmorpholine, 1-isopropyl-

  pyrrolidine, 2-methylpyrrolidine, 1,4-dimethyl-

  perazine, 2-methylpiperidine, etc., as well as

  amines containing hydrophilic groups or solubilizing

  in water, for example mono-, di-, and tri-

  thanolamines, ethyldiethanolamine, N-butylethanolamine,

  2-amino-1-butanol, 2-amino-2-ethyl-1,3, propanediol, 2-amine

  no-2-methyl-1-propanol, tris (hydroxymethyl) aminomethane, N-

  phenylethanolamine, N- (p-tert-amylphenyl) diethanolamine,

  galactamine, N-methylglycamine, N-methylglucosamine, ephedrine

  drine, phenylephrine, epinephrine, procaine, etc. Examples of quaternary ammonium cations

  pharmacologically acceptable are tetra-

  methylammonium, tetraethylammonium, benzyltrimen-

  thylammonium, phenyl triethylammonium, etc. Salts containing pharmacologically acceptable cations are prepared from the

  compounds of formulas 4 and 15 in the form of a-

  free radical, that is to say in which R 1 represents -COOH, by neutralization with appropriate amounts of the corresponding inorganic or organic base, of which

  Examples correspond to the aforementioned cations and amines.

  These transformations are realized by a series of

  dice known in the art as being generally used for the preparation of inorganic salts, i.e.

  metal salts or ammonium salts, addition salts of

  and amine, and quaternary ammonium salts. The choice of process depends in part on the solubility characteristics of the particular salts prepared. In the case of inorganic salts, it is usually appropriate to dissolve the acid of formula 4 or 15 in water containing the stoichiometric amount of a hydroxide, carbonate or bicarbonate corresponding to the salt. inorganic desired. For example, a use of this type

  of sodium hydroxide, sodium carbonate or bicarbonate

  Sodium Bonate makes it possible to obtain a solution of the salt of

  sodium. Evaporation of water or addition of soil

  For example, a water-miscible monomer, eg a lower alkanol or a lower alkanone, provides the solid inorganic salt if this form is desired. The amine and quaternary ammonium salts are prepared by similar methods using

appropriate solvents.

  Referring now to Figure 2, there is

  presented a process for the preparation of the compounds of

  pe I in which M1 represents: H

-C CH2,

  that is PGI1 type compounds. Starting materials 16 are converted to a mercury compound of formula 19, which is then subjected to reductive demercuration to form the product of formula 20.

  the generalities on mercury-cyclization

  For example, reference is made to U.S. Patent No. 4,125,712 and the references cited therein, including H.C. Brown et al.

Organometal. Chem. Syn. 1.7 (1970).

  In step "a" of Scheme 2, the starting material is reacted with an appropriate mercury salt (II) corresponding to Hg (G) 2, for example nitrate, mercuric acetate chloride. It is preferred to use mercuric acetate or trifluoroacetate. The reagent is dissolved in water or in an acid, for example the acid

  acetic acid, and it is combined with a solution of

  of formula 16 in a suitable solvent.

  such as chloroform or tetrahydrofuran.

  The reaction in a suitable manner is carried out at a

temperature of about 15 -35 C.

  In step "b" of Diagram 2, the component

  mercury to a reductive demercuration. Reagents

  interesting for this stage are the sodium borohydride

  dium, sodium amalgam and hydrazie. A reagent

  particularly interesting is the sodium borohydride

  dium in alkaline solution, for example hydroxide

  aqueous sodium. The reaction is carried out in a soil

  such as tetrahydrofuran, at a temperature of about 15-35 C. Then, the mercury is separated and

  isolates the product by methods described herein.

  In a modification of the process of Scheme 2, the

  starting material is formed from a compound of the type 19,20-

19 "1

  didehydro- ("19) PGF2a, blocked with tetrahydro-

  pyran (THP) at C-11 and C-15. Treatment with

  mercuric acetate then forms the compounds of the

  corresponding cure. Subsequent treatment with sodium borohydride leads to demercuration and

  the formation of 9-deoxy-6,9a-epoxy- (19R, S) -

  19-hydroxy-PGF1 under bis (THP ethers). The release

  cage then gives the compounds of formula 4. See,

for this purpose, Example 2.

  Figure 3 illustrates the process used for

  Compounds 2 of Formula 24 of Group I, where L1 represents

  -CH2-CH = CH-. For generalities relating to the pre-

2 2

  parations of S-prostaglandin analogs, we

  for example, to the United States patent of

that n 4.024.174.

  In step "a", selenylation is carried out by first forming 2-lithium derivatives of lower alkyl esters of formula 21, for example by reaction with a lithium amide formed from a

  secondary amine, such as N-isopropylcyclohexyl

  mine. The compounds of formula 22 are then obtained by reaction with diphenylseliene or benzene-selenyl bromide using about 3 equivalents for each molecular equivalent of the lithium derivative.

  C-2 at a temperature of about -78 C.

  In step "b", compounds 2 of formula 23 are formed by oxidative removal, for example with hydrogen peroxide or periodate

sodium.

  In step "c", the final compounds of

  formula 24 being within the framework of R, by means of

  methods known in the art or described in the context of

the present invention.

  Figure 4 illustrates another method for obtaining

  compounds of the PGI1 type using

  5-halo diuns of formula 25, including compounds of formula 17 of Scheme 1 and compounds 82 of

formula of Scheme 5.

  In step "a" of Scheme 4, the compound is subjected to

  halo of formula 25 to dehalogenation by reduction.

  Useful reagents are tributyltin hydride, triphenyltin hydride, sodium borohydride in ethanol or dimethyl sulfoxide, and zinc

  in acetic acid. A particularly interesting reagent

  the most important is the fresh triethyltin hydride

  trimmed with tributyltin chloride and lithium aluminum hydride. The reaction is carried out in

  a solvent, such as benzene, at a temperature of

  $ 15 q35oC, and is controlled by means of a chromato-

  thin-layer graphs, to give the compounds of

formula 26.

  Figure 5 illustrates a way to obtain

  The X 5-halo compounds of formula 30 are

  starting point of Form 27 are in the frame

  compounds of formula 17 of Scheme 1 and use of

  for steps (a) - (c) the same chemical process

  than for the compounds of Scheme 3.

  Scheme 6 illustrates the preparation of Group I hydroxy-PGI1 compounds in Calls M1 represents OH

it CH2_-

  In step "a", the halo compound is converted to an equilibrium mixture of the 6-hydroxy compound of formula 32 and the 6-oxo compound of formula 33 by contacting with silver carbonate. and perchloric acid. The reaction is carried out in an inert organic medium such as tetrahydrofuran and is monitored by means of thin layer chromatography.

  to determine its completion, which is normally

  It lasts 15-24 hours at a temperature of about 250C. The reaction is preferably carried out in the absence

from light.

  Although the product of step "a" contains normal

  In the case of compounds 32 and 33, a better balance can be achieved simply by preparing a solution of this product in an organic solvent, for example acetone or dichloromethane, and allowing it to stand for several days. The resulting mixture is concentrated and separated, for example by means of a

silica gel chromatography.

  Another way to obtain the mixture of the 6-hydroxy and 6-oxo compounds 32 and 33 is to treat the halo compound of the formula 25 in alcoholic solution,

  for example methanol, with a metal hydroxide

  aqueous hug, for example potassium hydroxide

  at a temperature of the order of 0 to 300C for several

  several hours. After acidification, one obtains a

  a mixture of the acid form of the compound of the formula 25 and the hemiketal of the formula 32 together with a certain amount of the compound 6-oxode Formula 33, which

  for example, by means of chromatography,

  on silica gel or fractional crystallisation

  born. Scheme 7 merely shows a preferred route leading to the amides of the 6-hydroxy and 6-oxo compounds,

  forming the amides of formula 35 from the

  5-halo formula 34, and then applying

  the processes in Figure 6 so as to obtain the

  Compounds 36 and 37 are in equilibrium.

  Group II Compounds Schemes 8 to 12 relate to Group II compounds, as defined above, i.e.

  PGI2 and PGI1 compounds of the enlarged heterocyclic type.

  Figure 8 shows, in step 'la', the dehalogenhydrochloride

  of compound 38 to give compound 39. The reactions

  The conditions and conditions are the same as those used for Scheme 1, step "b". The starting materials of formula 8 are readily available, for example by

  the methods of Schemes 9 and 10 described hereinafter. The-

  Step "b" of Figure 8 shows the dehydrohydrate step

  Reduction to give compound 40 using the same reagents and conditions as for Scheme 4.

  Figure 9 shows the preparation of the compounds 4-

  Halo 42, using X -19-hydroxy-PGFia41 compounds, for which reference is made to Scheme 45. The step "an" uses the same halogenation-cyclization reagents and

  the same conditions as in Diagram 1, step "a" above.

  above. Scheme 10 makes it possible to obtain the compounds a2 of the formula 46 by the steps (a) - (c) which follow the

  same chemical process as in Figure 5.

  Schemes 11 and 12 lead to equilibrium mixtures

  free of the 5-hydroxy and 5-oxo compounds of formulas 47 and 48, respectively. In Scheme 11, the enol ether of formula 39 of Scheme 8 is subjected to a mild acid,

  for example a buffer of pH 2, at a temperature of

  25 C for 30 minutes. Figure 12 applies the same process as Figure 6 above, using

  silver carbonate and perchloric acid.

  Group III Compounds Schemes 13-17 relate to Group III compounds as defined above, i.e.

  expanded heterocyclic compounds of the 9-deoxygen type

  6,9a-epoxymethano-PGF. Figure 13 shows, in the

  step "a", the formation of the corresponding 5-halo-9-deoxy-6,9a-epoxymethanoPGF compounds of formula 50,

  followed in step "b" by the dehydrohalogenation step.

  The halogenation-cyclization and dehalogenation-dehydrogenation processes and reagents are the same as those used in Scheme 1. Starting materials

  of formula 49, that is to say analogues of 9-deoxyribonucleic acid

  xy-9-hydroxymethyl-PGF2a are available from the

Figure 14 process.

  In Scheme 14, the final starting materials are 19-hydroxy-PGE 2 compounds of the formula

  52. Some of these compounds are known in the literature.

  erasure; for example, refer to J.C.Sih, Prostaglan-

  Disl 13, 831 (1977) and the references cited therein.

  The methods of general preparation are given in the Preparations below, with reference to the Schemes

  and 41. The compounds 52 are obtained in the form of

  Lower alkyls, in which R 10 represents

  an alkyl of 1 to 6 carbon atoms.

  In step "a", a silylated compound 53 is obtained from compound 52 by processes known in the art or by processes described in connection with

  present invention. See, for example, Pierce, "Silyla

  The silylating agents required for these transformations are known in the art or are prepared by methods known in the art, see, for example, "Silicones". Other Organic Silicon

  Compounds ", Reinhold Publishing Corp., New York, N.Y.

  (1949). These reagents are used in the presence of a tertiary base such as pyridine at

  order of about 0 to more than 50 C. For this purpose,

  of trisubstituted monochlorosilanes are chlorinated

  trimethylsilane, chlorotriisobutylsilane, tert-butyl-

  dimethylchlorosilane, chlorotriphenylsilane,

  chlorotris (p-chlorophenyl) silane, chlorotri-m-tolylsi-

lane and tribenzylchlorosilane.

  Or, a chlorosilane is used with a disinfectant

  corresponding lazane. Examples of other

  lylation are pentamethylsilylamine, pentaethylsilyl

  amine, N-trimethylsilyldiethylamine, 1,1,1l-triethyl-N, N-

  dimethylsilylamine, N, N-diisopropyl-1,1,1-trimethylsilyl;

  amine, 1,1,1-tributyl-N, N-dimethylsilylamine, N, N-dibutyl-

  1,1,1-trimethylsilylamine, 1-isobutyl-N, N, 1,1-tetramethyl-

  silylamine, N-benzyl-N-ethyl-1,1,1-trimethylsilylamine,

  N, N, l, l-tetramethyl-l-phénylsilylamine, N, N-diethyl-1-

  dimethyl-1-phenylsilylamine, N, N-diethyl-1,1-dimethyl-

  1-phenylsilylamine, N, N-diethyl-1-methyl-1,1-diphenylsulfonyl

  lylamine, N, N-dibutyl-1,1,1-triphenylsilylamine and 1-

  methyl-N, N-l, l-tétraphénylsilylamine. Although a wide variety of silylating agents are available, it is preferable that the silyl groups on the ring or nucleus contain at least one group

  with steric hindrance, for example: an isopropyl group

  pyle, secondary butyl, tertiary butyl, cyclohexyl

or phenyl.

  Silyl groups with substituents

  a steric hindrance are characterized as being

  less sensitive to hydrolysis than, for example,

  methylsilyl, and therefore more resistant to replacement for subsequent steps, particularly during step (d). Examples of preferred silyl groups for the cyclopentane ring or ring are:

  isopropyldimethylsilyl, sec-butyldimethylsilyl, tert-

  butyldimethylsilyl, triisopropylsilyl, cyclohexyldimetri

thylsilyl, and triphenylsilyl.

  In addition to the silylation methods discussed above, it is advantageous to silylate with a chlorosilane in the presence of imidazole in a solvent, such as dimethylformamide. See Corey et al., J. Am.Chem. Soc. 94, 6190 (1972). The temperature range

  for the reaction is about -10 to + 80 ° C.

  In step "b", the compounds of the type

  9-deoxy-9-methylene of the formula 54 from the compounds

  of Formula 53 Using Known Processes

  in practice. See, for example, the United States Patent

  United States of America No. 3,950,363, applying the process of C.A.Johnson et al., J.Am.Chem.Soc. 95, 6.462

  (1973). Here, the carbanion of a sulfoxi-

  formula 229, for example, with a

  alkyllithium or alkylmagpsium housing, with

  of Formula 53 to form a sulfonimidoyl adduct of Formula 230

C6H5

  m 229 OuS = N-CH3 CH3 é.Sncî: 0 t'i4 C5H5

0 = S = N-CH3

  CH2 H "L. COORo1 230 It4 sQ2 Ra OSi (R, 7) 3

R14 Q2

  Then, a reduction elimination with,

  for example, an amalgam of aluminum in the presence of

  such as acetic acid or hydrochloric acid, gives the intermediates of formula 54, generally free of blocking groups. In step "c", compound 54 is again silylated to replace any lost silyl groups.

  in step "b". In step "d", a boundary is used

  hydration-oxidation to transform the 9-methyl group

  binds compound 55 to 9-hydroxymethyl (-CH 2 OH).

