CH645369A5 - PROSTACYCLINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

The present invention relates to prostacyclin derivatives and pharmaceutical compositions containing them. The prostacyclin derivatives according to the invention are bicyclic, 45 like the prostacyclin itself, although in some cases the bicyclic compounds are in equilibrium with corresponding monocyclic compounds, as is the case with corresponding 6-oxoprostaglandin analogues.

Prostacyclins are understood to mean a group of organic compounds, such as, for example, prostacyclin itself, which is also referred to as prostaglandin I2 (PGI2), and that the following formula 1

20th

having. Prostacyclin is called (5Z) -9-deoxy-6,9a-epoxy-A5-6 PGF] "when using the prostaglandin nomenclature or as (5Z, 9a, lia, 13E, 15S), - 6 , 9-epoxy

7

645 369

1 l, 15-dihydroxyprosta-5,13-diene-l-oie acid. Formula 1 also gives the numbering of the basic carbon skeleton. Furthermore, the absolute configurations (5Z, 8R, 9S, 11R, 12R, 13E and 15S) with regard to the potential isomer centers of this molecule can also be seen from this structural formula.

Regarding what is known so far about prostacyclin, reference is made, for example, to the publications by R.A. Johnson et al. in Prostaglandine 12,915-928 (1976) and R.A. Johnson et al. in J.Am.Chem.Soc. 100, 7690-7704 (1978) and regarding the pharmacological activity, reference is made to the references cited in these publications. Regarding the compounds that can be referred to as analogues of prostacyclin, reference is made, for example, to the publications by J. Fried et al. in proc. Nati. Acad. Sci. U.S.A. 74,2199-2203, K.C. Nicolaou et al. in J.C.S. Chem. Comm. 1977, 331-332, N.A. Nelson, in J.Am.Chem.Soc. 99,7362-7363 (1977) and K. Kojima et al. in Tetra. Letters, 1978,3743-3746.

Regarding the nomenclature of analogues of PGI2, reference is made to the publication by R.A. Johnson et al. in Prostaglandine 15, 737-740 (1978).

Prostacyclins are related to prostaglandins, which are themselves related to prostanoic acid, which have the following formula 2

The aim of the present invention was to produce new products which have pharmacological activity. In addition, efforts were made to develop a process for the production of these products and the intermediate products required therefor.

The prostacyclin derivatives according to the invention are those which have a

10th

15 have designated radical, which resulted from the loss of the carbon atom 19 and the carbon atom 20 from certain compounds of the prostacyclin type, with the compounds according to the invention introduced at this radical instead of the carbon atoms 19 and 20, a 20 grouping of the formula ri

25th

-c-ch3

OH

c00h

20th

owns.

There is extensive literature on prostaglandins and in this regard, for example, the publication by Bergstrom et al. in Pharmacol. Rev. 20.1 (1968).

The PGF2 has the following formula 3

) in which R13 represents a hydrogen atom or a * methyl group.

The present invention therefore relates to prostacyclin derivatives which are characterized in that they have the formula

35

on.

"" Have in which

40

Ri 3 is a hydrogen atom or a methyl group and '(pç) represents a radical which has resulted from the loss of carbon atom 19 and carbon atom 20 from a compound of the prostacyclin type of one of the following groups:

I) compounds of the formula

In the form shown here, the formulas represent a special optically active isomer which has the same absolute configuration as PGEh obtained from mammalian tissues.

In the formulas given, broken-line bonds to the cyclopentane ring or to a side chain show that the substituents in question are in the a configuration, that is to say that they lie below the plane of the cyclopentane ring or the side chain. Fully excellent thick bonds indicate that the substituents in question are in the β configuration, that is to say that they lie above the ring plane or the plane of the side chain.

Regarding the use of the symbols "R" and "S", reference is made to the publication by R.S. Cahn, in J. Chem. Ed. 41, 116 (1964).

With regard to the use of the symbols “Z” and “E”, reference should be made to the nomenclature regarding stereoisomerism in the case of a double bond, in particular to the publication by J.E. Blackwood et al. in Am. Chem. Soc. 90 509 (1968).

50

55

I 19 20

x-c-c- (ch2) 2-ch2ch3

ii i q re in which

60

A] an oxa group of the formula -O- is E, represents a group of the formula -CH2-,

L] has one of the following meanings:

1. A grouping of the formula - (CH2) n-, in which n is 1 65 to 5 inclusive or

2. A grouping of the formula - (CH2) p-CF2-, in which p is 2, 3 or 4, provided that if Mj is a grouping of the following formulas

645369

H s

-C

■ eroder oh *

-C ^ i

• Cîu-

, Lj also has the meaning of a grouping of the formula - (CH2-CH = CH> -

M i is one of the following groups:

1. (A,) - C = C

(Li)

H

f) a phenyl radical which is substituted by 1,2 or 3 chlorine atoms or alkyl groups each having 1 to 3 carbon atoms inclusive g) a grouping of the formula

0

| y-cs3

h) a grouping of the formula

2. (a,) - c = c '

H

(L,)

3rd

H

5

l 2

or

OH

'CH0-

in which the wavy lines, i.e. the symbols ~, illustrate that the bond can be in the a configuration or the β configuration, Q one of the following groupings:

O, H H, R4 OH or R4 OH in which

R4 is a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms inclusive,

Ri has one of the following meanings:

1.-COOR3

2. -CH2OH

3.-CH2N (R7) (R8)

O

II

4.-C-N (R7) (R8)

O

II

5. -C-NH-S02-R13 or, NH-N

/

6. -C ..

Vi

25th

30th

35

45

55

being in these groups

R3 has the following meanings:

a) hydrogen b) an alkyl radical with 1 to 12 carbon atoms inclusive c) a cycloalkyl radical with 3 to 10 carbon atoms inclusive d) an aralkyl radical with 7 to 12 carbon atoms inclusive e) a phenyl radical

60

0 ii

i) a grouping of the formula

j) a grouping of the formula

0

ii

■ nh-c-ch3

k) a grouping of the formula

0 ii nh-c-nh '

.// \ Y

1) a grouping of the formula

0

■ ch-n-nh-c-nh *

m) a grouping of the formula n) a grouping of the formula

9

645369

o ii

-CH2-C-Ri6

in which s

R16 is a phenyl radical, a p-bromophenyl radical, a p-biphenyl-yl radical, a p-nitrophenyl radical, a p-benzamidophenyl radical or a 2-naphthyl radical or o) denotes a pharmacologically acceptable cation,

"9 20

x-c-c- (ch2) 2-ch2ch3

ii i Q Re

R7 and R8 are identical to or different from one another and have the meaning of hydrogen atoms, alkyl radicals having 1 to 12 carbon atoms, benzyl radicals or phenyl radicals,

R) 5 is a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, a phenyl radical or a phenyl radical which is substituted by 1,2 or 3 chlorine atoms or alkyl groups having 1 to 3 carbon atoms or a phenyl radical which is substituted by a hydroxycarbonyl group or an alkoxycarbonyl group with 1 to 4 carbon atoms is substituted,

R2 represents a hydrogen atom, a hydroxyl group or a hydroxymethyl group,

R5 and R6 are identical to or different from one another and denote hydrogen atoms, alkyl groups with 1 to 4 carbon atoms and fluorine atoms, but one of the radicals R5 and R6 may only mean a fluorine atom if the other of these two radicals is hydrogen or fluorine and

X one of the following groupings

1. trans-CH = CH-

2. cis-CH = CH-

3.-C = C-or

4. -CH2CH2-

means and wherein those compounds of the formula I in which Mi is a group of the formula oh

5

i 2

is in equilibrium with the corresponding monocyclic compounds of the formula Ia

10th

15

0

^ / e1-s-ch2-l1-r1

Rs

| 19 20

X-C-C- (CHa) a -OFECHa h i

Q R6

stand in which

Li has one of the following meanings:

in which

Mj, Q, Ri, R2, R5, Rfi and X have the same meaning as explained in connection with the compounds of group I,

A! is an oxa grouping of the formula -O-,

E2 is the grouping of the formula -CH2CH2- and L2 is one of the following:

1. A grouping of the formula - (CH2) j- in which j is an integer in the range from 1 to 4 inclusive, 20 2. A grouping of the formula - (CH2) q-CF2-, in which q is 1,2 or 3 is or

3. Has a grouping of the formula -CH = CH-, and when, in the compounds of group II M], a group of the formula oh i

-c ~ ch2-

30th

where the symbol ~ indicates that the bond may be in an a configuration or a β configuration, these compounds are in equilibrium with the corresponding monocyclic prostacyclin analogues of group IIa

35

40

qH P2-C-CK2-Lz-Rl

Rs

I 19 20

(CKa; 2 "CK -> 'CH3

45

stand in which

Q, R], R2, R5, R6, X, E2 and L2 have the same meaning as in the compounds of the formula II, and furthermore 50 III prostacyclin analogues of the formula aa x 1 £ 1

55

60

1. A group of the formula - (CH2) n-, in which n is an integer in the range 1-5 or

2. A group of the formula - (CH2) P-CF2-, in which p is 2, 3 or 4 or

3. A group of the formula -CH2-CH = CH- and where

Q, Ri, R2, R5, Rs, X and Ej have the same meaning as in the compounds of group I and also II prostacyclin analogues of the formula

- rs

I, 19 20

X-ç — Ç- (CHa) 2-CHaCHs

L

in which

Li, Mi, Q, Ri, R2, R5, R6 and X have the same meanings as were explained in connection with the compounds of group I and

645 369

10th

A2 represents a grouping of the formula -CH20-, of which the group -CH2- is bonded to the cyclopentane ring and

E] represents a group of the formula -CH2-, and also IV) prostacyclin analogues of the formula h oh

Î $

c ch-L3-r1

I 1 9 20

■ c-c- (ch2) 2-ch2ch3

Q R6

in which

A], E], Q, Rj, R2, R5, R6 and X have the same meanings as were explained in connection with the compounds of group I L3 has one of the following meanings:

1. A grouping of the formula - (CH2) n-, in which n is an integer in the range from 1 to 5 inclusive,

2. A grouping of the formula - (CH2) p-CF2-, in which p is 2, 3 or 4 or

3. A grouping of the formula -CH2-CH = CH-, and where the wavy line, ie the sign ~, indicates that the bond is in a cis configuration or a trans configuration, and further

V) Prostacyclin analogues of the formula in which

Q, R), R2, R5j R6 and X have the same meanings as were given in connection with the compounds of group I and the wavy line, i.e. the 5 sign of the formula ~ indicates that the bond in the cis configuration or the trans configuration is present, and wherein

L4 has the following meanings:

1. A grouping of the formula - (CH2) n-, in which n io represents an integer in the range from 1 to 5 or

2. A grouping of the formula - (CH2) p-CF2- in which p is 2, 3 or 4 and

R10 represents a straight-chain alkyl chain with 1 to 6 carbon atoms,

15 and further

VII) Prostacyclin analogs of the formula

0

ii

20th

25th

ch2-c-l5-r-,

FU

La-Ri n 9 20

x-c-c- (ch2) 2-ch2ch3

D | l i

Q Re in which the leftovers

A ,, E], Q, Rj, R2, R5j R6 and X have the same meanings as were explained in connection with the compounds of group I,

L2 has the same meanings as those given in connection with the compounds of group I and the wavy line, that is the sign ~, indicates that the bond is in the cis configuration or in the trans configuration, and further

VI) Prostacyclin analogues of the formula or1 o *

q- c ^ - ^ ch2-lt + -ri ch2

I5

I 19 20

x-c-c- (ch2) 2-ch2ch3

I 15 20

..- c-c- (ch2) 2-ch2ck3

Q L

in which

30 Q, Rj, R2, R5, Rô and X have the same meanings as were explained in connection with the compounds of group I and the wavy line, that is the symbol ~, shows that the bond in the cis configuration or the trans Configuration may be present and 35 being

L5 has the following meanings:

1. A grouping of the formula - (CH2) P-, in which p is 2, 3 or 4 or

2. The group of the formula-CH2-CF2-, and also 40 VIII) prostacyclin analogues of the formula

^ »C-CH2-Li (.- Ri

45

RE

50

I 19 20

x-c — c- {ch2) 2-ch2ch3

II I

Q Re in which the groups

Q, Rb R2, R5, R5 and X have the same meanings as were explained in connection with the compounds of group I and

L4 has the same meanings as given in connection with the compounds of group VI and further

IX) Prostacyclin analogs of the formula

60

65

o- "crch2-l6-ri v ch

Rs

Q Re

I 19 20

x-c-c- (ch2) 2-ch2ch3

I! I.

Q Re

11

in which the radicals I compounds of the following formula 5

Q, Rh R2, R5, Rf, and X have the same meanings,

as stated above in connection with the compounds of group I and L6 has one of the following meanings:

1. A grouping of the formula - (CH2) n-, in which n is an integer in the range from 1 to 5 or

2. The grouping of the formula -CH2CH = CH-,

as well as further

X) 6a-carba-prostacyclin analogues of the formula ch ^ YL3 "Ri

', ch2

I 19 20

x-c-c- (ch2) 2-ch2ch3

ii i

Q Re in which the groups

Q, Rj, R5, R6 and X have the same meanings,

as stated in connection with the compounds of group I,

L3 has the same meanings as explained in connection with the compounds of group IV

and where M1-L1-R1

M2 either l. A grouping of the formula

645 369

/

R2

x-c — c- (ch2) 2-ch2ch3 Q Re or

, "(L)

-C = C I ^ H

2. A grouping of the formula

^ H

(l)

-C = C

R5 l x-c — c- (ch2) 2-ch2ch3 Q Re

IV compounds of the following formula 8

40

and

R9 represents a hydrogen atom or a hydroxyl group.

If the radical RI3 in the compounds of the invention having the general structure given above 45 j is a hydrogen atom, then these compounds have the following general formula 4

(pc V-ch-ch3

H. oh t 't c ch-l3-r1

V J

oh x "j- ^ c- (ch2) 2-ch2ch3 Q L

V Compounds of the following formula 9

, in which in turn the group named

(PC '

represents a residue left by the loss of the carbon atom 19 and the carbon atom 20 from a prostacyclin type compound. The compounds of the prostacyclin type from which this residue is derived can, as already mentioned, be the following compounds / fertilizers: r2

x-c — c- (ch2) 2-ch2ch3 Q L

i

645 369

VI Compounds of the following formula 10

^ R-io

. C ^ CH2-U-RI (T \

'CH:

Rs

X-C-C- (CHa) 2 ~ CH2CH3 Ii>

Q Re

VII Compounds of the following formula 11

Ï «

CH2-C-L5-R1

X-C-C- (CH2-CH2CH3 II i

Q Re

VIII Compounds of the following formula 12

. C-CH2-Ltt-Ri o ^ li yCH

is x-c-c- (ch2) 2-ch2ch3

St.

Q R6

IX Compounds of the following formula 13

C-CH2-L 6-Ri

R =

/ \

(\ CH

a

Rs I

L

X-C — C- (ch2) 2-CH2ch3 k '

Q Re

X compounds of the following formula 14

M jj-L-3-Rn pH2 "^ /

X-C-C- (ch2) 2-ch2ch3

/ II I

Rs Q Re

12

In the compounds of the formulas 5-14, the residues Ai, Ei, Li, M] and similar residues have the meaning given below and also meanings which are given below.

s Definition of the residues in the formulas

Ai is an oxa grouping of the formula (-0-). 10 A2 is a grouping of the formula -CH20-.

O

II

10 Ac is an acetyl radical of the formula CH3-C-

E] is a methylene group of the formula -CH2-, E2 is an ethylene group of the formula -CH2CH2-

G means nitrate, iodine, chlorine, bromine, acetate, trifluoroacetate or benzoate.

15

Shark means chlorine, bromine or iodine.

L] has one of the following meanings:

1. A grouping of the formula - (CH2) n-, in which n represents a value from 1 to 5 inclusive or

20 2. A grouping of the formula - (CH2) P-CF2-, in which p is 2, 3 or 4, provided that then, 21 if Mi is a grouping of the formula

25th

H

CH "-

12

3o represents, Li also has the meaning of a grouping of the formula -CH2-CH = CH-.

L2 has the following meanings:

1. A grouping of the formula - (CH2) j—, in which j has a value from 1 to 4 inclusive,

35 2. A grouping of the formula - (CH2) q-CF2-, in which q has the value 1, 2 or 3 or

3. A grouping of the formula -CH = CH-;

L3 has the following meanings:

1. A grouping of the formula - (CH2) n-, in which n 40 has a value from 1 to 5 inclusive.

2. A grouping of the formula - (CH2) P-CF2-, in which p has the value 2, 3 or 4 or

3. A grouping of the formula -CH2-CH = CH-. L4 has the following meanings:

45 1. A grouping of the formula - (CH ^ ,, -, in which n has a value from 1 to 5 inclusive or

2. A grouping of the formula - (CH2) P-CF2-, in which p is 2, 3 or 4.

L5 has the following meanings:

13 1. A grouping of the formula - (CH2) P-, in which p is 2, 3 or 4 or

2. A grouping of the formula -CH2-CF2-,

L6 has the following meanings:

1. A grouping of the formula - (CH2) n-, in which n 55 has a value from 1 to 5 inclusive or

2. A grouping of the formula -CH2CH = CH-.

L7 has the following meanings:

1. A grouping of the formula - (CH2) j-, in which j has a value from 1 to 4 inclusive, or 60 2. A grouping of the formula - (CH2) q-CF2-, in which q has the value 1,2 or 3 has.

Mi has the following meanings:

14 1. A grouping of the formula

65

^ (L)

(A,) - C = C

I ^ H

13

645 369

2. A grouping of the formula / H

(A,) - C = C

(l)

3. A grouping of the formula

H

s

-C-i

-CH2-

or

4. A grouping of the formula

R4 represents a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms inclusive and

R] 7 is an alkyl radical with 1 to 4 carbon atoms inclusive, a phenyl radical or a phenyl radical substituted with 1 or 2 fluorine 5 atoms, chlorine atoms or alkyl groups with 1 up to and including 4 carbon atoms or an aralkyl radical with Represents 7 to 12 carbon atoms inclusive, and furthermore the groups R17 are identical or different from one another. 10 Q3 means a grouping of the formulas o o

H H, R4 OC — R20 or R4 O — C —R20 15 in which R20 represents an alkyl group with 1 to 7 carbon atoms inclusive.

Q4 means a grouping of the formulas

OH S

-r

'ch,

20th

where the bonds to Aj and L are as shown and the symbol ~ indicates that the bond in question can be in the a configuration or in the β configuration.

M2 has the following meanings: H *

1. A grouping of the formula

H H, R4 OR24 or R4 OR24 in which R24 is a carboxyacyl group as defined below.

Q5 means a grouping of the formulas

-C = C

(l) H

or

30th

35

2. A grouping of the formula

H, R4 OH or R4 OH R] has the following meanings:

1. A grouping of the formula -COOR3

2. A hydroxymethyl group of the formula -CH2OH

3. A grouping of the formula -CH2N (R7) (R8)

4. A group of structure o

-c = c i

H (l)

-C-N (R7) (R8) 5. A grouping of the formula

40

the bonds to L being in the manner indicated.

Ms is a mesyl residue, i.e. a methylsulfonyl residue of the following formula CH3-S02-.

Q means a grouping of the formulas o

II

-C-NH-SO2-R15 or 6. a grouping of the formula

NH-N

/

• ° v

50

O, H H, R, OH or R4 OH where in these groups R4 is a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms inclusive. Qi means grouping the formulas

H H, R4 OR25 or R4 OR25 in which R4 has the meaning of a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms inclusive and

R25 represents a protecting group or blocking group as defined below.

Q2 is a grouping of the formula

H H, R4 in which

OSi (R17) 3 or R4 OSi (Rj7) 3

In these groupings the rest R3 has the following meanings:

a) a hydrogen atom,

b) an alkyl group with 1 to 12 carbon atoms,

55 c) a cycloalkyl group with 3 to 10 carbon atoms,

d) an aralkyl group with 7 to 12 carbon atoms,

e) a phenyl radical,

f) a phenyl radical which is substituted by 1, 2 or 3 chlorine atoms or alkyl groups having 1 to 3 carbon atoms,

g) a grouping of the formula

-CH,

60

645 369

14

h) a grouping of the formula

'/ \\ - NJ-

0 II

■ nh-c-ch

3,

i) a grouping of the formula nh-c j) a grouping of the formula k) a grouping of the formula

1) a grouping of the formula

-CH-N-NH-C-NH2,

m) a grouping of the formula n) a grouping of the formula

O

II

-ch2-c-r16

in which R [6 has the meaning of a phenyl radical, a p-bromophenyl radical, a p-biphenylyl radical, a p-nitro-phenyl radical, a p-benzamidophenyl radical or a 2-naphthyl radical or o) is a cation, in particular a pharmacologically acceptable cation, and furthermore in the above-mentioned groups (3) and (4)

R7 and R8 have the meaning of hydrogen atoms, alkyl groups with 1 to 12 carbon atoms, benzyl groups or phenyl groups, the radicals R7 and Rg being identical to or different from one another and in group (5) the rest Rj5 has the meaning of a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, a phenyl radical, a phenyl radical substituted by 1, 2 or 3 chlorine atoms or alkyl groups having 1 to 3 carbon atoms, or a phenyl radical remainder which is substituted by a hydroxycarbonyl group or an alkoxycarbonyl group having 1 to 4 carbon atoms inclusive

R2 is a hydrogen atom, a hydroxyl group or a hydroxymethyl group,

R3 has the same meaning as explained above in connection with the definition of the remainder Ri,

R4 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms,

R5 and Rg have the meaning of hydrogen atoms, alkyl groups with 1 to 4 carbon atoms and ic fluorine atoms, the radicals R5 and R6 being identical or different from one another, provided that only then one of the radicals R5 and R6 is a fluorine atom may if the other has either the meaning of a hydrogen atom or also a fluorato-15 mes.

R7 and Rs have the meaning of hydrogen atoms, alkyl groups with 1 to 12 carbon atoms, benzyl groups or phenyl groups and the radicals R7 and R8 are identical or different from one another and 20 where R15 is a hydrogen atom, an alkyl radical with 1 up to and including 12 carbon atoms, a phenyl radical, a phenyl radical substituted with 1, 2 or 3 chlorine atoms or alkyl groups with 1 to 3 carbon atoms, or a phenyl radical with 25 hydroxycarbonyl groups or alkoxycarbonyl groups is substituted with 1 to 4 carbon atoms,

R9 is a hydrogen atom or a hydroxyl group, R10 means a straight-chain alkyl group with 1 to 30, finally 6 carbon atoms,

Rh is a hydrogen atom or a grouping of the formulas -OR25 or -CH2OR25, in which R25 is a protective group or blocking group, as defined below,

35 R12 means a chlorine atom, a bromine atom or an iodine atom,

Ru is a hydrogen atom or a methyl group, R] 4 stands for a hydrogen atom or a grouping of the formulas -0-Si (R] 7) 3 or -CH2OSi (R17) 3, in which R] 7 has the meaning given below owns

Ris is a hydrogen atom, an alkyl group of 1 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms, a phenyl group or one of 1, 2 or 3 chlorine atoms, or 45 alkyl groups of 1 to 3 carbon atoms substituted phenyl group or a phenyl group which is substituted by hydroxycarbonyl groups or alkoxycarbonyl groups, the alkoxy groups having 1 to 4 carbon atoms,

50 Ri6 is a phenyl group, a p-bromophenyl group, a p-biphenylyl group, a p-nitrophenyl group, a p-benzamidophenyl group or the 2-naphthyl group,

R17 has the meaning of an alkyl group with 1 to 4 carbon atoms, a phenyl radical, an SS with 1 or 2 fluorine atoms, chlorine atoms or alkyl groups with 1 to 4 carbon atoms substituted phenyl radical or an aralkyl radical with 7 up to and including 12 carbon atoms, where the radicals R17 can be identical to or different from one another. 60 R] 8 has the same meaning as R] but excluding the grouping of the formula -COOH,

Rj9 is a hydrogen atom or a grouping of the formulas

40

65

O

II

-o-c-r20

or

O

- II -CH20-C r2o

15

645 369

in which R20 has the meaning given below.

R20 is an alkyl group with 1 to 7 carbon atoms,

R2i has the same meaning as Ri, but instead of a grouping of the formula -COOR3 there is now a grouping of the formula -COOR26 in which R26 is an alkali metal cation.

R22 is a hydrogen atom or a group of the formula -OSi (RI7) 3, in which R17 has the meaning given above,

R23 is a hydrogen atom or a grouping of the formula -OR24, in which R24 is a carboxyacyl group, as defined below.

R24 is one of the following carboxyacyl groups:

a) a grouping of the formula r,

-O-C

i r32

H

i

-C-R

■ 34

r

33

0 II

-c-

(T),

in which

"T" is an alkyl group containing 1 to 4 carbon atoms, a bromine atom, a phenylalkyl group containing 7 to 10 carbon atoms or a nitro group and "e" has a value in the range 0 to 5 inclusive, provided that not more than 2 radicals “T” have other meanings than that of alkyl groups and that, moreover, the total number of carbon atoms in the radicals “T” is not more than 10 carbon atoms.

30th

b) a grouping of the formula

35

IQ

C00R

35

in which R35 is an alkyl group with 1 to 4 carbon atoms inclusive c) a grouping of the formula in which the substituents “T” and the symbol “e” have the same meaning as given above or d) a grouping of the formula o

II

- € -R36

in which

R36 is a hydrogen atom, an alkyl group with 1 to 19 carbon atoms or an aralkyl group with 7 to 12 carbon atoms, corresponding alkyl groups or aralkyl groups bearing 0-3 halogen atoms as substituents.

R25 is a protective group or blocking group, namely a tetrahydropyranyl radical, a tetrahydrofuranyl radical or a grouping of the formula in which R31 is an alkyl group having 1 to 18 carbon atoms inclusive, a cycloalkyl group having 3 to 10 carbon atoms inclusive, one Aralkyl group having 7 to 12 carbon atoms, a phenyl radical or 10 is a phenyl radical substituted by 1,2 or 3 alkyl groups having 1 to 4 carbon atoms, and in this grouping

R32 and R33 are identical to or different from one another and have the meaning of hydrogen atoms, 15 alkyl radicals with 1 to 4 carbon atoms, phenyl radicals or with 1,2 or 3 alkyl groups with 1 to 4 carbon atoms substituted phenyl radicals or

R32 and R33 together form a grouping of the formulas 20 - (ch2) a- or - (ch2) b-0- (CH2) c-, in which a) is 3, 4 or 5, b) 1, 2 or 3 and c) 1, 2 or 3, provided that the sum of b + c is 2, 3 or 4 and where,

25 R34 is a hydrogen atom or a phenyl radical, R26 means an alkali metal cation R27 stands for a hydrogen atom or a group of the formulas -OR24 or —CH2OR24, in which R24 is a car-boxyacyl group, as defined above.

R28 is a hydrogen atom or a methyl group, R29 means a straight-chain alkyl group with 3-7 carbon atoms,

R30 is an alkyl group with 1 to 4 carbon atoms,

R31, R32, R33 and R34 have the same meanings as explained above in connection with the definition of the remainder R25,

R35 and R36 have the same meaning as explained above in connection with the definition of the remainder R24 er-40,

R37 is an alkyl group with 1 to 4 carbon atoms,

R38 is a hydrocarbon residue with 1 to 18 inclusive carbon atoms,

45 SePh means a phenylselenidyl radical of the formula -Se-C6H5,

(T) e has the meaning of alkyl groups with 1 to 4 carbon atoms, phenylalkyl groups with 7 to 10 carbon atoms or nitro-50 groups, where e has a value from 0 to 5 inclusive and with the further proviso that not more than two radicals T have a meaning other than that of alkyl groups and that the total number of carbon atoms in the substituents T is not more than 10 carbon atoms.

