CH635836A5 - THERAPEUTICALLY EFFECTIVE PROSTACYCLIN ANALOGS. - Google Patents

Description

The present invention relates to new structural and pharmacological analogs of prostacyclin (PGI2). In particular, these are prostacyclin-like compounds in which the double bond between C-5 and C-6 is isomerized to the C-4 / C-5 position.

Prostacyclin is a mammalian endogenously produced compound that is structurally and biosynthetically related to prostaglandins. Prostacyclin has the following formula (with numbers):

50

(1) -CCH0) -CH.,

L m d

(2) - (CH0), 2 h

(T).

or

60

(3) -0

(T).

65 ho in which m is an integer from 1 to 5, h 0 to 3, s 0, 1, 2 or 3 and T chlorine, fluorine, the trifluoromethyl radical, an alkyl radical with 1 to 3 carbon atoms or alkoxy radical with 1 to 3 carbon atoms

(I)

5,6-Dihydroprostacyclin has the following formula:

635 836

cooh

(ii)

As can be seen from the formulas I and II, prostacyclin and 5,6-dihydroprostacyclin (ie PGIj) show a structural relationship PGF2a, which has the following formula:

cooh

(III)

As can be seen from formula III, prostacyclin and 5,6-dihydroprostacyclin in trivial names can be referred to as derivatives of PGF-like compounds. The common name for prostacyclin is therefore 9-deoxy-6,9a-epoxy (5Z) -5,6-didehydro-PGFi and for 5,6-dihydro-prostacyclin 9-deoxy-6,9a-epoxy-PGFj. A description of the geometric stereoisomerism used above is given by Blackwood et al., Journal of the American Chemical Society 90, 509 (1968). For a description of prostacyclin and its structural elucidation, reference is made to Johnson et al., Prostaglandins 12,915 (1976).

For the sake of simplicity, the new prostacyclin analogs are named for prostaglandins after the recognized trivial nomenclature system of N. A. Nelson, Journal of Médicinal Chemistry, 17,911 (1974). Accordingly, all new prostacyclin derivatives according to the invention are referred to as 9-deoxy-PGF-like compounds or alternatively and preferably as PGIr or PGI2 derivatives.

In the above formulas as well as in later formulas, dashed bond lines to a ring denote substituents in the a configuration, that is to say below the ring plane. Boldly marked bond lines to a ring denote substituents in the β configuration, that is, above the ring plane. A wavy line (~) denotes the binding of the substituents in the a or β configuration or in a mixture of the a and β configuration.

The side-chain hydroxyl group at C-15 in the above formulas is in the S or R configuration when determined according to the sequence rule of Cahn-Ingold-Prelog, compare J. Chem. Ed. 41:16 (1964). For a discussion of the stereochemistry of prostaglandins, which also applies to the new prostacyclin analogues, reference is made to Nature 212, 38 (1966). The carboxyl-terminated side chain is bound to the heterocyclic ring of PGI in the a or β configuration, which corresponds to the (6R) or (6S) configuration according to the above agreement. Terms such as C-4, C-5, C-6, C-15 and the like refer to the carbon atom in the prostaglandin or prostacyclin analog which is in a position that corresponds to the position with the same number in PGF2a or prostacyclin.

The molecules of PGIl5 PGI2 and the new asymmetric prostacyclin analogues have several asymmetry centers and can exist in racemic (optically inactive) form or in one of two enantiomeric (optically active) forms, i.e. right-handed or left-handed. In the present representation, the above formula for PGI2 corresponds to the compound that is produced endogenously by mammalian tissues. In particular, reference is made to the stereo configuration at C-8 (a), C-9 (a), C-II (a) and C-12 (ß) of endogenously produced prostacyclin. The mirror image of the above prostacyclin formula represents the other enantiomer. The racemic forms of io prostacyclin contain an equal number of both enanomeric molecules, and the above formula I and its mirror image are required to correctly reproduce racemic prostacyclin.

For the sake of simplicity, when using the term prostaglandin ("PG") or prostacyclin ("PGI2"), the optically active form of the prostaglandin or prostaticcycline in question is understood, which has the same absolute configuration as PGF2a from mammalian tissues.

A prostaglandin-like or prostacyclin-like product means all monocyclic or bicyclic cyclopentane derivatives which are useful for at least one of the pharmacological purposes for which the prostaglandins or prostacyclin are used.