  See in particular the patent of the United States of America

  No. 3,950,363 in columns 16-17 and 38. Then, in the

  "e", the silyl groups are replaced by hy-

  in a known manner, for example by acid hydrolysis in dilute acetic acid or by t-butyldimethylsilyl groups, by the use of tetrabutylammonium fluoride. See E.J.Corey et al., J.Am. Chem.Soc. 94, 6190 (1972). Finally, in step "f", compounds within the scope of

formula 49.

  Scheme 15 shows the preparation of 2,9-deoxy-6,9aepoxymethano-5-halo compounds useful as starting materials for Scheme 16. Starting with

  compounds of formula 58 from Scheme 13, formulate

  mule 50, steps (a) - (c) use the same processes

  and the same reagents as those described above for

Figure 5.

  Figure 16 shows the transformation of a

  5-halo compound of the formula 62 to a compound of the PGIi type of the formula 63, using dehydrohydration

by reduction.

  Scheme 17 shows the formation of the equilibrium mixture of a 6-hydroxy compound 64 and a 6-oxo compound

  from a 5-halo compound 62, applying the same

  my processes as for Figure 6 above.

  Group IV compounds Reference is made to Schemes 18 and 19. Scheme 18 illustrates a route for obtaining compounds of the 5-hydroxyPGI1 type of Formula 69, starting from compounds of PGF2a type of Formula 31. See FIG. U.S. Patent No. 4,110,532, in particular

columns 10 and 15.

  In step "a", a mercuroacetylation of compound 31 gives compound 66, by reaction with mercuric acetate, Hg (OAc) 2. We use in a way

  suitable organic solvents such as tetrahydro-

  furan, with temperatures of reaction to temperature

  ambient temperature or below it.

  In step "b", the compound 67 is obtained

  displacing the acetate radical of compound 66 and replacing it with

* placing by a radical halo. To this end, we use a

  aqueous NaHal sodium halide solution (e.g.

  sodium chloride or sodium bromide), shaking

  simply reagents together until the reaction

  completed, as can be seen by a chrono-

matography on thin layer.

  In step "c", compound 68 is obtained at 246o0944 with reductive oxygenation. The compound of formula 67 is reacted with a reducing agent (eg, sodium borohydride) in the presence of molecular oxygen. Finally, in step "d" the products of formula 69 are obtained from the alkyl esters

  represented by formula 68, by methods

  described in the context of the present invention or

  well by the methods known in practice.

  Figure 19 refers to the stages of preparation

  of the compounds A2-5-hydroxy of the formula 73. The

  starting material 70 is available from compound 69,

  Figure 18. The processes are the same as for the

pes (a) - (c) of Scheme 3.

Group V compounds

  Schemes 20 and 21 relate to

  type 4 -PGI1. See U.S. Patent No. 4,109,082 and E.J.Corey et al., J.Am.Chem. Soc.99, 2006-2008 (1977). Scheme 20 shows the steps for obtaining from a blocked PGF2a type compound of Formula 74 a product of Formula 77. The starting materials are readily available. For example, see Scheme 35 (Formula 171) and Scheme 41,

with the obvious-changes.

  When the blocking group R25 is the tetra-

  hydropyranyl (THP) or tetrahydrofuranyl, it is

  read the appropriate reagent, for example 2,3-dihydropyridine

  or 2,3-dihydrofuran, in an inert solvent

  such as dichloromethane in the presence of a coupling agent

  acid densification such as p-toluenesulfonic acid or pyridine hydrochloride. The reagent is used in one

  slight excess, at the rate of 1.0 to 1.2 times the theo-

  and the reaction is carried out at a temperature of

viron 20 -50 C.

  When R25 has the formula R31-O-C (R32) -

  CHR33R34 R as defined herein, encompassing the group

  For example, 1-ethoxyethyl, the appropriate reagent is a vinyl ether, for example ethyl vinyl ether, isopropenyl methyl ether, isobutyl vinyl ether, or any vinyl ether of the formula R31-OC (R32) = CR33R34 in which R31, R32, R33 and R34 are such that

  defined above, or a cyclic or heterogeneous compound

  unsaturated terocyclic, for example 1-cyclohexenyl ether

  1-methyl of the formula CH, 30x3 or 5,6-dihydro-4-methoxy-2Hpyran of the formula: C [H30 See C.B.Reese et al., J.Am.Chem. Soc. 89, 3366 (1967). The reaction conditions for these vinyl ethers and the unsaturated products are similar to those used for the above dihydropyran. In the sequence of the steps of Scheme 20, it is obviously essential that the C-9 hydroxyl of compound 74 is unblocked. In step "a", compound 75 is obtained by reaction with phenylselenyl bromide in a solvent, such as tetrahydrofuran at a temperature of about -20 ° C, in the presence of a base such as

  calcium carbonate in an equivalent amount.

  In step "b", the compound 76 is the result of an unblocking of the compound 75, for example by means of a mild acid hydrolysis using dilute acetic acid, aqueous citric acid, or 'Phosphoric acid

  aqueous solution in a mutual solvent such as tetrahydrofuran

  born. Temperatures of 30 ° C. are used.

  In step "c", an oxidative de-enenylenylation with hydrogen peroxide at a temperature of about 0 C in a solvent such as tetrahydrofuran,

allows to obtain the compound 77.

  Figure 21 illustrates the preparation steps 2 4

  compounds of type A 2, L PGI 1 of formula 81.

  78 is available from Figure 20,

  and the processes are the same as for steps (a) -

(c) of Scheme 3.

  Group VI compounds Figure 22 relates to compounds of the type

  6-alkoxy-PGI1. Starting materials 82 and 83 for the

  Step "a" are available, for example, from Scheme 6. The separated materials or their melanyl are brought into equilibrium with an alkanol of the formula

  RloOH, for example methanol if R10 represents the

  until the product 84 is obtained. The reaction proceeds at an interesting rate in a

  temperature range from 20 to 30 C but can also

  be carried out at temperatures below or below

  over a range of up to more than 50 C. In

  the other step "b", the starting materials are com-

  poses of the type PGI2 of the formula 18. These, at the time of the

  brought into contact with the appropriate alcohol R1oOH, in

  acid such as formic acid or acetic acid.

  or Lewis acids, such as

  boron fluoride, easily form the product 84 at a

temperature of 20-30C.

  Group VII Compounds The Scheme 23 relates to 4-keto-PGIl compounds. See the patent of the United States of America

  No. 4,166,744, in particular columns 15-18. In the-

  Step "a", the lactol of formula 85 is converted,

  optionally available to the intermediate product 86 by reaction with the anion of a suitable phosphonate ester of the formula 231:

(R300) 2PCH2-C-L5-CH2OSi (R17) 3,231.

  See W.S.Wadsworth and W.D.Emmons, J.Am.Chem.Soc., 423, 1733-1738 (1961). The anion, which is easily obtained in

  treating the phosphonate with sodium hydride,

  with lactol 85 at a temperature of 0 ° C - 25 ° C.

  Dan4 'step' b ', when X' is -CH-C- (Hal) -,

  dehalogenhydration gives -C = C-C13-C14. For example

  ple, compound 86 is reacted with a base such

only potassium t-butoxide.

  In step "c", compound 88 is obtained by desilylation, using selective hydrolysis as discussed previously for Scheme 14. In step "d", compound 89 is obtained by oxidation of the hydroxymethyl group to C-2, using, for example,

a Jones reagent.

  In step "e", compound 89 is released in the usual manner, by mild acid hydrolysis, for

obtain the product 90.

  Group VIII Compounds Figure 24 illustrates the preparation phases

  of compounds of the type <6-PGI1. See the United States Patent

  United States of America No. 4,128,113. Starting materials of

  Form 91 are available as part of the pre-

  this invention. It is preferable to use esters and not the free acid form of the starting material of the

type PGI2.

  In step "a", the free hydroxyl groups of compound 91 are blocked with acyl groups. of the

  aliphatic carboxyacylation agents for this trans-

  are known in the art or can easily be obtained by methods known in the art, and

  carboxyacyl halides, preferably

  chlorides, bromides or fluorides, and the

  carboxylic acid hydrides. The preferred reagent is an acid anhydride. Examples of acid anhydrides

  interesting for this purpose are: acetic anhydride, anhy-

  propionic acid, butyric anhydride, pentahydride

  noique, nonanoic anhydride, tridecanoic anhydride,

  stearic anhydride, anhydrides (mono, di, and tri) chloro

  roacetics, 3-chlorovaleric anhydride, 3- anhydride

  (2-bromoethyl) -4,8-dimethylnonanoic acid, cyclic anhydride

  propaneacetic anhydride, 3-cycloheptanepropionic anhydride,

  13-cyclopentanetridecanoic anhydride, phenyl anhydride

  acetic anhydrides (2 and 3) -phenylpropionics, anhy-

  13-phenyltridecanoic acid and phenoxyacetic anhydride.

  In step "b", we obtain intermediate 6-

  oxo of formula 93 from the compound of formula 92 by hydrolysis under mild acid conditions using, for example, dilute acetic acid

in tetrahydrofuran.

  In step "c", compound 94 is obtained by recycling compound 93 by refluxing in benzene or a substantially similar nonpolar aromatic solvent boiling over

50 C.

  In step "d", compound 95 is the result

  of an unblocking of the compound 94, for example by saponification

  with an alkali metal alcoholate. Any R18 ester is partially or completely converted to

alkali metal.

  In step "e", the products 96 are formed by methods well known in the art. For example, the sodium salts are converted to esters by the method Mukaiyama, Chem. Letters 1975, 1045, using

  N-methyl-2-bromo-pyridinium iodide.

  Compounds of Group IX Schemes 25 to 27 refer to compounds of

  b7pe.-PGI1 and intermediates for their preparation.

  See U.S. Patent No. 4,151,351.

  The end products of Formula 115 exist as two isomers, 6a and 63, and accordingly, Scheme 25 illustrates the preparation of intermediates

  6p and Figure 26 illustrates the preparation of

corresponding 6a.

  In Figure 25, we transform the material of

  starting 97, readily available in the context of

  invention, by 9 steps in the product 106

  In step "a", the free hydroxyl groups are

such as with THP.

  In step "b", compound 99 is obtained

  from the compound 98 by phenylselenylation, in use

  reading the known methods in practice. For example, we

  treated compound 98 with il-butyllithium in

  ne and diisopropylamine in tetrahydrofuran and

  then with phenylselenyl chloride.

  In step "c", the oxygenated deelenylation

  dante with hydrogen peroxide gives the compound of the

formula 100.

  In step "d", a second phenylselenylation gives compound 101. For this purpose, the reagent is prepared from diphenyl diselenide in an aqueous solution.

  alcoholic agent of a reducing agent formed of boron hydride.

  In step "e", lactol 102 is obtained from

  usual way, for example by reduction with hy-

  diisobutyl aluminum fiber at a temperature of about

-780C.

  In step "f", compound 103 is obtained by a Grignard reaction with a reagent of formula 232: Hal-Mg-CH2- (CH2) n-CH = CH2 232, or reagent which is added dropwise. to a solution

cold (0-5 C) of compound 102.

  In step "g", compound 104 is the result of cyclization of compound 103 with an aryl halide

  or alkysulfonyl (eg p-toluene chloride)

  sulfonyl) in an amine base.

  In step "h", the compound 105 is obtained by

  treatment with hydrogen peroxide as in the

pe "c".

  In step "i", the hydroxy compound is obtained

  methylated by borhydration, for example using 9-borobicyclo [3..3] Jaonane in an organic solvent

  at a temperature of 0 ° C, followed by addition of hydroxyl

  of sodium and hydrogen peroxide. See Fieser et al., Reagents for Organic Synthetics, Volume 2, page 31, 1969, Wiley Sons, N.Y .;

  In Figure 26, we transform the material of de-

  part 99, available from step "b" of Scheme 25, to the isomeric compound 6a 111. In step "a", lactol 108 is obtained by the usual reduction methods of

  a lactone, as in Scheme 25, step "e".

  In step "b", the Grignard reaction of Scheme 25, step "f", is used to obtain compound 109. In step "c", compound 110 is the result of a cyclization of compound 109 through the process of

Figure 25.

  In step "d", there are in fact two stages, an oxidative deselenylation forming the saturation and a borhydration forming the primary alcohol, as in Scheme 25, steps "h" and "i", to obtain

compound 111.

  Scheme 27, using either compound 106

  the compound 111 above, represented here by the

  posed 112, illustrates the three steps leading to the product 115.

  In step "a", compound 112 is unblocked, e.g.

  by acid hydrolysis 12. In step "b", the

  The primary alcohol group is oxidized to carboxyl, using

  a catalyst from Adams. See Fieser and Fieser, Rea-

  Organic SyntheBis, Volume 1, page 890, John Wiley

Sounds, N.Y. (1967).

  Finally, in step "c", the carboxylic acid 114 is converted by the usual methods to give

  compounds falling within the scope of formula 115.

  C-6 stereochemistry is observed from product 112 throughout the processing steps leading to

compound 115.

  Compounds of Group X LE Scheme 28-31 refer to 6a-carba-PGI2 compounds and intermediates for their preparation.

  Figure 28 illustrates the steps to achieve

  from different aldehyde 116 of Scheme 29 different intermediates 118,119,120 and 121 which, by applying the prostaglandin numbering system, vary at the location of the latent C13-C14 position according to the definition of X. In the step " a ", the Wittig reaction is used using a ylide from a phosphonate of the formula 233; 0 0 Rs R12 -. He (R3o00) 2 PClH2-C --- C- (CH2) 2-C-CH3 233

R6 OH

  In the preparation of final products of the type 19-hydro-

  xy having a specific configuration in C-19, we use

  the appropriate optically active isomer of compound 233.

  It is preferred to use the isomer which gives a final product having the highest pharmacological activity as

  determined by ordinary biological tests.

  In step "b", the 3'-oxo group of compound 117 is reduced and all free hydroxyl groups are blocked with R25 blocking groups to give the

compound 118.