THP is a tetrahydropyranyl residue,

X has the following meanings:

1. a grouping of the formula trans-CH = CH-

2. a grouping of the formula cis-CH = CH-

3. a grouping of the formula -C = C- or

4. A grouping of the formula -CH2CH2-Xj has the following meanings:

1. a grouping of the formula trans-CH = CH-

2. a grouping of the formula cis-CH = CH-

3. a grouping of the formula -CH2CH2- or

4. a grouping of the formula -CH = C (Hal) -,

in which shark the meaning of a chlorine atom, bromine

possesses atomic or iodine atom.

55

60

65

645369

16

e is a value in the range from 0 to 5 inclusive,

j is a value from 1 to 4 inclusive,

m is a value from 2 up to and including 5,

n is a value from 1 to 5 inclusive,

p means 2, 3 or 4,

q means 1, 2 or 3 and the symbol ~, i.e. the wavy line, indicates that the binding is in the eis or trans configuration (i.e. the alpha or beta configuration).

If the radical R13 in the compounds of the general formula given above is a methyl group, these compounds are 19-hydroxy-19-methyl compounds of the following formula 15

^ r ch3 c-ch3

15

In the compounds of formula 15, the structure with the designation again has the same meaning as was explained in connection with the compounds of formula 4.

The compounds of the formulas 4 and 15 include those of group I, as illustrated by the formula 5, which are PGI2 compounds, if M! In the formula 5! the meaning of a residue of the formula

(A,) - C = C

I.

and also PGI compounds, if in the formula 5 M! the meaning of a residue of the formula

H

4th

has and also

6-Hydroxy-PGI compounds, namely if in formula 5 M! a grouping of the formula ck2-

is.

As already mentioned, in the latter case the corresponding cyclic 6-hydroxy-PGI compounds are in equilibrium with the corresponding 6-oxopro-staglandin-analogue, i.e. the corresponding 6-oxo-PGF (a-compounds.

Group II compounds illustrated by Formula 6 include the 5,9-epoxy analogs of PGI 2 or PGI t. In this case too, if M i is a grouping of the formula, there is an equilibrium with the corresponding monocyclic compounds, that is to say the corresponding 6-oxoprostaglandin analogs. Regarding the background of the prior art, reference is made to the U.S. Pa-5 tent script no. 4 123 441.

Group III compounds illustrated by Formula 7 include the 6,9-epoxymethano-analogs of PGI2 or PGI ^. Regarding the background of the prior art, reference is made to U.S. Pat. Patent specification no. 4 124 599.

Group IV compounds illustrated by Formula 8 include 5-hydroxy-PGIrver compounds. Regarding the background of the prior art i5, reference is made to the U.S. Patent specification no. 4 110 532.

Group V compounds illustrated by Formula 9 include the 4-didehydro ("A4") PGIi compounds. Related to the background art, reference is made to U.S. Pat. Patent Specification No. 4,109,082.

Group VI compounds illustrated by Formula 10 include the 6-alkoxy-PGIr compounds.

25 Group VII compounds illustrated by Formula 11 include the 4-oxo-PGI] compounds. In connection with the background of the prior art, reference is made to U.S. Patent No. 4,126,744.

Group VIII compounds illustrated by Formula 12 include the A6-PGIrver compounds. Regarding the background of the state of the. Technology is to the U.S. Patent No. 4,128,713.

35 The Group IX compounds illustrated by Formula 13 include the A7-PGI compounds. Regarding the background of the prior art, reference is made to the U.S. Patent No. 4 151 351 pointed out.

Group X compounds illustrated by For-40 mei 14 include the 6a-carba-prosta-cyclin-analogs.

In addition, compounds of the invention are the 11-deoxy compounds when R2 is a hydrogen atom.

45 Other compounds according to the invention are the 11-deoxy-11-hydroxymethyl compounds, if R 2 is a hydroxymethyl group.

Further compounds according to the invention are acids, esters and salts, namely those compounds in which R [50 is a grouping of the formula -COOR3.

Further compounds according to the invention are C1-alcohols, that is to say the corresponding 2-decarboxy-2-hydroxy-methyl derivatives, if R is a group of the formula -CH2OH.

Further compounds according to the invention are the C-1-amines, that is to say the 2-decarboxy-2-aminomethyl derivatives, when R] is a group of the formula -CH2N (R7) (R8).

55

60

The compounds according to the invention include C-1-amides, if R 1 is a grouping of the formula ok

65

O

-C-N (RV) (R8)

is.

17th

645 369

The compounds according to the invention also include sulfonylamides, if R, a group of the formula o

II

Ri, OH

»/ R_

\ l I5

-C-NH-SO, -R

15

is.

Nm /

\

H

/

"c-

I.

r,

The compounds according to the invention also include io

C-1 tetrazole derivatives, if Ri is a grouping of the formula

/ "V

■ NH-N

N-N

is.

In those compounds of the formulas 4 and 15 in which Q is a grouping of the formula which is described for the S configuration with the hydroxyl group on the carbon atom 15 in a 15 β configuration. In this context, Patent specification no. 4 026 909 column 13.

A typical example of a compound of formula 4 is the compound of the following formula 228

(ch2) 3-cooch3

r *

OH

is that for those compounds in which the hydroxyl group on carbon atom 15 is attached to the side chain in the a configuration, the configuration on carbon atom 15 is identical to that of the naturally occurring prostaglandins, such as that of the PGE] , which is obtained from mammalian tissues.

The 15-epimeric compounds are illustrated by formulas 4 and 15 when Q is a grouping of the formula

228

30th

/H

x = cc

6h h ^ c- (ch2) 3-ch-ch3

\ f noh s

oh r4

oh and these connections are identified differently by using the prefix "15-Epi" or the prefix "15ß" or the prefix "15R" in the corresponding names. As is known to a person skilled in the art, the designations “R” and “S” depend on the substituents in the adjacent position. In this context, it is due to the publication of R.S. Cahn, in J. Chem. Ed. 41, 116 (1964).

The cis-13 prostaglandin derivatives are generally illustrated here with a lower side chain, which is sometimes referred to as follows:

and this compound is referred to here as «(19R, S) -19Hydroxy-35 PGI2-methyl ester». The full chemical name of this compound is (5Z, 9a, 1 lß, 13E, 15S, 19R, S) -6,9-Epoxy-ll, 15,19-trihydroxyprosta-5,13-dien-l-ol-acid- methyl ester. The above-mentioned compound having the formula 228 is a compound which falls under the group of the compounds of the formula 4, namely when the grouping with the designation PC falls under the group I, which is illustrated by the formula 5, if any Li is a grouping of the formula - (CH2) 3-,

45 Mi the following formula (0) -C = C; has I

Q is a grouping of the formula

[(CH2) 3-] H

50

h oh is

\

r <

X-C-C-II I q r6

being in this grouping

X is the group cis-CH = CH- and for the S configuration,

Q is the group of the formula

55

r4 is oh. This is said to be equivalent to the cowardly spelling

Ri represents the group of the formula -COOCH3,

R2 is a hydroxyl group,

R5 and R6 denote hydrogen atoms and X is the group of the formula trans-CH = CH-. The nomenclature of these compounds is in agreement with that of the prostacyline. For example, compounds which have a longer side chain are referred to as homo compounds and compounds which have a shorter side chain are referred to as nor compounds. The compounds according to the invention, which fall under the types 65 and 4 and 15, are very effective in causing biological reactions. For these reasons, the compounds in question are well suited as active pharmaceutical ingredients.

645 369

18th

Another object of the present invention is therefore a pharmaceutical preparation, which is characterized in that it is a compound of the formula as active ingredient

'-i 3

pc J-c-ch3

un contains, in which the symbols have the meanings given above.

A few of the biological effects of the compounds according to the invention are now listed:

The inhibition of aggregation of blood platelets, the inhibition of gastric secretion and the reduction of undesirable side effects in the gastrointestinal tract that occur when systemic administration of inhibitors of prostaglandin synthetase is carried out and also the fight against cramps (spasms) , the relief of breathing in asthmatic conditions and the removal of nasal congestion.

Because of these biological effects, the new compounds according to the invention are useful for investigating, preventing, combating or alleviating a large number of diseases and undesirable physiological conditions, namely in mammals, including humans, useful pets, farm animals and animals which are considered to be domestic animals of humans, animals kept in the zoo, animals kept in laboratories such as, for example, for the treatment of mice, rats, rabbits and monkeys.

The compounds according to the invention are useful wherever it is desired to inhibit the aggregation of blood platelets, that is to say the aggregation of the platelets, in order to reduce the adhesive properties of the platelets and to prevent the formation of blood clots, that is to say thrombi in mammals, including humans, To prevent rabbits and rats or to dissolve blood clots that have already formed. For example, the new compounds are well suited to treat a heart attack (myocardial infarction) or to prevent its occurrence, to prevent the formation of blood clots after a surgical operation, as well as pathological conditions such as arthrosclerosis, arteriosclerosis, and blood clotting errors due to a too high level Treat fat levels in the blood and other clinical conditions in which the underlying cause of the disease is caused by an imbalance in the fat balance or an excessively high level of fat in the blood. Other in vivo applications are, for example, the treatment of geriatric patients to prevent seizures of bloodlessness in the brain (cerebral ischaemia) and to carry out long-term prophylactic treatment after heart attacks and strokes. For these purposes, the compounds according to the invention are administered systemically, for example intravenously, subcutaneously or intramuscularly or in the form of sterile implants, if one wants to achieve a long-lasting effect. If prompt response is required, especially in an emergency situation, intravenous administration is preferable. Dosages ranging from about 0.01 to about 10 mg per kg of body weight per day are used, the exact dosage depending on the age, weight and condition of the human or animal patient and also on the frequency of administration and from the route of administration.

An in vitro application of the compounds according to the invention consists in adding them to whole blood, for example when storing whole blood which is to be used in heart-lung machines. In addition, whole blood containing these compounds can be circulated through organs and organs, for example hearts or kidneys, regardless of whether these organs are in the donor's body, whether they have already been removed from the body, or whether they are cons -ic four or be prepared for the transplant or whether they are already attached to the body of the recipient. Blockage or blocking of aggregated platelets is prevented by the presence of the compounds according to the invention. For this purpose, the compounds in question are gradually or in single or multiple portions added to the circulating blood or to the blood of the donor or donor animal or the organ or body part through which it flows, regardless of whether it is connected to a circulatory system or not , or are administered to the recipient or are added in two or all of these cases in a constant dosage, in an amount of about 0.001-1.0 Hg / ml. The compounds are also well suited for producing platelet-rich concentrates from blood used to treat platelet deficiency (thrombocytopenia) or used in chemotherapy.

The compounds according to the invention are also suitable for mitigating and controlling excessive gastric secretion in mammals, including humans and certain useful animals, such as, for example, dogs and pigs. Treatments of this type are carried out to prevent ulcers from forming in the gastrointestinal tract or to make them less likely to occur 35 and to accelerate healing of the ulcers that have already occurred in the gastrointestinal tract. For this purpose, the compounds in question are administered by injection or infusion intravenously, subcutaneously or intramuscularly, with the dose being in the range of about 40 from about 0.01 to about 10 mg per kg of body weight per day and the exact dosage depending on the age, the Weight and depends on the condition of the human or animal patient and also on the frequency of administration and the route of administration.

The compounds according to the invention are also suitable for alleviating undesirable influences in the gastrointestinal tract which are caused by the systemic administration of anti-inflammatory prostaglandin synthase inhibitors. For this purpose, the compounds of formula 4 or formula 15 and the anti-inflammatory prostaglandin synthease inhibitor are administered simultaneously. In this context, Patent no. 3,781,429 to Partridge et al. pointed out in which the administration of certain prostaglandins 55 of the series E and A is explained. The anti-inflammatory inhibitors for prostaglandin synthease, for example the products indomethacin, aspirin or phenylbutazone, are administered in any known manner to alleviate an inflammatory condition, for example in the ir-60 range of a usual dosage range and according to any of the known routes of administration for a systemic one Administration are suitable. Compounds of formula 4 or 15 are then administered together with the anti-inflammatory inhibitor for prostaglandin synthease, either by the same route of administration as this or by a different route of administration. The dosage range in which the compounds of formula 4 or 15 are used for such treatment

19 645 369

depends on a variety of factors to produce a medium, such as sodium chloride, sodium

finally the type of administration, the age of the patient citrate, citric acid and similar additives can

weight, gender and medical. When administered in the form of a self

Condition of the patient who is a mammal, e.g. a sprayable dosage unit of the active ingredient

Is human, and furthermore on the type and administration in aerosol form which is suitable for inhalation therapy,

the anti-inflammatory inhibitor for the pro, the composition can suspend the active ingredient

staglandin synthease administered to the mammal contained in an inert propellant such as egg

and finally the sensitivity of the respective Verner mixture of dichlorodifluoromethane and dichlorotetra-

Binding of formula 4 or 15 to be administered. fluorethane, together with a co-solvent such as

For example, not every human patient, such as ethanol, and together with olfactory agents,

treatment with an anti-inflammatory substance and stabilizers. Instead of using a co-solvent, the same adverse side effects in the measure can also be used as a dispersant, as for the beige intestinal tract, if he uses this anti-inflammatory sub-game oleyl alcohol. Appropriate means of applying the punch takes. These side effects on gastric aerosol inhalation therapy and the corresponding work

The intestinal tract often varies greatly in terms of its type. Procedures are described in detail in the U.S. Patent-

and also regarding their extent. It lies within the font no. 2,868,691.

Decision area of the treating doctor or animal. The compounds according to the invention are

Doctors determine that the administration of an inflamed, including humans, is also useful as an anti-inflammatory agent for the undesirable side effects of nasal congestion and they are used for this purpose in the gastrointestinal tract for a human or 20 purpose in a dose in the range from about 10 ng to about animal patients, and it is also in its 10 mg per ml in a pharmacologically acceptable liquid

Decision area, an effective amount of a compound carrier material or in the form of an aerosol spray, to prescribe the formula 4 or 15 in order to first alleviate these and these two types of formulation mentioned undesirable side effects and then both are intended for external use.

ultimately to eliminate essentially. 25th

The compounds of the invention are also also. The compounds of the invention are also useful in the treatment of asthma. They are suitable, for example, for combating diseases of the circulatory system or the peripheral mode, as a means of expanding the bronchial vessels in humans. The expression or as an inhibitor for mediators, such as "diseases of the peripheral vessels", as used here SRS-A and histamine, which is released by those cells, means diseases of any blood vessels that are set by an antigen -Antibody complex outside of those of the heart and diseases that have been activated. Accordingly, the invented lymphatic vessels, such as frostbite, diseases of the compounds according to the invention fight the occurrence of cramps. in which there is an empty blood in the vessels of the brain (spasms), and they make breathing easier in such conditions (ischemic cerebrovascular disease), arteriovenous finds, such as bronchial asthma, bronchitis, bronchiectasis, stone, ischemic leg ulcers, phlebitis, Inflammatory vein pneumonia and emphysema. For this zienz, gangren, hepatorenal syndrome, ductus arteriosus, purpose the compounds in question are administered in a variety not clogged blood emptiness of the blood vessels of the mesentery (non-lack of dosage forms, for example obstructive mesenteric ischemia), arteritis, lymphangitis orally in the form of Tablets, capsules or liquids, rec- and similar illnesses. These examples are given in the form of suppositories, parenteral, subcutaneous or intra- 40 for illustrative purposes only and are intended to be muscular, with intravenous administration in emergency counts being in no way preferred as a restriction on expression . They can also be understood by inhaling “diseases of the peripheral vessels”. The devices of the invention are used for tion in the form of aerosols or solutions for nebulizing treatment of these disease states or by blowing them in orally or parenterally in the form of compounds according to the invention via in-a powder. Dosages that are in the range of approximately 45 injections or infusions directly into a vein or artery - 0.01-5 mg per kg body weight - are administered 1-4 times a day. The dosages of such compounds are currently used, with the exact dose depending on the age, the range of 0.01-1.0% when administered by weight and condition of the patient and by the frequent fusions at an hourly rate or by speed and route of administration. For the above injections based on a daily dose, the specified uses can be called the compounds 50 1 ~ 4 times a day. Again, the exact dosage advantageously depends on other asthma treatment agents, on the age, weight and condition of the patient So anti-asthmatic agents are used, such as the frequency and the type of administration. Example sympathomimetic agents such as treatment is continued for 1-5 days whether isoproterenol, phenylephrine, ephedrine and the like, and probably 2 days of treatment are generally sufficient with xanthine derivatives such as theophylline and 55 by one lasting therapeutic effect to ge-aminophylline and also with corticosteroids, such as to ensure. In the event that systemic effects or play ACTH and Prednisolone. Side effects are observed, the dosage is changed

The compounds according to the invention are effectively reduced, namely below the threshold value at which such a systemic effects or side effects are established in human asthma patients through oral inhalation.

or administered by aerosol inhalation. To be delivered 60. The compounds according to the invention are enriched by oral inhalation using, accordingly, useful for treating diseases of the peripheral nebulizers or oxygen aerosolization vessels in the extremities of humans, it is common to use the compounds of the formula 4 or 15 as legs Have poor circulation in these extremities,

Part to use in a dilute solution, preferably - such treatment is necessary to wise the patient in concentrations of about a part of the medication- 65 from pain or residual pain to form about 100-200 parts by weight of and around the Initiate ulcer healing.

Complete solution. Completely common additives can be used with respect to a complete discussion of the type and to be used to stabilize these solutions or to achieve isotonic clinical manifestations of peripheral diseases

645 369

20th

Vessels in humans and methods that have been used to treat such disease states with prostaglandins are referred to the South African patent no. 74/0149, which is reproduced as a short presentation in Derwent Farmdoc No. 58400V. It should also be noted that Elliott et al. in Lancet, January 18, 1975, pages 140-142.

The compounds according to the invention are also suitable as antihypertensive agents, that is to say as agents with hypotensive activity for reducing the blood pressure in mammals, including humans. For this purpose, the compounds in question are given by intravenous infusion in an amount of about 0.01 - about 50 | xg per kg body weight per minute or in single or multiple doses of about 25-500 ng per kg body weight as a total dose for one day . The exact dosage for this purpose again depends on the age, the weight and the condition of the human or animal patient to be treated.

Various methods for preparing the compounds of formulas 4 and 15 will now be described.

For Group I type compounds corresponding to either Formula 4 or Formula 15, i.e. which are either 19-hydroxy compounds or 19-hydroxy-19-methyl compounds, a method can be used which is as follows Reaction scheme 1 is illustrated. In this reaction scheme, a compound of the formula 16 is converted in a process step a) into the compound of the formula 17 and this in process step b) into the compound of the formula 18.

Reaction scheme 1

• Ln ~ R-i

18th

Stage b

0H

16

17th

Stage a

15 In the procedure which is illustrated in reaction scheme 1, one starts from a PGF2a compound of the formula 16 and converts this starting compound in step a into the halogen compound of the formula 17. In process step b, the product of step a is subjected to a halo-20 release of hydrogen, preferably using a tertiary amine or a reagent selected from the group consisting of sodium or potassium peroxide, sodium or potassium carbonate, sodium or Potassium hydroxide, sodium or potassium benzoate, Na 25 trium or potassium acetate, sodium or potassium trifhior acetate, sodium or potassium bicarbonate, silver acetate and trialkylammonium peroxides of the following formula

30th

(r37) 4no2

includes in which

R37 is an alkyl group with 1 to 4 carbon atoms. atoms means. An enol ether is formed

Formula 18 and in a reaction stage c, the desired products are separated.

The conversion on carbon atom 1 and on carbon atom 2 into an ester group, an alcohol group, an amine group, an amide group, a 40 sulfonamide group or a tetrazolyl group, which has all possible meanings for the rest Rj represent is carried out by methods which are known in the art or which are described in more detail here. In the same way, conversions or substitutions for the 45 residues L4, Q, R2, R5, R6 and X are carried out according to methods which are described in the literature or which are explained in more detail here.

The reaction schemes shown here are intended to explain processes for the preparation of compounds according to the invention. Reaction schemes 1-21 essentially relate to the preparation of compounds which fall under groups I-X, as explained above and as is also explained in more detail in the examples below.

Reaction schemes 32-45 relate to the preparation 55 of intermediates or starting materials which are required to produce these compounds, and these processes are explained in more detail in the preparations below.

Those procedures that are not illustrated in the reaction schemes 60 are based on chemical procedures known to those skilled in the art. The individual steps of the reaction schemes are explained in detail below.

With reference to Reaction Schemes 1 to 1 to 45 finally, the following explanations are now given:

Examples of alkyl groups with 1 to 4 carbon atoms inclusive are the methyl radical, the ethyl radical, the

21st

645 369

Propyl residue, the butyl residue and isomeric forms of these residues.

Examples of alkyl groups with 1 to 7 carbon atoms inclusive are those which have already been mentioned for the alkyl radicals with 1 to 4 carbon atoms and additionally the pentyl radical, the hexyl radical, the heptyl radical and isomeric forms of these radicals.

Examples of alkyl groups with 1 to 19 carbon atoms inclusive are those which have been mentioned for the alkyl radicals with 1 to 7 carbon atoms and additionally the octyl radical, the nonyl radical, the decyl radical and the undecyl radical , the dodecyl residue, the tridecyl residue, the tetradecyl residue, the pentadecyl residue, the hexadecyl residue, the heptadecyl residue, the octadecyl residue, the nonadecyl residue and isomeric forms of these residues.

Examples of cycloalkyl radicals having 3 to 10 carbon atoms, including alkyl-substituted cycloalkyl radicals, are the following radicals:

Cyclopropyl,

2-methylcyclopropyl,

2,2-dimethylcyclopropyl,

2,3-diethylcyclopropyl,

2-butylcyclopropyl,

Cyclobutyl,

2-methylcyclobutyl,

3-propylcyclobutyl,

2,3,4-triethylcyclobutyl,

Cyclopentyl,

2,2-dimethylcyclopentyl,

2-pentylcyclopentyl,

3-tert-butylcyclopentyl,

Cyclohexyl,

4-tert-butylcyclohexyl,

3-isopropylcyclohexyl,

2,2-dimethylcyclohexyl,

Cycloheptyl,

Cyclooctyl,

Cyclononyl and cyclodecyl.

Examples of aralkyl radicals which have 7 to 12 carbon atoms inclusive are the following radicals:

Benzyl,

Phenethyl,

1-phenylethyl,

2-phenylpropyl,

4-phenylbutyl,

3-phenylbutyl,

2- (l-naphthylethyl) and 1 - (2-naphthylmethyl).

Examples of phenyl radicals which are substituted by 1,2 or 3 chlorine atoms or alkyl groups having 1 to 3 carbon atoms inclusive are the following radicals: p-chlorophenyl,

m-chlorophenyl,

o-chlorophenyl,

2,4-dichlorophenyl,

2,4,6-trichlorophenyl,

4-chloro-2-methylphenyl,

2,4-dichloro-3-methylphenyl,

(o-, m- or p-) tolyl,

p-ethylphenyl and

2,5-dimethylphenyl.

Examples of phenyl radicals which are substituted by hydroxycarbonyl groups or alkoxycarbonyl groups, the alkoxy groups in the last-mentioned groups having 1 to 4 carbon atoms inclusive, are the following radicals:

(o-, m- or p-) carboxyphenyl,

Methyl (o-, m- or p-) carboxyphenyl [or

(o-, m- or p-) carbomethoxyphenyl] and isopropyl (o-, m- or p-) carboxyphenyl [or

(o-, m- or p-) isopropoxycarboxyphenyl]

s Examples of hydrocarbon radicals with 1 to 18 carbon atoms inclusive are all the aforementioned examples of alkyl radicals with 1 to 18 carbon atoms inclusive or all the aforementioned examples for optionally alkyl-substituted cycloalkyl radicals with 3-10 carbon atoms and all the above examples of aralkyl radicals with 7 to 12 carbon atoms inclusive.

In order to achieve the optimal combination with regard to the specificity of the biological response of the activity and the duration of the activity, certain compounds which fall under the general formulas 4 and 15 are preferred.

For example, it is preferred if Q is a grouping of the formula

20th

r4 is oh, with particular preference given to those compounds in which R4 is a hydrogen atom or a methyl group.

However, if Q is for grouping the formula

30th

r4 'oh, then those compounds are preferred in which R4 is a methyl group.

35

Further preferred compounds which fall under the formulas 4 and 15 are those relating to the radical R (those in which the radical R [is a grouping of the formula -COOR3, in which grouping R3 either a hydrogen atom or an alkyl of those compounds in which R3 represents an alkyl group, those in which the alkyl group contains 1 to 4 carbon atoms are particularly preferred has, of which again the methyl group or the ethyl group is very particularly preferred.

Further preferred compounds of the 19-hydroxy compounds of the formulas 4 and 15 are those in which 50 the 19-hydroxy configuration is a radical “R”.

Because of their relative instability, enol ethers of the formulas 18, 39, 51 and 96 are preferably not stored for longer periods in the form of their free acids, in which R] is a group of the formula -COOH, but the storage of these compounds takes the form of their salts, their esters or other derivatives on the carbon atom 1.

Preparation of Group I compounds

The reaction scheme relates to Group 601 compounds as defined earlier in which

M [for a grouping of the formula

(a,) - c = c:

65

(left)

H

stands, that means connections of the PGI2 type.

According to reaction scheme 1 given above

645 369 22

are the starting materials used of formula 16 in which R37 is an alkyl group with 1 to 4 inclusive

Compounds of the PGF 2 a type, which means the 19-hydroxy carbon atoms.

have group with or without the 19-methyl group. In the tertiary amines, the following are particularly preferred in relation to compounds of the 19-hydroxy type, the PGF used in brackets in each case, for example, due to the publication by J.C. Sih, s abbreviation is given:

in Prostaglandin 13,831-835 (1977) and the Li, 5-diazabicyclo [4.3.0] nonen-5 (“DBN”) cited here,

referenced locations. The in this reaction scheme as 1,4-diazabicyclo [2.2.2] octane («DABCO»),

Starting material used compounds of formula 16, l, 5-diazabicyclo [5.4.0] undecen-5 ("DBU").

are not compounds according to the invention, but they are other preferred reagents for carrying out those which can be prepared by processes which are, in the preparations, elimination of the hydrogen halide being sodium or tert and also in the reaction schemes 32 to a potassium peroxide and tetramethylammonium peroxide. Loading

finally 45, which will be followed by more detailed information about the use of the genes. Peroxides mentioned on the publication by Johnson

According to Reaction Scheme 1, das and Nidy are mentioned in stage a in J. Org. Chem. 40, 1680 (1975).