The present formulas, which represent a prostaglandin-like or prostacylin-like product or an intermediate product suitable for their production, each represent the stereoisomer of the prostaglandin-like or prosta-cyclin-like product in question, the same stereochemical configuration as a corresponding prostaglandin or prostacyclin Mammalian tissues, or the respective stereoisomer of the intermediate product, which is suitable for the production of said stereoisomer of the prostaglandin-like or prostacyclin-like product.

A prostacyclin analog is understood to mean the stereoisomer of a prostacyclin-like product which has the same relative stereochemical configuration as prostacyclin from mammalian tissues, or a mixture of this stereoisomer and its enantiomer. When a formula is used to represent a prostacyclin-like product, the term prostacyclin analog refers to compound 40 of this formula or a mixture of this compound and its enantiomer.

Later than the present invention, trans-4,5-didehydro-PGIi was developed by Nicolau et al., J.C. S. Chem. Comm. 1977: 331-332 and Corey et al., JACS 99: 2006-2008 (1977). 45 The present invention relates to a prostacyclin analog of the formula

50

(ch ^) (ch2) (

55

(IV)

y „c — C ~ R •

m, l

60

where Z2 the rest

'c = c.

65 '

(1)

o-ch-ch ^

or

5

635 836

\

c = c. !

'H

o-ch-ch ^

one of the symbols p and q 0 or the number 1 and the other 0, Zi one of the residues

(1) - (CH2) g-CH2-CH2-or

(2) - (CH2) g-CH2-CF2-,

where g is 0 or the number 1 or 2,

Rs is hydrogen, the hydroxyl group or the hydroxymethyl residue, Y! one of the remains

(1) trans-CH = CH-,

(2) cis-CH = CH-,

(3) -CH2CH2- or

(4) -C = C— /%

Mj one of the groups R5 OH or R5 ÓH,

where Rs is hydrogen or an alkyl radical having 1 to 4 carbon atoms,

/ \ / X

Lj one of the groups R3 R4, R3 R4,

/ \

or a mixture of R3 R4 and R3 R4,

wherein R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, with the proviso that one of the radicals R3 or R4 only means fluorine if the other is hydrogen or fluorine,

X! one of the remains

(1) -COORb wherein Rj is hydrogen, an alkyl group with 1 to 12 carbon atoms, cycloalkyl group with 3 to 10 carbon atoms, aralkyl group with 7 to 12 carbon atoms, the phenyl group, one substituted by 1,2 or 3 chlorine atoms or alkyl groups with 1 to 3 carbon atoms Phenyl residue, one in the p-position

(2) -CH2OH,

(3) -CH2NL2L3, in which L2 and L3 are hydrogen or alkyl radicals having 1 to 4 carbon atoms, or

(4) -COL4, where L4

W s (a) denotes an amino group of the formula -NR21R22, in which R21 and R22 are hydrogen, alkyl radicals having 1 to 12 carbon atoms, cycloalkyl radicals having 3 to 10 carbon atoms, aralkyl radicals having 7 to 12 carbon atoms, the phenyl radical, by 1,2 or 3 chlorine atoms or alkyl radicals with 1 to 3 10 carbon atoms, the hydroxyl group, carboxyl group, alkoxycarbonyl groups with 1 to 4 carbon atoms or the nitro group substituted phenyl radicals, carboxyalkyl radicals with 1 to 4 carbon atoms, carbamoylalkyl radicals with 1 to 4 carbon atoms, cyanalkyl radicals with 1 to 4 carbon-15 atoms, acetylalkyl radicals with 1 to 4 carbon atoms, benzoylalkyl radicals with 1 to 4 carbon atoms, through 1,2 or 3 chlorine atoms or alkyl radicals with 1 to 3 carbon atoms, the hydroxyl group, alkoxy radicals with 1 to 3 carbon atoms, the carboxyl group, alkoxycarbonyl radicals with 1 up to 4 carbon atoms or the nitro group substituted benzoylalkyl radicals, pyridyl radicals, by 1, 2 or 3 Chlorine atoms or alkyl radicals with 1 to 3 carbon atoms or alkoxy radicals with 1 to 3 carbon atoms substituted pyridyl radicals, pyridylalkyl radicals with 1 to 4 carbon atoms, 25 or 1,2 chlorine atoms or alkyl radicals with 1 to 3 carbon atoms, the hydroxyl group or alkoxy radicals with 1 to 3 Carbon-substituted pyridylalkyl radicals, hydroxyalkyl radicals with 1 to 4 carbon atoms, dihydroxyalkyl radicals with 1 to 4 carbon atoms or trihydroxyalkyl radicals with 1 to 4 carbon -30 atoms, with the proviso that no more than one of the radicals R21 and R22 is different from hydrogen or alkyl can be,