  In step "c", compound 119 is obtained by photoisomerization so that the latent C13-C14 double bond of the trans configuration is isomerized to the cis configuration. See, for example, U.S. Patent No. 4,026,909. The compound is irradiated

  117, preferably with a source producing

  by producing photons of a wavelength

  approximately 3,500 A, until we obtain a

  lange in equilibrium of cis and trans isomers. The development

  is controlled in an appropriate manner by means of

  thin layer chromatography. We then separate

  The mixture is mixed by ordinary methods, for example by chromatography on silica gel. Then, the 3'oxo groups are replaced by Q as described

  above, and the hydroxyl groups are blocked with R25.

  In step "d", compound 120 is obtained in which there is a triple bond at the location of latent C13-C14. The general process follows that of U.S. Patent No. 4,029,681. A mono-halo compound is obtained by halogenation of the compound 117

  followed by dehalogenation and dehalogenation.

  tion. Halogenation is carried out in an appropriate manner

  with a reagent such as N-bromosuccinimide or

  with bromine solution in carbon tetrachloride

  bone. The dehydrohydration is carried out by addition of a base, such as pyridine or methanolic sodium acetate. The dehalogenation is carried out with the usual reagents, for example a mixture of zinc and

  of acetic acid, to give the compound 120.

  In step "e", the compound 118 is reduced catalytically, for example with hydrogen at atmospheric pressure, using palladium on

  charcoal to give compound 121.

  The starting material of Figure 28, namely

  Dehyde 116, is obtained by the steps of Scheme 29.

  In Scheme 29, tricyclic acetal ketone

  of formula 122 is known. See, for example, the breed

  United States of America No. 3,873,571. Become part of

  Interestingly 'e composed. endo, called 3- (5,5-

  dimethyl-l, 3-dioxolan-2-yl) tricyclo [4.2,0,02,4] -octan-7-

  one. Epoxidation is carried out, applying the method

  E.J.Corey et al., J.Am.Chem.Soc. 87, 1353 (1965).

  For this purpose, demethylsulfonium methylide is obtained by reaction of sodium dimethylsulphinylcarbanyldis ("dimethyl") (prepared from diethyl sulfoxide and sodium hydride).

  sodium) and trimethylsulfonium iodide.

  In step "a", the epoxymeric compound is obtained.

  thano of formula 123 by reaction of ketone 122 with dimethylsulfonium methylide ylke. We realize the

  reaction at a temperature of about 0 OC and it is me-

finalized within 1 hour.

  In step "b", the cyclopentanol structure

  No. 124 is developed following a modification of the

  method of M. L. Leriverend and collaborators, C.R.Acad.

  Sc.Paris, Series C, 280, 791 (1975). The product of step "a" is treated with lithium iodide in a solvent,

  such as tetrahydrofuran at room temperature.

  It will be noted in formula 124 that the position of the carbonyl on the ring is recognized by the C-8 carbon atom for this structure as well as for the other cyclic structures of formulas 125 to 129,

  In step "c", consisting of two separate stages

  In this case, compound 124 is first reduced to the corresponding 8-hydroxy compounds, for example with a metal borohydride, particularly sodium, potassium, lithium or zinc borohydride. Other interesting reducing agents are lithium hydride

  and (tri-tert-butoxy) aluminum, diisobutyl hydride

  aluminum, and various borohydrides such as trimethoxy

  sodium borohydride. The resulting 8-hydroxy compounds, representing both the a and f epimers, should not be

  not be separated. The mixture is then acylated for

  to produce the carboxyacyl blocking groups R24 and

  therefore, compound 125.

  The group R24 may represent an aromatic group

  such as a benzoyl, substituted benzoyl, phthalogen

  mono-esterified iron, naphthoyl or substituted naphthoyl,

  or an aliphatic group such as acetyl or pivaloyl. To introduce these blocking groups, we use

  read the methods known in practice.

  This is how an aromatic acid is reacted

  of the formula R240: H, wherein R24 represents an aromatic group falling within the scope of R24

  as defined above, for example benzol

  that with the 8-hydroxy compound in the presence of a dehydrating agent, for example sulfuric acid, zinc chloride or phosphoryl chloride, or

  an anhydride of the aromatic acid of the formula

  mule (R24) 20, for example benzoic anhydride. For this purpose, as examples of reagents giving R24, the following reagents will be noted in the form of acids

  (R240H), anhydrides ((R24) 20), or acyl chlorides.

  (R24C1); benzoyl; substituted benzoyl, for example (2-, 3-, or 4-methylbenzoyl), (2-, 3-, or 4-ethylbenzyl), (2-, 3-, or 4-isopropylbenzoyl, (2-, 3- or 4-) tert-butyl-benzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, α-phenyl- (2-, 3-, or 4-) toluyl, (2-, 3-, or 4-) phenethylbenzoyl, (2-, 3-, or 4-) nitrobenzoyl, (2,4-, 2,5-, or 3,5-) dinitrobenzoyl, 4,5-dimethyl -2-nitrobenzoyl, 2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; mono-esterified, for example: O 3, -I-CH 3, isophthaloyl, for example

C - C-2H5

or terephthaloyl, for example

-E-0-C4H9

  (1- or 2-) naphthoyl; and substituted naphthoyl, for example (2-, 3-, 4-, 5-, 6- or 7-) -methyl-1-naphthoyl, (2- or 4-) ethyl-1-naphthoyl, 2-isopropyl- Naphthoyl, 4,5-dimethyl-1-naphthoyl, 6-isopropyl-4-methyl-1-naphthoyl, -8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 8-) - nitro- 1-Naphthoyl, 4,5-dinitro-naphthoyl, (3-, 4-, 6-, 7- or 8-) -methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 8-) - For this purpose, examples of aromatic acid anhydrides are: benzoic anhydride, (o, m, or β-bromobenzoic anhydride, 2,4- (or 3,4) -dichlorobenzoic anhydride, anhydride p-trifluoromethylbenzoic acid, 2-chloro-3-nitrobenzoic anhydride, (o, m, or p) -nitrobenzoic anhydride, (o, m, or p) -toluic anhydride, 4-methyl-3-nitrobenzolec anhydride, 4-octylbenzoic anhydride (2,3- or 4) -biphenylcarboxylic anhydride, 3-chloro-4-biphenylcarboxylic anhydride, 1 -5-isopropyl-6-nitro-3-biphenylcarboxylic anhydride, and

anhydride (1 or 2) -naphthoic.

  Anyway, it is preferred to react a halogenide

  aromatic acyl, for example benzoyl chloride,

with the 8-hydroxy compound in the presence of a tertiary amine, such as pyridine, triethylamine, etc. The reaction is carried out under a series of conditions in

  using processes generally known in the art.

  In general, mild conditions are used, for example 60 C, by contacting the reagents in a liquid medium, for example an excess of pyridine or an inert solvent, such as benzene, toluene or chloroform. The acylating agent is used either in stoichiometric amount or in excess. Benzoyl chloride, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride, etc., ie compounds R24C1 corresponding to R24 groups above can be used as a result. If acyl chloride is not

  available, it can be obtained from the acid cor-

  respondent and phosphorus pentachloride, as well as

this is well known in practice.

  The use of carboxyacylation agents

  such as acetic anhydride has been described above.

2 6op4 4

above for Scheme 24.

  In step "d", the aldehyde 126 is obtained at

  from compound 125 by hydrolysis of the acetal. We use

  For this purpose, an acid such as aqueous formic acid is used at a temperature of about 0 ° C. In step "e", the Wittig reaction is used to introduce the future R29 side chain. For general information on the Wittig reaction, see, for example, A.W. Jonhson, "Ylid Chemitry", Academic

  Press, N.Y., 1966. If group R29 represents n-pen

  tyl, ylide is prepared from n-hexyl bromide

  triphenylphosphonium. Since group R29 is sacrificed

  by forming the aldehyde 116, it is preferable that R29

  has pentyl or an even shorter alkyl group

  having from 3 to 7 carbon atoms. The ylides are ob-

  held in an appropriate manner using n-butyl? lithium. After Wittig's action, the groups are separated

  R24 acyl blocking to form the compounds of the formula

  Here, as for step (d) of Scheme 24, it is interesting to use a base in a hydroxylic medium. In step "f", the 8-oxo compound of Formula 128 is formed by oxidation. For that, Jones's reagent is interesting. See J.Chem.Soc. page 39 (1946). Another interesting reagent for this purpose is Collins's reagent, for example chromium trioxide in pyridine. See J.C.Collins et al.

  Tetrahedron Lett., 3363 (1968). To this end, the dichloro-

  methane is a suitable diluent. We must use

  a reaction temperature below 30 C.

  Preferred reaction temperatures are in the range of 0 to + 30 C. Oxidation occurs rapidly and is

  usually after about 5 to 20 minutes.

  In step "g", alkene 128 is hydroxylated in

  129. For this purpose, the osmium tetroxide is

  a suitable reagent, for example in combination with a complex of N-methylmorpholine dihydrate oxide, is employed.

  Fieser et al., "Reagents for Organic Synthe-

  "(volume 1), page 690, John Wiley r Sons, Inc.,

New York (1967).

  In step "h", several methods are available

  to obtain the intermediary of Formula 230.

  According to one of these methods, the glycol is converted to a bis (alkanesulfonic acid) ester and then hydrolyzed to the compound 130 by known methods (see, for example, the German patent application issued prior to

  Examination No. 1,937,676, Derwent Farmdoc 6862R); see also

  United States of America Gazette 3,843,712. Another of these methods is via a diformate by formolysis of the glycol; see the patent of

United States of America No. 3,873,771.

  A preferred method is via a cyclic ortho ester. For this purpose, the glycol 129 and an ortho ester of the formula 234 are reacted:

/ OCH3

R4-C --- OCH3 234

  OCH3 The reaction is easily done in a temperature range of -50 ° C. to + 100 ° C., although it is generally preferred to use temperatures ranging from 0 ° C. to + 50 ° C. 1.5 to 10 molar equivalents are used.

  ortho ester, together with an acid such as cataract

  lyst. The amount of catalyst is usually a small fraction of the weight of the glycol, i.e. 1%, and typical catalysts are pyridine hydrochloride, formic acid,

  hydrogen chloride, p-toluenesulfonic acid, the

  trichloroacetic acid and trifluoroacetic acid. The reaction is preferably carried out in a solvent, by

  benzene, dichloromethane, ethyl acetate,

  thyl or diethyl ether. She is usually

  finalized within a few minutes and followed suitably by thin layer chromatography (thin layer

basic silica gel plates) ..

  Ortho ester reagents are known in the art.

  that are readily available by known methods

  in practice. See, for example, S.M.McElvain et al.

  rators, J.Am.Chem.Soc. 64, 1925 (1942), where we start

  of a suitable nitrile. Examples of ortho esters

  interesting are trimethylorthoformate, orthoacetate

  trimethyl titrate, trimethyl orthopropionate, and

trimethyl orthobutyrate.

  Then, cyclic orthoester 235 is reacted with anhydrous formic acid to obtain a diol diester of formula 236:

254 235 236

iC = C / H

È OO OCHOH '"C R29

OCR.

R4 Cit3 R, OCtt3

  The expression "anhydrous formic acid" is understood to mean

  of formic acid which does not contain more than

  0.5% water. The reaction is carried out with an excess of

  of formic, which can itself serve as a solvent for the reaction. Solvents may be present, for example dichloromethane, benzene or ether

  diethyl, but usually in

  yielding not more than 20% by volume of formic acid. yarn may also be organic acid anhydrides,

  for example, acetic anhydride, or ortho-

  alkyl esters, for example tri-orthoformate

  methyl, which are useful as drying agents for formic acid. Although the reaction can be carried out over a wide range of temperatures, it is

  preferably carried out at a temperature of about 200-

   C, and it is usually finalized after

a period of about 10 minutes.

  Next, the diol diester 236 is converted to the intermediate product 130 by methods known in the art, for example by hydrolysis in the presence of a base in an alcoholic medium. Examples of the base are sodium and potassium carbonates or sodium or potassium alkoxides, especially methylates or ethylates. The reaction is carried out

  suitably in an excess of the solvents reagent.

  lysis, for example methanol or ethanol. The gam-

  The period required to complete the reaction varies depending on the nature of R30 and the base, ranging, for example, in the case of alkaline carbonates of a few minutes. when R30 is hydrogen but up to

  several hours when R 30 is ethyl.

  The bicyclic compounds of formulas 130-134

  as well as formula 116 are referred to as

  Talene; for example, compound 130 is a 5-hydroxy

4-substituted pentalen-2-one.

  In step "i", the C-5 hydroxyl of the compound is optionally converted to a deoxy group

  C-5, using mesylation and reduction of

  sylate as shown in more detail in Scheme 30.

  In step "j", R9 and Q5 are blocked with

  silyl blocking groups to form compound 132.

  In step "k", compound 132 is reduced to

  2-hydroxy compounds referred to above.

  known for step "c", to form compound 133.

  In step "1", the 2-hydroxy compounds

  ss are acylated as above for step "c" for

form the compound 134.

  In step "m", compound 116 is obtained by subjecting compound 134 to ozonolysis using methods well known in the art; see Fieser and Fieser, Reagents for Organic Synthesis, Volume 1, pages

773-777, John Wiley> N.Y. (1967).

  Figure 30 illustrates the preparation phases

  5-deoxy pentalen-2-ones of interest as intermediates

  in the preparation of 11-deoxy analogues

  prostacyclins falling within the scope of Group X. The

  Form 135 starting materials are available at

  from the processes of Figure 28.

  In step "a", position C-5 is unlocked

by desilylation.

  In step "b", the product 136 of step "a"

  is mesylated so as to form the 5-mesylate of the

  137. It is preferred to use chlorine for this reaction.

  methane sulfonyl chloride, CH3S C1, in the presence of a base such as pyridine, dimethylamine, or other tertiary amine. The reaction is carried out at a temperature of about 0-25 ° C. Alternatively, t-osyl (p-toluenesulfonyl) groups may be used and applied as known in the art. See the patent of

  United States of America No. 4,033,989, column 135.

  In step "c", the mesylate group (or tosylate

  te) is cleaved by methods known in the art. We

  may use reducing agents, including

  metal hydrides (such as sodium borohydride),

  metal cyanoborohydrides (such as cyanoborohydride)

  sodium hydride) or aluminum hydride (such as sodium aluminum hydride) in a neutral solvent

  (such as dimethyl sulfoxide or diethyl ether).