Starting material of formula 16 a halogenation and 15 If the production takes place on a larger scale, it can be subjected to a cyclization, whereby the halogen is an electrochemical production of the peroxides, which also

receives bonds of formula 17. To perform this peroxides may be desirable. In

Various working methods are available during the process. This connection is based on the publication of gung. For the preparation of iodine compounds one can Dietz et al., In J. Chem. Soc. (B), 1970, pages 816-820 hinge-

Use an aqueous system that showed iodine, Kahum iodide and 20.

contains an alkali carbonate or bicarbonate, or an organic. The step in which the Halogenwasserstoffab-system, for example dichloromethane, which iodine is carried out in cleavage, is expediently in the presence of an alkali metal carbonate. The Renem inert organic medium, as for the reaction, is carried out at temperatures below 25 ° C., preferably dimethylformamide, and then a thin layer chromatography is carried out at temperatures in the range from 0-5 ° C., to find that performed during 10-20 hours. Then the starting material has disappeared. The reaction proceeds rapidly with sodium sulfite and sodium at 25 ° C and can be accelerated by adding carbonate and heating the compounds of formula 17 to 40-50 ° C.

separated from the reaction mixture. When working up the reaction mixture, it is advantageous

For the production of bromine compounds, N-3 "can adhere to basic conditions, for example by

Bromosuccinimide or N-bromoacetamide can be used. one uses triethylamine so that an acidic decomposition

It should be prevented in this connection to the book with the title or changes in the structure of the product

"Reagents for Organic Synthesis", Volume I, pages 74 and 78. will. Purification is achieved by recrystallizing

and Volume IV, page 51 of Fieser et al., Verlag John Wiley siert and accordingly a separation of contaminants

and Sons, Inc., N.Y. pointed out. 35 or unreacted raw material,

Various products are left in the mother liquor to produce the chlorine compounds. Methods are available, for example the exchange can also be carried out by column chromatography of a bromine atom with chlorine using the silver salt. With a chromatographic separation

Chlorodifluoroacetic acid. In this connection, it is a column made of magnesium silicate (the product with the brand

prefers the book “Compendium of Organic Synthetic Methods”, 40 “Florisil R”) and over

Page 346, 1971 from I.T. Harrison et al., Publisher Wiley Inter- chromatography on silica gel. A decomposition of science, N.Y. pointed out. Product is avoided by having a preliminary

The halogen compounds of formula 17 are carried out in the columns with triethylamine.

Form obtained from two isomers, one in smaller Group I 5E compounds in which M {a group

Quantity that the other has in larger quantities. The two positions of the formula isomers differ in their running speed on the chromatogram. Usually these isomes- H

ren cannot be separated from each other because each of the two (A i) -C = C ^

Isomers in process stage b of reaction scheme 1 '(Li)

delivers the desired products. 50

In stage b of reaction scheme 1, the compound is represented, are produced by replacing the compound of formula 17 with the corresponding enol ether compound of formula gene of formula 16 in reaction scheme 1

18 converted by using the compound of the formula 17 compounds of the 5,6-trans-PGF 2 type as starting material

with a reagent that releases hydrogen halide.

treated with a dehydrohalogenating agent. Reasss such ester groups, such as a p-phenylphe-

For example, genes are found in the book entitled “Renacyl group on the carboxyl group on carbon atom 1

agents for Organic Synthesis », page 1308 by Fieser and Fie- through the transformation of the reaction scheme 1

ser, John Wiley and Sons Publishing House, New York, N.Y. 1967 not changed if they wrote in the starting material of the formula. Preference is given to carrying out the reac- 16 and, accordingly, they also occur in step b, tertiary amines and reagents which contain 60 in the product of the formula 18. For end products selected from the following group of reagents: Formula 18, which are esters or amides, is preferred.

Sodium or potassium peroxide, sodium or potassium-made manufacturing processes, the one that is used by the halogen

bonat, sodium or potassium hydroxide, sodium or Ka compounds of formula 17, which already contains the

lium benzoate, sodium or potassium acetate, sodium or speaking esters or amides.

Potassium trifluoroacetate, sodium or potassium bicarbonate, Sil-65. Other conversions on carbon atom 1 are generally over either acetate or tetraalkylammonium peroxides of either the starting material or the

Intermediate or intermediates or on

(R37) 4N02 finished product by chemical processing

23

645 369

driving uses that are known to a person skilled in the art. For example, if a lower alkyl ester is available or is made according to Reaction Scheme 1 or Reaction Schemes 2 through 31 inclusive, then this ester can be readily converted to the corresponding acid by saponification. The acid is then used to prepare the various esters of formulas 4 and 15 which are within the definition of the R 3 group, using again methods known to those skilled in the art. For example, alkyl esters, cycloalkyl esters or aralkyl esters can be prepared by carrying out a reaction of the corresponding acids with a suitable diazo-substituted hydrocarbon. For example, the corresponding methyl esters can be prepared by carrying out a reaction with diazomethane. In the same way, by using diazoethane, diazobutane, l-diazo-2-ethylhexane, diazo-cyclohexane and phenyldiazomethane, for example a corresponding ethyl ester, butyl ester, 2-ethylhexyl ester, cyclohexyl ester or benzyl ester esters are produced. Of these esters, the methyl esters and ethyl esters are preferred.

Esterification with diazo hydrocarbons is carried out by mixing a solution of the diazo hydrocarbon in a suitable inert solvent, preferably diethyl ether, with an acidic reactant, preferably in the same or in another inert diluent. After the esterification reaction has ended, the solvent is removed by evaporation and, if desired, the ester is purified by customary methods, preferably by chromatography. It is preferred that the contact time between the acid reactants and the diazo hydrocarbon is no longer than the time required to produce the desired esterification. This is preferably the case after a period of about 1 to about 10 minutes. Longer contact times should therefore be avoided in order to prevent undesired changes in the molecule. The diazo hydrocarbons are described in the literature or can be prepared by methods which are explained in the literature. In this context, reference is made, for example, to the book “Organic Reactions”, published by John Wiley & Sons, New York, N.Y., Volume 8, pages 389-394 (1954).

Another method of esterifying the carboxyl groups of acidic compounds corresponding to formulas 4 or 15, or of esterifying intermediates, is to convert the free acid to the corresponding silver salt and then convert this silver salt with an appropriate alkyl iodide, Cycloalkyl iodide or substituted alkyl iodide. Examples of such useful iodides are the following:

Methyl iodide,

Ethyl iodide,

Butyl iodide,

Isobutyl iodide,

tert. Butyl iodide,

Cyclopropyl iodide,

Cyclopentyl iodide,

Benzyl iodide,

Phenethyl iodide and similar iodides.

The silver salts can be prepared by conventional methods, for example by dissolving the acid in cold dilute aqueous ammonia, evaporating the excess of the ammonia under reduced pressure and then adding a stoichiometric amount of silver nitrate.

The phenyl esters and the esters with substituted phenyl

Groups of the compounds of the formulas 4 and 15 or the corresponding intermediates are expediently prepared by silylating the acid in order to protect the hydroxy groups, for example by passing each group of the formula -OH through a radical of the formula -O- Si (CH3) 3 replaced. If this silylation is carried out, the carboxyl group of the formula -COOH can also be converted into the grouping of the formula -COO-Si (CH3) 3. A short treatment of the sily-lo herten compound with water, however, leads to the group of the formula -COO-Si (CH3) 3 being converted back again to form the carboxyl group of the formula -COOH. Working methods for carrying out this silylation are described in the literature and are available. Treatment with the silylated compound with oxalyl chloride then takes place, the acid chloride being obtained, which is then reacted with phenol or a suitably substituted phenol and the silylated phenyl ester or substituted phenyl ester is thus obtained. Then the silyl groups, for example the groupings of the formula -O-Si (CH3) 3, are converted back into the hydroxyl groups, ie the groups of the formula -OH, by carrying out a treatment with a dilute acid. Working methods for these conversions are described in the literature.

A preferred method for the preparation of substituted phenyl esters is that described in U.S. Patent specification no. 3,890,372, in which a mixed acid anhydride is reacted with a suitable phenol or naphthol. The mixed anhydride is prepared from the corresponding acid with isobutyl chloroformate (isobutyl chlorocarbonate) in the presence of a tertiary amine.

Phenacyl-type esters are prepared from the corresponding 35 acids using an appropriate phenacyl bromide, such as p-phenylphenacylbro-mid and operating in the presence of a tertiary amine. In this context, for example, the U.S. Patent specification no. 3 984 454 and the German Offenlegungs-40 Schrift-Nr. 2 535 693 and the short presentation in Derwent Farmdoc no. 16828X noted.

The reaction schemes 36 through 40 relate to the conversions at carbon atom 1, specifically with regard to these 19-hydroxy compounds of the formulas 4 and 15 45 and with regard to the corresponding intermediates.

If a 2-decarboxy-2-hydroxymethyl product is desired, that is, if the radical R] is a group of the formula -CH2OH, the corresponding acid or the corresponding lower alkyl ester is reduced by using 50 reagents from who are known to reduce the car bon acids to the corresponding primary alcohols. In this context, reference is made to Reaction Scheme 36 regarding the conversion of the compound of formula 177 to the compound of formula 178. Regarding the reducing agents that can be used, reference is made, for example, to US Pat. No. 4,028,419, regarding the use of lithium aluminum hydride or diisobutyl aluminum hydride. Examples of solvents that can be used are diethyl ether, tetrahydrofuran or dimethoxy-60 ether. The reaction can be carried out at a temperature in the range from -78 ° C to +100 ° C, although temperatures in the range from 0 ° C to 50 ° C are preferred. Other carbonyl groups present in the molecule are also reduced if they are not protected in a suitable manner, for example as oximes, as ketals or as similar carbonyl derivatives, which can easily be converted back into the corresponding carbonyls after the reduction has been carried out .

645369

24th

A 2-decarboxy-2-hydroxymeth-yl-PGE type compound can also be prepared by protecting or blocking alcohol groups on carbon atom 1, as illustrated in Reaction Scheme 36 using Formula 180. The hydroxyl group on the carbon atom 9 is then oxidized, the compound of the formula 181 of the reaction scheme 36 being formed, and finally the protective group, namely the grouping of the formula -Si (Rn) 3, is removed by hydrolysis. A preferred protecting group of the formula -Si (Ri7) 3 is the tert-butyldimethylsilyl group.

Compounds in which Rj is a grouping of formulas

O

II

-CH2-N (R7) (Rg) or -C-N (R7) (R8)

reacting sodium methoxide in methanol (methanolic sodium methoxide) with an equimolar amount of the corresponding sulfonylamide. Process step b) illustrated in reaction diagram 38 is favored by the addition of a small amount of hexamethylphosphoramide because this ensures the homogeneity of the reaction system.

Compounds in which the radical Rj is a grouping of the formula

10th

15.

-c

N-

can be conveniently prepared by starting with such products of formulas 4 or 15, or those intermediates that are acids, i.e. in which the radical Rj is a grouping of the formula COOH. With regard to the background of the prior art, reference is made in this connection to US Pat. No. 4,085,139. These compounds can easily be converted to a mixed anhydride by using an alkyl ester, an aralkyl ester, a phenyl ester or a substituted phenyl ester of chloroformic acid in the presence of a tertiary amine. A preferred reagent is the isobutyl chloroformate (isobutyl chlorocarbonate). The anhydride is then reacted with ammonia or a suitable amine of the formula (R7) (R8) NH, an amide being formed in which Rj is a grouping of the formula

O

II

-C-N (R7) (R8)

is. The corresponding 2-decarboxy-2-aminomethyl compound can be prepared from the amide by a carbonyl reduction by carrying out working processes which are described in the literature, for example carrying out a reduction with lithium aluminum hydride. In this connection, reference is made to reaction scheme 37.

Compounds in which R is a grouping of the formula

O

II

-C-NH-S02-R, 5

is, i.e. the corresponding N-sulfonylamides can be prepared from the compounds of the formula 16 in their acid form. Reaction steps 38 explain process steps by which those acids which have the formula 183 in the reaction scheme 38 are converted into the corresponding sulfonylamides of the formula 189. In process step a) of Reaction Scheme 38, the acid of Formula 183 is converted to the mixed acid anhydride of Formula 188 by reacting the acid with isobutyl chloroformate in the presence of a tertiary amine, such as in the presence of triethylamine. Other mixed acid anhydrides are also suitable. In process step b), the anhydride of formula 188 thus prepared is then reacted with the sodium derivative of a sulfonylamide, which has the following formula Na-NH-S02Ri5. This sodium salt of sulfonylamide can be prepared, for example, by either by the method illustrated in Reaction Scheme 39 or by the method shown in Reaction Scheme 40.

20 In reaction scheme 39, the lactone of formula 190 is used as the starting material, which can be prepared, for example, by reducing the compound of formula 170. If the Wittig reaction is used and a ylide is used which has been prepared from a phosphonium compound 25 of the formula 239, the compound of the formula 191 is obtained. In this connection, reference is made to US Pat. No. 3,928,391. If the protective group R25 is replaced in the compound of the formula 191, the product of the formula 192 is obtained. The 30 compounds of the formula 191 can be converted into the corresponding tetrazolyl compounds by the process described here or by the process described in the literature that come under Formula 4.

35 In Reaction Scheme 40, a process is explained in which an amide is gradually converted into a corresponding Nitrii and this is then converted into the tetrazolyl compound. The starting materials of formula 193 used in this reaction scheme 40 can be obtained by, for example, starting from an acid which is protected, preferably with a radical R25 on the carbon atom 11 and on the carbon atom 15, and this acid in the corresponding acid amide using the mixed acid anhydride and then protecting it with a silyl group on the carbon atom 9 4S.

In reaction step a) of reaction scheme 40, the nitrii of formula 194 is prepared by subjecting the acid amide of formula 193 to water elimination using a carbodiimide. In this context, reference should be made to the publication by C. Ressler et al., In J. Org. Chem. 26.3354 (1961). As a carbodiimide, for example, the N, N'-dicyclohexylcarbodiimide, abbreviated as DCC, can be used, this being used in pyridine at room temperature. 55 In process step b) of reaction scheme 40, the tetrazolyl group of the compound of formula 195 is prepared by subjecting the nitrii of formula 194 to reaction with sodium azide and ammonium chloride in a reaction medium, for example in dimethylformamide un-6o. In this context, reference is made to the book “Hete-rocyclic Compounds”, R.C. Elderfield, John Wiley and Sons Inc., N.Y., Vol. 8, pp. 11-12.

In steps c) and d) of the reaction scheme 40, the protective groups of the formulas -Si (R17) 3 and R25 are replaced, 65 by performing desilylation and mild acid hydrolysis in the usual way, firstly by the compound of the formula 196 and then receives the compound of formula 197. The compound of formula 196 is as

25th

645 369

Intermediate for the preparation of the tetrazolyl compounds, which fall under the formula 4, suitable.

The compounds of general formulas 4 and 15 include the salts, i.e. those compounds in which the radical R3 is a pharmaceutically acceptable cation. Examples of such pharmacologically acceptable salts which are suitable for the purposes stated above are those which are formed with pharmaceutically acceptable metal cations or with ammonium cations, amine cations or quaternary ammonium cations.

Particularly preferred metal cations are those which are derived from the alkali metals, for example the lithium salts, sodium salts and potassium salts, and also those which are derived from the alkaline earth metals, for example the magnesium salts and calcium salts. However, cations of other metals such as aluminum, zinc and iron can also be used for salt formation, and these salts are also the subject of the present invention.

Examples of pharmaceutically acceptable amine cations are those derived from primary, secondary or tertiary amines. The following may be mentioned as specific examples of suitable amines:

Methylamine,

Dimethylamine,

Trimethylamine,

Ethylamine,

Dibutylamine,

Triisopropylamine,

N-methylhexylamine,

Decylamine,

Dodecylamine,

Allylamine,

Crotylamine,

Cyclopentylamine,

Dicyclohexylamine,

Benzylamine,

Dibenzylamine,

a-phenylethylamine,

§-phenylethylamine,

Ethylenediamine,

Diethylene triamine,

as well as other, similar aliphatic amines, cycloaliphatic

Amines and araliphatic amines, up to a total of 18

Have carbon atoms. More examples of suitable ones

Amines are heterocyclic amines and specific examples include the following:

Piperidine,

Morpholine,

Pyrrolidine and

Piperazine.

Further examples include the lower alkyl derivatives of heterocyclic amines, such as the following amines:

1-methylpiperidine,

4-ethylmorpholine,

1-isopropylpyrrolidine,

2-methylpyrrolidine,

1,4-dimethylpiperazine,

2-methylpiperidine and similar compounds.

Further examples of amines which are suitable for salt formation are those which contain groups which make the compounds water-soluble or hydrophilic groups, such as the following amines: Monoethanolamine,

Diethanolamine,

Triethanolamine,

Ethyl diethanolamine,

N-butylethanolamine,

2-amino-1-butanol,

2-amino-2-ethyl-1,3-propanediol, 5 2-amino-2-methyl-l-propanol, tris (hydroxymethyl) aminomethane,

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

Galactamine,

io N-methylglycamine,

N-methylglucosamine,

Ephedrine,

Phenylephrine,

Epinephrine,

is procaine,

and similar amines.

Examples of suitable pharmaceutically acceptable quaternary ammonium cations are the tetramethylammonium ion, the tetraethylammonium ion, the benzyltrimethyl-20 ammonium ion, the phenyltriethylammonium ion and similar quaternary cations.

Salts containing pharmacologically acceptable cations can be prepared from end products of formulas 4 and 15 which are in the form of free acids, i.e. 25 from those compounds in which Rj is a grouping of the formula -COOH. The preparation from these acids can be carried out by carrying out a neutralization with a suitable amount of a corresponding inorganic base or organic base, the examples for the bases which can be used corresponding to the cations and amines indicated above. These conversions can be carried out by a variety of procedures described in the literature which are more generally used to prepare inorganic salts, i. Metal salts or ammonium salts, or of organic salts, such as acid addition salts with amines, or quaternary ammonium salts are suitable. The selection of the working process depends in part on the solubility properties of the respective salts that are to be produced.

If you want to produce inorganic salts, it is generally favorable to dissolve the corresponding acids of the formulas 4 and 15 in water which contains a stoichiometric amount of a hydroxide or a carbonate or a bicarbonate of the corresponding inorganic salt, the cation of which is introduced shall be. For example, the corresponding sodium salts can be prepared by using sodium hydroxide, sodium carbonate or sodium bicarbonate in a solution. If one then evaporates the water or adds a water-miscible solvent with moderate polarity, such as a lower alkanol or a lower ketone (lower alka-non), then the solid inorganic salt is obtained, if this is the desired form.

55 Amines and quaternary ammonium salts are produced using similar working methods, using suitable solvents.

Reaction Scheme 2 below explains a process for the preparation of compounds of group I in which the radical M] is a grouping of the formula

§

65

is.

These are PGI type connections. According to reaction scheme 2, starting materials

645369

26

Materials of the formula 16 are converted into corresponding mercury compounds of the formula 19, which are then subjected to reductive mercury elimination, the products of the formula 20 being obtained. With regard to the background of the prior art regarding this mercury introduction, i.e. the mercurization, and also regarding the cyclization and the mercury elimination, i.e. for the demerkurie-cyclization, reference is made, for example, to U.S. Patent No. 4,125,712 and the references cited in that patent, including the publication of H.C. Brown et al., In Organometal. Chem. Syn. 1.7 (1970).

Reaction scheme 2

Oh

16

J, level (a)

25th

19th

subject. Suitable reagents for carrying out this process step are sodium borohydride, sodium amalgam and hydrazine. Sodium borohydride in an alkaline solution, for example in aqueous sodium hydroxide, is very particularly preferred. The reaction is carried out in a solvent such as tetrahydrofuran at a temperature in the range of about 15-35 ° C. The mercury is then separated off and the product is isolated using the methods described here.

In a modification of the working procedure according to reaction scheme 2, the starting material consists of a 19,20-didehydro ("A19") PGF2a compound which is protected on the carbon atom 11 and on the carbon atom 15 with a tetrahydropyran-2yl group, which subsequently is abbreviated as THP. Treatment with the mercury-II acetate then leads to the formation of the corresponding mercury compounds. A further treatment with sodium borohydride leads to demerkuration and the formation of the corresponding 9-deoxy-6s, 9a-epoxy- (19R, S) -19-hydroxy -PGFr compounds in the form of their bis- (tetrahydro py-ran -2- yl ether) (abbreviated as bis (THP ether)). Elimination of these protective groups then gives the compounds of the formula 4. Reference is made to Example 2 in this connection.

Reaction Scheme 3 illustrates the process used to prepare those Group I A2 compounds in which Lj is a group of the formula -CH2-CH = CH-. These compounds have the formula 24. With regard to the background of the prior art in the production of A2 prostaglandin analogs, reference is made, for example, to US Pat. No. 4,024,174.

Reaction scheme 3

Level (b)

35

40

CH2-L ^ -Rt

H

l / CH2- (ch2) 3-c00r1O 0 ^

21st

50

In process step (a) of reaction scheme 2, the starting material is reacted with a suitable salt of the divalent55 mercury, i.e. a mercury II salt of the general formula Hg (G) 2, for example with mercuricide, mercuric chloride or mercuric acetate. Particularly preferred salts of divalent mercury are mercuric acetate and mercuric trifluoroacetate. The reagent is either dissolved in water or in acid, such as acetic acid, and then mixed with a solution of the starting material of the formula 16 in a suitable solvent, such as in chloroform or in tetrahydrofuran. The reaction is usually carried out at a temperature in the range 65 of 15-35 ° C.

In process step (b) of reaction scheme 2, the mercury-II compound undergoes reductive demerkuration

22

27th

645 369

£> level (b)

pu / \ _ ^> ~ vCOOR-io

Reaction scheme 4

h $ 12 5 o ^ -u-r,

'> H

15

25th

Level (a)

\ /

level ^ c)

26

In reaction step (a) of reaction scheme 3, selenylation is achieved by first preparing the 2-lithium derivatives of the compounds of formula 21, which are lower alkyl esters. This production of the 2-lithium derivatives can be carried out, for example, by carrying out a reaction with a lithium amide which has been prepared using a secondary amine, such as, for example, using N-isopropylcyclohexylamine. The compounds of the formula 22 are then prepared from these lithium derivatives of the compounds of the formula 21 by carrying out a reaction with diphenyldiselenide or benzene-selenyl bromide, using about 3 equivalents of these selenium compounds per mole equivalent of the lithium derivative on the carbon atom 2 and in one Temperature of about - 78 ° C works.

In process step (b), the A2 compounds of the formula 23 are formed by an oxidative cleavage of the selenium-containing radical of the compounds of the formula 22, for example by carrying out a reaction with hydrogen peroxide or sodium peiodate.

In process step (c), the end products of the formula 24 are then produced from the compounds of the formula 23, in which R] has the meanings given, by using processes which are described in the literature or are explained in more detail here.

In Reaction Scheme 4, another process for the preparation of PGIr-type compounds is explained, in which 5-halogen intermediates of Formula 25 are used as starting material, such as, for example, the compounds of Formula 17 of Reaction Scheme 1, or the A2 compounds of Formula 30 of reaction scheme 5.

3o In stage (a) of reaction scheme 4, the halogen compounds of the formula 25 are subjected to a reductive dehalogenation. Reagents which are suitable for carrying out this dehalogenation are, for example, tributyltin hydride, triphenyltin hydride, sodium borohydride in 35% ethanol or in dimethyl sulfoxide, and zinc in acetic acid. Of these reducing agents, preference is given to tributyltin hydride which is freshly prepared by reacting tributyltin chloride with lithium aluminum hydride. The reaction is allowed to proceed in a solvent, such as 40 in benzene, at a temperature of about 15-35 ° C, and the progress of the reaction to form the compounds of Formula 26 is followed by thin layer chromatography.

Reaction scheme 5 describes a process 45 according to which A2-5 halogen compounds of formula 30 can be prepared. According to this reaction scheme, a starting material of formula 27, which belongs to the compounds of formula 17 of reaction scheme 1, is used, and then process steps (a), (b) and so (c) are carried out by doing the same carries out chemical reactions, which were explained in connection with the preparation of the A2 compounds on the basis of reaction scheme 3.

55 Reaction scheme 5

h o a

27th

645 369

28

I level Y (a)

Reaction scheme 6 is used to explain the preparation of 6-hydroxy-PGIj compounds, namely compounds of group I in which Mj is a grouping of the formula

2-

25th

OH

r2

h2-l3-r1

9

& -

^ 13

OH

0 -II

^ c-ch2-l3-ri

Rn5

32

55

33

In this reaction scheme 6, in step (a), the compound of formula 25 is converted into an equilibrium mixture of a 6-hydroxy compound of formula 32 and 6-oxo compound of formula 33 by using the compound of formula 27 in contact with silver carbonate and perchloric acid. The reaction is allowed to proceed in an inert organic medium, such as tetrahydrofuran, and the progress of the reaction is monitored by thin layer chromatography to determine when the reaction is complete. In general, the reaction is completed in 15-24 hours at a reaction temperature of about 25 ° C. This reaction step (a) is preferably carried out in the absence of light.

Although the product of reaction step (a) of Reaction Scheme 6 usually contains both compounds of formula 55 with 32 and compounds of formula 33, further adjustment of the equilibrium can be achieved by simply dissolving the product in question in an organic solvent , such as

29

645 369

in acetone or in chloromethane, and this solution is left to stand for several days. The resulting mixture is then concentrated and separated, for example by chromatography on silica gel.

A further production process which leads to a mixture of 6-hydroxy compounds of the formula 32 and 6-oxo compounds of the formula 33 consists in treating the halogen compounds of the formula 25 in alcoholic solution with an alkali metal hydroxide, for example in methanolic solution with potassium hydroxide. This treatment is generally carried out at a temperature in the range of 0-30 ° C for several hours. After acidifying, a mixture of the acid form of the compounds of the formula 25 and the hemiketal of the formula 32 is obtained together with a certain amount of the 6-oxo compounds of the formula 33. This mixture can be separated, for example, by perform silica gel chromatography or fractional crystallization.

Based on the reaction scheme 7, only a preferred type of preparation for the amides of the 6-hydroxy compounds and the 6-oxo compounds is explained.

According to this reaction scheme 7, the corresponding amides of the formula 35 are prepared from the 5-halogen gene compounds of the formula 34 in reaction step (a). The same working processes which were explained in reaction scheme 6 are then carried out in order to produce the equilibrium mixture from the hydroxy compounds of the formula 36 and the oxo compounds of the formula 37 in process step (b).

Reaction scheme 7

H Rl2

: h-l3-cooh o o

"11, S, X

c-CH2-l3-c-n (rv) (r8)

for 5 Rl3

37

Preparation of Group II Compounds

Reaction Schemes 8-12 explain the preparation of Group II compounds defined earlier, i.e. the production of such PGI2 compounds and PGIj compounds which have an enlarged heterocyclic ring.

Reaction scheme 8 explains the preparation of Verbin-2o fertilizers of formula 40.

In step (a) of this reaction scheme 8, compounds of the formula 38 are subjected to a hydrogen halide elimination, the compounds of the formula 39 being obtained. The reagents used to carry out this hydrogen halide cleavage, ie the dehydrohalogenation, are the same as those used in reaction scheme 1 to carry out reaction step (b). The starting materials of formula 38 required in reaction scheme 8 are easily accessible, for example by carrying out the working procedures of reaction schemes 9 and 10 explained immediately below.

Step (b) of this reaction scheme 8 explains a reductive elimination of hydrogen halide from the compounds of the formula 38, the compounds of the formula 40 being obtained in this reaction step (b). To carry out reaction step (b), the same reagents and working conditions are used, which were explained in connection with reaction scheme 4. i40 reaction scheme 8

step

(a)

o; st ^ fe (b)

ch2-l3-ï-n (r7) (r8)

38

Level (a)

39

Level (b)

645 369

30th

Reaction scheme 10

ch2-l2-r1

uS

4010

Re ri:

OH

The preparation of the 4-halogen compounds of the formula 42 is explained on the basis of the reaction scheme 9, the A4-19-hydroxy-PGFia compounds of the formula 41 being used as the starting material. For the preparation of these compounds of formula 41, reference is made to reaction scheme 45.

Reaction scheme 9 25

OH \

Level ^ a)

35

40

50

55

In step (a) of reaction scheme 9, the same reagents for halogenation cyclization and also the same working conditions are used, which were explained above in connection with step (a) of reaction scheme 1.