(b) one of the following cycloamino groups

35

k22

(c) -O-C

R27 or

45

y-v

50 / \

-N NR2i r ~> <"21

O

(d) -CH = N-NHC-NH2

substituted phenyl radical, in which R25 is methyl, phenyl, acetamido-dophenyl, benzamidophenyl or -NH2, R26 methyl, phenyl, -NH2 or methoxy and R27 is hydrogen or the acetamido radical, the phenacyl radical of the formula I 2

55

or

60

22

wherein R21 and R22 have the meaning given above,

65 (c) a carbonylamino group of the formula -NR23COR21, a in the p-position by chlorine, bromine, the phenyl or benz- in which R23 is hydrogen or an alkyl radical with 1 to 4 carbon-amido radical or a pharmacologically substituted atom, and R2i is Permitted cation given above means

owns interpretation,

635 836

6

(d) a sulfonylamino group of the formula -NR23S02R21, in which R21 and R23 have the meaning given above, or

(e) a hydrazino group of the formula -NR23R24, in which R23 has the meaning given above and R24 is an amino group of the formula -NR21R22 as defined above or cycloamino group as defined above, and

R7 one of the residues

(1) - (CH2) B-CH3,

(T), or

(2) - (ch2) h- / j ^ t

(3)

wherein m is an integer from 1 to 5, h 0 or an integer from 1 to 3, s 0 or the number 1, 2 or 3 and T is chlorine, fluorine, the trifluoromethyl radical, an alkyl radical with 1 to 3 carbon atoms or alkoxy radical 1 to 3 carbon atoms, provided that no more than two radicals T are different from alkyl, and the pharmacologically acceptable acid addition salts of these compounds in which X1 is -CH2NL2L3;

with the proviso that when R7 is n-butyl, R3, R4 and R5 are all hydrogen, Y5 is trans-CH = CH-, R8 is hydroxy, p and q are both 0 and Z5 is only - (CH2) 2 - means if Xj is not -COOH.

A particularly preferred compound is the prostacyclin analog of the formula

Zi-Xj

(CH2) (CH2) q

(V)

y2-rc- ^

Hl Li wherein Xj, Z1; Z2, p, q, R8, Mb Lj and R7 have the meaning given above and Y2 denotes the radical -C = C ~, and their pharmacologically acceptable acid addition salts in the case of compounds in which X1 denotes the radical -CH2NL2L3.

Another preferred compound is prostacyclin. Analog of the formula

/ Z3-X1

(CHk) p JCK2) q

(VI)

where Xi, Z2, p, q, R8, Mb and R7 have the meaning given above, and Z3 the radical trans -CH = CH- and Y3 one of the radicals 5 (1) trans-CH = CH-,

(2) cis-CH = CH-,

(3) -CH2CH2— or

(4) -C = C—

represent, and their pharmacologically acceptable acid addition salts for compounds in which X! the remainder means -CH2NL2 L3.

The new compounds in which Zx represents the residue - (CH2) g-CH2-CF2- are referred to as 2,2-difluoro-PG-like compounds. The new compounds in which Z3 denotes the residue trans-CH = CH- are referred to as 2,3-didehydro-PG-like compounds.

If q 0 and g denotes the number 1 or 2, the compounds are additionally named as 2a-homo-PG-like or 2a, 2b-dihomo-PG-like compounds. In this case, the additional methylene or ethylene group is considered to be inserted between the carbon atoms C-2 and C-3 for the purposes of nomenclature. These additional carbon atoms are numbered C-2a and C-2b, counting from C-2 to C-3.

25 If q denotes the number 1 and g 0 or the number 1 or 2, the corresponding compounds are referred to as 7a-homo-PG, 2a, 7a-dihomo or 2a, 2b, 7a-trihomo-PG-like compounds. In the former case it is assumed that a methylene group is inserted between C-7 and the cyclopentane ring, 30 from which the binding to this ring is transferred to C-7a. In the latter case, the above nomenclature rules apply to compounds in which g is 1 or 2.