  For other methods, see U.S. Patent No. 4,033. 989, column 79. Position C-2 is

unlocked in this step.

  In step "d", we obtain the pentalen-2-one

of formula 139 on oxidation.

  Finally, in step "e" we unblock the chai

  not lateral by mild acid hydrolysis to give

the compounds of formula 140.

  The 6α-carba-prostacyclin compounds of formula 237:

-MI-L3-R1

2, CH2 Rs R13

R / X-C - C- (C2) 2-C-CH3

Q R6 OH

  comprising Group X are obtained by applying known methods to the compounds of formulas 149 and 150

of Figure 31.

  Scheme 31 illustrates the process which consists of starting from a compound of the formula 141 and: (1) transforming it into a compound of the formula 142, (2) reacting this compound with the sulfoximine carbanion of the formula 238 to form a compound of Formula 143 (see Formula 238 below), (3) to subject this compound of Formula 143 to

  elimination by reduction so as to form a

posed of the formula 144,

  (43 to preferentially separate the groups

  -Si (R17) 3 of the compound of formula 144 to form a compound of formula 145, (5) to acylate compound of formula 145 to form a compound of formula 146, (6) to transform the compound of formula Formula 146 to a compound of Formula 147, (7) optionally separating the C-5 isomers of the compound of Formula 147, -8) to oxidize the compound of Formula 147 to form a compound of Formula 148., and

  (9) to deacylate to form the C-5 isomers

  presented by formulas 149 and 150.

  The pentalene structures of formulas 141 and 142 use the same numbering of carbon atoms

  than for formula 135. The compounds of formulas 143-

  150 carrying an upper side chain follow the

numbering of prostacyclines.

  In Figure 31, the starting materials of

  formula 141 are available by further treatment

  Compounds 118-121 are deacylated, for example in a mild base, to convert -OR24 to -OH. An oxidation then gives the corresponding pentalen-2-ones which are released in a mild acid hydrolysis. Formula 141 comprises the compounds of formula 140 of Scheme 30. In step "a", compounds of formula 141 are silylated by the processes described within the scope of the present invention. It is preferable that the R16 groups are sterically hindered alkyl groups,

for example t-butyldimethyl.

  In step "b", the products of addi-

  sulfonimidoyl of formula 143 by addition of a carbanion of a sulfoximine. For generalities on this reaction, see C.R. Johnson et al., J.Am.Chem.Soc. 95, 6462 (1973). Here, sulfoximine is represented by the formula 238: C6H5

O =: SN-CH3 238

CH2-CH2-L3-OR25

  this sulfoximine being easily synthesized by

  the methods described below or well known in the art. The carbanion is obtained by reacting sulfoximine with any of the usual reagents that will extract active hydrogen from these sulfoximines, for example

  alkyl lithium or alkyl magnesium halide. We use

  is a molecular equivalence of the hydrogen extraction reagent

  for each equivalent of sulfoximine. In the formation of the adduct with the silylated ketone of formula 142, it is preferred to use sulfoximine

  in excess, in a range of 1.2 to 3.0 molar equivalents.

  sulfoximine rings per equivalent of ketone.

  2. The reaction is carried out in the range of about 00 ° C to about 78 ° C, preferably 0 ° C to -40 ° C. in

  an inert reaction diluent such as tetrahydrofuran

  ranne. In this reaction, carbonyl groups compete

  either on compound 142 or on

solvent are undesirable.

  In step "c", we get the intermediates

  of Formula 144 by means of reductive elimination

  by bringing the adduct of Formula 143 into contact with an amalgam of aluminum (see Johnson et al.

  Collaborators, quoted above) in the presence of acetic acid

  or other carboxylic acid, such as propionic acid, butyric acid, or acid

  citric. It is also possible to use for this purpose

  minerals, such as hydrochloric acid. The report

  reagents is not critical; however, it is

  fable to use a large excess of amalgam of aluminum and acid. Also, a sufficient amount of an inert inorganic water-miscible liquid diluent is used to obtain a mobile reaction mixture. A range of temperatures from about 0 ° C to about 50 ° C,

  preferably about 20 to 30 ° C, is interesting.

  The isomers (E) and (z) in mixed C-5 are obtained under the

form of a mixture. -

  In step "d", the silyl groups of

  Form 144 are replaced by hyphenated

  to obtain the compounds of formula 145. For this desilylation the reagents and the conditions are

  chosen so as not to unblock the C-1 ethers.

  For the silyl groups having no steric hindrance, a base such as

  alkali metal carbamate in dioxane or tetra-

  hydrofuran, in a temperature range from

  viron -10 to + 100 C. The silyl groups are preferably

  t-butyldimethylsilyl, in which case their separation

  This is done with tetrabutylammonium fluoride.

  See Corey et al., J.Am.Chem.Soc. 94, 6190

(1972).

  In step "e", compounds of formula 146 are obtained from the compounds of formula 145 above, by blocking free hydroxyls with

  carboxyacyl groups R24. For example, R24 may represent

  an aromatic group such as benzoyl, benzoyl

  the substituted mono-esterified phthaloyl, naphthyl or substituted naphthoyl, or an aliphatic group such as acetyl or pyvalyl. To introduce these blocking groups, methods known in

  practice or described in the context of this invention.

  tion. In step "f", the compounds of formula 146 are released at C-1 to obtain the alcohols of the formula

  147. For this purpose, methods known in the art are

  for example, mild acid hydrolysis for these tetrahydropyranyl groups or similar ether-bonded R25 groups using dilute acetic acid. aqueous citric acid, or aqueous phosphoric acid in a mutual solvent, such as tetrahydrofuran. We can use temperatures in

the range of 25 -55 C.

  The isomers (E) and (Z) at C-5 are preferably separated at this stage, for example by chromatography of the compounds of formula 147. For this purpose, a silica gel column, preferably a column, is used. of high pressure liquid using silica gel with an average particle diameter of 40 microns. For general information about high-level liquid chromatography

  pressure, see, for example, "Modern Practice of Li-

  Quid Chromatography, J. J. Kirkland, Editor, Wiley Interscience, N.Y., 1971. Compounds of Formulas

  144,145,146 or 148 may possibly be

  matographed to give bsisomers (5E) and (5Z). In step "g", the compounds of Formula 148 are obtained either from the currently separated isomers (5E) and (5Z) or from the mixed isomers.

  of formula 147 by oxidation. The reagents used

  for this transformation are known in practice.

  A particularly interesting reagent for this purpose is Jones' reagent, that is to say chromic acid.

  acidified. See J.Chem. Soc. 39 (1946). For this purpose, I

  ketone is a suitable diluent, etc.

  excessively beyond the amount required to oxidize

  the hydroxy groups of the reagent. Time must be used

  Reaction temperatures are at least as low as about 0 C. Preferred reaction temperatures are in the range of -10 to -50 C. Oxidation is rapid

  and is usually terminated after a period of

  5 to 20 minutes. The excess oxidant is removed by

  by addition of a lower alkanol, advantageously

  isopropyl alcohol, and the product is isolated

  of formula 148 by ordinary methods.

  Finally, in step "h" we get the

  formula 149 by unblocking the carbon groups

  zyacyl R24, that is to say by decarboxylation, for example

  by means of a base such as hydroxide or

  potassium carbonate in methanol or in a mixture

  methanol and water at a temperature of about 25 ° C.

  During the transformations of Figure 31, the

  stereoconfiguration at C-8, C-9, C-11 and C-15 remains

  exchange. For example, a product of the formula

  149 with lla-hydroxy groups from the material

  starting re 141 having 11-d hydroxy groups. In the same way, the whole fragment represented by the formula: x

1R5 I 13

X-C-C - (CI42) 2-c-CH3

Q5R6 OH

  is preserved intact, so that we obtain a

  15S from 15S starting material.

  Schemes 32 to 45 refer to intermediates

  and serve as guides for the treatment steps.

  for the Preparations discussed below.

  The compounds of formulas 4 and 15 which are not specifically illustrated or exemplified in the context of

  the present invention are obtained by transforming

  using the chemical processes described in

  the scope of the present invention or known to the specialists

lists of the technique.

  For example, converting R4 to Q from hydrogen to methyl at C-15 requires the preparation of the intermediate 15-oxo compound by oxidation followed by

  of an alkylation with CH3Mg Hal Grignard or trimer

  3g9 thylaluminum, and subsequent separation of the products

  a and 15e, for example by chromatography, preferably

  this methyl esters. The preparation of esters and sset of various modifications in C-1, for example

  amides and sulfonamides, follow the general processes

  discussed in the context of the present invention and

* known in practice.

  It will be noted that a large number of intermediaries

  which are discussed here have interesting

  not only for the mentioned applications but also for many of the previous transformations

  as is known in practice.

  The products obtained from each stage of the treatment are often mixtures, and, as is well known in the art, they can be used as such for a next stage, or they can be

  separate and purify them by fractionation methods.

  is lying. ordinary liquid extraction, etc. before treatment. It should be noted that the compounds are within the scope of the present invention not only in their purified form but also in the form of mixtures, for example the compounds of the 19-hydroxy type of the formula

  4 in their mixed or mixed form (R, S).

  The invention can be better understood yet

  thanks to the Preparations and Exemplars presented here

  after. All temperatures are given

in degrees Celsius.

  Absorption spectra in the infrared were recorded on an infrared spectrophotometer

  Perkin-Elmer model 421. Unless otherwise specified

  pure samples (undiluted) were used.

  The nuclear magnetic resonance spectra were recorded on a Varian A-60 spectrophotometer,

  A-60D, T-60 or XL-100, in deuteron solutions

  chloroform with tetramethylsilane as a standard

  born. Mass spectra were recorded on a

  Varian mass spectrometer model MAT CH7, a

  high resolution mass spectrometer, with dual

  COD, model llOB, or on a LKB model 9000] 44 gas chromatograph mass spectrometer (ionization voltage of 22 or 70 ev), the samples being ordinarily made in the form of TMS (tetramethylsilylated) derivatives. The term "brine" refers to a saturated aqueous solution of sodium chloride. "Celite R" is a calcium aluminosilicate,

  useful as a filter aid.

  "Collins reagent" is chromium trioxide

  me in pyridine. See Tetrahedron Lett. pages

3363 (1968).

  "DIBAL is diisobutylaluminum hydride.

  MNC. "Florisil R" is a chromatographic magnesium silicate produced by the Floridin Company.

  Fieser et al., "Reagents For Organic Synthe-

  ", page 393, John Wiley and Sons, Inc., Nex York,

N.Y. (1967).

  The abbreviation "HPLC" refers to chromatography

high pressure liquid.

  "Jones' teactant" is chromic acid,

see J.Chem.Soc. page 39 (1946).

  The "Rf" refers to the measurement in a chromato-

  thin-layer graphing, of the movement of the

  sample compared to that of the solvent front, on

  silica gel plates unless otherwise specified

  re, and in a solvent system that is identified.

  "Skellysolve B" refers to mixed isomeric hexanes.

  The abbreviation "THP" refers to tetrahydropyran

t30 2-yl.

  The abbreviation "TLC" refers to chromatography

on thin layer.

  The term "concentrate" refers to a concentration under reduced pressure, preferably at - 50 mmHg

  and at temperatures below 35 ° C.

  The term "drying" refers to contacting a compound, in solution, with an anhydrous agent such as sodium sulphate or magnesium sulphate, to remove

  water, and filtration to remove

  lides. Chromatography on silica gel, such as

  in this case, includes elution,

  fractions and the combination of fractions which, after a thin layer of chromatography, contain

  the desired product free of starting materials and

purities.

  The solvent system A-IX used in the chromato-

  thin-layer graphy, is formed by the system:

  ethyl acetate-acetic acid-2,2,4-trimethylpentane

  water (90/20/50/100) according to M.Hamberg and B.Samuelsson,

J. Biol. Chem. 241, 247 (1966).

  Preparation 1-Lactone of 5α-hydroxy-3α-tetrahydro-acid

  pyran-2-yloxy-2e- (trans-2-formyléth-nyl) -

  1-cyclopentaneacetic acid (Formula 158 of Scheme 32) Refer to Scheme 32. The title compound is obtained in seven steps from the tricyclic lactone aldehyde of Formula 151, for which

  will refer to U.S. Patent No. 3,816,612.

  at. y-Lactone of exo-3-hydroxy-endo-6-vinyl-acid

  bicyclo [3.1.0] -hexae-esD2-acetic (Formula 152). We treat

  a solution of the tricyclic lactone aldehyde

  formula 151 (20 g) in 150 ml of benzene at a temperature of

  at 5 ° -10 ° C., with a solution of the ylide prepared from methyltriphenylphosphonium bromide (54 g) and 95 ml of 1.6 M butyllithium in 1 liter of benzene (previously heated at reflux temperature for 1 hour). hour and cooled). The addition is done during a

  period 1 to 1.5 hours, and after additional agitation

  half an hour, filter and concentrate the mixture

  lange. The residue is taken up in 100 to 200 ml of a mixture of ethyl acetate and Skellysolve B (40/60) and left to stand for the by-product formed.

  of triphenylphosphine oxide separates into crystals.