60

Reaction scheme 10 is used to explain the preparation of A 2 compounds of the formula 46, reaction steps (a), (b) and (c) being carried out, which are based on the same chemical processes as those in connection with the reaction scheme 5 have been explained.

? "

H CH \ / ^ C00R1o

/

r2

43

R.

Qs

Rl3 0H

I level. . Yes)

44

Level V

(b)

45

step

(c)

46

31

645 369

Processes 11 and 12 are used to explain processes which lead to equilibrium mixtures which contain the 5-hydroxy compounds of the formula 47 and the 5-oxo compounds of the formula 48.

According to reaction scheme 11, the enol ethers of formula 39 of reaction scheme 8 are subjected to a mildly acidic treatment, for example by allowing a buffer with a pH of 2 to act at a temperature of about 25 ° C. for 30 minutes.

The same conditions are applied to the reaction scheme 12 as to the reaction scheme 6 explained further above, in that silver carbonate and perchloric acid are used again as the reactants.

Reaction Scheme is

48

-cha-la-ri

20th

39 Reaction scheme 12

Level (a)

30th

35

47

40

45

v

38

Level (a)

47

Preparation of Group III Compounds

Reaction Schemes 13-17 illustrate the preparation of Group III compounds as set out above, i.e. the preparation of compounds of the 9-deoxy-6,9a-epoxymethano-PGF type which have an enlarged heterocyclic ring.

48

Reaction scheme 13 explains the preparation of enol ether compounds of the formula 51.

In reaction step (a) of reaction scheme 13, the corresponding 5-halogeno-9-deoxy-6,9a-epoxymethano-PGF compounds of formula 50 are prepared from the starting materials of formula 49.

645369

32

In step (b) of this reaction scheme 13, hydrogen halide is then split off, i.e. a dehydrohalogenation step, the corresponding enol ether compounds of the formula 51 being obtained. The halogenation cyclization according to step (a) and the hydrogen halide splitting off according to step (b) are carried out according to the same working methods and using the same reagents that are described in connection with reaction scheme 1. The starting materials of Formula 49 required to carry out Reaction Scheme 13, i.e. the corresponding 9-deoxy-9-hydroxymethyl-PGF2a analogs can be prepared by the working process which is explained in reaction scheme 14.

Reaction scheme 13

The starting materials used in this reaction scheme 14 are compounds of the 19-hydroxy-PGE2 type, which have the formula 52. Some of these compounds have already been described in the literature, such as in the publication by J.C. Sih, in Prostaglandine 13, 831 (1977) and in the references cited in this publication. General working methods for production are given in the preparations below, and reference is made to reaction schemes io 35 and 41 in this regard. The compounds of formula 52 used as starting material in reaction scheme 14 are used in the form of lower alkyl esters, that is to say in the form of those compounds in which the Rio radical is an alkyl radical having 1 to 6 carbon atoms, inclusive.

çh2oh

49

20th

25th

Reaction scheme 14

0

Level (à)

v

30th

- ✓u-coorm

52

J, level (a)

50

40

45

^ l ^ -coor-, q Rs

53

Level (b)

50

V

Level (b)

51

55

60

«-COOR1 (

54

In reaction scheme 14, starting from the compounds of the formula 52, the compounds of the formula 49 are finally prepared in stages (a) to (f) inclusive.

f level (c)

33

645 369

Reaction Scheme 14 (continued)

4-COOR1o ds i (ri -7) 3

J / level (d)

ch20h

- ^ La-COOR-10

56

OSl (Riv) a

ch2oh \

Chemical Co., Rockford, Illinois (1968). The silylating agents necessary to carry out these conversions are described in the literature, or they can be prepared by the methods which are explained in the literature. In this context it is for example to the book entitled "Silicones and Other Organic Silicon Compounds" by Post, Reinhold Verlag, New York, N.Y. (1949). These reagents are used in the presence of a tertiary base, such as in the presence of pyridine, at temperatures ranging from about 0 ° C to about + 50 ° C. Examples of trisubstituted monochlorosilanes which are suitable for this purpose are the following compounds: chlorotrimethylsilane,

Chlorotriisobutylsilane,

tert-butyldimethylchlorosilane,

Chlorotriphenylsilane,

Chlorotris (p-chlorophenyl) silane,

Chlorotri-m-tolylsilane, and

20 tribenzylchlorosilane.

According to another embodiment of the silylation, a chlorosilane can be used together with the corresponding disilazane. Examples of other silylating agents are the following compounds:

Stage (s) 25 pentamethylsilylamine,

Pentaethylsilylamine,

N-trimethylsilyldiethylamine, 1,1, l-triethyl-N, N-dimethylsilylamine, N, N-diisopropyl-1,1,1-trimethylsilylamine, 30 1,1,1 -tributyl-N, N-dimethylsilylamine,

N, N-dibutyl-1,1,1-trimethylsilylamine,

1-isobutyl-N, N-1,1-tetramethylsilylamine,. N-benzyl-N-ethyl-1,1,1-trimethylsilylamine,

N, N, 1,1-tetramethyl-1-phenylsilylamine,

35 N, N-diethyl-1,1-dimethyl-1-phenylsilylamine, N, N-diethyl-1,1-dimethyl-1-phenylsilylamine, N, N-dibutyl-1,1,1 -triphenylsilylamine, and 1 - Methyl-N, N-1,1-tetraphenylsilylamine.

Although a large variety of silylating agents are available, it is preferred that the silyl group on the ring contains at least one sterically hindered group, such as one of the following groups: isopropyl,

sec-butyl,

45 tert-butyl,

Cyclohexyl, or phenyl.

The silyl groups with sterically hindering substituents are distinguished by the fact that they are less sensitive to hydrolysis than, for example, trimethylsilyl groups. Therefore, they are more resistant to cleavage or exchange during subsequent reaction steps, particularly during reaction step (d) of reaction scheme 14.

4955 Examples of preferred silyl groups for the cyclopentane ring are the following:

Isopropyldimethylsilyl,

sec-butyldimethylsilyl,

tert-butyldimethylsilyl,

60 triisopropylsilyl,

Cyclohexyldimethylsilyl, and in process step (a) of the reaction scheme 14 triphenylsilyl.

the compounds of Formula 52 to the compounds of In addition to the silylation processes described above

Formula 53 silylated by carrying out working methods, it is advantageous to silylie with a chlorosilane in which the silylation has already been described in the literature, 65 essence of an imidazole in a solvent, or which are explained in more detail here. Regarding the ren, an example of a usable solvent is silylation reaction, for example on the publication dimethylformamide. In this context, it is referred to by Pierce, in "Silylation of Organic Compounds", Pierce the publication by Corey et al., In J. Am. Chem. Soc.

Lit-COOR-, o

57

Stage (f)

ch20h

645369

34

io

94,6190 (1972). The temperature range for this reaction is generally from -10 ° C to + 80 ° C.

In reaction step (b) of reaction scheme 14, the 9-deoxy-9-methylene compounds of the formula 54 are prepared from the compounds of the formula 53 by carrying out the working processes described in the literature. In this connection, reference is made, for example, to U.S. Patent No. 3,950,363, in which the method of C.A. Johnson et al., Which is described in J. Am. Chem. Soc. 95,6462 (1973) is used. In this process, the carbanion of a sulfoximine of the following formula 229

c6h5

I. 15

0 = S = N-CH3 229

i ch3

formed, for example using an alkyl lithium or an alkyl magnesium halide compound, and 20 this is reacted with the compounds of formula 53 of reaction scheme 14, whereby a sulfonimidoyl adduct of the following formula 230

Reaction scheme 15 explains the preparation of A2-9-deoxy-6,9a-epoxymethano-5-halogen compounds, which are suitable as starting materials for carrying out reaction scheme 16.

Reaction scheme 15

^ 12 •

-CH - ^ \ ^^ C00R1o

58

25th

Li, -C00R-io

230 '

'Si (R17):

35

forms. After reductive cleavage, which is carried out, for example, with aluminum amalgam in the presence of acids, such as, for example, acetic acid or hydrochloric acid, the intermediates of the formula 54 of the reaction scheme 14 are generally free of any protective groups.

In process step (c) of reaction scheme 14, the compounds of formula 54 thus obtained are silylated again in order to replace all silyl groups which have been lost during the course of reaction step (b).

In reaction step (d) of Reaction Scheme 14, hydroboration oxidation is used to convert the 9-methylene group of the compound of formula 55 obtained in step (c) to a 9-hydroxymethyl group of formula (-CH2OH). With regard to the implementation of this reaction, reference is made in particular to US Pat. No. 3,950,363, specifically to columns 16 and 17 and 38.

40

50

55

In the reaction step (e) of reaction scheme 14 which is subsequently carried out, the silyl groups are replaced by hydrogen atoms, as is known to a person skilled in the art. This can be carried out, for example, by acidic hydrolysis in dilute acetic acid, or if the protective group contains a tertiary Butyl-dimethyl-silyl group is through the use of tetrabutylammonium fluoride. In this connection, reference is made to the publication by E. J. Corey et al., In J. Am. Chem. Soc. 94, 6190 (1972).

Finally, compounds of formula 49 are obtained in reaction step (f) of reaction scheme 14.

65

59

step

(b)

H R12

CH / ^^^ COORn,

CH2 \

60

I level V - (c)

61

35

645 369

In reaction scheme 15, the starting materials used are the compounds of the formula 58, which were obtained in reaction scheme 13 as compounds of the formula 50. In reaction scheme 15, the same working procedures s are carried out for carrying out steps (a), (b) and (c) and the same reagents are used as were explained above in connection with reaction scheme 5.

The reaction scheme 16 below explains the conversion of the 5-halogen compound of the formula 62 into a io compound of the PGIp type of the formula 63, a reductive dehalogenation being carried out for this purpose. Reaction scheme 16

/ 0 -TN .—- CH2-L3-R-

ÇH = \

/

Level (a)

63

Reaction scheme 17 explains the conversion of a 5-halogen compound of the formula 62 into the equilibrium mixture of the 6-hydroxy compound of the formula 64 and 15 of the 6-oxo compound of the formula 65. For this purpose, the same working procedures are carried out as were explained above in connection with reaction scheme 6.

62

20th

Reaction scheme 17

30th

/ o ch2

H

1

/

r2

r-12

l-l3-r1

62

l r "I3 oh

35

CH2-I_3-R <i

I.

c-ch2-l3-r-, ç5 r-i:

64

65

Preparation of Group IV compounds.

The preparation of Group IV compounds is illustrated in Reaction Schemes 18 and 19.

Reaction scheme 18 describes a process in which the corresponding 5-hydroxy-PGIr compounds of the formula 69 are prepared starting from compounds of the PGF2a type of the formula 31. In this connection, reference is made to US Pat. No. 4,110,532, in particular to columns 10-15.

Reaction scheme 18

60

65

31

645369

Reaction Scheme 18 (continued)

J, level (c)

Level (d)

H OH

36

In the reaction scheme 18 given above, in step (a) a mercury-acetylation is carried out on the compounds of the formula 31 by carrying out a reaction with mercury-II-acetate of the formula Hg (OAc) 2 and 5 the compounds containing mercury Formula 66. Solvents, such as, for example, tetrahydrofuran, are usually used for this reaction of reaction step (a), the reaction temperatures being at room temperature or below room temperature.

10th

In step (b) of the reaction scheme 18, the mercury compounds of the formula 67 are prepared from the mercury compounds of the formula 66 by replacing the acetate residue of the compounds 15 of the formula 66 bound to the mercury by a halogen atom. For this purpose, an aqueous solution of a sodium halide of the formula NaHal is generally used, for example a solution of sodium chloride or sodium bromide, and the reactants are simply stirred together until the reaction is complete, and this can be determined by means of thin layer chromatography will.

In step (c) of reaction scheme 18, the corresponding compounds of formula 68 are prepared from the compounds of formula 67 by reductive oxygenation. For this purpose, the compounds of formula 67 can be reacted with a reducing agent in the presence of molecular oxygen. Sodium borohydride, for example, can be used as the reducing agent.

Finally, in stage (d) of reaction scheme 18, the corresponding products of formula 69 are prepared from the lower alkyl esters of formula 68 by working. uses procedures that are described here or that are known from the literature.

3S In Reaction Scheme 19, those work steps are explained which are used to produce the corresponding A2-5-hydroxy compounds of the formula 73 starting from compounds of the formula 17.

40 In this reaction scheme 19, the starting material of the formula 70 is used, which is obtainable from the compound of the formula 69 of the reaction scheme 18. Reaction steps (a), (b) and (c) used in reaction scheme 19 are the same as reaction steps (a) to (c) 45 of reaction scheme 2.

68

Reaction scheme 19

OH

v / level (a)

37

645 369

Level (c)

play in dichloromethane, and one works in the presence of an acidic condensing agent, such as in the presence of p-toluenesulfonic acid or pyridine hydrochloride. The reagents used to introduce the protecting group are used in a slight excess, preferably in an amount which corresponds to 1.0 to 1.2 times the theoretical amount, and the reaction is carried out at a temperature which is at is about 20-50 ° C.

If the protecting group R25 is a grouping of the formula

10th

B-31-O-C (R32-CHR33R34

is as it is defined here, these groupings include, for example, the 1-ethoxyethyl group. The one

Suitable reagents for these groups are a vinyl ether, such as, for example, ethyl vinyl ether, isopropenyl methyl ether, isobutyl vinyl ether, or any vinyl ether of the formula

20 R3i-0-C (R32) = CR33R34

in which the remains

R3I, R32, R33 and R34 have the meanings given in the present description.

72 25 To introduce the above grouping, however, an unsaturated cyclic or heterocyclic compound, such as, for example, the 1-cyclohexen-1-yl-methyl ether of the formula, can be used instead of a vinyl ether

30th

35

CH30.

73 or the 5,6-dihydro-4-methoxy-2H-pyran of the formula

40

CH30

45

Preparation of Group V compounds

Reaction schemes 20 and 21 illustrate the preparation of compounds of the A4-PGI type. See U.S. Patent No. 4,109,082 and the publication by E.J. Corey et al. In J. Am. Chem. Soc. 99, 2006-2008 (1977).

Reaction Scheme 20 shows the steps that must be performed by protected PGF 2a-type compounds that have Formula 74 to produce Product 55 of Formula 77. The starting materials required to carry out these reactions are easily accessible. In this connection, reference is made, for example, to reaction scheme 35, where the preparation of compounds of the formula 171 is explained, and to reaction scheme 41, together with easily implementable modifications of these preparation processes.

In this context, it is due to the publication of C.B. Reese et al., In J. Am. Chem. Soc. 89.3366 (1967). The reaction conditions used in the reaction with such vinyl ethers and unsaturated compounds are similar to those discussed above for the reaction with the dihydropyran.

Reaction scheme 20

If the protective group R25 is a tetrahydropyranyl radical, that is to say a radical with the abbreviation THP, or if it is a tetrahydrofuranyl radical, then the corresponding reagent, for example 2,3-dihydropyran or 2,3-dihydrofuran, is used in an inert solvent, such as for

74

65

J stage (a)

645369

38

In step (c) of the reaction scheme 20 there is then an oxidizing elimination of selenium, that is an oxidative deselination, using hydrogen peroxide at a temperature of about 0 ° C. This reaction is also carried out in a solvent, for example in tetrahydrofuran, and the end products of the formula 77 are obtained.

75 In Reaction Scheme 21, those reaction steps are explained that are used to prepare À2, A4-PGIrVer-io compounds of the formula 81.

The starting material of formula 78 used in this reaction scheme 21 can be obtained from the process which is explained in reaction scheme 20. Steps (a), (b) and (c) used in reaction scheme 21 are the same as steps (a) to (c) explained in reaction scheme 3.

Reaction scheme 21

20th

76

25th

30th

35

77

40

45

In the course of the reaction steps used in Reaction Scheme 20, it is of course essential that the hydroxyl group on carbon atom 9 be present in the compounds of the formula 74 in free form, that is to say not protected.

In step (a) of reaction scheme 20, the starting materials of the formula 74 are reacted with phenylselenyl bromide, and the compounds of the formula 75 are obtained. This reaction is carried out in a solvent, for example in tetrahydrofuran, at a temperature of about -20 ° C. Presence of an equivalent amount of a base, such as calcium carbonate.

In step (b) of reaction scheme 20, the protective groups are cleaved from the compounds of the formula 75, and the compounds of the formula 76 are obtained in this way. The cleavage of the protective groups can be carried out, for example, by mild acid hydrolysis using dilute acetic acid or aqueous citric acid or aqueous Phosphoric acid can be carried out in a solvent suitable for all partners, for example tetrahydrofuran. Temperatures in the range of 30-50 ° C. are generally used to remove the protective groups.

50

55

60

65

78

Level (a)

SePh oor10

L

rl3

79

Level (b)

> /

80

Step. / (c)

39

645 369

81

Preparation of Group VI compounds.

The preparation of compounds of the 6-alkoxy-PGIr type is explained using reaction scheme 22.

The starting materials used in reaction scheme 22, namely the equilibrium mixture of the compounds of the formulas 82 and 83, can be obtained, for example, from reaction scheme 6.

In this reaction scheme 22, either the separate compounds of the formulas 82,

or 83 is used, or the equilibrium mixture of the compounds of the formulas 82 and 83 is used. This mixture is brought into contact with an alkanol of the formula RioH, for example with methanol, if the product of the formula 84 R10 contains a methyl group in s. The reaction takes place at a suitable rate at temperatures in the range from 20 to 30 ° C. However, the reaction can also be carried out at lower or higher temperatures up to a range of about 10 ° C.

In the other preparation process for the compounds of formula 84, which is illustrated in reaction scheme 22, the starting materials used are compounds of the PGI2 type which have the formula 18. 15 These are converted in step (b) into the desired end products of the formula 84. This process step is carried out by combining the starting materials of the formula 18 with a suitable alcohol of the formula RIOOH in the presence of an acid, for example in the presence of formic acid or acetic acid, or else in the presence of a Lewis acid such as, for example, boron trifluoride. etherate. The product of formula 84 forms easily at a reaction temperature in the range of 20-30 ° C.

Reaction scheme 22

^ 0h

CH2-L4-R1

82

^ 13

Oh

| level (a)

or-io

84

18th

645 369

40

Preparation of Group VII compounds

Reaction scheme 23 explains the preparation of compounds of the 4-keto-PGIr type. In this connection, reference is made to US Pat. No. 4,126,744, and in particular columns 15-18 of this US patent.

In step (a) of this reaction scheme 23, a lactol of formula 85, which is readily available, is converted into the intermediate of formula 86 by reacting the lactol with the anion of a suitable phosphonate ester, io the following formula 231

o o

II II

(R30O) 2P CH2-C-L ^ CH2OSi (R17) 3

231 is H-j -s. Regarding this implementation, please refer to the publication of W.S. Wadsworth and W.D. Emmons, in J. Am. Chem. Soc. 83, 1733-1738 (1961). The anion, which is easily formed by treating the phosphonate 20 of formula 231 with sodium hydride, reacts with the lactol of formula 65 at temperatures ranging from 0-25 ° C.

If in the compounds of the formula 86 X 'there is a grouping of the formula -CH-C (Hal) -, then the hydrogen halide elimination carried out in step (b) leads to the introduction of a carbon-carbon double bond between the carbon atoms 13 and 14. To carry out such a hydrogen halide removal, the compound of the formula 86 can be reacted, for example, with a base, such as, for example, with potassium tert-butoxide (potassium tert-butoxide).

Reaction scheme 23

Level Ca)

35

40

85

50

V

Level (b)

V

r CH2-C-L5-CH20Si (R17) 3

87

25th

Level (c)

W

II

ch2-c-l5-ch2oh

88

25th

V

Level (d)

0

• ch2-c-l5-cooh

89

CH2-c-L5-CH2OSÌ (ri 7) 3

25th

fio

86

65

Level (s)

90

41

645 369

In step (c) of reaction scheme 23, the compounds of formula 87 are subjected to a cleavage of the silicon-containing group, the compounds of formula 88 being obtained. This desilylation is carried out using selective hydrolysis, as described above in connection with Reaction Scheme 14.

In step (d) of reaction scheme 23, the compounds of formula 88 are then subjected to an oxidation, the hydroxymethyl group on carbon atom 2 being oxidized to the io carboxyl group. This oxidation can be carried out, for example, using the Jones reagent.

In step (e) of reaction scheme 23, the protective groups from the compounds of formula 89 are then split off in a conventional manner by mildly acidic hydrolysis, and the desired end product of formula 90 is thus obtained.

Level (c)

94

| Level (d)

CH2 ~ 1-4 ~ R21

Preparation of Group VIII compounds

Reaction scheme 24 describes those process steps which are used to prepare the compounds of the A6-PGIp type in question. In this connection, reference is made to U.S. Patent No. 4,128,713.

Reaction scheme 24

CH-Li »-Ri e

20th

25th

30th

95

Level (s)

91

35

40

—CH2-Lu-Rl

96

Level (a)

, CH-U-Ris

92

20th

Step (b) CH2-La-R-i8

In the reaction scheme 24, starting materials 45 of the formula 91 are used which are easily accessible. It is preferred that esters are used and not the starting materials of the PGI2 type in the form of the free acids.

so in step (a) of reaction scheme 24, the hydroxyl groups of the starting materials of formula 91 are protected with the aid of acyl groups. Aliphatic agents introducing a carboxyacyl group are well suited for carrying out this reaction and are described in the literature 55 or can be easily prepared by processes described in the literature. Examples of such acylating agents are carboxylic acid halides, preferably chlorides, bromides or fluorides, and furthermore carboxylic acid anhydrides.

6o The preferred acylating agent for carrying out reaction step (a) is an acid anhydride. Examples of acid anhydrides that can be used for this purpose are the following acid anhydrides: 93 acetic anhydride,

65 pripionic anhydride,

Butyric anhydride,

Pentanoic anhydride,

Nonanoic anhydride,

645 369

42

Tridecanoic acid anhydride,

Stearic acid anhydride,

Mono-, di- or trichloroacetic anhydride,

3-chloro-valeric anhydride,

3- (2-bromoethyl) -4,8-dimethylnonanoic acid anhydride,

Cyclopropane acetic anhydride,

3-cycloheptane propionic anhydride,

13-cyclopentane tridecanoic acid anhydride,

Phenylacetic acid anhydride,

2- or 3-phenylpropionic anhydride,

13-phenyltridecanoic acid anhydride, and

Phenoxyacetic anhydride.

In step (b) of Reaction Scheme 24, the 6-oxo intermediates of Formula 93 are obtained from the compounds of Formula 92 by performing hydrolysis under mildly acidic conditions, for example using dilute acetic acid in tetrahydrofuran.

In step (c), the compounds of the formula 94 are obtained by subjecting the compounds of the formula 93 to a renewed cyclization. To carry out this process step, the compounds of the formula 93 are heated to the reflux temperature in benzene or in a similar, essentially non-polar, aromatic solvent, the solvent having to have a boiling point above 50 ° C.

In step (d) of reaction scheme 24, the compounds of the formula 94 are subjected to a deprotection to give the compounds of the formula 95. This deprotection can be carried out, for example, by saponification with an alkali metal alcohol (alkali metal alkoxide). If the radical R18 has any ester groups, these are partially or completely saponified in step (d), and. the corresponding alkali metal salts are obtained.

In step (e) of reaction scheme 24, the products of formula 96 are prepared by methods that are described in the literature. For example, sodium salts can be converted to the esters using the method described by Mukaiyama in Chem. Letters 1975, 1045 and using N-methyl-2-bromopyridium-iodide.

Preparation of Group IX compounds

Reaction schemes 25, 26 and 27 describe the preparation of compounds of the A7-PGIr type and the preparation of intermediates in their production. In this connection, reference is made to US Pat. No. 5,151,351. The end products of formula 115 obtained in reaction scheme 27 can exist in the form of two isomers, namely the corresponding 6a compounds and the corresponding 6β compounds. Accordingly, the preparation of the 6β-intermediate products is explained in the reaction scheme 25 and the preparation of the corresponding 6a-intermediate products is explained in the reaction scheme 26.

According to reaction scheme 25, the starting material of formula 97, which is available here, is converted into the end product of formula 106 by a 9-step reaction.

Reaction scheme 25

10th

15

20th

25th

30th

35

40

55

A

Rl3

Ì

97

Level (a)

98

Level (b)

') —SePh

99

4 /

Level (c)

13

100

25th

Ni '

Level (d)

43

645 369

Reaction Scheme 25 (continued)

0

v

Level (d)

/ - "- f — SePh

25th

Level (s)

Stage (f)

l

Ri 1

0- ^ ÇÎch2) / —f- SePh n-l ^

25th

j ^ levelCh)

0- ^ XCH2) n-lv ^ -

Level (i)

: CH2) n-CH20H

lOl io

15

106

25th

In step (a) of reaction scheme 25, the free hydroxyl groups of the starting materials of formula 20 97 are protected, for example by introducing a tetrahy-dropyran-2-yl residue (THP).

In stage (b) of the reaction scheme 25, the

102 compounds of formula 98 converted to compounds of formula 25 99 by introducing the phenylselenyl group.

This phenylselenidylation is carried out according to working methods described in the literature. For example, the compounds of formula 98 can be treated with n-butyl lithium in hexane and diisopropylamine in tetrahydrofuran 30 and then reacted with phenylselenyl chloride.

In step (c) of reaction scheme 25, the residue containing selenium is cleaved from the compounds of formula 99 by oxidation, the compounds of formula 100 being obtained. This oxidative deselenylation is

103 35 carried out preferably with hydrogen peroxide.

In step (d) of Reaction Scheme 25, a phenylselenyl residue is introduced a second time. This second phenylselenidylation gives the compounds of the formula 101. For this purpose, the required reagent is prepared from di-40-phenyldiselenide in an alcoholic solution of a boron hydride reducing agent.

In step (e) of reaction scheme 25, the corresponding lactol of formula 102 is prepared from the compounds of formula 101. This process step is carried out in a customary manner, for example by carrying out a reduction with diisobutylaluminum hydride at a temperature of approximately -78 ° C.

In stage (f) of reaction scheme 25, the connection

104 formula 103 prepared by performing a Grignard 50 reaction with a Grignard reagent of formula 232

Hal-Mg-CH2- (CH2) n_1-CH = CH2

232

carries out. For this purpose, the reagent of formula 55 232 is added dropwise to a solution of the compound of formula 102 cooled to 0-5 ° C.

In step (g) of Reaction Scheme 25, the compound of Formula 103 is cyclized to give the compound of Formula 104. Cyclization is carried out with an aryl-6o sulfonyl halide, such as p-toluenesulfonyl chloride, or an alkyl sulfonyl halide in an amine base by-

105 Leadership

In step (h) of reaction scheme 25, the compounds of formula 104 are prepared from compounds of formula 104 by treatment with hydrogen peroxide, in the manner described in connection with step (c) of the reaction scheme 25 has already been explained.

i

645 369

44

io

20th

Finally, in step (i) of the reaction scheme 25, the corresponding hydroxymethyl compounds of the formula 106 are prepared from the compounds of the formula 105.

This reaction is carried out with the aid of hydroboration, for example by using 9-borbicyclo- [3.3. l] nonane used in an organic solvent at 0 ° C, and then a reaction with sodium hydroxide and hydrogen peroxide. In this context, reference should be made to the book “Reagents for Organic Synthesis” by Fieser et al., Volume 2, page 31, 1969, published by Wiley & Söhne, N.Y.

In reaction scheme 26, the compounds of formula 99 are used as starting material, which are obtained in process step (b) of reaction scheme 25. In reaction scheme 26, the 6a isomer 15, namely the compound of the formula 111, is then finally produced from this starting material 15.