If p denotes the number 1, then 9-deoxy-6,9a-epoxymethylene-PGF-like compounds are involved. 35 The novel prostacyclin analogs according to the invention, in which Rg denotes hydrogen or the hydroxymethyl group, are referred to as 11-deoxy-PG or 11-deoxy-ll-hydroxy-methyl-PG-like compounds. If Yb is Y2 or Y3 is cis-CH = CH-, -CH2CH2- or -C = C-, then 40 is 13-cis-PG-, 13,14-dihydro-PG- or 13,14-didehydro -PG-like connections.

Compounds in which Mj is one of the groupings

/ N

Rs OH or Rs OH 45 and R5 denotes an alkyl radical are referred to as 15-alkyl-PG-like compounds.

With the exception of the above 13-cis-PG-like compounds, all of the above compounds having a hydroxyl or alkoxy group in the β configuration at the C-15 are additionally referred to as 15-epi-PG-like compounds. In the case of the 13-cis-PG-like compounds, only the compounds having the hydroxyl or alkoxy group in the a configuration at the C-15 are referred to as 15-epi-PG-like compounds. The convention on which this nomenclature system for natural and epimeric 55 configurations on the C-15 is based is described in U.S. Patent No. 4,016,184.

If R7 is a radical of the formula - (CH2) ln-CH3, in which m has the meaning given above, the corresponding compounds are 19,20-dinor-PG-, 20-nor-PG-, 20-methyl-PG- or 20-ethyl-PG-like compounds, where m denotes the number 1, 2, 4 or 5.

R7 represents a radical of the formula

50

60

I.

r8

vc

-C-R,

65

i!

mi

7

635 836

in which T and s have the meaning given above, where neither R3 nor R4 represent methyl, they are 16-phenyl-17,18,19,20-tetranor-PG-like compounds if s is the number 0. If s is the number 1, 2 or 3, 16- (substituted phenyl) -17,18,19,20-tetranor-PG-like compounds are present. If one or both of the radicals R3 and R4 are methyl, then compounds with R7 as defined above are classified as 16-phenyl- or 16- (substituted phenyl) -18,19,20-trinor-PG- or 16-methyl-16-phenyl- or 16-methyl-16- (substituted phenyl) -18,19,20-trinor-PG-like compounds.

R7 is a radical of the formula ch2

(t)

so it is 17-phenyl-18,19,20-trinor-PG-like compounds if s is the number 0. If s denotes the number 1, 2 or 3, then there are 17- (substituted phenyl) -18,19,20-trinor-PG-like compounds.

R7 represents a radical of the formula

(CH,),

(T),

so it is 19-phenyl-20-nor-PG-like compounds if s is the number 0. If s denotes the number 1, 2 or 3, the corresponding compounds are referred to as 19- (substituted phenyl) -20-nor-PG-like compounds, s denotes R7 a radical of the formula

(T) c

0

10th

so it is 18-phenyl-19,20-dinor-PG-like compounds, if s is the number 0. If s is the number 1, 2 or 3, the corresponding compounds are referred to as 18- (substituted phenyl) -19,20-dinor-PG-like compounds.

R7 represents a radical of the formula

(ch

(t)

where neither R3 nor R4 are methyl, the name for the corresponding compounds is 16-phenoxy-17,18,19,20-tetranor-PG-like compounds if s is the number 0. If s denotes the number 1, 2 or 3, there are 16- (substituted 15 phenoxy) -17,18,19,20-tetranor-PG-like compounds. If one or both radicals R3 and R4 are methyl, then the compounds with R7 as defined above are 16-phenoxy- or 16- (substituted phenoxy) -18,19,20-trinor-PG- or 16-methyl-16-phenoxy - or 16- (substituted phenoxy) -20 18,19,20-trinor-PG-like compounds.

If at least one of the radicals R3 and R4 is not hydrogen, then (with the exception of the above 16-phenoxy or 16-phenyl compounds) 16-methyl-PG- (a radical R3 or R4 = methyl), 16.16 -Dimethyl-PG- (R3 and R4 25 both methyl), 16-fluoro-PG- (a radical R3 or R4 = fluorine) and 16,16-difluoro-PG-like (R3 and R4 both fluorine) compounds. If R3 and R4 are different, the corresponding prostaglandin analogs have an asymmetric carbon atom on C-16. Accordingly, two epime-30 re configurations are possible, namely «(16S)» and «(16R)». The invention also relates to the C-16 epimer mixtures “(16RS)”.