  After filtration, the filtrate is subjected to

  matography on silica gel, diluting with a

  of ethyl acetate and Skellysolve B (40/60). The compound of formula 152 is obtained in the form

  of an oil of 16.2 g, having resonance peaks of

  nuclear genetics at 1.3-3.0; 4.6 to 4.9; and 5.0 -5.4e; and an Rf of 0.74 (in a mixture of ethyl acetate and

of Skellysolve B (50/50)).

  b. 3-Lactone of endo-6- (1,2-dihydroxyethyl) acid

  exo-3-hydroxy-bicyclo [3.1.0] -hezane-exo-2-acetic acid (For-

  mule 153). A solution of the alkene of the

  mule 152 (step a, 8.0 g) in 80 ml of acetone with a solution of N-methylmorpholine dihydrate oxide (9.0 g) in 12 ml of water, followed by a tetraoxide solution. osmium (130 mg) in 6.5 ml of t-butanol. When the reaction is carried out, the acetone is separated under pressure

  scaled down. The residue is diluted with 100 ml of water,

  with ammonium sulphate and extracted with tetrahydrofuran. The organic phase is dried on

  sulfate and magnesium and is concentrated under

  to obtain 12 g of a crude oily product. The Hui

  is subjected to chromatography on silica gel and the compound of the formula 153 is obtained in the form of an oil of 8.5 g, having resonance peaks

  nuclear magnetic at 0.7-1.2; 1.3 to 9; 2.4-3.4; 3,4

  2 _. 5 days to 4, 3.7; 3.7-4.2; and 4.7-5.0 5; and a Rf of 0.66 (in a

  mixture of methanol and dichloromethane (15/85)).

  c. y-Lactone of 3c-formyloxy-5α-hydroxy-2f-

  (3-propionyloxy-trans-11-propenyl) -1α-cyclopenaneacetic acid (Formula 154). A solution of the glycol of the

  formula 153 (step b, 7.2 g) and tri-orthopropionate

  thyl (15 g) in 30 ml of tetrahydrofuran with 3

  After 1 hour, the solvent is separated under reduced pressure and treated.

  residue with 100 ml of anhydrous formic acid with stirring

  tion. After 15 minutes, 100 ml of sodium hydroxide

  1N sodium and 100 ml crushed ice. We extract the

  The mixture is washed with chloromethane and the organic phase is washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated. The oil (9.6 g) thus obtained is subjected to chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1/1), to give the compound of formula 154, 4.1 g, having 1.1 nm nuclear magnetic resonance peaks; 1.9 to 3.0; 4.4-4.6; 4.8-5.2; , From 6 to 5.8; and 8.0 i; and a Rf of 0.49 (in a mixture

  ethyl acetate and cyclohexane (1/1)).

  d. y-Lactone acid 3a, 5a-Dihydroxy-29-

  pionyloxy-trans-1-propenyl) -1α-cyclopentaneacetic acid (Formula 155). A solution of the formate of formula 154 (step c, 4.1 g) in 35 ml of dry methanol is treated with sodium bicarbonate (0.5 g). When the reaction is complete after a period of about 2 to

  3 hours, the solvent is removed under reduced pressure.

  The residue is partitioned between water and dichloromethane,

  and the organic phase is dried over magnesium sulphate

  sium and concentrate it. The oily residue is subjected to chromatography on silica gel, eluting with ethyl acetate to give the title compound.

  Formula 155, 2.8 g, having magnetic resonance peaks

  nuclear tick at 1.13; 3,7-4.3; 4.3 to 4.7? 4.7-5.2- and 5-5.8; and an Rf of 0.65 (in ethyl acetate). e. Y-Lactone of 3atetrahydropyran acid -2-

  yloxy-5a-hydroxy-23- (3-propionyloxy-trans-l-propenyl) -

  cyclopentaneacetic (Form 156). We treat a

  5-hydroxy actone of formula 155 (step d, 2.8 g) in 10 ml of dichloromethane with 5 ml of

  dihydropyran and 5 mg of p-toluenesulfonic acid

  under in 1 ml of tetrahydrofuran. Once the reaction

  After about 0.5 hours, the mixture is washed with 5% aqueous sodium bicarbonate. The organic phase is dried over sodium sulphate and

  we concentrate it. The residue is chromatographed

  on silica gel, eluting with a mixture of

  Ethyl acetate and Skellysolve B (60/40) so

  obtaining the compound of formula 156.

  f. y-Lactone of 3-tetrahydropyran-2-yloxy acid

  5a-hydroxy-2 - (3-hydroxy-trans-l-propenyl) -la-cyclopentyl

  teacetic acid (Form 157). The propionate of formula 156 (step e, 3.0 g) is added in 10 ml of methanol.

  to a solution of sodium methoxide (freshly

  trimmed with 20 mg of sodium in 40 ml of methanol

  anhydrous l. Once the reaction is complete, within

  20 minutes, the methanol is separated under re-pressurized

  pick. The residue is partitioned between dichloromethane and a 0.4M phosphate buffer of pH 4.5. The organic phase is dried over sodium sulphate and concentrated

  to obtain the compound of formula 157.

  g. y-Lactone of 3a-tetrahydropyran-2-yloxy acid

  α-hydroxy-2D- (trans-2-formylethenyl) -1α-cyclopentane-acetic acid (Formula 158). An oxidizing reagent is prepared

  from chromium trioxide (5.5 g) and 3,5-

  dimethylpyrazole (5.2 g) in 150 ml of dichloromethene, and

  it is stirred for 15 minutes. Then add to the

  1, the 3-hydroxy compound of formula 157 (step 1.8 g) dissolved in 20 ml of dichloromethane. Once the reaction is complete, within 5 minutes

  the mixture is washed with 5% aqueous bicarbonate. We are

  the organic phase over sodium sulfate and concentrate. The residue is subjected to chromatography on silica gel, eluting with a mixture of acetone and

  dichloromethane (1/9) to give the compound of the

the 158.

  Preparation 2 11,15-bis methyl ester (tetraether ether)

  hydropyran-2-yl) of 19,20-didehydro (or, "19,) -PGF2

  at. We are preparing a 3'3'-bis (ether tetrahydro-

  pyran-2-yllicene-lactone of 3a, 5a-dihydroxy-2g-

  [(3R, S) -3-hydroxy-trans-1,7-octadienyl] -la-cyclopentane

acetic,

  A solution of 5-y-lactone of 5α-acid is treated.

  3a-hydroxy-tetrahydropyran-2-yloxy-21- (trans-2-formyl-

  ethenyl) -α-cyclopentaneacetic acid (2.775 g;

  1) in 40 ml of diethyl ether and 10 ml of tetrahydryl

  drofuran at a temperature of -70 C with bromide

  1-pentenylmagnesium (prepared from 5-bromo-1-

  pentene (4.115 g) and magnesium (0.667 g) in 40 ml of diethyl ether) added dropwise to a

  period of about 17 minutes. The mixture is then shaken

  at a temperature of about -60 C for 22 minutes

  and it is suddenly immersed in ammonia chloride.

  saturated aqueous medium. Pulp sodium sulfate is added

  verulent for coagulation and separated by filtration

  solids. The filtrate, along with the

  vines with ether, are dried and concentrated under the

  me of an oil of 3,109 g. The product is chromatographed

  by eluting with a mixture of methyl chloride

  ne and acetone (6/1) and the monoether is obtained

  THP, in the form of mixed C-15 epimers, due to

  of 2.427 g, having Rf of 0.34 and 0.29 (in one

  methylene chloride / acetone (4/1)), nuclear magnetic resonance peaks at 6.20-6.5.4; , From 2 to 4.78; 4.68; 4.3 to 3.2; 3.02 to 2.4; 2,351,85; and 1.8-1.2 A, absorptions in the infrared at 3450.2995,

  1775, 1200, 1180, 1120, 1075, 1030, 1020, 975, 920,

  -1 870 and 815 cm, as well as peaks of mass spectrum

  at 422.2446, 407.353, 337, 321.320, 269, 251 and 85.

  The mono-THP state above is treated in a

  methylene chloride solution with an excess of dihy-

  dropyran in the presence of pyridine hydrochloride at a temperature of about 25 C for 16 hours. The mixture is diluted with about 300 ml of methylene chloride and washed with 5% aqueous sodium bicarbonate.

  water and brine, and dry it. A concentration

  This gives the bis-THP ether compound, y-lactone 3,3'-bis (tetrahydropyran-2-yl)

  of 3a, 5a-dihydroxy-2p - [(3R, S) 3-hydroxy-trans-1,7-

  octadienyl] -la-cyclopentaneacetic.

  b. The corresponding lactol is then prepared. The lactone of part "a" (9.82 g) was treated in 100 ml of toluene at -68 ° C. with diisobutylaluminum hydride (DIRAL) (22.65 ml of toluene solution 1). M) added dropwise over a period of 8 minutes. The mixture is stirred at a temperature of

  75 ° C. for 1 hour and 10 ml of sulphate are then added.

  saturated aqueous sodium. The mixture is heated to room temperature, diluted with 700 ml of diethyl ether, and treated with sodium sulfate spray. The solids are separated on a Celite filter. The filtrate is dried and concentrated to give the lactol compound having a Rf of 0.35 (in a mixture of acetone and methylene chloride).

(1/6)).

  c. 11,15-bis (tetrahydropyryl ether) is prepared.

  rann-2-yl) of 19,20-didehydro (9,19) -PGF2 and its methyl ester. The lactol of Example 2 (9.87 g) is alkylated by the Wittig reaction. We prepare first

  Wittig's reagent from 4-carboxy bromide

  butyl triphenylphosphonium (35.1 g) which is added to the reaction product of sodium hydride (4.6 g) and

  180 ml of dimethyl sulphoxide previously heated

  at a temperature of 700-75 ° C for 1.5 hours and then cooled to a temperature of about 25 ° C for 25 minutes treated with (3S) lactol in 65 ml of dimethyl sulfoxide added dropwise

  over a period of 25 minutes, and it lasts for a period of

  additional 30 minutes. The mixture is acidified

  in ice-cold water with hydrogen sulphate

  2N potassium and then extracted with ether. Gold wash the organic phase with brine, or dry it,

  it is concentrated and the bis-THP-free acid is obtained.

  The acid is then esterified with diazomethane.

  Ethereal, the resulting methyl ester is chromatographed and 9.37 g of the methyl ester mentioned above are obtained with an Rf of 0.62 (in a mixture of acetone).

  and methylene chloride (1/6)), and peaks in

  nuclear magnetic sound at 6.18-4.56; 4.37-3,20;

3.65; and 2.78-1.11.

  Preparation 3 (19R) -19-Hydroxy-PGF2a and its (19S) epitope

mother (Formula 172 of Figure 35).

  We refer to Schemes 33, 34 and 35. Dodging

  the processes of J.C.Shi, Prostaglandins, volume 13.

  5, 831-835 (1977), the compound (19R) is obtained

cited in section.

  In the same way, following these processes but substituting the Grignard reagent prepared from

  THP blocked bromide obtained from (S) - (+) - l-pen-

  Ten-4-ol with Grignard reagent prepared from bromine

  blocked by THP obtained from (R) - (-) - l-penten-4-

  ol, the corresponding (19S) epimer is obtained.

  In the same way, using dl-l-pentenene

  4-ol, the product is obtained in the form l9RS.

  In addition, the corresponding PGE compounds are obtained.

  by oxidizing the blocked PGF2a compounds of the

  the 171 and then unlocking them in order to get

the compounds of formula 174.

  In Scheme 33, the steps leading to the deoxy-jactones of Formula 163 are also shown by C-15 mesylation, followed by demesylation.

as used here.

  In Figure 34, steps are shown

  using chemical processes leading to modifications

  C 13 -C 14 cations of the lactones of formulas 166, 167, 168 and 169, which taken together are represented by formula 170 of Scheme 35.

  Preparation 4 2-Decarboxy-2-hydroxymethyl-19-hydroxy-

  PGF2 "and -PG22. (Respectively Formulas

179 and 182 of Figure 36).

  Refer to Figure 36. Starting from the metal ester

  19-hydroxy-PGF2a, the compound PGF is obtained

  cited in the section by reduction with hydride of li-

thium and aluminum.

  Then, with C-1 and C-19 blocking, the C-9 hydroxy was oxidized and the blocking groups were separated to give the title compound PGE. Preparation 5 19% -hydroxy-PGF2a Amide (Formula

of Figure 37).

  Refer to Figure 37. First, prepare the year

  mixed hybrid. A 19-hydroxy-solution is treated

  PGF2a in methylene chloride with triethyl

  amine (2 equivalents) and isobutyl chloroformate

  (1.01 equivalent) at a temperature of about 25 C

  0.5 hours. Then add to a temperature of

  viron -5 C, a saturated solution of ammonia in the acetone

  nitrile and the mixture is stirred at -20 ° C. for 10 minutes. The reaction mixture was diluted with brine and water (5: 1) and extracted with ether. The organic phase is washed with brine and 2N hydrochloric acid, with brine and with brine.

  sodium bicarbonate at 5%, finally with sau-

  ripe, dry and concentrate. The residue is chromatographed on a silica gel column using high pressure liquid chromatography, and eluting with acetone to obtain the compound.

cited in section.

  Preparation 6 2-Decarboxy-2-aminomethyl-19fr-hydroxy-PGF2a (Formula 86 of Scheme 37). Reference is made to Scheme 37. Following the method of US Pat. No. 4,085,139, Example 32, 19% hydroxy-PGF 2a (Preparation 5) is treated.

  with lithium aluminum hydride in the tetra-

  hdrofuran at a temperature of about 25 for 48

  hours and one obtains the, compound cited in heading.

  Preparation 7 19-Hydroxy-PGF2a Methanesulfonamide

  Refer to Scheme 38. A solution of mixed anhydride in dimethylformamide (step "a") is treated.

  of Scheme 37, Preparation 5) with agitation, at a

  0 C, with about 4 equivalents of sodium salt

  methanesulfonamide (prepared from methane-

  sulfonamide and methanolic sodium methylate in

* methanol, by concentration and azeotropic distillation

  pique with benzene), and then add a quantity

  sufficient hexamethylphosphoramide to obtain a

  homogeneous mixture. The mixture is stirred at a temperature of about 25 ° C for 16 hours, then acidified with cold dilute hydrochloric acid and extracted with ethyl acetate. We wash the organic phase

  with water and brine, it is dried and

  center. The residue is chromatographed on silica gel, eluting with a mixture of methanol and carbon dioxide.

  methylene, so as to obtain the compound cited in

brick.

  Preparation 8 2-Decarboxy-2- (1H-tetrazol-5-yl) -19T-hy-

  droxy-PGF2a (Formula 197, Scheme 40).

  Refer to Figure 40. Amide is transformed

24609.44

  of formula 193 to the nitrile of formula 194 by reaction with N, N'-dicyclohexylcarbodiimide (DDC)

  in pyridine at a temperature of about 25 C.

  The precipitated dicyclohexylurea is filtered off and the filtrate is concentrated to the nitrile of formula 194. The tetrazolyl compound of formula 194 is obtained from the foregoing nitrile by reaction with

  sodium azide and ammonium chloride in the di-

  methylformamide at a temperature of about 115 C.

  iO that the reaction is complete as indicated by a

  thin layer chromatography, the mixture is cooled

  ge and concentrated. The residue is taken up in chlorine

  roformed, washed with brine, dried and concentrated to the compound of Formula 195. Next, deblocking separates the silyl groups and the THP or

  other blocking groups so as to obtain the

duit cited in topic.