In step (a) of the reaction scheme 26, the lactol of the formula 108 is prepared from the compounds of the formula 99 by customary processes which serve to reduce a lactone. This process step is carried out in the same manner as step (e) of reaction scheme 25.

In step (b) of reaction scheme 26, the same Grignard reaction is carried out as in step (f) of reaction scheme 25. The compound of formula 109 is obtained.

In step (c) of reaction scheme 26, the compound of formula 109 is cyclized to give the compound of formula 110. This cyclization is carried out according to the procedure described in Reaction Scheme 25.

In step (d) of reaction scheme 26, a two-step reaction actually takes place, namely an oxidative cleavage of the selenium-containing group, that is, an oxidative deselenylation, which leads to compounds with an A 7 unsaturation. The corresponding primary alcohol of the formula III is then obtained by the hydroboration. These steps are carried out in the same manner as described in process steps (h) and (i) of reaction scheme 25.

Reaction scheme 26

OH Se Ph

\ \ m

J ^ level (b)

(CH2) n-1

109

\ K

Level (c)

^ (CH2) n-l ^

35

110

about 25

'Level (d)

Iii

40

50

99

In Reaction Scheme 27, either the compound of Formula 106 of Reaction Scheme 25 or the compound of Formula 111 of Reaction Scheme 26 is used as the starting material, and these two compounds are illustrated in Reaction Scheme 27 by Formula 112. According to reaction scheme 27, the product of formula 115 is obtained from these compounds of formula 112 by a three-stage reaction.

In step (a) of reaction scheme 27, the protective groups are cleaved off from the compounds of the formula 112 by mild acid hydrolysis, and the compounds of the formula 113 are thus obtained.

) R25

j ^ level (a)

In step (b) of Reaction Scheme 27, the primary alcohol grouping of the compounds of Formula 113 is oxidized to the 55 carboxyl group using an Adams catalyst. In this context, reference should be made to the book “Reagents for Organic Synthesis” by Fieser and Fieser, Volume 1, page 890, published by John Wiley u. Sons, N.Y. (1967).

60

In step (c) of reaction scheme 27, the carboxylic acid of the formula 114 is finally converted into further derivatives by customary working processes, so that the compounds obtained which fall under the formula 115 are obtained. The steric configuration at carbon atom 16 is not changed in the reactions which are carried out in order to convert the compounds of the formula 112 into the compounds of the formula 115.

45

645 369

Reaction scheme 27

CH2- (CH2) n-CH2OH

112

25th

V

Stuferà)

Preparation of Group X Compounds The following reaction schemes 28 through 31 include the preparation of 6a-carba-PGI2 compounds and intermediates in their preparation.

5 Reaction Scheme 28 shows the process steps that have to be carried out in order to produce the various intermediates of the formulas 118, 119, 120 and 121 starting from the aldehyde of the formula 116, which is the end product of the reaction scheme 29. These compounds differ when using the prostaglandin numbering system at the latent C13-C14 position in accordance with the definition of X.

In step (a) of reaction scheme 28, a Wittig reaction is carried out using a ylide which is different from a phosphonate of formula 233

O

II

O R,

R

13

50

11555

645 369

Reaction Scheme 28 (continued)

46

.OR2U

0R2t *

OR25

Level (s)

117

118

119

120

121

47 645 369

In step (b) of reaction scheme 28, the reaction of sodium dimethylsulfinyl carbanide, which as

3'-oxo group of the compound of formula 177 reduced, and "dimsyl" is abbreviated, with trimethylsulfonium iodide all free hydroxyl groups are carried out with protective groups R25. The sodium dimethylsulfmylcarba is protected, the compounds of the formula 118 not being prepared from dimethyl sulfoxide and sodium hydride,

receives. s in stage (a) of reaction scheme 29 is

In step (c) of reaction scheme 28, from the settlement of the ketone of the formula 122 with dimethylsulfonium compounds of the formula 117, the compounds of the formula methylid-ylide and the epoxymethano compound of the formula 123 119 are prepared by obtaining a photoisomerization. This reaction is carried out at a temperature through which the latent CI3-C14 double bond is carried out at 0 ° C., and after 1 hour it is completely isomerized to the cis form in the trans form. It ran into this.

In this context, reference is made, for example, to that in process step (b) of reaction scheme 29

which is described in U.S. Patent No. 4,026,909. the Cyclopentanone Structure of the Compound of Formula To carry out this reaction step (c), compound 124 is formed by irradiating a modification of the working dilution of formula 117, preferably with a sol-driving method developed by M.L. Leriverend et al. in C.R. Chen photon-providing radiation source, the photon is Acad. Sc. Paris, series C, 280, 791 (1975). Delivers at a wavelength of approximately 3500 angstroms. This process is continued by radiation from process step (a) until an equilibrium mixture of the formula 123 with lithium iodide is obtained in egg from the cis isomers and trans isomers. The solvent treated, such as in Tetrahy's progression of this conversion, can conveniently be drofuran, operating at room temperature. It should be observed with the aid of thin-layer chromatography 20 that the compound of formula 124 contains the. The mixture is then separated according to customary procedures, the position of the carbonyl group on the ring as carbonyls, for example by identifying a silica gel chromatogram on the carbon atom 8, and this is done tography. The 3'-oxogrup for the present compound of the formula 124 of the pen are then replaced by a group Qt in the manner described above and for the other tricyclic structures of the For-, and the hydroxyl groups are again with group 25 125 up to and including 129.

pen R25 protected.

Reaction scheme 29

In process step (d) of reaction scheme 28, the compounds of formula 120 are prepared in which there is a triple bond between latent carbon atoms 30, 13 and 14. The general procedure is the same as that described in U.S. Patent No.

4,029,681. At this stage of the reaction a.

Monohalogen compound prepared by halogenation of the compounds of formula 117, and then 35 then a hydrogen halide is split off (ie a dehydrohalogenation) and a dehalogenation. The halogenation is conveniently carried out using a reagent such as N-bromosuccinimide,

or, according to another embodiment, a solution of 40 bromine in carbon tetrachloride. Hydrogen halide removal is accomplished by adding a base, such as pyridine, or using sodium acetate in methanol.

The dehalogenation is also carried out using the usual reagents, for example using 45 zinc and acetic acid. The compounds of formula 120 are then obtained.

In step (e) of Reaction Scheme 28, the compounds of formula 118 are catalytically reduced, for example by using hydrogen at atmospheric pressure using a palladium-on-carbon catalyst. The compounds of the formula 121 are thus obtained from the compounds of the formula 118.

The starting material of reaction scheme 28, i.e. the aldehyde of Formula 116 is prepared from the starting material of Formula 122 by performing the process steps outlined in Reaction Scheme 29.

In reaction scheme 29, a tricyclic acetal ketone is used as the starting material of formula 122.

This connection is described in the literature. In this context, reference is made, for example, to US Pat. No. 3,873,571. The corresponding endo compound, which is referred to as 3- (5,5-dimethyl-1,3-dioxolan-2-yl) tricyclo [4,2,0,02,4] octan-7-one, is particularly useful . Epoxidation is accomplished using the method described by E.J. Corey et al., In J. Am. Chem.

Soc. 87.1353 (1965). For this purpose, dimethylsulfonium methylide is produced by using a

0 //

, c ^ CH2; /

CH;

^ 0

.P /

Ç-ch2 '/

CH

0-CH2

/ ^ c

/ CH3

n> o-ch2 / vch3

Level (a)

\

Level (c)

122

123

124

645369

Reaction Scheme 29 (continued)

48

.0-ch2 ^ / ch3 C ^ 0-CH2 / C ^ CH3

Level (d)

^ r

0-R

2 «

cho

^ Level (s)

ch = ch-r29

Stage (f)

u r \

ch = ch-r29

I level (g)

ch ch-r29

s oh oh

I.

Level (h)

125

15

126

25th

30th

127

35

128

Level (i)

29

50

55

60

129

65

| Level (j)

tuf e (k)

Step 1 )

Level ^ m)

49

645 369

In the reaction step (c) of the reaction scheme 29, two closely related steps are carried out. The compound of the formula 124 is first reduced to the corresponding 8-hydroxy compound, for example by using a metal borohydride, in particular sodium borohydride or the corresponding potassium, lithium or zinc compound. Other well-suited reducing agents are lithium (tri-tert-butoxy) aluminum hydride, diisobutylaluminum hydride and various borohydrides such as sodium tri-methoxy borohydride. The 8-hydroxy compounds thus obtained, which are intended to illustrate both epimers, namely the a-epimer and the β-epimer, do not have to be separated. This mixture is then acylated to introduce the protective group R24. This is a carboxyacyl protective group, and the compounds of the formula 125 are thus obtained.

Examples of carboxyacyl protective groups R24 are aromatic carboxyacyl groups, such as, for example, a benzoyl radical, a substituted benzoyl radical, a monoesterified phtahloyl radical, a naphthoyl radical or a substituted naphthoyl radical. The carboxyacyl protective groups R24 can also be aliphatic groups, for example an acetyl radical or a pivaloyl radical. Working procedures described in the literature are used to introduce these protective groups.

Accordingly, an aromatic acid of the formula R24OH, in which R24 is an aromatic group, as explained above in connection with the definition of the radical R24, can be reacted with the 8-hydroxy compound in the presence of a water-releasing agent, for example in the presence of sulfuric acid, zinc chloride or phosphoryl chloride. An example of an aromatic acid that can be used for this purpose is benzoic acid. It is also possible to use an aromatic acid anhydride having the following formula (R24) 20 for the reaction, for example benzoic acid anhydride.

Examples of reagents which provide the radical R24 for carrying out the processes according to the invention are the following radicals, which are used as corresponding radicals in the acids of the formula (R24OH), in the acid anhydrides of the formula ((R24) 20) or in the acid chlorides of the formula (R24C1) can occur:

Benzoyl, substituted benzoyl radicals, such as the following radicals:

(2-, 3-, or 4-) methylbenzoyl,

(2-, 3-, or 4-) ethylbenzoyl,

(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,

a-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,

simply esterified phthaloyl, for example the rest of the formula:

simply esterified isophthaloyl, such as the rest of the formula:

20 simply esterified terephthaloyl, such as the rest of the formula:

25th

C4H9

(1- or 2-) naphthoyl, and 30 substituted naphthoyl, such as the following radicals:

(2-, 3-, 4-, 5-, 6-, or 7-) methyl-l-naphthoyl,

(2- or 4-) ethyl-1-naphthoyl,

2-isopropyl-l-naphthoyl,

35 4,5-dimethyl-l-naphthoyl, 6-isopropyl-4-methyl-l-naphthoyl,

8-benzyl-1-naphthoyl,

(3-, 4-, 5-, or 8-) nitro-l-naphthoyl,

4,5-dinitro-1-naphthoyl,

40 (3-, 4-, 6-, 7- or 8-) methyl-l-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 8-) nitro-2-naphthoyl.

Examples of aromatic acid anhydrides which are suitable for this purpose are the following: 45 benzoic anhydride,

(o, m, or p) -bromobenzoic acid anhydride, 2,4- (or 3,4) -dichlorobenzoic acid anhydride, p-trifluoromethylbenzoic acid anhydride, 2-chloro-3-nitrobenzoic acid anhydride,

50 (o, m, or p) -nitrobenzoic anhydride,

(o, m, or p) toluic acid anhydride, 4-methyl-3-nitrobenzoic acid anhydride,

4-octylbenzoic acid anhydride,

(2,3, or 4) -biphenylcarboxylic acid anhydride, 55 3-chloro-4-biphenylcarboxylic acid anhydride,

5-isopropyl-6-nitro-3-biphenylcarboxylic acid anhydride and (1 or 2) -naphthoic acid anhydride.

However, an aromatic halide of acid, such as benzoyl chloride, is preferably reacted with the 8-hydroxy compound in the presence of a tertiary amine such as pyridine or triethylamine or similar amines. The reaction can be carried out under various conditions using procedures known to those skilled in the art. Generally mild conditions are used

645 369

50

such as temperatures in the range of 20-60 ° C, and the reactants are contacted in a liquid medium, for example in an excess of pyridine or in an inert solvent such as benzene, toluene or chloroform. The acylating agent is either used in stoichiometric amounts or an excess of the acylating agent is used. Accordingly, examples of acid halides which can be used are benzoyl chloride, 4-nitro-benzoyl chloride, 3,5-dinitrobenzoyl chloride and similar acid chlorides, i.e. Acid chlorides which have the following formula R24CI, in which R24 is one of the groups defined above. If the acid chloride is not available, then it can easily be prepared from the corresponding acid and phosphorus pentachloride, as is known in the art.

The use of aliphatic carboxyacylating agents, such as acetic anhydride, was discussed in detail above in connection with Reaction Scheme 24.

In step (d) of reaction scheme 29, the aldehyde of formula 126 is obtained from the acetal of formula 125 by hydrolysis. To carry out this hydrolysis of the acetal, an acid such as aqueous formic acid is used at a temperature of about 0 ° C.

In reaction step (e) of Reaction Scheme 29, the Wittig reaction is used to introduce the side chain in question that carries the R29 residue. With regard to general information on the Wittig reaction, reference is made, for example, to the book “Ylid Chemistry” by A.W. Johnson, Aca-demic Press, N.Y., 1966.

If the R2g radical is an n-pentyl radical, the corresponding ylide is prepared from the n-hexyltriphenylphosphonium bromide. Since the R29 radical later disappears when the aldehyde of the formula 116 is prepared, it is preferred that the R29 radical is a pentyl radical or even a shorter alkyl radical. Examples of corresponding alkyl radicals are those which have 3 to 7 carbon atoms. The ylides are conveniently made using n-butyl lithium.

After the Wittig reaction, the acyl protective group, that is to say the radical R24, is split off again, giving the compounds of the formula 127. This removal of the acyl group can be carried out in the same manner as process step (d) of reaction scheme 24, i.e. a base in a medium for hydrolysis is well suited for this purpose.

In process step (f) of reaction scheme 29, the 8-oxo compound of formula 128 is produced from the compound of formula 127 by oxidation. The Jones reagent is well suited for carrying out this oxidation. In this connection, reference is made to the publication in J. Chem. Soc., Page 39 (1946). Another well-suited reagent for performing this oxidation is the Collins reagent, such as chromium trioxide in pyridine. In this context, it should be noted that J.C. Collins et al., In "Tetrahedron Lett.", 3363 (1968).

Dichloromethane is a suitable diluent for this purpose. Reaction temperatures below 30 ° C should be used. The preferred reaction temperatures are in the range from 0 ° to + 30 ° C. The oxidation takes place rapidly and is usually complete after about 5 to 20 minutes.

In process step (g) of reaction scheme 29, the alkene of formula 128 is hydroxylated, giving the glycol of formula 129. Osmium tetroxide is a suitable reagent for carrying out this reaction, for example in conjunction with the N-methylmorpholine oxide dihydrate complex. In this context, reference is made to the book “Reagents for Organic Synthesis” by Fieser et al., 5 Volume 1, page 690, published by John Wiley & Sons Inc., New York (1967).

Various methods are available for carrying out process step (h) of reaction scheme 29 in order to produce the intermediate product of formula 130 from the glycol of formula 129. In one method, the glycol is converted to a bis (alkanesulfonic acid) ester, and then this is hydrolyzed to form the compound of Formula 130 using the procedures described in the literature. In this connection, reference may be made, for example, to German Offenlegungsschrift 1 937 676 and the corresponding abstract in Derwent Framdoc 6862R, and also to U.S. Patent 3,843,712 carried out by formolysis of the glycol. In this connection, reference is made to US Pat. No. 3,873,571.

A preferred method is carried out with the help of a Cychian orthoester. For this purpose the glycol 25 of formula 129 is used with an orthoester of formula 234

R4-C

OCH3 OCH3 OCH3

234

implemented. This forms the cyclic orthoester of formula 235

235

CH- £ H-R29 0 0

45 \ /

c / \

Ru OCH3

This reaction proceeds smoothly in a temperature range which is between -50.degree. C. and +100.degree. C., a temperature in the range from 0.degree. C. to + 50.degree. C. being generally preferred for reasons of convenience. The 1.5 to 10 molar equivalents of the orthoester are used together with an acid catalyst. The amount of catalyst used is usually only a small fraction of the weight of the glycol reacted, for example 1% by weight, based on the weight of the Gly-60 kol. Examples of typical acidic catalysts are pyridine hydrochloride, formic acid, hydrogen chloride, p-toluenesulfonic acid, trichloroacetic acid or trifluoroacetic acid. The reaction is preferably carried out in a solvent, such as, for example, in benzene, dichloromethane, 65 ethyl acetate or diethyl ether. The reaction is generally complete in a few minutes and is usually checked by thin layer chromatography on basic silica gel plates.

51

645 369

The ortho-ester reagents required to carry out this reaction are either described in the literature, or they can easily be prepared by the working methods described in the literature. In this context, for example, the publication of S.M. McElvain et al., In J. Am. Chem. Soc. 64, 1925 (1942), according to which an appropriate nitrii is used as the starting product for the preparation of the orthoesters.

The following compounds are examples of usable orthoesters:

Trimethyl ortho-formate, trimethyl ortho-acetic acid, trimethyl ortho-propionate, trimethyl ortho-butyrate.

The cyclic orthoester of formula 235 is then reacted with anhydrous formic acid, giving a diol ester of formula 236

however, it takes up to several hours if, for example, the R30 radical is an ethyl radical.

The bicyclic compounds of the formulas 130 to 134 s and also the compounds of the formula 116 are referred to as pentalenes. For example, the compound of formula 130 can be referred to as a 4-substituted 5-hydroxypentalen-2-one.

In reaction step (i) of reaction scheme 29, the compound of formula 130 which has a hydroxyl group on the carbon atom 5 is optionally converted into the corresponding deoxy compound, i.e. the C-5 deoxy compound, by using a mesylation and a mesylate reduction as will be explained in more detail later in connection with reaction scheme 30.

In step (j) of Reaction Scheme 29, residues R5 and Q5 are protected by introducing silyl protecting groups, and the compounds of the formula 132 are thus obtained.

receives.

The expression "anhydrous formic acid" means that it contains no more than 0.5% water. The reaction is carried out with an excess of formic acid, which can itself serve as a solvent for the reaction. Other solvents may also be present, such as dichloromethane, benzene or diethyl ether, which are usually present in an amount which is not more than 20% by volume, based on the volume of the formic acid. Organic acid anhydrides, such as acetic anhydride or alkyl orthoesters, such as trimethyl orthoformate, may also be present, and these agents act as drying agents for formic acid. Although the reaction proceeds over very wide temperature ranges, it is usually carried out at a temperature which is about 20-30 ° C., and the reaction is usually complete in about 10 minutes.

The diol diester of formula 236 is then converted into the intermediate product of formula 130 by using the working methods described in the literature, for example hydrolysis in the presence of a base in an alcoholic medium. Examples of suitable bases are sodium carbonate, potassium carbonate, sodium or potassium alcoholates, alkoxides, such as the corresponding methanolates (methoxides) or ethanolates (ethoxides). The reaction is usually carried out in an excess of the reagent for carrying out the solvolysis, for example in an excess of methanol or ethanol. The reaction temperature is generally in the range from - 50 ° C to 100 ° C. The time required for the reaction to proceed to completion depends on the nature of the R30 residue and on the base used. If alkali metal carbonates are used as the base, it expires within a few minutes if the radical R30 is a hydrogen atom,

20 In step (k) of reaction scheme 29, the compound of formula 132 is reduced to the corresponding 2-hydroxy compounds, in the same manner as explained above in connection with process step (c) 236 of this reaction scheme has been. With this reduction, the compounds of formula 133 are obtained.

In step (1) of the reaction scheme 29, the mixed 2-hydroxy compounds are acylated in the manner as has already been explained in connection with step (c) of the reaction scheme 29. The compounds of the formula 134 are obtained.

In step (m) of the reaction scheme 29, the compounds of the formula 116 are finally obtained from the compounds of the formula 134 by carrying out ozonolysis using the method described in the literature. In this context, reference is made to the book “Reagents for Organic Synthesis” by Fieser and Fieser, Volume 1, pages 773-777, published by John Wiley, N.Y. (1967).

40

Reaction scheme 30 describes the process steps which are used for the preparation of the 5-deoxypenta-len-2-ones, which are suitable as intermediates for the preparation of the 11-deoxy-prostacyclin-analogs which are suitable for the compounds of the group X belong. In reaction scheme 30, compounds of the formula 135 are used as starting materials, which are obtained after the process steps of reaction scheme 28.

50

Reaction scheme 30

55

60

65

135

25th

^ level (a)

645369

Reaction Scheme 30 (continued)

, OR21 »

Level (b)

jstufe (c)

Level (d)

Stage e)

52

In step (a) of the reaction scheme 30, the protective group on the carbon atom 5 is cleaved from the compounds of the formula 135 by performing a desilylation. The compounds of formula 136 are obtained.

5

In step (b) of reaction scheme 30, the compounds of the formula 136 are mesylated, the corresponding 5-mesylates of the formula 137 being obtained. To carry out this mesylation, the methanesulfo-136 10 nyl chloride of the formula CH3S02C1 is preferably used, in the presence of a base such as, for example, pyridine, dimethylaniline or another tertiary amine. The reaction is carried out at a temperature ranging from about 0 ° to 25 ° C. According to another embodiment, isTosyl groups, ie p-toluenesulfonyl groups, can be used, and the working methods described in the literature are used. In this connection, reference is made, for example, to US Pat. No. 4,033,989, column 135.

20th

In step (c) of reaction scheme 30, the mesylate group or tosylate group is cleaved from the compounds of formula 137 according to methods described in the literature. Reducing agents 25 such as metal borohydrides such as sodium borohydride or metal cyanoborohydrides such as sodium aluminum hydride can be used for this purpose. The process is carried out in a solvent containing no free protons (aprotic solvent), such as, for example, in dimethyl-30 sulfoxide or in diethyl ether. With regard to other working methods, reference is made to US Pat. No. 4,033,989, column 79. In process step (c), the protective group on carbon atom 2 can also be split off from the compounds of the formula 137, and the 35 compounds of the formula 138 are thus obtained.

138 In step (d) of reaction scheme 30, the compound of the formula 138 is oxidized and the penta-40 len-2-one of the formula 139 is thus obtained.

Finally, in step (e) of reaction scheme 30, the protective group of the side chain is cleaved off by mild hydrolysis, and the compounds of the formula 45 140 are thus obtained.

The 6a-Carba-prostacychn compounds of formula 237

M ^ -L3 ~ RI

237

x-c-c- (ch2) 2-c-ch3

11 1 i

Q Re oh have a group X. They are prepared using known procedures on the compounds of For 140, 149 and 150 of Reaction Scheme 31.

Reaction scheme 31 describes a process 6S in which a compound of the formula 141 is used as the starting material and finally a compound of the formula 150 is obtained as the end product over several reaction stages.

53

645369

Reaction scheme 31

y

Level (b)

CH-L3-CH2-OR25

CH-L3-CH2-0R25 \ k level (c)

.CH-L3-CH2-OR25 j, level (d)

Level (s)

Reaction Scheme 31 (continued)

CH-L3-CH2-0R;

vj / level e [e)

141

10th

20th

142

143

40

45

50

144

55

J ^ tufe (f)

CH-L3-CH2-0H

/

R23

Rl3

6 uR

2K

CH-L3-C00H ■ J / level (g)

35 I

145

65

146

147

148

149

150

645 369 54

In the reaction scheme 31, the starting material sulfoximines is added. With regard to the background of the Stander Formula 141, initially in reaction stage (a) in the technical description of this reaction, reference is made, for example, to

Compound of formula 142 converted. Publication of C.R. Johnson et al., In J. Am. Chem.

In step (b), this compound of formula 142 with Soc. 95,6462 (1973). The sulfoximine of the formula 238 used for this reaction in a sulfoximine of the formula 238 5 can easily be prepared by using those working methods which are explained in more detail in the following Qfj5, or by using the work processes described in the literature. The carbanion is formed by reacting the sulfoximine with any of the usual reagents which draw an active hydrogen atom from such CH2-L3-CH2-UR25 sulfoximines, such as a reaction with, for example , and one obtains the compound of the formula an alkyl-lithium or with an alkyl-magnesium halo-143. performed genid. One mole equivalent of the reagent, which in step (c) of reaction scheme 31 removes the compound from the hydrogen atom, uses one reductive cleavage of the sulf 15-oximines per equivalent of the sulfate of formula 143. In the adduct formation with the silylating-oximine group, and the compounds ketones of the formula 142 are obtained, the sulfoximine is preferably used in the formula 144. in excess, for example in one leg of stage (d) of the reaction scheme 31 The silyl group valent des ketones is preferably from 1.2 to 3 molar equivalents of sulfoximine per equivalent of the compounds of the formula 144.

of the formula -Si (R17) 3 is split off, and the ver 20 is thus obtained. The reaction is carried out at a temperature

bonds of formula 145. which is in the range from about -78 ° C. to about 0 ° C., preferably

In step (e) of the reaction scheme 31, these compounds of the formula 145 are then wise at a temperature which is in the range from -40 ° C., the 0 ° C. being found. An inert diluent is used to obtain compounds of the formula 146. such as tetrahydrofuran. In this reaction In stage (f) of reaction scheme 31, the 25 carbonyl groups competing are converted both in the compound of formula 146 into the compounds of the starting material of formula 142 and in the molecule of solvent 147. solvent undesirable.

In step (g) of Reaction Scheme 31, the hydride In Step (c) of Reaction Scheme 31, the intermediate oxymethyl group of the compounds of Formula 147 are obtained as intermediate products of Formula 144 by oxidizing a re-formation of a carboxyl group, and is obtained 30 ductile elimination is carried out, in which the adducts the compounds of the formula 148. of the formula 143 with aluminum amalgam in the presence of an egg-In step (h) of the reaction scheme 31 then the ner aqueous acetic acid or another carboxylic acid in compounds of Formula 148 is subjected to deacylation, for example in the presence of grafts, with the two isomers on the carbon atom 5 pionic acid, butyric acid or citric acid. Regarding this, the reaction illustrated by formulas 149 and 150 35 can be obtained from the publication cited earlier. by C.R. Johnson et al. referred. For this purpose

Also suitable in the pentalen structure of the compounds of the formula are mineral acids, such as, for example,

141 and the formula 142 of the reaction scheme 31 is the acid. The quantitative ratio of the reactants to one another uses the same numbering of the carbon atoms, as is not critical, but it is preferable to use a large number for the compounds of the formula 135. 40 excess of the aluminum amalgam and the acid one

Add the compounds of formulas 143 to 150 inclusive. A sufficient amount of a water-based reaction scheme 31 also carries an upper side chain, and miscible inert organic liquid diluents are numbered after prostacyclin numbering. is used to prepare a mobile reaction mixture-Tm Reaction Scheme 31 are the starting materials of the. A temperature that is in the range of about 0 ° C to Formula 141, and these are about 45 ° C to 50 ° C, is well suited, with temperatures in the treatment of compounds of Formula 118 up to and including 20 -30 ° C are preferred. The isomers at carbon 121 of reaction scheme 28 are obtained. For this purpose, atomic substance 5, i.e. the E isomer and the Z isomer are obtained in the compounds of formulas 118 to 121 of the reaction form of a mixture.

schémas 28 are subjected to a deacylation, for example in step (d) of reaction scheme 31 the silyl is removed by carrying out a treatment with a weak base group from the compounds of the formula 144, so that the group of the formula -OR24 in a hydroxyl and replaced by hydrogen, converting the compounds group of the formula -OH. Oxidation of the formula 145 is obtained. To carry out these desiccant compounds, the corresponding pentalenes are then obtained. Such reagents and working conditions are selected from which, by means of mild acid hydrolysis, the protective genes are selected which are not split off to prevent the ether groups from being split off. 55 lead group on carbon atom 1. If the silyl protecting compound of formula 141 of the reaction scheme group is a sterically unobstructed silyl group, then 31 also includes compounds of formula 140 of the reac- a base, such as an alkali metal carbonate in diation scheme 30, oxane or tetrahydrofuran, where Applies temperatures that are around -10 ° C to + 100 ° C. In stage (a) of reaction scheme 31, the compounds 60, as already mentioned, the silyl protecting groups of compounds of formula 141 are silylated by such processes, preferably tert-butyldimethylsilyl groups, and in this the ones described here . It is preferred if a Grup case can be cleaved by using Te-pen Rj7 as a sterically hindered alkyl group and using a trabutylammonium fluoride. It is in this interplay for such a radical that the tert-butyldimethylsime is based on the publication by Corey et al., In J. Am. lylrest. 65 Chem. Soc. 94,6190 (1972).

In step (b) of reaction scheme 31, the compounds of formula 145 are converted from compounds of formula 142 into the sulfonimidoyl adducts of compounds of formula 145 in step (e) of reaction scheme 31

Formula 143 converted to obtain the carbanion of a 146 by free hydroxyl groups with solid

55

645 369

R24 groups protect, i.e. with carboxyacyl groups. For example, the radical R24 can represent an aromatic carboxyacyl group, for example a benzoyl group, a substituted benzoyl group, a monoesterified phthaloyl group, a naphthoyl group or a substituted naphthoyl group. The carboxyacyl radical R24 can also be an aliphatic group, for example an acetyl radical or a pivaloyl radical. Working methods which are described in the literature or which are explained in more detail here can be used to introduce these protective groups.

In step (f) of the reaction scheme 31, the protective groups on the carbon atom 1 are split off from the compounds of the formula 146, and the alcohols of the formula 147 are obtained in this way. Methods described in the literature are used for this purpose. If, for example, the protective groups are tetrahydropyranyl groups or similar protective groups which are bonded via an ether oxygen, then mild acidic hydrolysis is carried out, using dilute acetic acid, aqueous phosphoric acid in a solvent for all reactants, such as, for example, in tetrahydrofuran. Temperatures in the range of 25-55 ° C can be used.

The isomers on carbon atom 5, namely the E isomers and the Z isomers, are preferably separated in this stage, for example by subjecting the compounds of the formula 147 to chromatography. A silica gel column is well suited for this purpose, preferably a column with a high pressure liquid, for which purpose silica gel with an average particle diameter of 40 microns is used. With regard to the background of the prior art relating to chromatography with a high-pressure liquid, which is abbreviated as HPLC on the basis of the corresponding English expression “high pressure liquid chromatography”, reference is made, for example, to the book entitled “Modern Practice of Liquid Chromatography”, published by Wiley Interscience, NY, 1971. If appropriate, the compounds of the formulas 144, 145, 146 or 148 can be chromatographed in order to prepare the corresponding 5E isomers or 5Z isomers.

In step (g) of reaction scheme 31, the compounds of formula 148 are now prepared from one of the two now separate 5E isomers or 5Z isomers, or else from the mixture of the isomers of formula 147, by oxidation. Reagents which are suitable for carrying out this oxidation have been described in the literature. A particularly useful reagent for this purpose is the Jones reagent, i.e. acidified chromic acid. In this connection, reference is made to the publication in J. Chem. Soc. 39 (1946). Acetone is a suitable diluent for this purpose, and a slight excess of the oxidizing agent over the amount required to convert the hydroxymethyl group of the compounds of formula 147 to the carboxyl group of the compounds of formula 148 is used. A reaction temperature should be used that is at most 0 ° C or lower. Reaction temperatures in the range from −50 ° C. to −10 ° C. are preferred. The oxidation takes place rapidly and is usually complete in about 5-20 minutes. The excess oxidizing agent is destroyed, for example by adding a lower alkanol, and preferably isopropyl alcohol, and the product of formula 148 thus obtained is isolated by customary working methods.

Finally, in step (h) of the reaction scheme 31 compounds of the formula 149 are prepared by splitting off the protective group R24, namely the carboxyacyl group, from the compounds of the formula 148. Such cleavage of the carboxyacyl group can be carried out, for example, with a base, such as, for example, potassium hydroxide or potassium carbonate in methanol, or in a mixture of methanol and water, at a temperature of about 25 ° C.

During the reactions, which are explained in Reaction Scheme 31, the steric configuration on the carbon atoms 8,9,11 and 15 remains unchanged. For example, from a starting material of formula 141 which has an 11-a-hydroxy group, a product of formula 149 is obtained which also has an 11-a-hydroxy group. In the same way, the entire grouping, which is represented by 15, the following formula

\

R $

R,

X-C-C- (CH2) 2-C-CH3 II I I

Q5R6 OH

is maintained unchanged during the reactions so that a 15S end product is correspondingly obtained from a 15S starting material.

The preparation of intermediates is explained in reaction schemes 32 to 45, and these reaction schemes therefore serve as guidelines for the process steps described in the following preparations 30.

Compounds of formulas 4 or 15, which are not specifically illustrated or exemplified, can be obtained by conversions using chemical methods, either described in detail here or known to those skilled in the art.

For example, the conversion of the R ^ to Q radical from hydrogen to methyl at the carbon atom 15 requires that the intermediate is a 15-oxo compound that was prepared by oxidation. This is followed by alkylation with a Grignard reagent of the formula CH3MgHal, or with trimethylaluminum, and then the separation of the 15a products from the 15β products, which can be carried out, for example, with chromatography, namely preferably by means of chromatography of the corresponding methyl ester. The preparation of the esters and the salts and the various modifications to the carbon atom 1, such as the preparation of the amides and sulfonamides, is carried out according to general working methods, which are either described here.

or which are known in the professional world.

It should be noted that many of the intermediates described herein are useful not only for the purposes shown, but also for many of the above-mentioned conversions, as is known in the art.

The products that result from each step of the process are often mixtures and, as is clear to one skilled in the art, they can either be used as such to carry out the next step or they can be separated and by conventional methods be cleaned, for example by fractionation, by liquid extraction and similar working processes, before carrying out the next process step 65. It should be noted that the compounds according to the invention are not only claimed in their purified form, but also in the form of mixtures, so that, for example, for the 19-hydroxy compounds

645 369

56

Formula 4 also claims its mixture of the R-shape and the S-shape.

Preferred embodiments of the invention will now be explained in more detail below.

The preparation of starting materials is explained using the following preparations, and the production of end products using the following examples. The following information applies to the preparations and the examples, unless expressly stated otherwise.

All temperatures are given in degrees Celsius.

The infrared spectra were determined on an infrared spectrophotometer from Perkin-Elmer, model 421. Unless expressly stated otherwise, the infrared spectra were determined using pure, undiluted samples.

The nuclear magnetic resonance spectra were determined on a spectrophotometer from Varian, namely on the models with the designation A-60, A-60D, T-60 or XL-100, and the products were dissolved in deuterochloroform and as a comparison, that is as internal standard, served tetramethylsilane.

The mass spectra were determined using a CEC Model 110B, double-focusing, high resolution mass spectrometer, using the Varian model called MAT CH7 Mass Spectrometer, or they were determined using a combination of a gas chromatograph and mass spectrum, namely in the LKB model 9000 gas chromatograph mass spectrometer (ionization voltage 22 ev or 70 ev). The samples are usually examined in the form of their trimethylsilyl derivatives, ie as TMS derivatives.

The term “saline solution” here means an aqueous saturated sodium chloride solution.

The product with the brand name “Celit R” is a calcium aluminosilicate that is well suited as a filter aid.

The term “Collins reagent” means chromium trioxide in pyridine (see the publication in “Tetrahedron Lett.”, Page 3363 (1968)).

The abbreviation «DIB AL» is used for diisobutylaluminum hydride.

The product with the brand name «Florisil R» is a magnesium silicate for chromatographic purposes, which is manufactured by the Floridin Co. In this context, reference is made to the book “Reagents for Organic Synthesis” by Fieser et al., Page 393, published by John Wiley u. Sons, .N.Y. (1967).

The abbreviation «HPLC» means high pressure liquid chromatography.

The Jones reagent is chromic acid. See the publication in J. Chem. Soc., Page 39, (1946).

The term «RrWert» in connection with thin layer chromatography has the usual meaning, i.e. it is the migration distance of the spot of the sample, based on the solvent front. The thin-layer chromatograms are carried out on silica gel plates, unless expressly stated otherwise, with the solvent system that is mentioned in each case.

The product with the brand name “Skellysolve B” is a mixture of isomeric hexanes.

The abbreviation «THP» means tetrahydropyran-2-yl.

The abbreviation «TLC» means thin layer chromatography.

The term “concentrate” or “narrow down” means concentration or evaporation under reduced pressure, preferably a pressure of less than 50 mm, at temperatures below 35 ° C.

“Drying” means contacting the fragile compound in solution with an anhydrous agent such as sodium sulfate or magnesium sulfate. This removes the water from the solution and then filters to remove the solids.

The term “silica gel chromatography” ver-io stands for the implementation of a chromatography including the elution and the collection of fractions, whereby those fractions are combined with one another, in which thin-layer chromatography has determined that the desired product is free of Aus -15 contain transition materials and contaminants.

The expression “A-IX solvent system”, which is used in thin layer chromatography, means a solvent system which consists of a mixture of ethyl acetate + acetic acid + 2,2,4-trimethyl-20pentane + water in a mixing ratio of 90:20: 50: 100 was made in the manner described in the publication by M. Hamberg and B. Samuelsson in J. Biol. Chem. 241, 247 (1966).

23 Preparation 1

Preparation of the y-lactone of 5a-hydroxy-3a-tetrahy-dropyran-2-yloxy-2ß- (trans-2-formylethenyl) -1 a-cyclopen-tanoacetic acid.

30 The preparation is carried out according to the reaction scheme 32, the product mentioned in the title being the compound 158 of the reaction scheme 32.

According to the process described in Reaction Scheme 32, the compound mentioned in the title is prepared in 7 process steps, using the tri-cyclic lactonaldehyde of the formula 151 as the starting material. With regard to this starting material, reference is made to US Pat. No. 3,816,462.

40

Reaction scheme 32

151

—CH0

Level (a)

152

65

H = CH:

Level (b)

■ - /

57

645 369

Reaction scheme 32 (continued) 0

/ W OH OH

qj «-»

Level (c)

153

154

OCHO

'J ^ level (d)

155

OH

Level (s)

\ /

156

THPO

Stage (f)

\ /

157

THPO

\ /

Level (g)

158

io thpo

15 reaction stage (a) of reaction scheme 32

Preparation of the y-lactone of exo-3-hydroxy-endo-6-vinyl-bicyclo [3,1,0] -hexane-exo-2-acetic acid.

The compound mentioned in the title is the compound of Formula 152 of Reaction Scheme 32.

A solution of 20 g of the tricyclic lactonaldehyde of the formula 151 in 150 ml of benzene is treated at a temperature of 5-10 ° C. with a solution of the ylide, which consists of 54 g of methyltriphenylphosphonium bromide and 95 ml of 25 1.6 molar butyllithium in 1 liter of benzene (previously heated to reflux for 1 hour and then cooled).

The addition of the ylide is complete within 1 hour to 11/2 hours, and the mixture is then stirred for a further 30 minutes and the mixture is filtered and concentrated. The residue thus obtained is taken up in 100-200 ml of a mixture of 40 parts of ethyl acetate plus 60 parts of Skellysolve B, and the mixture is left to crystallize out of the starting product, which is triphenylphosphine oxide. The mixture is then filtered and the filtrate is subjected to silica gel chromatography using a mixture of 40 parts of ethyl acetate plus 60 parts of Skellysolve B as eluent. This gives 16.2 g of the compound of formula 152 in the form of egg-4o nes oil.

In the nuclear magnetic resonance spectrum, this product shows peaks at 1.3-3.0.4.6-4.9 and 5.0-5.4 8.

When thin-layer chromatography using a mixture of 50 parts of ethyl acetate plus 50 45 parts of Skellysolve B as the eluent, it shows an Rr value of 0.74.

Reaction stage (b) of Reaction Scheme 32

so preparation of the 3-lactone of endo-6- (1,2-dihydroxy-ethyl) - exo-3-hydroxy-bicyclo [3, 1,0, -hexene -exo-2-acetic acid.

The compound mentioned in the title is the compound of Formula 153 of Reaction Scheme 32.

A solution of 8.0 g of the alkenes of the formula 152 prepared according to process step (a) 55 in 80 ml of acetone is treated with a solution of 9.0 g of N-methylmorpholine oxide dihydrate in 12 ml of water, and then it is set a solution of 130 mg of osmium tetroxide in 6.5 ml of tert-butanol. Once the reaction is complete, the acetone is removed under reduced pressure. The residue is diluted with 100 ml of water, saturated with ammonium sulfate and extracted with tetrahydrofuran. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, giving 12 g of the crude oily product.

This oil is subjected to silica gel chromatography to give 8.5 g of the compound of formula 153 in the form of an oil.

645369

In the nuclear magnetic resonance spectrum this product shows peaks at 0.7-1.2, 1.3-1.9.2.4-3.4.3.4-3.7.3.7-4.2 and 4, 7-5.0 8.

In thin layer chromatography using a mixture of 15 parts of methanol and 85 parts of dichloromethane as the eluent, the product has an Rr value of 0.66.

Reaction stage (c) of Reaction Scheme 32

Preparation of the y-lactone of 3a-formyloxy-5a-hydr-oxy-2ß- (3-propionyloxy-trans-l-propenyl) -la-cyclopentane-acetic acid.

The compound mentioned in the title is the compound of Formula 154 of Reaction Scheme 32.

A solution of 7.2 g of the glycol of formula 153 prepared in process step (b) and of 15 g of triethyl ortho-propionate in 30 ml of tetrahydrofuran is treated with 3 μl of trifluoroacetic acid. After 1 hour the solvent is removed under reduced pressure and the residue is treated with 100 ml of anhydrous formic acid with stirring. After 15 minutes, 100 ml of 1 normal sodium hydroxide solution and 100 ml of crushed ice are added. The mixture is shaken with dichloromethane and the organic phase washed with 5% aqueous bicarbonate solution and then dried over magnesium sulfate and concentrated. This gives 9.6 g of an oil which is subjected to silica gel chromatography. The mixture is eluted with a mixture of ethyl acetate plus cyclohexane in a mixing ratio of 1: 1 and 4.1 g of the compound of the formula 154 are obtained.

In the nuclear magnetic resonance spectrum, this product shows peaks at 1.1.1.9-3.0.4.4-4.6.4.8-5.2.5.6-5.8, and 8.08

In thin-layer chromatography using a mixture of ethyl acetate plus cyclohexane in a mixing ratio of 1: 1 as the eluent, this product shows an Rr value of 0.49.

Reaction stage (d) of Reaction Scheme 32.

Preparation of the y-lactone of 3a, 5a-dihydroxy-2ß- (3-propionyloxy-trans-l-propenyl) -la-cyclopentane-acetic acid.

The compound mentioned in the title is the compound of Formula 155 of Reaction Scheme 32.

A solution of 4.1 g of the formic acid ester of the formula 154, which was prepared according to process step (c), in 35 ml of dry methanol is treated with 0.5 g of sodium bicarbonate. Once the reaction is complete, which is the case after about 2-3 hours, the solvent is removed under reduced pressure. The residue is partitioned between water and dichloromethane and the organic phase is dried over magnesium sulfate and concentrated.

The oily residue obtained is subjected to silica gel chromatography, using ethyl acetate as the eluent. This gives 2.8 g of the compound of formula 155.

In the nuclear magnetic resonance spectrum, this product shows peaks at 1.13.3.7-4.3.4.3-4.7.4.7-5.2 and 5.5-5.85.

In thin-layer chromatography using ethyl acetate as the eluent, the Rr value is 0.65.

Process stage (s) of reaction scheme 32

Preparation of the y-lactone of 3a-tetrahydropyran-2-yloxy-5a-hydroxy-2ß- (3-propionyloxy-trans-l-propenyl) -la-cyclopentane-acetic acid.

58

The compound mentioned in the title is the compound of formula 156 of reaction scheme 32.

A solution of 2.8 g of the 5-hydroxy-lactone of formula 155 obtained in process step (d) in 10 ml of di-chloromethane is dissolved in 5 ml of dihydropyran and 5 mg of p-toluenesulfonic acid in 1 ml of tetrahydrofuran are treated. Once the reaction is complete, which is the case after about 1/2 hour, the mixture is washed with a 5 percent aqueous sodium bicarbonate solution. The io organic phase is dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography, using a mixture of ethyl acetate plus Skellysolve B in a mixing ratio of 60:40 as the eluent. The compound of formula 156 is obtained.

Process stage (f) of reaction scheme 32

Preparation of the y-lactone of 3a-tetrahydropyran -2-yloxy-5a-hydroxy -2ß- (3-hydroxy-trans -1-20 propenyl) -1 a-cyclopentanacetic acid.

The compound mentioned in the title is the compound of Formula 157 of Reaction Scheme 32.

3.0 g of the propionate of the formula 156 prepared in stage (e) in 10 ml of methanol are added to a solution of 25 sodium methoxide (sodium methoxide). The sodium methoxide was freshly made from 20 mg of sodium metal and 40 ml of anhydrous methanol. Once the reaction is complete, which is the case after about 20 minutes, the methanol is removed under reduced pressure 30. The residue is partitioned between dichloromethane and a 0.4 molar phosphate buffer with a pH of 4.5. The organic phase is dried over sodium sulfate and concentrated to give the compound of formula 157.

35

Process stage (g) of reaction scheme 32

Preparation of the y-lactone of 3a-tetrahydropyran-2-yloxy-5a-hydroxy-2ß- (trans -2-formylethenyl) -la-cyclopen-tanoacetic acid.

40 The compound mentioned in the title is the compound of formula 158 of reaction scheme 32.

An oxidizer is prepared from 5.4 g of chromium trioxide and 5.2 g of 3,5-dimethylpyrazole in 150 ml of dichloromethane and stirred for 15 minutes. 1.8 g of the 3-hydroxy compound of the formula 157 prepared in process step (f), dissolved in 20 ml of dichloromethane, are then added to this solution 45. As soon as the reaction is complete, which is the case after about 5 minutes, the mixture is washed with a 5% aqueous bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated. The residue is subjected to chromatography on silica gel, using a mixture of acetone plus dichloromethane in a mixing ratio of 1: 9 as the eluent. starts.

55 The compound of formula 158 is obtained.

Preparation 2:

Preparation of the 19,20-dihydro (or "A19") - PGF2a ll-15-bis (tetrahydropyran-2-yl ether) methyl ester.

60

(a) First prepare the 3a, 5a-dihydroxy-2β - [(3R, S) -3-hydroxy-trans -1,7-octadienyl] -la-cyclopentanacetic acid-re-y-lactone-3,3'- bis-tetrahydropyran-l-yl ether.

A solution of 2.775 g of the y-lactone of 5a-hydroxy-3a-tetrahydropyran-2-yloxy-2ß- (trans-2-formyläthenyl) -la-cyclopentane-acetic acid prepared in preparation 1 according to preparation 1 in 40 ml of diethyl ether and 10 ml of tetrahydrofuran is mixed with 1-pentenyl magnesium bromide at a temperature of - 70 ° C.

59 645 369

mid, which is added dropwise over 17 minutes. (c) The 19,20-didehydro (or «A19») PGF2a-

is set. The 1-pentenyl magnesium bromide 11,15-bis (tetrahydropyran-2-yl ether) and its corresponding

prepared from 4.115 g of 5-bromo-1-pentene and 0.667 g of magnesium of the methyl ester.

prepared in 40 ml of diethyl ether, and this mixture was alkylated 9.87 g of the lactole according to Example 2, in

then - as mentioned - added dropwise. This is how you get a Wittig reaction. The Wittig re

reaction mixture is then at a temperature of agens is first from 35.1 g of 4-carboxybutyltriphenyl

- 60 ° C is stirred for 22 minutes and the reaction is made phosphonium bromide which is quenched to the reaction using a saturated aqueous ammonium product of 7.6 g of sodium hydride and 180 ml of dimethylsulf chloride solution. Then sodium sulfate oxide is added, the powder being added beforehand over 11/2 hours in order to achieve coagulation, and the solids had been heated to a temperature of 70-75 ° C., and substances are filtered off. The filtrate is washed with ether, then cooled to 25 ° C. for about 25 minutes, combined and dried and concentrated, where appropriate, and then treated with (3S) to obtain 3.109 g of an oil. This product is chroma-lactol in 65 ml of dimethyl sulfoxide, which is added dropwise tography by adding a mixture of about 25 minutes with stirring as the eluent, and the mixture of methylene chloride and acetone in a mixing ratio of 6: 1 is then stirred for a further 30 Minutes. Then that is used. This gives 2.427 g of the mixed C-15 mixture in ice water with a 2-normal solution of Ka epimers of the mono-THP ether. acidified hydrogen sulfate, and shaken with ether

This product shows in the thin-layer chromatograph. The organic phase is washed with saline

See phie using a mixture of methylene chlorine, dried and concentrated to give the free acid plus acetone in a mixing ratio of 4: 1 as eluent 20, ie the bis-THP acid.

an Rr value of 0.34. This acid is then esterified using a steric

In the nuclear magnetic resonance spectrum show solution of diazo metal used, and the so obtained

Peaks at 6.20-5.4.5.2-4.78.4.68.4.3-3.2.302-2.4.2.35-1.85 methyl ester is then chromatographed, giving 9, 37 g and 1.8-1.2 8th of the methyl ester mentioned in the title.

In the infrared spectrum, the absorptions at 3450, 25 This product shows in the thin layer chromatograph

2995,1775,1200,1180,1120,1075,1030,1020,975,920,870 phie using a mixture of acetone plus and 815 cm ~ 1. In the mass spectrum, lines with methylene chloride in a mixing ratio of 1: 6 were shown as running

422,2446,407,353,337,321,320,269,251 and 85. mean Rr value of 0.62.

The mono-THP ether prepared as above is shown in a nuclear magnetic resonance spectrum showing methylene chloride solution with an excess of dihydropy-30 peaks at 6.18-4.56.4.37-3.20.3.65 and 2.78 -1.11 8.

ran treated in the presence of pyridine hydrochloride at about 25 ° C for 16 hours. The mixture is diluted with about 300 ml of methylene chloride and with a 5% aqueous sodium bicarbonate solution, with water and with preparation 3

Washed saline and dried. Concentrated 3S preparation of the (19R) -19-hydroxy-PGF2a and its triert and thus the bis-THP ether compound, i.e. the (19S) epimers.

3a, 5a-Dihydroxy-2ß - [(3R, S) -3-hydroxy-trans-l, 7-octadiene- The compound mentioned in the title is the compound of yl] -la-cyclopentane-acetic acid-y-lactone-3 , 3'-bis (tetrahydropy formula 172 of reaction scheme 35.

ran-2-yl ether). . Reaction schemes 33, 34 and 35 are referred to here.

(b) The corresponding lactol 40 is then added.

produced. Following the working procedures developed by J.C. Sih in «prostate

For this purpose 9.82 g of the according to the procedural land », volume 13, No. 5,831-835 (1977) are described,

Step (a) prepared lactones with 100 ml of toluene, the (19R) compound mentioned in the title is obtained.

- 68 ° C with 22.65 ml of a 1.5 molar solution of diisobu- In the same way tylaluminium hydride (DIBAL) is treated in toluene according to these working procedures. This 45 also made the corresponding (19S) epimer, with each solution being added dropwise over 8 minutes. but now the Grignard reagent, which is made from the THP-ge-Then, the mixture is stirred at - 75 ° C for 1 hour protected bromide, which is made from the (S) - (+) - l - and then sets 10 ml of a saturated aqueous sodium sul-penten-4-ol was obtained instead of the Grignard re-fat solution. The mixture is used at room temperature, which is warmed with THP-protected, diluted with 700 ml of diethyl ether and then prepared with pul-50 bromide, which is treated from the corresponding (R) -shaped sodium sulfate. The solids are (-) - l-penten-4-ol was obtained. In this way, the corresponding (19S) epimer is obtained using a filter of the “Celite” brand name.

away. The filtrate is dried and concentrated. In the same way, using the corresponding

the lactol compound is obtained. corresponding dl-l-penten-4-oles received the (19RS) product.

In thin layer chromatography using 55 In addition, the corresponding PGE2 compounds

a mixture of acetone plus methylene chloride in the mine by protecting PGF2a

ratio of 1: 6, this product oxidized an Rr value of Formula 171 and then removed the protective groups.

of 0.35. cleaves and thus receives the compounds of formula 174.

645 369

Reaction scheme 33

60

0

? A

ór

25th

CHO

159

Level e (a)

V

25th

Several levels

25th

160

161

25 W ^ 25

25th

162

163

Reaction scheme 34

61

U

A

/ R

CHO

37

164

rtufe (a)

165

27th

Actual stages (b), J, (c) and (d)

r \

k h

Rs

OR

25th

166

Level (s)

\ k

645369

Reaction Scheme 34 (continued)

62

Level (s)

167

168

Level (g)

si r \

11

OR

25th

169

63

645 369

645 369

Reaction Scheme 35 (continued)

i

OR25

174

64

driving, you get, starting from the 19 £ -hydroxy-PGF2a methyl ester, the PGF compound mentioned in the title by performing a reduction with lithium aluminum hydride.

5 The protective groups on carbon atom 1 and on carbon atom 19 are then split off and the hydroxyl group on carbon atom 9 is oxidized, and then the protective groups are removed, giving the PGE compound mentioned in the title.

10th

Reaction scheme 36

15

n /

175

30th

35

level (b)

ch2oh

176

Reaction Scheme 33 also explains the steps leading to the 15-deoxy-lactones of Formula 163. For this purpose, a mesylation is carried out on the carbon atom 15 and then a de-mesylation or demesylation as described here.

Reaction Scheme 34 describes the steps in which chemistry known procedures are used to make modifications to the carbon atoms 13 and 14 of the lactones of formulas 166, 167, 168 and 169. These lactones are all encompassed by Formula 170 of Reaction Scheme 35.

Preparation 4

Preparation of 2-decarboxy-2-hydroxymeth-yl-19Ç-hydroxy-PGF2a and -PGE2.

The compounds mentioned in the title are the compounds of formulas 179 and 182 of reaction scheme 36.

Reference is made to reaction scheme 36.

In the process shown in this reaction scheme 36

55

65

V

Level (d)

177

Level (a)

178

179

Level (c)

Reaction Scheme 36 (continued)

Level (c)

- ^ ln-cho-o-si (7) 3 R_

òsi (r-17);

180

65

645 369

(Continuation)

U-CH2-0-SÌ (RIV)

^ Level (s)

0

Preparation 5

Preparation of l9 £ -hydroxy-PGF2a-amide

The compound mentioned in the title is the compound of Formula 185 of Reaction Scheme 37.

Reference is made here to reaction scheme 37.

In Reaction Scheme 37 below, the mixed acid anhydride is first prepared. For this purpose a solution of l9C-hydroxy-PGF2a in methylene chloride is treated with 2 equivalents of triethylamine and 1.01 equivalents of isobutyl chloroformate at a temperature of about 25 ° C. for 1/2 hour.

A saturated solution of ammonia in acetic acid nitrile is then added to the mixture at a temperature of about -5 ° C. and the mixture is stirred at -5 ° C. for 10 minutes. The reaction mixture is then diluted with a mixture of saturated saline and water in a mixing ratio of 5: 1 and shaken out with ether. The organic phase is washed with saturated saline and 2-normal hydrochloric acid and then again with saturated saline and 5 percent sodium bicarbonate solution and finally again with saturated saline. The organic phase is then dried and concentrated.