  Figure 39 illustrates another method of application

  reaction of Wittig and use of a ylide

  prepared from a phosphonium compound of the formula

  239 Br (CaHS) 3P-CH2- (CH2) 3-C 239

  See U.S. Patent No. 3,928,391.

  The starting material of the formula 190 is obtained from any of the lactans represented by the formula 170 by a reduction well known in the art, for example see J.C.Sih, Prostaglandins 13,

831-835 (1977).

  Preparation 9 19-Hydroxy-19-methyl-PGF2a (Formula 203 of Scheme 41) and PGE- (Formula 205)

Refer to Figure 41.

  at. 3,3'-bis- (tetrahydropyran-2-yl ether)

  3a, 5a-dihydroxy-2H- (3RS) -3-hydroxy-3-yl lactone

  7-oxo-trans-1-octenyl-la-cyclopentaneacetic (Formula 199). The 7-hydroxylactone of formula 198 (10.02 g) is treated in 300 ml of acetone at a temperature of

  -30 C with Jones reagent (14.95 mL, 2.67M) added

  drop by drop within a period of 10 minutes.

  The mixture is stirred at -25 ° C. to -20 ° C. for an additional period of 1.8 minutes.

  then cooled with 20 ml of isopropanol and

  for an additional period of $% inutes, the

  The mixture is added to 500 ml of cold sodium bicarbonate and 800 ml of ethyl acetate, separated, and

  the organic phase is combined with the ethereal extracts

  res of the aqueous phase. The organic phase is washed with 5% sodium bicarbonate, ice water, brine, dried, concentrated and the title compound (9.93 g) is obtained. having a Rf of 0.64 (thin layer chromatography with gel of

  silica in a mixture of acetone and methyl chloride

  lene (1/3), and nuclear magnetic resonance

  re at 5.50; 5.0; 4.63; 4.25 to 3.0; 2.13; and 3.00-1.20%.

  b. 3,3'-bis (tetrahydropyran-2-yl ether) 'from

  y-lactone of 3a, 5a-dihydroxy-23 [3R, SY-3,7-

  dihydroxy-7-methyl-trans-l-octényll-la-cyclopentyl

taneacetic (Formula 200).

  The 7-oxo lactone of formula 199 is treated

  (0.500 g) in 33 ml of diethyl ether at a temperature of

  of -78 C with 2 equivalents of methylmagnesium bromide

  sium (0.766 ml, 2.9 M) added dropwise to a

  triode of a minute. The mixture is stirred at a temperature of

  at -78 ° C for an additional 30 minutes and quenched with 2 additional equivalents of methylmagnesium bromide at -78 ° C for 2 hours. The mixture was added to 40 ml of saturated aqueous ammonium chloride and extracted with ether. The organic phase is washed with brine, dried and concentrated. The concentrate is chromatographed using a high pressure chromatograph and eluting with a mixture of acetone and methylene chloride (1/5) to give the title compound, 0.391 g. with a Rf of 0.39 (thin layer chromatography on silica gel in a mixture of acetone and methylene chloride (1/3)), nucleic magnetic resonance peaks at 5.66-5.33; , From 18 to 4.81; 4.81 to 4.47; 4.29 to 3.16; 2.97-1.29; and 1,166, infrared absorptions at 3550, 3000, 1770, 1460, 1440, 1430, 1350, 910, 865, 840, 810, 765, and 735 cm 1, and mass spectral peaks at 523.3118. , 430, 437, 436,

421, 395, 131, and 85.

  c. 3,3'-bis (tetrahydropyran-2-yl) ether

  3x ace-lactol, B-dihydm xy-2p - [(3R S) -3,7-

  dihydroxy-7-methyl-l-trans-octenyl) -la-cyclo

  pentaneacetaldehyde (Formula 201).

  The 7-hydroxy-7-methyllactone of the

  mule 200 (6.98 g) in 100 ml of toluene at a temperature of

  -78 C with diisobutylaluminum hydride (DIBaL) (25 ml of 1.5 M in toluene) added drop

  drop by drop over a period of 13 minutes. We add the

  At a temperature of -78 ° C. for 1 hour, it is treated with additional DIBAL (5 ml), stirred for 2.25 hours and treated again with water.

  DIBAL (5 ml). After a period of further agitation

  After 0.75 hours, the mixture is heated to -40 ° C over a period of 30 minutes, then cooled to -78 ° C and carefully immersed in saturated aqueous sodium sulfate. The mixture is diluted with 850 ml of diethyl ether, stirred with powdered sodium sulfate (20 g) until the aluminum salts coagulate, and filtered.

  then. The filtrate is concentrated and chromatographed.

  on silica gel eluting with a mixture of

  ketone and methylene chloride (1/2 to 1/1) in a manner

  to obtain the compound of lactcl cited above, at

  4.89 g. The product has a Rf of 0.24 (chroma-

  thin layer tography with silica gel in a mixture of acetone and methylene (1/2)), 5.775.0 nuclear magnetic resonance peaks; 4.86 to 4.33; 4.33 to 3.18; 3.11 to 1.27; and 1.15%, infrared absorptions at 3500, 3000, 1750, 1730, 1470, 1450, 1440, -1 1370, 1340, 1200, 1120, 910, 865, and 810 cm, and mass spectral peaks. at 527.3201, 426.336, 247.246,

131 and 85.

  d. Mixed C-15 epimers of 11,15-bis (ether

  Trahydropyran-2-yl M methyl ester 19-hy-

  droxy-19-methyl-PGF2a (Formula 202).

  Wittif's reagent is first prepared from

  of 4-carboxybutyl triphenylphosphonium bromide (16.19.

  added to the reaction product of sodium hydride (3.51 g) and 85 ml of dimethyl sulfoxide, previously heated at a temperature of 70 ° C. for 1.5 hours, and cooled to about 25 ° C. The mixture is stirred at a temperature of about 25 ° C. for 25 minutes.

  minutes, it is then treated with lactol from the

  mule 201 (4.89 g) in 35 ml of dimethyl siloxane

  drop by drop over a period of 15 minutes and

  shake it for an additional 30 minutes

  your. The mixture is added to 1 liter of ice water con-

  taking 250 ml of 2N Potassium Argosilfate and it is

  then treat with ether. The organic phase is washed with brine, dried and concentrated. The product is esterified in 100 ml of ether and 5 ml of

  methanol, with diazomethane. Concentrate the

  The solution is then chromatographed on a high pressure liquid chromatography column eluting with a mixture of ethyl acetate and Skellysolve B.

  (1/1) so as to obtain the compounds mentioned in

  that at 4.08 g having Rf of 0.20 (chromate

  thin layer graphite on silica gel in a

  of ethyl acetate and Skellysolve B (2/1)) and 0.60 (thin layer chromatography on silica gel in a mixture of acetone and methylene chloride (1/2)), nuclear magnetic resonance peaks at 77-529; 4.89 to 4.60; 4.34 to 3.16; 3.67; 2.82 to 1.33; and 1.20 ', and infrared absorptions at 3550.3000, 1740, 1430, 1350, 1200, 1130, 1070, 1020.970.900, 865, and -1

- 810 cm.

  e. Methyl ester of 19-hydroxy-19-methyl-

  PGF2a and its (15R) epimer (Formula 203).

  The bis (THP ether) compounds are hydrolysed

  Formula 202 (0.590) in 33 ml of a mixture of

  acetic acid, water and tetrahydrofuran (20/10/3)

  a temperature of about 25 C during the night. We are

  center the mixture using toluene and then ethyl acetate. The residue is chromatographed on a high pressure liquid chromatography column.

  eluent with a mixture of acetone and methyl chloride

  lene (3/2) to obtain, first, the title compound (15R) at 0.129 g. The compound in the form (15R) has a Rf 38 and

  the compound in the form (15S) has an Rf of 0.27 (chromatin

  Silica gel thin film tography in a

  acetone and methylene chloride (3/1). The

  compound in the form (15S) represents peaks of

  nuclear magnetic sound at 5.75-5.04; 4.32 to 3.03;

  3.65; 2.66 to 1.31; and 1.17 5, absorptions from the

  frarouge at 3450, 3000, 1740, 1430, 1360, 1200, 1150, 965, 920, and 900 cm, and peaks of mass spectrum at

  671, 400, 686, 596, 581, 513, 506, 491, 423, 397, 333, 307,

  243 and 217. The compound in the form (15R) has almost the

same spectral properties.

  f. 9-Hydroxy-19-methyl-PGE 2 Methyl Ester

  and its (15R) epimer (Formula 204).

  The mixed Formula 202 bis (ether THP) PGF2a compounds were oxidized with Jones' reagent and then hydrolyzed to replace the THP blocking groups. Epimers are separated into C-15 mixed

  by chromatography on a chromatographic column

  liquid at high pressure, eluting with a

  of acetone and methylene chloride (1/1) to obtain

  first, the title compound (15R), 0.119 g, and then the

  cited under the heading 15S, 0.138 g. Compound 15R has an Rf of 0.48 and 15S has an Rf of 0.36

  (Thin layer chromatography on gel

  silica in a mixture of acetone and methyl chloride

  thylene (3/1)). The compound in the 15S form has nuclear magnetic resonance peaks at 5.83-5.02; 4.56 to 3.33; 3.66; 3.04 to 1.34; and 1.20 i, infrared absorptions at 3450, 3000, 1.740, 1430, 1360, 1300, 1230, 1150, 1070, 1000, 965, 900, and 760 cm, and 597 mass spectral peaks. , 3441, 581, 522, 507, 439, 349, 295, and 231. The compound in the form 15R has

  spectral properties very similar.

  Preparation 9-bis (dimethyl-tbutylsilyl) -19-keto-PGF2a bis (tetrahydropyranyl ether)

  (Formula 207 of Scheme 42) and methyl ester

  19-keto-PGF2a-ethyl (Formula 208).

  at. Refer to Figure 42. Add the compound

  of formula 206 (0.500 g) in 8 ml of

  thylene to a Collins reagent (prepared from

  chromic hydride (0.526 g) in pyridine (0.831 g))

  and methylene chloride at a temperature of 0 C.

  The mixture is stirred at a temperature of about 25.degree.

  for 1.2 hours, then diluted with 200 ml of

  ther, it is filtered and concentrated. The residue (0.502 g)

  is formed of 9-silyl-11,15-bis (THP ether).

to of formula 207.

  b. The product of "a" is hydrolyzed in a mixture of

  tetrahydrofuran, acetic acid and water

  (3/20/10) at a temperature of 47 -50 C for 4 hours.

  The mixture is concentrated and then chromatographed, eluting with a mixture of acetone and methylene chloride (1/1). The title compound (0.126 g) was obtained with a Rf of 0.33 (chromatography

  in a thin layer on silica gel in a mixture of

  and methylene chloride (1/1)), peaks

  nuclear magnetic sound at 5.86-5.06; 4.60 to 3.12; 3.65; 2.69 to 0.84; and 2.13, absorptions in infrared -1 at 3.350, 2.900, 1730, 1430, 1350, 1220, 1160, and 965 cm and peaks in the mass spectrum at 598.3545, 583, 513, 508,

493, 423, 418, 217 and 187.

  c. (15R) -19-keto-PGF2a (Formula 208).

  Replacing the (3S) lactone isomer with the corresponding (3R) isomer yields the title compound with a Rf of 0.27 (chromatography

  thin layer on silica gel in a mixture of chlorine

  methylene and acetone (1/1)), nuclear magnetic resonance peaks 5.70-5.15; 4.10; 3.67; 3.20;

  2.17; and 2,70-1,20 o, absorptions in the infrared

  at 3.300, 2.990, 1710, 1420, 1350 and 965 cm, and

  high resolution mass spectrum peaks at 598.3516.

  d. Methyl ester of 19-keto-13,14-dihydro-

PGFla

  The product of the formula 206, that is to say the

  11,15-bis methyl ether (tetrahydropyran-2-ether)

  9-dimethyl-t-butylsilyl- (19R, S) -19-hydroxy-

  PGF, is reduced to C5-C6 and C13 -C4 by hydrogenation.

2at 56 etC13- 14 pruehdoé

  catalytic group in 75 ml of ethyl acetate in use

  reading 200 mg of a 5% palladium catalyst

  on carbon into a mixture of PGFla and 13,14-

  corresponding dihydro-PGFla, which is subsequently hydro-

  generated in the compound 13,14-dihydro.

  II. By applying oxidation processes

  nude, 9-silyl-ll-15-bis methyl ester is obtained

  (THP ether) -13,14-dihydro-19-keto-PGF1a corresponding.

  Then, by hydrolysis in a mixture of tetrahydrofuran

  rane, acetic acid and water, the composition is

  quoted in section. Thin layer chromatography and nuclear magnetic resonance results show the presence of a less polar acetal form as well as the 19-keto form, Rf of 0.26; 0.54; and 0.67 (thin layer chromatography on silica gel in solvent A-IX), nuclear magnetic resonance peaks at 4.52-3.30; 3.62; 3.38; 3.00 to 0.87; 2.08; and $ 1.18, and mass spectrum peaks at 512.3336, 2d0 44

  528, 517, 497, 427, 422, 412, 369 and 217.

  Preparation 11 Methyl ester of 19-hydroxy-19-methyl

PGF2a (Formula 215 of Scheme 43).

  Refer to Scheme 43. The 9-silyl-11,15-bis (THP) -19-keto compound of Formula 212 is treated

  (0.500 g) in 500 ml of benzene at a temperature of

  Viron C with 2.3 equivalents of trimethylaluminum added dropwise over a period of one minute. The mixture is stirred for 30 minutes and then added

  to 50 ml of saturated aqueous ammonium chloride and this is

  treated with ethyl acetate. We wash the organic phase

  with brine, dry and concentrate.

  The residue is chromatographed and the corresponding 19-hydroxy-methyl compound is obtained, which is then freed in a mixture of tetrahydrofuran, acetic acid and water (3/20/10) in order to obtain

the compound cited in section.

  Preparation 11A Methyl Ester of 15,19-Dimethyl-19-

  hydroxy-PGF2a and its (15RYepimer (For-

mule 215 of Scheme 43).

  The starting material used is the methyl ester

  (15R, S) -15-methyl-tetrahydropyranyl ether

  thyl-l9,20 didéhl &-o-PGF 2. After saponification and

  In the form of the free acid, the compound is treated first with the silylating agent and then with dihbedropyran in the presence of the hydrochloride.

  pyridine. Next, the compound of the type 15-methyl is prepared.