The residue obtained is chromatographed on an HPLC silica gel column, using acetone as the eluent. You get the connection mentioned in the title.

Reaction scheme 37

OH \

-COOH

\ 3stage (er)

[

itufe (b)

^ U-C-N (R7) (R8)

Level (c)

Preparation 6

Preparation of 2-decarboxy-2-aminomethyl-19Ç-hydr-oxy-PGF2a

The compound mentioned in the title is the compound of formula 186 of reaction scheme 37.

Reference is made to reaction scheme 37. According to the working procedure of Example 3B of US Pat. No. 4,085,139, the 19C-hydroxy-PGF2a-amide prepared according to preparation 5 is treated with lithium aluminum hydride in tetrahydrofuran at a temperature of about 25 ° C. for 48 hours. Reaction stage (c) of reaction scheme 37 is thus carried out. You get the connection mentioned in the title.

Preparation 7

Preparation of 19i; -hydroxy-PGF2a-methanesulfonamide. In this context, reference is made to reaction scheme 38.

Reaction scheme 38

OH

\

Level (a)

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

645369

66

(Continuation)

Reaction scheme 39

0 0 ch3

W II I

U-C-0-C-0-CH2-CH1 ch3

l

Level (b)

190

«-C-nh-s02-ri5

I9l

35

In the process shown in Reaction Scheme 38, the mixed anhydride obtained in step (a) of Reaction Scheme 37, that is, the end product of Preparation 5, is used. A solution of this mixed anhydride in dimethylformamide is stirred with 0 ° C with about 4 equivalents of the methanesulfonamide sodium salt, and then a sufficient amount of hexamethylphosphoramide is added to ensure that a homogeneous mixture is formed. The methanesulfonamide sodium salt used for this reaction was prepared from methanesulfonamide and methanolic sodium methoxide (methanolic sodium methoxide) in methanol by concentrating and performing an azeotropic distillation with benzene.

The mixture is stirred at about 25 ° C for 16 hours and then acidified with a cold, dilute hydrochloric acid and shaken with ethyl acetate. The organic phase is washed with water and brine, dried and concentrated. The residue is chromatographed on silica gel, eluted with methanol + methylene chloride, and the compound mentioned in the title is thus obtained.

Preparation 8

Preparation of 2-decarboxy-2- (1H-tetrazol-5-yl) -19Ç-hydroxy-PGF2a

The compound mentioned in the title is the compound of Formula 197 of Reaction Scheme 40.

In this context, reference is made to reaction schemes 39 and 40.

40

45

50

Reaction scheme 40

OSi (* 7) 3 \

.NH-N / H

N-N

192

193

^ LevelU)

67

645 369

(Continued) (} Si {R * 1 7) 3

U-C = N

25th

OSi {Ri 7) 3

\ ^ NH-N

^ = JLu-C

rN-N

jstufe (b)

ÖR25

Jstufe (c)

NH-N

OR25

jßtufe (d) NH-N

194

see, dried and concentrated to give the compound of formula 195. The silyl protective group and the THP protective group or other protective groups are then removed, giving the product mentioned in the Ti-5 tel.

Another scheme using the Wittig reaction is illustrated in Scheme 39 and uses a ylide derived from the phosphonium compound of Formula 239

Br i ^ nh-n

(qh5) 3p-ch2- (ch2) 3-c. II

^ n-n

239

15

195

196

was produced. In this connection, reference is made to US Pat. No. 3,928,391.

In Reaction Scheme 39, the starting material of Formula 190 is made from any of the lactones illustrated by Formula 170 by performing a reduction as is known in the art. In this context, it should be noted that J.C. Sih, pointed out in "Prostaglandine" 13,831-5 (1977).

25th

Preparation 9:

Preparation of 19-hydroxy-19-methyl-PGF2a and PGE2.

The compound 19-hydroxy-19-methyl-PGF2a mentioned in the title is the compound 203 of the reaction scheme 41.

The second compound mentioned in the title is compound 205 of reaction scheme 41.

Regarding the reactions to be carried out, reference is made to reaction scheme 41.

Reaction scheme 41

197

• ^ ■ <x

198

11

OH

50

First, the reaction scheme 40 is explained.

In the process described there, step (a) converts the amide of formula 193 to the nitrite of formula 194 by reacting with N, N'-dicyclo-hexylcarbodiimide, which is abbreviated to DCC, in pyridine at one temperature of about 25 ° C. The dicyclohexyl urea precipitated in this reaction is removed by filtration and the filtrate is concentrated to give the nitrii of formula 194.

In reaction step (b) of reaction scheme 40, the tetrazolyl compound of formula 195 is then obtained from the nitrii of formula 194 by carrying out a reaction with sodium azide and ammonium chloride in dimethylformamide at a temperature of about 115 ° C. Once the reaction is complete, as can be seen from thin layer chromatography, the mixture is cooled and concentrated. The residue is taken up in chloroform, washed with saline.

^ Level Ca)

55

A

ex

R:

55

ii 6

R-m Qn

199

65

Level (b)

645 369

Reaction Scheme 41 (continued)

0

A

R Q

11

J?

tuf e (c)

11

Jstufe (d)

Level (s)

La-COORS

200

201

202

203

204

205

68

Step (a) of Reaction Scheme 41

In this stage the 3a, 5a-dihydroxy-2ß - [(3RS) -3-hydroxy-7-oxo-trans-l-octenyl) -la-cyclopentanacetic acid-Y-lactone-3,3'-bis- (tetrahydropyran -2-yl ether) of the formula 199 5.

To prepare this compound of the formula 199, 10.02 g of the 7-hydroxy-lactone of the formula 198 in 300 ml of acetone at a temperature of −30 ° C. are treated with 14.95 ml of a 2.67 molar Jones reagent which is added dropwise within 10 minutes. The mixture is stirred at a temperature in the range of -25 ° C to -20 ° C for a further 18 minutes, and then the reaction is stopped by adding 20 ml of isopropanol and stirring is continued for a further 5 minutes. This mixture is added to 500 ml of cold 5 percent sodium bicarbonate and 800 ml of ethyl acetate. The organic phase is separated off, the aqueous phase is extracted with ether and the two organic materials are combined. Then the organic phase is washed with 5% sodium bicar-20 bonat, then with ice water and then with saline, dried and concentrated. This gives 9.93 g of the compound mentioned in the title.

This product shows an Rf value of 0.64 in thin layer chromatography on silica gel using a mixture of Ace-25 ton plus methylene chloride in a mixing ratio of 1: 3.

In the nuclear magnetic resonance spectrum, the peaks are 5.50.5.00.4.63.4.25-3.0.2.13 and 3.00-1.20 S.

30 stage (b) of reaction scheme 41

In this step the compound of formula 200, namely 3a, 5a-dihydroxy-2ß [(3R, S) -3,7-dihydroxy-7-meth-yl-trans-1-octenyl] -1 a-cyclopentane acetic acid-y-lactone-3,3'-bis (tetrahydropyran-2-yl ether) prepared.

35 0.500 g of the 7-oxo-lactone of the formula 199 in 33 ml of diethyl ether are treated at a temperature of -78 ° C. with 2 equivalents, namely 0.766 ml, of a 2.9 molar methylmagnesium bromide, which is added dropwise over a period of 1 minute is added. The mixture is then stirred at a temperature of -78 ° C for a further 30 minutes and then treated with another 2 equivalents of methyl magnesium bromide at a temperature of -78 ° C for 2 hours. The mixture is added to 40 ml of a saturated aqueous ammonium chloride solution and shaken out with ether. The organic phase is washed with brine, dried and concentrated. The concentrate is chromatographed on an HPLC column and eluted with a mixture of acetone plus methylene chloride in a mixture 50 ratio of 1: 5. This gives 0.391 g of the compound mentioned in the title.

This shows an Rr value of 0.39 in thin layer chromatography using a mixture of acetone plus methylene chloride in a mixing ratio of 1: 3. 55 In the nuclear magnetic resonance spectrum, the peaks are 5.66-5.33.5.184.81.4.81 ^ 1.47.4.29-3.16.2.97-1.29 and 1.165.

In the infrared spectrum, the absorptions are at 3550, 3000, 1770, 1460, 1430, 1350, 910, 865, 840, 765 and 60 735 cm-1.

The lines in the mass spectrum are 523.3118.439, 437.436.421.395.131 and 85.

Step (c) of the reaction scheme 41 ss In this step the 3a, 5a-dihydroxy-2ß - [(3R, S) -3,7-dihydroxy-7-methyl-trans-l-octenyl) -la-cyclopentane-acetal -dehyd-y-lactol-3,3'-bis (tetrahydropyran-2-yl ether) of the formula 201.

69

645369

6.98 g of the 7-hydroxy-7-methyl-lactone of the formula 200 in 100 ml of toluene are reduced at -78 ° C. with 25 ml of a 1,5-molar diisobutylaluminum hydride (abbreviated as DIBAL) in toluene. The hydride is added dropwise over a period of 13 minutes. The mixture is stirred at a temperature of -78 ° C. for 1 hour, then treated with a further 5 ml of DIBAL, the mixture is stirred for 21/4 hours and then treated again with 5 ml of DIBAL. The mixture is then stirred again for 45 minutes and the mixture is then allowed to warm to -40 ° C. over a period of 30 minutes and then cooled again to -78 ° C. and the reaction is interrupted by carefully adding a saturated aqueous sodium sulfate solution. The mixture is then diluted with 850 ml of diethyl ether, stirred with 20 g of powdered sodium sulfate until the aluminum salts coagulate and then filtered. The filtrate is concentrated and then chromatographed on silica gel using mixtures of acetone plus methylene chloride as the eluent, starting with a mixing ratio of 1: 2 and ending with a mixing ratio of 1: 1. This gives 4.89 g of the lactol compound mentioned in the title.

When thin-layer chromatography on silica gel using a mixture of acetone plus methylene chloride in a mixing ratio of 1: 2, this product shows an Rr value of 0.24.

In the nuclear magnetic resonance spectrum, the peaks lie at 5.77-5.0.4.86-4.33.4.33-3.18.3.11-1.27 and 1.15 5.

In the infrared spectrum, absorptions are found at 3500, 3000, 1750, 1730, 1470, 1450, 1440, 1370, 1340, 1200, 120, 910, 865 and 810 cm-1.

Lines in the mass spectrum are found at 527.3201.426, 336.247.246.131 and 85.

Step (d) of Reaction Scheme 41

In this stage, the mixed C-15 epimers of 19-hydroxy-19-methyl-PGF2a-methyl ester-11,15-bis (tetra-hydropyran-2-yl ether) of the formula 202 are prepared.

The Wittig reagent is first prepared by adding 16.19 g of 4-carboxybutyl triphenylphosphonium bromide to the reaction product of 3.51 g of sodium hydride and 85 ml of dimethyl sulfoxide, which had previously been at a temperature of 70 for 11/2 hours -75 ° C and then cooled to about 25 ° C. The mixture is stirred at a temperature of about 25 ° C for 25 minutes and then treated with 4.89 g of the lactole of formula 201 in 35 ml of dimethyl sulfoxide This solution of the lactole is added dropwise over a period of 15 minutes with stirring and after the addition is complete stirring is continued for a further 30 minutes.

The mixture thus obtained is added to one liter of ice water containing 250 ml of 2-normal potassium hydrogen sulfate and then shaken out with ether. The organic phase is washed with brine, dried and concentrated. The product is mixed with 100 ml of ether and 5 ml of methanol and esterified using di-azomethane. The solution is concentrated and then chromatographed on an HPL column and eluted with a mixture of ethyl acetate plus Skellysolve B in a mixing ratio of 1: 1. This gives 4.08 g of the compound mentioned in the title.

In thin layer chromatography on SiCagel using a mixture of ethyl acetate plus Skellysolve B in a mixing ratio of 2: 1, this product has an Rr value of 0.20. If the thin layer chromatography on silica gel is carried out using a mixture of acetone plus methylene chloride in a mixing ratio of 1: 2 as the eluent, the Rr value is 0.60.

The nuclear magnetic resonance spectrum shows peaks at 5.77-5.29.4.89-4.60.4.34-3.16.3.67.2.82-1.33 5 and 1.20 5.

In the infrared spectrum, absorption occurs at 3550.3000, 1740, 1430, 1350, 1200, 1130, 1070, 1020, 970, 900, 865 and 810 cm-1.

Stage (e) of Reaction Scheme 41

The 19-hydroxy-19-methyl-PGF2a methyl ester and its corresponding (15R) epimer are produced in this stage. The second of these compounds mentioned is the compound of formula 203 of reaction scheme 41. 0.590 g of the mixture of the bis (THP ether) compounds of formula 202, which were obtained in process step (d), are in 33 ml a mixture of acetic acid plus water plus tetrahydrofuran in a mixing ratio of 20: 10: 3 at a temperature of about 25 ° C hydrolyzed overnight. This mixture is concentrated from toluene and then from ethyl acetate. The residue is chromatographed on an HPLC column using a mixture of acetone + methylene chloride in a mixing ratio of 3: 2 as the eluent. In this way, only -.129 g of the (15R) compound mentioned in the title are obtained.

If you perform thin layer chromatography on SiCagel and use a mixture of acetone plus methylene chloride in a mixing ratio of 3: 1 as the eluent, then the (15R) compound has an Rr value of 30 0.38 and the corresponding (15S) compound one Rr value of 0.27.

The (15S) compound shows peaks at 5.75-5.04.4.32-3.03.3.65.2.66-1.31 and 1.17 5 in the nuclear magnetic resonance spectrum.

35 The (15S) compound adds absorptions in the infrared spectrum at 3450,3000,1740,1430,1360,1200,1150,965, 920 and 900 cm-1.

The (15S) compound adds lines at 671,4000,686,596,581,513,506,491,423,397,333,307, 40,243 and 217 in the mass spectrum.

The (15R) compound shows properties in the nuclear magnetic resonance spectrum, in the infrared spectrum and in the mass spectrum which are very similar to those of the (15S) compound.

45

Step (f) of reaction scheme 41

The 19-hydroxy-19-methyl-PGE2 methyl ester and its corresponding (15R) epimer are prepared in this stage. The (15R) epimer is the compound of formula so 205 of Reaction Scheme 41.

0.602 g of the mixed bis (THP ether) compounds of Formula 202 are oxidized with the Jones reagent and then subjected to hydrolysis to replace the THP protecting groups.

55

The epimers mixed with respect to the carbon atom 15 are separated from one another by chromatography on an HPLC column, using a mixture of acetone + methylene chloride in a mixing ratio of 1: 1 as the eluent. This gives 0.119 g of the (15R) compound mentioned in the title and then 0.138 g of the (15S) compound mentioned in the title.

In thin-layer chromatography on SiCagel using a mixture of acetone + methylene chloride in a mixing ratio of 3: 1 as the eluent, the (15R) compound shows an Rr value of 0.48 and the (15S) compound shows an Rr value of 0.36 .

The (15S) compound shows in the nuclear magnetic resonance

645369

70

nance spectrum peaks at 5.83-5.02.4.56-3.33.3.66.3.04-1.34 and 1.20 5.

The (15S) compound has absorptions in the infrared spectrum at 3450, 3000, 1740, 1430, 1360, 1300, 1230, 1150, 1070, 1000, 965, 900 and 760 cm- '.

The (15S) compound shows lines at 597.3441.581.522.507.439.349.295 and 131 in the mass spectrum.

In the nuclear magnetic resonance spectrum, in the infrared spectrum and in the mass spectrum, the (15R) compound shows properties which are very similar to those of the (15S) compound.

Preparation 10

Preparation of the 9- (dimethyl-6-butylsilyl) -19-keto-PGF2a-bis (tetrahydropyranyl ether) and the 19-keto-PGF2a-methyl ester.

The tetrahydropyranyl ether mentioned in the title is the compound of formula 207 of reaction scheme 42.

The methyl ester mentioned in the title is the compound of formula 208 of reaction scheme 42.

Reference is now made to Reaction Scheme 42.

5

Step (a) of Reaction Scheme 42

0.500 g of the compound of formula 206 in 8 ml of methylene chloride are added to the Colhns reagent and methylene chloride at a temperature of 0 ° C. The Collins re-io agent was prepared from 0.526 g of chromic acid anhydride in 0.831 g of pyridine.

After the addition is complete, the mixture is stirred at a temperature of 25 ° C. for 1.2 hours and then diluted with 200 ml of ether, filtered and concentrated. This gives 0.502 g of a residue which consists of the 9-silyl-l 1,5-bis (THP ether) -19-keto compound of the formula 207.

Reaction scheme 42

(Rl7) 3 ^^ —Q

R <m Qn

(R ^ JaSI-O

R, 1st

0H \

0H

0H

^ Level (a)

a ■

i-LL-COOR3O

5

^ Level (b)

-— ^ l /.- cqor-a

206

207

208

cc

RH Q

u-c00h

209

Oh

I.

Reaction Scheme 42 (continued)

I.

.U-COOR.

30th

Ly — COOR30

Step (b) of reaction scheme 42

The product from stage (a) is hydrolyzed in a mixture of tetrahydrofuran plus acetic acid plus water in a mixing ratio of 3:20:10 at a temperature in the range from 47-50 ° C. for 4 hours. The mixture is concentrated and then chromatographed by eluting with a 1: 1 mixture of acetone plus methylene chloride. This gives 0.126 g of the methyl ester compound of the formula 208 mentioned in the title.

In thin-layer chromatography on silica gel using a mixture of acetone + methylene chloride in a mixing ratio of 1: 1 as the eluent, this compound has an Rr value of 0.33.

In the nuclear magnetic resonance spectrum there are peaks at 5.87-5.06.4.60-3.12.3.65.2.69-0.84 and 2.13 S.

In the infrared spectrum, the compound provides absorptions at 3350, 2900, 1730, 1430, 1350, 1220, 1160 and 965 cm "1.

In the mass spectrum there are lines at 598.3545.583, 513.508.493.423.418.217 and 187.

Step (c) of reaction scheme 42

In this stage, the (15R) -19-keto-PGF2a methyl ester of formula 208 of reaction scheme 42 is prepared.

If the corresponding (3R) -lactone isomer is used instead of the (3S) -lactone isomer, the (15R) -19-keto-PGF2a-methyl ester compound of the formula 208 is obtained. This shows in thin-layer chromatography on silica gel using a mixture of methylene chloride + acetone in a mixing ratio of 1: 1 as the eluent, an Rr value of 0.27.

In the nuclear magnetic resonance spectrum, peaks are found at 5.70-5.15.4.10.3.67.3.20.2.17 and 2.70-1.20 8.

In the infrared spectrum, absorptions at 3300, 2990, 1710, 1420, 1350 and 965 cm "-1 are shown.

A line at 598.3516 is found in a high resolution mass spectrum.

71 645 369

Step (d) of reaction scheme 42

The 19-keto-13,14-dihydro-PGF ia-methyl ester is prepared in this stage.

5 Process stage I

2.0 g of the starting product of reaction scheme 42 of formula 206, i.e. on the 9-dimethyl-t-butylsilyl- (19R, S) -19-hydroxy-PGF2a-11,15-bis (tetrahydropyran-2-yl ether) methyl ester on the carbon atoms 5-6 and 10 13-14 reduced by catalytic hydrogenation in

210 75 ml of ethyl acetate using 200 mg of a 5 percent palladium-on-carbon catalyst. This gives a mixture of the corresponding PGFla product and the corresponding 13,14-dihydro-

15 PGFla product, and this mixture is then further hydrogenated to the corresponding 13,14-dihydro compound.

Process stage II

Using known oxidation processes, the corresponding 9-silyl-11-15-bis (THP ether) -13,14-dihydro-19-keto-PGFla methyl ester is obtained.

Then by hydrolysis in a mixture of tetrahydrofuran + acetic acid + water, which in

Received 211 title compound. The results of the core-25 magnetic resonance spectrum and the thin-layer

Matography show that the less polar acetal form and also the 19-keto form are present.

Thin layer chromatography on SiCagel using the A-IX solvent system gives a 30 Rf value of 0.26, an Rr value of 0.54 and an Rr value of 0.67.

In the nuclear magnetic resonance spectrum, peaks are found at 4.52-3.30.3.62.3.38.3.00-0.87.2.08 and 1.18 o. The mass spectrum adds lines at 512.3336.528 , 35 517,497,427,422,412,369 and 217.

Preparation 11

Preparation of the 19-hydroxy-19-methyl-PGF2a-methyl ester.

40 The compound mentioned in the title is compound 215 of reaction scheme 43.

Reference is now made to Reaction Scheme 43.

45 Reaction scheme 43

U-C00H

212

55

Stu, fe (a)

(A) 3Si-

65

^ .L ^ -COOH Rs

213

Level (b)

645369

Reaction Scheme 43 (continued)

72

a-COOH

R «tt

R11 Q,

Lit-COOH

grade f)

219

214

0.500 g of the 9-silyl-l, 15-bis (THP ether) -19-keto compound of the formula 212 of the reaction scheme 43 are in 50 ml of benzene at a temperature of about 25 ° C with 2.3 Equivalents of trimethyl aluminum treated, which is added dropwise over a minute. The mixture is stirred for 30 minutes and then it is added to 50 ml of a saturated aqueous ammonium chloride solution and shaken out with ethyl acetate. The organic phase is washed with brine, dried and concentrated. The residue is chromatographed to give the corresponding 19-hydroxy-19-methyl compound, which is then deprotected by treatment with a mixture of tetrahydrofuran + acetic acid + water in a mixing ratio of 3:20: 10 performs. You get the connection mentioned in the title.

Preparation 11A

Preparation of the 15,19-dimethyl-19-hydroxy-PGF2a-30 methyl ester and its (15R) epimer.

The (15R) epimer mentioned in the title is the compound of formula 215 of reaction scheme 43.

The (15R, S) -15-methyl-19,20-didehydro-PGF2a-II-tetrahydropyranyl ether methyl ester 35 is used as the starting material. This is saponified and the free acid is obtained. The compound is treated first with the silylating agent and then with dihydropyran in the presence of pyridine hydrochloride. The 15-meth-yl-19-keto compound of the formula 212 is then prepared by using the 40 processes described here and then producing the compound mentioned in the title.

Preparation 12

Preparation of the (2E) -A2-19-Hydroxy-19-methyl-PGF2a-45 methyl ester.

The compound mentioned in the title is the compound of Formula 223 of Reaction Scheme 44.

217 Reference is made here to reaction scheme 44.

50

Step (a) of Reaction Scheme 44

The 2-phenyl-selenidyl compound of the formula 221 is first prepared. The starting material is the methyl ester of formula 220, which is used in the form of bis (tetrahydropyran-2-yl-55 ether). A solution of 0.4 g of this bis (THP) methyl ester in 5 ml of tetrahydrofuran is added dropwise to the amide, which consists of 0.3 g of N-isopropylcyclohexylamine and 1.6 equivalents of n-butyllithium in the form a 1.6 molar solution in hexane was prepared. 6o The amide was in 7 ml of tetrahydrofuran and the mixture was cooled to -78 ° C. The mixture is stirred at -78 ° C. for 45 minutes and then phenylselen-2-yl chloride, dissolved in tetrahydrofuran, is added over a period of 7 minutes. The mixture is stirred at -78 ° C. for a further hour and then poured into 30 ml of a mixture of saturated ammonium chloride and ice water step (g), and the mixture is shaken with diethyl ether. The organic phase is dried and concentrated. The back

73

645 369

is chromatographed on silica gel, and the mixture is eluted with a mixture of ethyl acetate + toluene in a mixing ratio of 1: 8. The compound of formula 221 of reaction scheme 44 is obtained.

Reaction scheme 44

OR

25th

OOR

30th

220

II

'' Stage (a)

the compound of Formula 222 of Reaction Scheme 44 is obtained.

Step (c) of the reaction scheme 44 s The compound of formula 223 mentioned in the title is obtained by splitting off the protective groups from the product of reaction step (b), ie the compound of formula 222, by removing them at a temperature of 40 ° C treated with a mixture of acetic acid + water + tetrahydrofuran io in a mixing ratio of 20: 10: 3.

Preparation 13

Production of (4Z) -A4-19e-Hydroxy-PGF-1? ..

The compound mentioned in the title is the compound of the formula 227 of the reaction scheme 45.

Reference is now made to Reaction Scheme 45. In the process described there, a 6-membered lactol of the formula 226 is first prepared.

20 Reaction scheme 45

224

225

226

227

645 369

Step (a) of Reaction Scheme 45

In step (a) of this reaction scheme, the enol ether of the formula 225 is prepared by the following process:

A suspension of 32.4 g of methoxymethyltriphenylphosphonium chloride (for the preparation thereof, reference is made to the publication by Levine in J. Am. Chem. Soc. 80,6150 (1958)) in 150 ml of tetrahydrofuran is set to —15 ° C cooled, and to this suspension is added 69.4 ml of a 1.6 molar solution of butyllithium in 45 ml of tetrahydrofuran. After 30 minutes, a solution of 10.4 g of the compound of formula 224 in 90 ml of tetrahydrofuran is then added. The compound of formula 224 is 3a, 5a-dihydroxy-2ß- (3a, 74-dihydroxy-trans-l-octen-yl) -1 a-cyclopentane-acetaldehyde-y-lactol-tris (tetrahydropyranyl ether), and it was in this regard to the publication of JC Sih in "Prostaglandine" 13,831-5 (1977) pointed out. The mixture is stirred for 11/2 hours and warms to about 25 ° C, and then concentrated under reduced pressure. The resulting residue is partitioned between dichloromethane and water, and the organic phase is dried and concentrated. This residue is then subjected to chromatography on silica gel using a mixture of cyclohexane and ethyl acetate in a mixing ratio of 2: 1 as the eluent. Those fractions in which the thin layer chromatography shows that they contain the intermediate of formula 225 are combined and concentrated to give this enol ether of formula 225.

Step (b) of Reaction Scheme 45

The enol ether of the formula 225 thus prepared is hydrolyzed in 20 ml of tetrahydrofuran with 50 ml of a 66 percent acetic acid at about 57 ° C. for 21/2 hours. The mixture is concentrated under reduced pressure. Toluene is added to the residue and the solution is concentrated again. Finally, the residue is subjected to chromatography on silica gel using a mixture of chloroform + methanol in a mixing ratio of 6: 1 as the eluent. The lactol of formula 226 is obtained by combining the appropriate fractions and concentrating them.

Step (c) of Reaction Scheme 45

In step (c), the compound mentioned in the title is produced as follows:

The 3-carboxypropyltriphenylphosphonium bromide is prepared by refluxing 156.8 g of triphenylphosphine and 100 g of 4-bromobutyric acid in 125 ml of benzene for 18 hours. The crystalline product is filtered off, washed with benzene and recrystallized from a mixture of ethanol + acetic acid nitrile + ether. This gives 150 g of the product mentioned, which has a melting point of 247-249 ° C.

10.6 g of this phosphonium bromide are then added to sodium methylsulfinylcarbanide, which was prepared from 2.08 g of a 57% sodium hydride and 30 ml of dimethyl sulfoxide, and the Wittig reagent thus obtained is then mixed with the lactol of the formula 226 , which was obtained in process step (b), mixed in 20 ml of dimethyl sulfoxide. Then this mixture is stirred overnight and diluted with about 200 ml of benzene and washed with a potassium hydrogen sulfate solution. The two layers are washed with dichloromethane and the organic phases are combined, washed with a saline solution, dried and concentrated under reduced pressure. The residue obtained is subjected to a chromatographic

74

subjected to graphics over an acid-washed silica gel, a mixture of ethyl acetate and isomeric hexanes in a mixing ratio of 3: 1 being used as the eluent. Those fractions which can be seen from the thin-layer chromatography that they contain the compound mentioned in the title are combined and concentrated to give the compound mentioned in the title.