  19-keto-keto compound of formula 212 using the methods used herein, and subsequently the compound cited

in heading.

  Preparation 12 (2E) - 2-19-Hydroxy-Methyl Ester

  19-methyl-PGF2 (Formula 223 of Scheme 44). at. Refer to Figure 44. Prepare first

  the 2-phenylselenidyl compound of the formula

  221. The starting material is the methyl ester of

  Formula 220 in the form of bis (tetrahydropyryl ether)

  rann-2-ylique) (0.4 g). A solution of this methyl ester (THP) in 5 ml of tetrahydrofuran is added.

  dropwise with the amide formed from N-isopropyl-

  cyclohexylamine (0.3 g) and n-butyllithium (equivalent

  to a solution in hexane (1.6 M) in tetrahydro-

  furan (7 ml) cooled to -78 C. The mixture is stirred

  The mixture is stirred at -78 ° C for 45 minutes and then phenylselenenyl chloride dissolved in tetrahydrofuran is added over a period of 7 minutes. The mixture is stirred at a temperature of -78 ° C. for an additional hour, then poured into

  ml of a mixture of water, ice and ammonium chloride

  saturated monium and extracted with diethyl ether

  than. The organic phase is dried and concentrated.

  The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and toluene.

  (1/8) and the compound of formula 221 is obtained.

  b. Formula L2 of form 222 is formed by oxidative removal. The product was treated in methylene chloride with 10% hydrogen peroxide at room temperature.

  about 25 ° C while stirring thoroughly for 1 hour.

  Organic halide with sodium bicarbonate, saturated sodium carbonate and brine,

  dry and concentrate to obtain the compound of

mule 222.

  c. The title compound is obtained by unblocking the product of "b" using a mixture of acetic acid, water and tetrahydrofuran.

  (10/20/3) at a temperature of 40 C.

  Preparation 13 (4Z) - 4-19-hydroxy-PGF1 (Formula

227 of Figure 45).

  Refer to Scheme 45. The hexagonal lactol of formula 226 is first prepared. In step "a", the enol ether of formula 225 is prepared as follows. We cool a

  suspension of methoxymethyltriphenylphosphoric acid

  nium (Levine, J.Am.Chem.Soc.80, 6150 (1958) 32.4 g) in 150 ml of tetrahydrofuran (THF) at a temperature of -15 Cetony added 69.4 ml of butyllithium (1.6 M in

  hexane) in 45 ml of THF. After 30 minutes, we add

  a solution of tris (tetrahydropyranyl ether)

  3a, 5a-dihydroxy-23- (3a, 7 5-dihydroxy-trans) γ-lactol

  1-octenyl) -α-cyclopentaneacetal of 224 (J.C.Sih, Prosta

  glandins 13, 831-835 (1977) 10.4 g) in 90 ml of THF.

  The mixture is stirred for 1.5 hours while heating.

  at a temperature of about 25 ° C, and then concentrated under reduced pressure. The residue is partitioned between dichloromethane and water, the phase is dried

  organic and concentrated. Then submit the resi-

  by chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (2/1). Fractions showing by chromatography on

  thin layer they contain the intermediate product

  formula 225, are combined and concentrated for

give the ether-ether.

  In step "b", the pre-ether is hydrolyzed.

  yield in 20 ml of THP with 50 ml of acetic acid

  at 66% at a temperature of about 57 C for 2.5 hours.

  The mixture is concentrated under reduced pressure. Toluene is added to the residue and concentrated again.

  solution. Finally, the residue is subjected to a chroma-

  tography on silica gel, eluting with a mixture

  chloroform and methanol (6/1). We obtain the lake

  tol of formula 226 by combining and concentrating

the appropriate fractions.

  In step "c", the title compound is obtained as follows. 3-carboxypropyltriphenylphosphonium bromide is prepared by heating the

  triphenylphosphine (156.8 g) and 4-bromobutin

  (100 g) in 125 ml of benzene at reflux temperature for 18 hours. Filtration is separated

* Crystalline product, it is the eavac of benzene, and it is

  crystallizes from a mixture of ethanol, acetonitrile and ether; 150 g of product from one point is thus obtained

247 -249C melting point

  This phosphonium bromide (10.6 g) was then added to sodium methylsulfinylcarbanyl prepared from sodium hydride (2.8 g, 57%) and 30 ml of dimetyl sulfoxide, and the Wittig reagent was combined. resulting with the lactol of the formula 226 of step "b", in 20 ml of dimethyl sulfuycb. The mixture is stirred overnight, diluted with about 200 ml of

  benzene, and washed with a solution of hydrogenosulphonate

  potassium fate. The two lower layers are there-

  The organic phases are combined, washed with brine, dried and concentrated under reduced pressure. The residue is chromatographed on acid-washed silica gel, eluting with a mixture of ethyl acetate and isomeric hexanes (3/1). Fractions showing by thin layer chromatography that they contain the

  desired compound, are combined and concentrated to give

the compound mentioned in section.

  Example 1 (5Z) -9-Deoxy-6,9a-epoxy methyl ester

  - (19R, S) -19-hydroxy-PGF1 (Formula 228). I. Refer to Diagram 1. Prepare first

  the isomeric 5-iodo compounds of formula 17.

  A solution of (19R, S) -19-hydroxy-methyl ester

  PGF2a of formula 16 (Preparation 3: 0.655 g) in 14 ml of methylene chloride is treated with 14 ml of

  saturated aqueous solution of sodium bicarbonate and

  The mixture is cooled to 0.degree.-5.degree. C. Then, under intense stirring, a solution of iodine (0.474 g)

  ml of methylene chloride. The mixture is agitated

  for a total time of one hour with a final temperature of 10 C. The organic phase is separated off, washed with aqueous sodium sulphite (10%), dried and

  it is concentrated into an oil (0.803 g), formed mainly

6R, 5R isomer.

  II. Previous iodine compounds in 32 ml of

  benzene, are treated with 1.70 ml of DBN (1,5-diazabine)

  cyclo [4.30J-nonene-5) at a temperature of about 45 C for 25 hours. The mixture is diluted with 125 ml of benzene containing 1% triethylamine and washed with a mixture of ice-water and brine, dried and concentrated. The traces of DBN are removed by taking up the concentrate in 150 ml of benzene and washing with ice water. The organic phase is dried and

  concentrate in order to obtain the compound listed in

  that of formula 228 (0.300 g) with an Rf of 0.34 (in a mixture of acetone and hexane (3/1)), nuclear magnetic resonance peaks at 5.52; 4.55; 4.30 to 3.60;

  3.66; 2.90 to 1.30; and 1.13 i, absorption in the

  -1 frarouge at 3,400,2,995, 1735, 1695, 1430 and 970 cm and high resolution mass spectral peaks at

598.3563.

  Example 2 (6R) -9-Deoxy-6,9a-epoxy methyl ester

  (19R, S) -19-hydroxy-PGF1 (Formula 20) and

its (6S) isomer.

  I. A solution of es-

  bis (tetrahydropyranyl ether) methyl ester

  PGF2a (Preparation 2.100 g) in 23 ml of tetrahydrofuran.

  hydrofuran to a suspension of mercuric acetate

  (1.445 g) in 23 ml of water and 23 ml of tetrahydrofuran.

  Stirring is continued for 2.5 hours at a temperature of

  about 25.degree. C. The mixture is cooled to 0.degree.

   And treated with solid sodium borohydride (0.388 g) added in small portions over a period of

  2.5 minutes. Then, the mixture is stirred at a temperature of

  at about 25 ° C for 3.5 hours and diluted with ml of ether. The solution is decanted into mercury and separated. The aqueous phase is then extracted with

  ether and the combined organic phases are

  centered. The residue is taken up in 300 ml of ether,

  brine, dried, and concentrated to an oil (1,230 g) containing the bis- (THP ethers) of the compounds

in heading.

  II. We unblock the previous product in a melange

  of acetic acid, water and tetrahydrofuran

  (20/10/3) at a temperature of about 45 C for 2.5 hours.

  res. The mixture is concentrated and then subjected to azeotropic distillation with benzene in a controlled manner.

  to obtain the mixed C-6 epimers of formula 20.

  III. The preceding product is chromatographed by means of high pressure liquid chromatography.

  a Merck "B" column, eluting with a mixture of

  tone and hexane (2/1), so as to obtain a

  less polar (0.086 g) methyl ester of (6R) -

  9-deoxy-6,9a-epoxy- (19R, S) -19-hydroxy-PGF1 with an Rf of 0.28 (in a mixture of acetone and hexane (3/1)), resonance peaks 5.50 nuclear magnetic; 4.35 to 3.10; 3.67; 2.60 to 1.30; and 1.13 <, and high resolution mass spectrum peaks at 600.3681. The most polar fraction (0.150 g) consisting of

  (6S) -9-deoxy-6,9a-epoxy- (19R, S) methyl ester -

  19-hydroxy-PGF1 with a Rf of 0.25 (in a mixture of acetone and hexane (3/1)), nuclear magnetic resonance peaks at 5.50; 4.40; 4.25 to 3.30; 3.67; 2.65 to 1.30; and

  1,13 M, and high resolution mass spectrum peaks

600.3705.

  Example 3 (5Z) -9-Deoxy-6,9a-epoxy-sodium salt

  (19R, S) -19-hydroxy-PGF1 (Formula 240).

/ (CH2) 3-COONa C-HH

OH -> (CH2) .3-CH-CH,

H OH OH

  A solution of (5z) -9-deoxy-6,9a-epoxy- (19R, S) -19-hydroxy-PGF1 methyl ester (Example 1, 0.140 g) was treated in 6 ml of methanol and 4 ml of water with 4.10 ml of 0.1 N aqueous sodium hydroxide

  temperature of about 250C for 25 hours. We concentrated

  the mixture and then dried by freezing to give the title compound as a free-flowing, white solid of 0.130 g,

  with a melting point of 152-158 ° C and a peak of

  high resolution mass at 656.3761.

  Example 4 (5Z) -9-Deoxy-6, 4-actylphenyl Ester

  9α-Epoxy-L5- (19R, S) -19-hydroxy-PGF1.

Two methods are described.

  I. Mixed anhydride method. A stirred suspension of 19-hydroxy-PG 2 sodium salt (Example 3, 0.195 g) in 15 ml of methylene chloride and 0.120 g of triethylamine is treated at a temperature of about 0 ° C. with chloroformate. isobutyl (0.0656 g) in 1 ml of methylene chloride. The mixture is stirred at a temperature of approximately 25 ° C. for 2 hours,

  then cools it again to a temperature of about

  0 ° C. and treated with 4-hydroxyacetophenone (0.0653 g) in 1 ml of methylene chloride containing about 0.25 ml of triethylamine. The mixture is stirred at a temperature of approximately 25 ° C. for 1 hour,

  cooled to 0 ° C, diluted with 25 ml of a

  methylene chloride / triethylamine (95/5), and washed with sodium bicarbonate

  5% aqueous and 0.1 N potassium hydroxide.

  The organic phase is dried and concentrated

  re to obtain the compound cited in section.

  II. 2-halo-pyridinium salt method. We treat

  a solution of sodium salt of 19-hydroxy-PGI 2 (Example 3, 1.04 g) in 35 ml of dimethylformamide and

  0.352 g of triethylamine with 2-bromine iodide

  1-methylpyridinium (J.Chem.Soc., Perkins Crans., 2

  (1974) 790 (0.81 g) at a temperature of about 25 C

  one hour. The mixture is then treated with

  4-hydroxyacetophenone (0.364 g) in 2 ml of dimethyl

  formamide and 0.4 g of triethylamine at a temperature of about 25 ° C. Onatelmnang for about 16 hours, then poured into ice water containing 4 ml of 1N potassium hydroxide and extracted with water. diethyl ether. The organic phase is washed with cold 0.02N potassium hydroxide, dried and concentrated to give the title compound.

heading.

: - A, O9

Claims (5)

REVENDI CTIOINS   1. Prostacyclin compound of the formula: R13 X P -C U LH3   wherein R13 represents hydrogen or methyl   le, c represents a radical represented by the loss   of C19 and C20 from a prostatic compound   cycline belonging to one of the following groups   respectively: (I) compounds of the formula: M1-LI-R1 ! 1 R5 Is.19 X-C-C- (CH2) 2-CHi2CH3 2 Q R6   wherein A1 represents -O- (oxa) and E.1 represents -CH H2- 'L1 represents:   (1) - (CH2) n- where n is 1 to 5 inclusive , or () -C) -   (2) - (CH 2) p-CF 2 where p is equal to 2.3 or 4, with the proviso that when M 1 represents H OH   CH 2 - or -C -CH 2 -, L 1 also represents -CH 2 -CH = CH-, M 1 represents (L) (1) (Al) -: = C H (2) K (Al) -C = C (L) (3) H -CCH2- or (4) OH -C CH2-,   or the sign represents a binding or attachment in alpha or beta configuration; Q represents: OH, R4 OH or R4 OH where R4 represents hydrogen or an alkyl of 1 to 4 carbon atoms inclusive, R1 represents: (1) -COOR3 (2) -CH20H (3) -CH2N (R7) (R8) (4) 0 -C-N (R7) (R8) (5) o It is -C-NH-SO2-R15 or (6) NH-N   N-N o R3 represents (a) hydrogen, (b) an alkyl of   1 to 12 carbon atoms inclusive, (c) a cycloalkyl   kyle of 3 to 10 carbon atoms inclusive, (d) aralkyl of 7 to 12 carbon atoms inclusive, (e)   phenyl, (f) a phenyl substituted with 1,2 or 3   chloro or alkyl radicals of 1 to 3 carbon atoms   clusively, o0) (g) C-CH3 1 ((i) - (- NH- - C -NHi) -N-C-CH3,   ## STR2 ## ## STR2 ## ## STR2 ## (m) I ".   ## STR5 ## represents a phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p -benzamidophenyl or 2-naphthyl radical, or else a pharmaceutically acceptable uletion, o R7 and R8, being the same or different, represent hydrogen, alkyl of 1 to 12 carbon atoms inclusive, benzyl or   phenyl, and R15 represents hydrogen, a   alkyl of 1 to 12 carbon atoms inclusive, phenyl, phenyl substituted with 1,2 or 3 chloro or alkyl radicals of 1 to 3 carbon atoms inclusive, or   a phenyl substituted by a hydroxycarbonyl radical   or alkoxycarbonyl of 1 to 4 carbon atoms   sively; R2 is hydrogen, hydroxyl, or hydroxymethyl, R5 and R6, being the same or different, are hydrogen, alkyl of 1 to 4 carbon atoms inclusive, or fluoro, to the   provided that one of R5 and R6 does not represent a radi-   when the other is hydrogen or a fluoro radical; and X represents: (1) trans-CH = CH- (2) cis-CH = CH- (3) -C-C- or (4) -CH 2 Cl 2 -;   (II) prostacyclin analogues of the mule: <41-L2-R1 R5 C. 5 119 20 X-CC- (CH2) 2-CH2CH3   In which M1, Q, R1, R2, R5, R6 and X are as defined above, A1 represents -O- (oxa) and E2 represents -CH2CH2-, and L2 represents:   (1) - (CH2) j- where j is a value from 1 to 4 inclusive   (2) - (CH2) q-CF2-o q is equal to 1.2 (3) -CH = CH-   (III) prostacyclin analogs or 3, or of the _M, -Lt-Rt A2 l Rs 1 19 20 X-C - C- (CH2) 2-CH2CH3 R2 II   Wherein L1, M1, Q, R1, R2, R5, R6 and X are as defined above, and A2 represents -CH2O- with -CH2 linked to the cyclopentane ring and E1 represents -CH2-;   (IV) Prostacyclin analogs of the mule: ## STR2 ## R 19 20   ! X-C --- C- (CH 2) 2 -CHiCH 3 Q R 6 mule: in which A1, E11Q, defined above, L 3 represents: (1) - (CH 2) n-o (2) - (CH 2) p- CF2 (3) -CH 2 -CH = CH,   the sign _ represents or trans; R1, R2, R5, R6 and X nt such that n is from 1 to 5 inclusively, where p is equal to 2.3 or 4, and the cis (V) configuration is binding of the prostacyclin analogs of the formula: H S H .. L2-R1 C1E C: C R5 1 - -C (CH2) 2-CI12CH3 ii I Q R6   wherein A], E1, L2, Q, R1, R2, R5, R6, X and the   gne --- are as defined previously; (VI) prostacyclin analogs of the formula: OR o 0. _C. "- CH2-L.-RI R5 19 R (CH2) 2-Cl2CH3 R2 Q R6   wherein Q, R1, R2, R5, R6, X and the sign. are as previously defined L4 represents: (1) - (CH2) n- 1 to 5 inclusive, or 1 (VII) in such (2) - (CH2) p-CF2 op is equal to 2, 3 or 4, and RiO represents a linear alkyl radical with 6 carbon atoms inclusive; prostacyclin analogs of the formula: H 0 0- C "CH2-C-L, -R1  H2 R5 19 20 -C-C- (CH2) 2-CH2CH3   Wherein Q, R 1, R 2, R 5, R 6, X and the sign - are as previously defined, and L 5 is: (1) - (CH 2) p-o p is 2.3 or 4, or (2) -CH2-CF2-;   (VIII) prostacyclin analogs of the formula: X 19 20 X-C --- C- (CH2) 2-CH2CH3 2 IQ R R2 Q R6   wherein L4, Q, R1, R2, R5, R6 and X are as previously defined; (IX) Prostacyclin analogs of the formula: -CCH 2 -L, 5-Ri R 5 \ 9 20 X-C-- C- (CH2) 2-CH2CH3 2 Q R6 Q R6   wherein Q, R1, R2, R5, R6 and X are as defined   previously defined, and L6 represents: (1) - (CH2) n- where n is 1 5, or (2) - -H2CH = CH-; and (X) prostacyclin 6a-carba analogs of the formula: cGM -L3-Ri CH2 R5 -19 20 - CH2) 2-CH2CH3   In which L3 # Q, R1, R5, R6 and X are as previously defined, M2 represents: ((t) (1) -C = C H or H (2) -C = C /, and HE)   R9 represents hydrogen or hydroxyl.   2. A compound according to claim 1, characterized   in that it is selected from the following group of compounds:   (5Z) -9-Deoxy-6,9a-epoxy-d -191 methyl ester hydroxy-PGFF1,   (5Z) -9-deoxy-6,9a-epoxy-L -19-hy- sodium droxy-PGF ,,   (6R) -9-deoxy-6,9a-epoxy-1,93-hydroxy-methyl ester   PGF1, to (6S) -9-deoxy-6,9a-epoxy-19-hydroxy-PGF1 methyl ester,   (5Z) -2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9a-epoxy   α-19-hydroxy-PGF1, (5Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-epoxy-16,16-difluoro-19-hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6%, 9a-epoxy-195- hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-epoxy-16,16   difluoro-195-hydroxy-PGF1,2-decarboxy-2-hydroxymethyl-9-deoxy-6,9aepoxy-6g, 19-dihydroxy-PGF1,2-decarboxy-2-hydroxymethyl-9-deoxy-6%, 9c9a-epoxy -: 6,19-16,16-difluoro-PGF1,   (4Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-5,9a-epoxy-  4, 19, -hydroxy-PGF1,   (4Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-5,9a-epoxy-   4,16,16-difluoro-19-hydroxy-PGFi,   (2E, 4Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-5,9a-epoxy- , 4 -192-hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-5,99a-epoxy-19% - hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-5,9a-epoxy-16,16 difluoro-19 (hydroxy-PGF1,   (5Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-époxymé- thano- a5-19% -hydroxy-PGF1,   (5Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-époxymé- thano- 5,16,16-19 -hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6%, 9a-époxymétha- No. 9% -hydroxy-PGF 1   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9c-époxymétha- no-16,16-difluoro-19-hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-poxy- , 19, -dihydro-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6, 9a-epoxy   19-dihydroxy-16,16-difluoro-PGF1, (4E) -2-decarboxy-2-hydroxymethyl-9-deoxy-6,9-epoxy-A4 -19-hydroxy-PGF1,   (4E) -2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9a-   epoxy-A4-! 6,16-difluoro-19-hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-epoxy- 6-methoxy-19-hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-epoxy-   methoxy-16,16-difluoro-19-hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-epoxy- 4-oxo-19-hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6, 9a-epoxy   4-oxo-16,16-difluoro-19-hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-epoxy-   6-19-hydroxy-PF1,2-decarboxy-2-hydroxymethyl-9-deoxy-6,9ga-pcc-16,6-difluoro-19-hydroxy-PGF1,2-decarboxy-2-hydroxymethyl-9-deoxy -6, 9α, 17β-hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-epoxy- 7-16.16-difluoro-19frhydroxy-PGF1,   (2E) -2-decarboxy-2-hydroxymethyl-9-deoxy-63,9a- epoxy a2,67-19_-hydroxy-PGF1,   (5E) -2-decarboxy-2-hydroxymethyl-6a-carba-9-de-   soxy-6,9a-epoxy-L35-19-hydroxy-PGF1,   (5E) -2-decarboxy-2-hydroxymethyl-6a-carba-9-de-   6,9-Soxo-epoxy-45-16,16-difluoro-19-hydroxy-PGF1,   (5Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-   epoxy-A5-19-hydroxy-19-methyl-PGF1,   (5Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-   epoxy L5-16,16-difluoro-19-hydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-6,9a-EPO-9édésoxy   xyl-19-hydroxy-19-methyl-PGF1,2-decarboxy-2-hydroxymethyl-9-deoxy-6,9aepoxy-16,16-difluoro-19-hydroxy-19-methyl-PGF1   2-decarboxy-2-hydroxymethyl-9-deoxy-6 ', 9a-epoxy 6%, 19-dihydro-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6%, 9a-EPO-   xyl-6,19-dihydroxy-19-methyl-16,16-difluoro-PGF1,   (4Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-5,9a-   epoxy-19-hydroxy-19-methyl-PGF1,   (4Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-5,9a-   Y4-16,16-difluoro-19-hydroxy-19-methyl-PGF1 epoxy,   (2E, 4Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-   2,4a, 9a-epoxy-, 4 -19-hydroxy-19-methyl-PGF1,   2-dicarboxy-2-hydroxymethyl-9-deoxy-5,9a-epoxy- 19-hydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-5%, 9a-epoxide   xy-16,16-difluoro-19-hydroxy-19-methyl-PGF1,   (5Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-   epoxymethano-5-19-hydroxy-19-methyl-PGF1,   (5Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-   epoxymethano- L-16,16-difluoro-19-hydroxy-19-methyl- PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6-9a-epoxy   xyméthano-19-hydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-EPO-   xyméthano-16,16-difluoro-19-hydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6%, 9a-EPO- xy-5,19-dihydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-EPO-   xy-5-19-dihydroxy-19-methyl-16,16-difluoro-PGF-1, 4E) -2-decarboxy-2-hydroxymethyl-9-deoxy-69a-epoxy-19-hydroxy-19-methyl-PGF1,   (4E) -2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9a   epoxy-16,16-difluoro-19-hydroxy-19-methyl-PGF1,2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-epoxy-6α-methoxy-19-hydroxy-19-methyl- PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-epoxy-   6-methoxy-16,16-difluoro-19-hydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-69a-epoxy 4-oxo-19-hydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6G, 9a-epoxy   xy-4-oxo-16,16-difluoro-19-dihydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-EPO- xy-6 -19-hydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6 ', 9a-EPO-   xyl-16,16-difluoro-19-hydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-EPO- xy-8-19-hydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a-   epoxy-α-16,16-difluoro-19-hydroxy-19-methyl-PGF1, (2E) -2-decarboxy-2-hydroxymethyl-9-deoxy-6%, 9α-epoxy-7-19-hydroxy-19 -methyl-PGF   (5E) -2-decarboxy-2-hydroxymethyl-6a-carba-9-de-   6,9-epoxy-6,9-epoxy- (5-19-hydroxy-19-methyl-PGF1, and   (5E) -2-decarboxy-2-hydroxymethyl-6a-carba-9-de-   6,9-epoxy-6,9-epoxy- / -16,16-difluoro-19-hydroxy-19-methyl- PGF1.   3. Intermediate compound required for the preparation   compounds according to claims 1 or 2, having as formula: q RD-RR3 t -R <R, R, 3 Ii X-C - C- (-CH) 2-C.-3 R2 Q R6 01t E4 09 '   in which D represents -CH CCH2-1-2- or Il o -CH2-C-CH2-L3_   L 2 represents: (1) - (CH 2) j - where j is from 1 to 4 inclusive, (2) - (CH 2) qCF 2 - where q is equal to 1.2 or 3, or (3) -CH = CH-,   L3 represents: (1) - (CH2) n-o n is from 1 to 5 inclusive, (2) - (CH2) pCF2- where p is equal to 2.3 or 4, or (3) -CH 2 CH = CH-, R1 represents: (1) -COOR3 (2) -CH20H t2S1 (3) -CH2N (R7) (R8) (4) O he -C-N (R7) (R8) * (5) O -C-NH-SO2-R-15 or (6.) NH-N   ## STR2 ## represents (a) hydrogen, (b) alkyl of 1 to 12 carbon atoms inclusive, (c) cycloalkyl   from 3 to 10 carbon atoms inclusive, (d) an aral-   kyle of 7 to 12 carbon atoms inclusive, (e) phenyl, (f) phenyl substituted with 1,2 or 3 radicals   chloro or alkyl of 1 to 3 carbon atoms inclusive   o (g) eH3 (h) -3N- - HOC 3 - (i) - / -Nil-C 3 i (g) CC H3 o (h) () N- - NHH-C- i3, lO <> IlI CH-CR1   R1 represents a phenyl radical, p-bromophenyl, p-   biphenylyl, p-nitrophenyl, p-benzamidophenyl or 2-   naphthyl, or (o) a pharmacologically acceptable cation, R7 and R8, being the same or different, are hydrogen, an alkyl of (k) 12 carbon atoms inclusive, benzyl, or ) CH2-CRl6   R16 represents a phenyl radical, p-bromophenyl, p-   biphenylyl, p-nitrophenyl, p-benzamidophenyl or 2-   naphthyl, or (o) a pharmacologically acceptable cationic cation, R 7 and R 8, being the same or different, are hydrogen, alkyl of 1 to 12 carbon atoms inclusive, benzyl, or phenyl and R15 represents hydrogen, or an alkyl radical of 1 to 12 carbon atoms inclusive, phenyl, phenyl substituted with 1,2 or 3 chloro or alkyl radicals of 1 to 3 carbon atoms inclusive, or phenyl substituted with a hydroxycarbonyl or alkoxycarbonyl radical of 1 to 4 carbon atoms inclusive,   R2 represents hydrogen or a hydrogen radical   xyl or hydroxymethyl, R5 and R6, being identical or different, represent hydrogen or an alkyl radical of 1 to 4 carbon atoms inclusive, or fluoro, with the proviso that one of R5 and R6 represents a radical when the other represents hydrogen or a fluoro radical, X represents: (1) trans-CH = CH- (2) cis-CH = CH- (3) -C -C- or (4) -CH2CH2-,   and the sign - represents a binding or binding in alpha or beta configuration.   4. A compound according to claim 3, characterized   in that it is selected from the following group of compounds:   2-decarboxy-2-hydroxymethyl-5-oxo-19_-hydroxy- PGF1,   2-decarboxy-2-hydroxymethyl-5-oxo-16,16-difluo- ro-19-hydroxy-PGF1,   2-Decarboxy-2-hydroxymethyl-6-oxo-19-hydroxy- PGF1,   2-decarboxy-2-hydroxymethyl-6-oxo-16,16-difluo- ro-19-hydroxy-PGF1,   2-decarboxy-2-hydroxymethyl-5-oxo - 19-hydroxy-19- methyl-PGF1,   2-hydroxymethyl-2-decarboxy - 5-oxo-16,16-difluo- ro-19-hydroxy-19-methyl-PGF1,   2-decarboxy-2-hydroxymethyl-6-oxo-16,16-difluo-   ro-19-hydroxy-19-methyl-PGF1. 2-Decarboxy-2-hydroxymethyl-6-oxodifluoro-19-hydroxy-19-methyl-PGF1. 5. Drug consisting of or comprising a   compound according to claims 1 or 2.