The preparation of compounds xo according to the invention will now be explained in more detail with reference to the following examples.

example 1

Preparation of the (5Z) -9-deoxy-6,9a-epoxy-A5- (19R, S) -19-hydroxy-PGFrmethyl ester.

is The compound mentioned in the title is the compound of formula 228.

20th

(CH3) 3-C00CH;

C- (CHJ3-ch-CH;

/ 'oh

To you

Reaction Stage I 35 Reference is made to Reaction Scheme 1. The isomeric 5-iodine compounds of the formula 17 are first prepared. For this purpose, a solution of 0.655 g of the (19R, S) -19-hydroxy-PGF2a methyl ester of the formula 16, which was prepared according to preparation 3, in 14 ml of meth-40 ylene chloride with 14 ml of a saturated aqueous solution of Treated sodium bicarbonate and cooled to 0 ° to 5 ° C. A solution of 0.474 g of iodine in 35 ml of methylene chloride is then added with vigorous stirring. The mixture is stirred for a total of one hour, where the temperature then rose to 10 ° C. The organic phase is separated, washed with a 10% aqueous sodium sulfite solution, dried and concentrated to give 0.803 g of an oil. This mainly consists of the 6R, 5R isomer.

50

Stage II

The iodine compound obtained from stage I is in 32 ml of benzene with 1.70 ml of l, 5-diazabicyc! O [4.30] -nonen-5, which is abbreviated as "DBN", at about 45 ° C for 25 Treated for 55 hours. Then the mixture is diluted with 125 ml of benzene, which contains 1% triethylamine and washed with ice water and brine, dried and concentrated. Traces of residual “DBN” are removed by taking up in 150 ml of benzene and washing with ice water 60. The organic phase is dried and concentrated to give 0.300 g of the compound of formula 228 mentioned in the title.

In a thin layer chromatography using a mixture of acetone plus hexane in a mixture 65 ratio of 3: 1 as the eluent, this compound has an Rf value of 0.34.

The nuclear magnetic resonance spectrum shows peaks at 5.52.4.55.4.30-3.60.366.2.90-1.30 and 1.13 5.

75

In the infrared spectrum, absorptions occur at 3400, 1995, 1735, 1695, 1430 and 970 cm.

A line at 598.3563 is found in a high resolution mass spectrum.

645 369

In the nuclear magnetic resonance spectrum, lines appeared at 5.50.4.40.4.25-3.30.3.67.2.65-1.30 and 1.13 8.

A high resolution mass spectrum showed a line at 600.3705.

Example 2

Preparation of the (6R) -9-deoxy-6,9a-epoxy- (19R, S) -19-hydroxy-PGFj-methyl ester and the corresponding (6S) -isomer.

The first compound mentioned in the title is the compound of Formula 20 of Reaction Scheme 2.

Level I

A solution of 1.00 g of the A19-PGF2a-bis (tetrahydro-pyranyl ether) methyl ester, which was prepared according to preparation 2, in 23 ml of tetrahydrofuran is added dropwise to a suspension of 1.545 g of mercury-II-acetate in 23 ml of water and 23 ml of tetrahydrofuran. The mixture is stirred at a temperature of about 25 ° C. for 21/2 hours. The mixture is then cooled to 0 ° -5 ° C. and treated with 0.388 g of solid sodium borohydride, which is added in small individual portions over a period of 2 1/2 minutes. The mixture is then stirred at a temperature of about 25 ° C for 3 1/2 minutes and diluted with 100 ml of ether. The solution is decanted from the mercury and separated. The aqueous phase is shaken out further with ether and the combined organic phases are concentrated. The residue is taken up in 300 ml of ether, washed with brine, dried and concentrated to give 1.230 g of an oil. This contains the bis (THP ether) of the compounds mentioned in the title.

Stage II

The protective groups are removed from the product obtained in stage I by treating it in a mixture of acetic acid plus water plus tetrahydrofuran in a mixing ratio of 20: 10: 3 at a temperature of about 45 ° C. for 21/2 hours. The mixture is concentrated and finally subjected to azeotropic distillation with benzene, whereby a mixture of the epimers with respect to the carbon atom 6 of the formula 20 of the reaction scheme 2 is obtained.

Stage III

The product obtained in this way is subjected to chromatography using the HPLC method using a column B from Merck. A mixture of acetone plus hexane in a mixing ratio of 2: 1 is used as the eluent in order to elute the less polar fraction. This is the (6R) -9-deoxy-6,9a-epoxy- (19R, S) -19-hydroxy-PGFrmethyl ester, and 0.086 g of this product is obtained.

In thin layer chromatography using a mixture of acetone plus hexane in a mixing ratio of 3: 1 as the eluent, this material has an Rf value of 0.28.

In the nuclear magnetic resonance spectrum, lines appear at 5.50.4.35-3.10.3.67.2.60-1.30 and 1.13 S.

A high resolution mass spectrum provides a line at 600.3681.

A more polar fraction was also obtained in an amount of 0.150 g. This was the (6S) -9-deoxy-6,9a-epoxy- (19R, S) -19-hydroxy-PGF1 methyl ester.

In the mass spectrum using a mixture of acetone plus hexane in a mixing ratio of 3: 1 as the eluent, this showed an Rf value of 0.25.

Example 3

Preparation of the sodium salt of (5Z) -9-deoxy-6,9a-epoxy-A5- (19R, S) -19-hydroxy-PGF1.

The compound mentioned in the title has the following 1 formula 240.

(CHa) 3-C00Na C-H

20th

25th

t- (ch2) 3-ch-ch3

h% 0h 0h

A solution of 0.140 g of the methyl ester of (5Z) -9-de-oxy -6,9a-epoxy-A5- (19R, S) -19-hydroxy-PGF1; which was prepared according to Example 1, in 6 ml of methanol and 4 ml of water was treated with 4.10 ml of a 0.1 N aqueous sodium hydroxide solution at a temperature of about 25 ° C for 25 hours. The mixture is concentrated and finally freeze-dried, the compound mentioned in the title being obtained in the form of a white free-flowing solid. The yield was 0.130 g and the product had a melting point of 152-158 ° C.

A line at 656.3761 was found in a high resolution mass spectrum.

40

Example 4

Preparation of the (5Z) -9-deoxy-6,9a-epoxy-A5- (19R, S) -19-hydroxy-PGFr4-acetylphenyl ester.

45 Two methods for producing this ester are described.

Method I

This process is carried out over the mixed acid-anhy-50 dride.

A stirred suspension of 0.195 g of the sodium salt of 19-hydroxy-PGF2, which was prepared by the process according to Example 2, in 15 ml of methylene chloride and 0.120 g of triethylamine is at a temperature of about 55 0 ° C with 0.0656 g of isobutyl chloroformate in 1 ml of methylene chloride. The mixture is stirred at a temperature of about 25 ° C for 2 hours and then cooled again to about 0 ° C and treated with 0.0653 g of 4-hydroxyacetophenone in 1 ml of methylene 60 chloride, which is about 0 , Contains 25 ml of triethylamine. The mixture is stirred at a temperature of about 25 ° C for 1 hour, then cooled to 0 ° C and diluted with 25 ml of a mixture of methylene chloride plus triethylamine in a mixing ratio of 95: 5. Then 65 is washed with a 5% aqueous sodium bicarbonate solution and with a cold 0.1N potassium hydroxide solution. The organic phase is then dried and concentrated to give the title compound.

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Method II

It is the 2-halogenopyridinium salt method.

A solution of 1.04 g of the sodium salt of 19-hydroxy-PGF2, which was prepared by the process according to Example 3, in 35 ml of dimethylformamide and 0.352 g of triethylamine is mixed with 0.81 g of 2-bromo-l -Methyl-pyridi-nium iodide treated at a temperature of 25 ° C for 1 hour. Regarding the 2-bromo-l-methyl-pyridinium iodide, reference is made to the publication in J. Chem. Soc., Perkins Trans.,

76

2 (1974) 790. The mixture is then treated with 0.364 g of 4-hydroxyacetophenone in 2 ml of dimethylformamide and 0.4 g of triethylamine at a temperature of about 25 ° C. The mixture is then stirred for about 16 s and poured into ice water which contains 4 ml of 1N potassium hydroxide and shaken out with diethyl ether. The organic phase is washed with a cold 0.02N solution of potassium hydroxide, dried and concentrated to give the compound io mentioned in the title.

Claims (5)

645 369 PATENT CLAIMS 1. Prostacyclin derivatives, characterized in that they have the formula d) OH j-C 2 "(CH 2 - (PC jC-CH 3 * 'OH, in which Ri 3 is a hydrogen atom or a methyl group and PC represents a radical which has arisen from the loss of carbon atom 19 and carbon atom 20 from a compound of the prostacyclin type of one of the following groups: I) compounds of the formula in which the wavy lines, that is to say the symbols, in these groupings illustrate that the bond can be present in the a configuration or the β configuration, Q io means one of the following groupings: II O, HH, R4 OH or R4 OH in which R4 is a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms inclusive , R, has one of the following meanings: i 19 20 ■ xc — c- (ch2) 2-ch2ch3 k ii i Kz Q Re in which A] is an oxa group of the formula -O- is E] for a group of the formula -CH2-, L! Has one of the following meanings: a) a grouping of the formula - (CH2) n-, in which nl is up to and including 5 or b) a grouping of the formula - (CH2) p-CF2-, in which p is 2, 3 or 4, provided that then if Mi is a grouping of the following formulas 20 a) -COOR3 b) -CH2OH c) -CH2N (R7) (R8) o II 2sd) -CN (R7) (R8) O II e) -C-NH-S02- Ri5 ■ NH-N or 30 / f ^ \ II «—N 35 where in these groups R3 has the following meanings: a) hydrogen b) an alkyl radical with 1 to 12 carbon atoms, including c) a cycloalkyl radical with 3 up to and including 10 carbon atoms d) is an aralkyl radical with 7 up to and including 12 carbon atoms, L] also has the meaning of a grouping of the form 45 e) a phenyl radical with - (CH2-CH = CH) - Mi has one of the following groups is: a) (A ^ -CcrC (Lx) f) a phenyl radical which is substituted by 1,2 or 3 chlorine atoms or alkyl groups each having 1 to 3 carbon atoms g) a group of the formula \ H b) / \ / (A ^ -Ç ^ C ^ H (L,) 55 60 <2r 0 ii c-ch3 h) a grouping of the formula - (/ VS-nh-8 - // vs-nh-c- ch3 c) H 5 -c I 'eroder i) a grouping of the formula 1 ^ (L) 15 R9 represents a hydrogen atom or a hydroxyl group. <1 is '19 20 x-c - <- (ch2) 2-ch2ch3 Q Re / r2 19 20 x-c-c- (ch2) 2-ch2ch3 ii i Q R6 in which From Ei, Q, R], R2, R5, R6 and X have the same meanings as were explained in connection with the compounds of group I. L3 has one of the following meanings: a) A grouping of the formula - (CH2) n-, in which n is an integer in the range from 1 to 5 inclusive b) A grouping of the formula - (CH2) p-CF2-, in which p is 2, 3 or 4 or c) a grouping of the formula -CH2-CH = CH- and where the wavy line, ie the sign ~, indicates that the bond is in a cis configuration or a trans configuration, and further V) Prostacyclin analogues of the formula in which 40 Q, Rb R2, R5, Rg and X have the same meanings as were given in connection with the compounds of group I and the wavy line, that is to say the sign of the formula ~, that the binding is in the cis configuration or the trans-45 configuration and wherein L4 has the following meanings: a) a grouping of the formula ~ (CH2) n-, in which n represents an integer in the range from 1 to 5 or b) a grouping of the formula - (CH2) P-CF2-, in which p2, 3 or 4 and Rio represents a straight-chain alkyl chain with 1 to 6 carbon atoms inclusive, and further VII) Prostacyclin analogs of the formula 55 60 65 h 0 5 il ch2-c-l5-Ri crc \ "'ch2 / r2 I 1 9 20 -c-c- (ch2) 2-ch2ch3 L in which 645 369 Q, Ri, R2, R5, Rfi and X have the same meanings as were explained in connection with the compounds of group I and the wavy line, i.e. the symbol ~, shows that the bond in the cis configuration or the trans configuration can exist and where L5 has the following meanings: a) A grouping of the formula - (CH2) P- in which p is 2, 3 or 4 or b) the group of the formula -CH2-CF2-and further VIII) Prostacyclin analogs of the formula ^ C-CH2-Li + -RI f \ h L3 has the same meanings as were explained in connection with the compounds of group IV and where M2 either i a) a grouping of the formula -C = C I (L) H or 10th I 19 20 x-c-c- (ch2) 2-ch2ch3 R '"I Rz Q Re in which the groups Q, Rb R2, R5, Rß and X have the same meanings as explained in connection with the compounds of group I and L4 has the same meanings as given in connection with the compounds of group VI, and further IX) Prostacyclin analogs of the formula I 19 20 X-C-C- (CH2) 2-CH2CH3 ii i Q R6 in which the remains Q, R], R2, R5, R6 and X have the same meanings as given above in connection with the compounds of group I and L6 has one of the following meanings: a) a grouping of the formula - (CH2) n-, in which n is an integer in the range from 1 to 5 or b) the grouping of the formula -CH2CH = CH- and further X) 6a-Carba-prostacyclin analogues of the formula M2-L3-R-, I 19 20 x-ç — c- (ch2) 2-ch2ch; in which the groups Q, R [, R5, R6 and X have the same meanings as were given in connection with the compounds of group I b) a grouping of the formula ^ H -C = C and 1) a grouping of the formula -ch = n-nh-c-nh2 m) a grouping of the formula n) a grouping of the formula O II -ch2-c-r16 in which R16 is a phenyl radical, a p-bromophenyl radical, a p-biphe-nylyl radical, a p-nitrophenyl radical, a p-benzamidophenyl radical or a 2-naphthyl radical or o) denotes a pharmacologically acceptable cation, R7 and R8 are identical to or different from one another and have the meaning of hydrogen atoms, alkyl radicals having 1 to 12 carbon atoms, benzyl radicals or phenyl radicals, R15 is a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, a phenyl radical or a phenyl radical which is substituted by 1,2 or 3 chlorine atoms or alkyl groups having 1 to 3 carbon atoms or a phenyl radical which is substituted with a hydroxycarbonyl group or an alkoxycarbonyl group with 1 to 4 carbon atoms, R2 represents a hydrogen atom, a hydroxyl group or a hydroxymethyl group R5 and R6 are identical or different from one another and denote hydrogen atoms, alkyl groups with 1 to 4 carbon atoms and fluorine atoms, but one of the radicals R5 and R6 may only mean a fluorine atom if the other of these two radicals is hydrogen or fluorine and is in equilibrium with the corresponding monocyclic compounds of the formula Ia 0 / E1-c! -Ch2-l1-r1 Rs ! 19 20 ! / ii | * ra q r6 stand in which | Lj has one of the following meanings: a) a group of the formula - (CH2) "-, in which n is an integer in the range from 1-5 or b) a group of the formula - (CH2) p-CF2-, in which p is 2, 3 or 4 or c) a group of the formula -CH2-CH = CH- and where Q, Ri, R2, R5, R6, X and E have the same meaning as in the compounds of group I and further II prostacyclin analogs of the formula A "" "'VN3 ~ l-2" Rl ^% 50 55 60 Î5 I 19 20 X-C-C- (CHaJa-CHaÇHa li I Q R6 in which M ,, Q, R], R2, R5, Rg and X have the same meaning as explained in connection with the compounds of group I. Aj is an oxa grouping of the formula -O- E2 means the grouping of the formula -CH2CH2- and L2 one of the following meanings a) a grouping of the formula - (CH2) - in which j is an integer in the range from 1 to 4 inclusive b) a grouping of the formula - (CH2) q-CF2-, in which q 1, 2 or 3 or c) has a group of the formula -CH = CH-, and when, in the compounds of group II Mj, a group of the formula 65 Oh 645369 2. Connection according to claim 1, characterized in that it is one of the following compounds: 20 The methyl ester of (5Z) -9-deoxy-6,9a-epoxy-A 5-19Ç-hydroxy-PGF] the sodium salt of (5Z) i -9-deoxy-6,9a-epoxy-A5-19Ç-hydroxy-PGFi the methyl ester of (6R) -9-deoxy-6,9a-epoxy-19i; -hydr-25 oxy-PGF] the methyl ester of (6S) -9-deoxy-6,9a-epoxy-19 £, -hydr-oxy-PGF j das (5Z) -2-decarboxy-2-hydroxymethyl-9-deoxy-6,9a- ep-oxy- A5-19 ^ -hydroxy-PGF i, 3o the (5Z) -2-decarboxy -2-hydroxymethyl-9-deoxy-6,9a-epoxy-A5-16,16-difluoro-19E, -hydroxy-PGF i, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 £, 9a-epoxy-19 ^ -hydroxy-PGFi, the 2 decarboxy -2-hydroxymethyl-9-deoxy-6i; 9a-epoxy-35 16,16-difluoro-19 ^ -hydroxy-PGF j, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6i ;, 9a-epoxy-6i ;, 19e-dihydroxy-PGFi, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6i; 9a-epoxy-6 ^, 19e-dihydroxy-16,16-difluoro-PGF i, 40 the (4Z) -2-decarboxy -2-hydroxymethyl-9-deoxy-5,9a-epoxy-A4,19Ç-hydroxy-PGFb the (4Z) -2-decarboxy -2-hydroxymethyl-9-deoxy-5, 9a-epoxy-A 4,16,16-difluoro-19 £ -hydroxy-PGF i, the (2E, 4Z) -2-decarboxy -2-hydroxymethyl-9-deoxy-5,9a-45 epoxy-A2, A4-19Ç-hydroxy-PGFi, the 2-decarboxy -2-hydroxymethyl-9-deoxy-5Ç, 9a-epoxy-19 ^ -hydroxy-PGFi, the 2-decarboxy -2-hydroxymethyl-9-deoxy-59a-epoxy-16,16-difluoro-19Ç-hydroxy-PGF x, so the (5Z) -2-decarboxy -2-hydroxymethyl-9-deoxy-6,9a-epoxymethano-A5,19 ^ -hydroxy-PGF ,, the (5Z) -2-decarboxy -2-hydroxymethyl-9-deoxy-6,9a-epoxymethano-A5,16,16-difluoro-19 ^ -hydroxy-PGF ,, the 2-decarboxy -2-hydroxymethyl-9- deoxy-6 £, 9a-epoxy-55 methano-19 ^ -hydroxy-PGFi, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 ^, 9a-epoxy-methano-16,16-difluoro-19 ^ -hydroxy-PGF i, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 £, 9a-epoxy-52 ,, 19 ^ -dihydro-PGF ,, so the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 ^, 9a-epoxy-5e, 19e-dihydroxy-16,16-difluoro-PGF i, the (4E) -2-decarboxy -2-hydroxymethyl-9-deoxy-6i; 9a-epoxy-A 4-19 ^ -hydroxy-PGF i, the (4E) -2-decarboxy -2-hydroxymethyl-9-deoxy-6Ç, 9a-65 epoxy-A4-16,16-difluoro-19 ^ -hydroxy-PGF i, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6E ,, 9a-epoxy-6e-methoxy-19e-hydroxy-PGF i, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6i ;, 9a-epoxy- 645369 6e-methoxy-16,16-difluoro-19C-hydroxy-PGF 1, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 ^, 9a-epoxy- 3. Compounds according to claim 1, thereby 15 indicates that they are the following monocyclic compounds of groups la and IIa: the 2-decarboxy-2-hydroxymethyl-5-oxo-19 ^ -hydroxy-PGF], the 2-decarboxy-2-hydroxymethyl-5-oxo-l 6,16-difluoro-19Ç-20 hydroxy-PGF], the 2-decarboxy-2-hydroxymethyl-6-oxo-19 ^ -hydr-oxy-PGF, the 2-decarboxy-2-hydroxymethyl-6-oxo-16,16-difluoro-19E-hydroxy-PGF], 25 the 2-decarboxy-2-hydroxymethyl-5-oxo-19-hydroxy-19-methyl-PGF] , the 2-decarboxy-2-hydroxymethyl-5-oxo-16,16-difluoro-19-hydroxy-19-methyl-PGF], the 2-decarboxy-2-hydroxymethyl-6-oxo-19-hydroxy-19-30 methyl-PGF] or the 2-decarboxy-2-hydroxymethyl-6-oxo-16,16-difluoro-19-hydr oxy-19- methyl-PGF]. 3rd 645 369 - // \ W !! .// W j) a grouping of formula 0 - // \ V | -nh-c-ch3 X one of the following groups a) trans-CH = CH- b) cis-CH = CH- c) -C = C- or; d) -CH2CH2- means and wherein those compounds of formula I in which Mj is a group of formula oh -? ~ ch2. k) a grouping of the formula 0 ii nh-c-nh2 4. Pharmaceutical preparation, characterized in that it is a compound as active ingredient according to claim 351 contains. 4-oxo-16,16-difluoro -19-hydroxy -19-methyl-PGF], das2-decarboxy-2-hydroxymethyl-9-deoxy-6Ç, 9a-epoxy-A -19-hydroxy -19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-6i; 9a-ep-oxy-A6-16,16-difluoro -19-hydroxy -19-methyl-PGF], the 2-decarboxy-2-hydroxymethyl-9 -deoxy-6Ç, 9a-epoxy-A7 -19-hydroxy -19-methyl-PGF], s the 2-decarboxy -2-hydroxymethyl-9-deoxy-6Ç, 9a-ep-oxy-A7-16,16-difluoro -19-hydroxy -19-methyl-PGF j, the (2E) -2-decarboxy - 2-hydroxymethyl-9-deoxy-6 £, 9a-epoxy-A 2, A7 -19-hydroxy -19-methyl-PGF j, the (5E) -2-decarboxy -2-hydroxymethyl-6a-carba-9-des-iooxy-6,9a-epoxy-A5 -19-hydroxy -19-methyl-PGF] or the (5E) -2-decarboxy -2-hydroxymethyl -6a- carba-9-des-oxy-6,9a-epoxy-A5 -16,16-difluoro -19-hydroxy -19-methyl-PGF], 4-oxo -19-hydroxy -19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 ^, 9a-epoxy- 4-oxo-16,16-difluoro-19 ^ -hydr oxy-PGF i, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6Ç, 9a-epoxy- - A 6-l 9s-hydr oxy-PGF ,, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6Ç, 9a-epoxy- A 6-16,16-difluoro-19 ^ -hydr oxy-PGF], the 2-decarboxy -2-hydroxymethyl-9- deoxy-6 ^, 9a-epoxy- - A7-192, -hydroxy-PGF ,, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 £, 9a-epoxy- A7-16,16-difluoro-19 ^ -hydroxy-PGF j, the (2E) -2- decarboxy -2-hydroxymethyl-9-deoxy-6Ç, 9a- epoxy-A2, A7-19 ^ -hydroxy-PGF], the (5E) -2- decarboxy -2-hydroxymethyl-6a-carba-9-des- oxy-6,9a-epoxy-A 5-19 ^ -hydroxy-PGF ,, the (5E) -2- decarboxy -2-hydroxymethyl-6a-carba-9-des- oxy-6,9a-epoxy-A5-16,16-difluoro-19 ^ -hydroxy-PGF t, the (5Z) -2- decarboxy -2-hydroxymethyl-9-deoxy-6,9a- epoxy- A5 -19- hydr oxy -19- methyl-PGF ,, the (5Z) -2- decarboxy -2-hydroxymethyl-9-deoxy-6,9a- epoxy-A5-16,16-difluoro -19-hydroxy -19-methyl-PGF !, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 ^, 9a-epoxy- 19-hydroxy-19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 £, 9a-epoxy-16,16-difluoro -19-hydroxy -19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy- 6 pounds, 9a-epoxy-6 pounds, 19-dihydro-19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 |, 9a-epoxy- 6Ç, 19-dihydroxy -19-methyl-16,16-difluoro-PGF ,, the (4Z) -2- decarboxy -2-hydroxymethyl-9-deoxy-5,9a- epoxy- A4 -19-hydroxy -19-methyl-PGF], the (4Z) -2- decarboxy -2-hydroxymethyl-9-deoxy-5,9a- epoxy- A4-16,16-difluoro -19-hydroxy -19-methyl-PGF], the (2E, 4Z) -2- decarboxy -2-hydroxymethyl-9-deoxy-5,9a- epoxy-A2, A4-19-hydroxy-19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-5Ç, 9a-epoxy- 19-hydroxy-19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-5 ^, 9a-epoxy-16,16-difluoro -19-hydroxy -19-methyl-PGF], the (5Z) -2-decarboxy -2-hydroxymethyI-9-deoxy-6,9a-epoxymethano-A5 -19-hydroxy -19-methyl-PGF], the (5Z) -2- decarboxy -2-hydroxymethyl -9- deoxy-6,9a-epoxymethano- A 5-16,16-difluoro -19-hydroxy -19-methyl-PGF ,, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6i ;, 9a-epoxy- methano -19-hydroxy -19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-6i ;, 9a-epoxy- methano-16,16-difluoro -19-hydroxy -19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 £ ,, 9a-epoxy- 5Ç, 19-dihydroxy -19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-6Ç, 9a-epoxy- 5Ç, 19-dihydroxy -19-methyl-16,16-difluoro-PGF], the (4E) -2-decarboxy -2-hydroxymethyl-9-deoxy-6i ;, 9a- epoxy-A4 -19-hydroxy -19-methyl-PGF], the (4E) -2- decarboxy -2-hydroxymethyl-9-deoxy-6E ,, 9a- epoxy-A4-16,16-difluoro -19-hydroxy -19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-6i ;, 9a-epoxy- 6Ç-methoxy -19-hydroxy -19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 ^, 9a-epoxy- 6e, methoxy-16,16-difluoro -19-hydroxy -19-methyl-PGF], the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 |, 9a-epoxy- 4-oxo-19 pounds, -hydroxy-PGFi, the 2-decarboxy -2-hydroxymethyl-9-deoxy-6 |, 9a-epoxy- 4th where the symbol ~ indicates that the bond can be in an a configuration or a β configuration, these compounds are in equilibrium with the corresponding monocyclic prostacyclin analogues of group IIa e2-c-ch2-l2-rl rs I 19 20 C ~ (CH2) 2-Gf ^ -CH3 stand in which Q, Ri, R2, RS, Rfi, X, E2 and L2 have the same meaning as in the compounds of the formula II, and also III prostacyclin analogues of the formula "M -.- l-i-ri 19 20 r X-J - ^ - (CH2) 2-CH2CH3 p ' Q Re in which the radicals is Ai, E], Q, Ri, R2, Rs, Rg and X have the same meanings as were explained in connection with the compounds of group I. L2 has the same meanings as were given in connection with the compounds of group II 20 and the wavy line, i.e. the symbol ~, indicates that the bond is in the cis configuration or in the trans configuration, as well as VI) prostacyclin analogues of the formula 25th I 19 20 x-c — c- (ch2) 2-ch2ch: 0 " I. L in which Li, Mt, Q, R], R2, R5, R6 and X have the same meanings as explained in connection with the compounds of group I and A2 represents a grouping of the formula -CH20-, • of which the group -CH2- is bonded to the cyclopentane ring and E] represents a group of the formula -CH2- and also IV) Prostacyclin analogs of the formula 35 OR-io C / -wCH2-U-R., ch2 5. Pharmaceutical preparation according to claim 4, characterized in that it contains as the active ingredient a compound according to one of claims 2 or 3.