If Xj denotes the radical -CH2OH, -CH2NL2L3 or the tetrazolyl radical, the corresponding compounds are called 2-decarboxy-2-hydroxymethyl-PG-, 2-decarboxy-2-ami-35 nomethyl-PG- or 2-decarboxy- Designated 2-tetrazolyl-PG-like compounds.

If Xj is the radical -COL4, the corresponding compounds are referred to as PG amides. If X [denotes the radical -COORi, it is a PG-like ester or Sal-40 ze if Ri is not hydrogen.

The following nomenclature table describes the convention according to which the new compounds are given trivial names:

Nomenclature table

45

z2 (1)

\

c = c.

H

0-ch-ch2 / \

p q connection type

0 0 (6S) -9-deoxy-6,9a-epoxy-trans-4,5-didehydro-PGFi

0 1 (6S) -7a-homo-9-deoxy-6.9ct-

epoxy-trans-4,5-didehydro-PGFi

1 0 (6S) -9-deoxy-6,9a-epoxymethylene-

trans-4,5-didehydro-PGFi

(2)

c = c '

, \

o-ch-ch? '\

0 0 (6R) -9-deoxy-6,9a-epoxy-trans-4,5-didehydro-PGFj

0 1 (6R) -7a-homo-9-deoxy-6,9a-epoxy-trans-4,5-didehydro-PGF1

0 1 (6R) -9-deoxy-6,9a-epoxymethylene-trans-4,5-didehydro-PGF1

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Alkyl radicals with 1 to 12 carbon atoms are the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, no-nyl, decyl, undecyl and dodecyl radical and their isomeric forms.

Examples of cycloalkyl radicals having 3 to 10 carbon atoms, including alkyl-substituted cycloalkyl radicals,

are the cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcy-clopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cy-clobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3, 4-tri-ethylcyclobutyl, 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 having 7 to 12 carbon atoms are benzyl, 2-phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2- (1-naphthylethyl) - and 1 - (2-N aphthylmethyl) rest.

Examples of phenyl radicals substituted by 1 to 3 chlorine atoms or alkyl radicals having 1 to 4 carbon atoms are the p-chlorophenyl, m-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m -Tolyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl and 2,4-dichloro-3-methylphenyl.

Examples of radicals of the formula in which T represents an alkyl radical having 1 to 3 carbon atoms, fluorine, chlorine, the trifluoromethyl radical or an alkoxy radical having 1 to 3 carbon atoms and s represents the number 0, 1, 2 or 3,

provided that no more than two radicals T are different from alkyl are phenyl, (o-, m- or p-) tolyl-, (o-, m- or p-) ethylphenyl-, 2-ethyl -p-tolyl-, 4-ethyl-o-tolyl-,

5-ethyl-m-tolyl-, (o-, m- or p-) propylphenyl, 2-propyl- (o-, m- or p-) tolyl-, 4-isopropyl-2,6-xylyl-, 3-propyl-4-ethylphenyl-, (2,3,4-, 2,3,5-, 2,3,6- or 2,4,5-trimethylphenyl-, (o-, m- or p -) Fluorophenyl-, 2-fluoro- (o-, m- or p-) tolyl-, 4-fluoro-2,5-xylyl-, (2,4-, 2,5-, 2,6-, 3rd , 4- or 3,5-) difluorophenyl-, (o-, m- or p-) chloiphenyl-, 2-chloro-p-tolyl-, (3-, 4-, 5- or

6-) Chloro-o-tolyl-, 4-chloro-2-propylphenyl-, 2-isopropyl-4-chlorophenyl-, 4-chloro-3,5-xylyl-, (2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-) dichlorophenyl-, 4-chloro-3-fluorophenyl-, (3- or 4-) chloro-2-fluorophenyl-, o-, m - or p-trifluoromethylphenyl-, (o-, m- or p-) methoxyphenyl-, (o-, m- or p-) ethoxyphenyl-, (4- or 5-) chloro-2-methoxyphenyl-, and 2,4-dichloro (5- or 6-) methylphenyl.

Examples of phenyl esters substituted in the p-position (i.e. X! = COORj, Rt = p-substituted phenyl) are the p-acetamidophenyl ester, p-benzamidophenyl ester, p- (p-acetamidobenzamido) phenyl ester, p- (p-benzamidobenzamido) ) phenyl ester, p-amidocarbonylamidophenyl ester, p-acetylphenyl ester, p-benzylphenyl ester, p-amidocarbonylphenyl ester, p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl ester, p- (p-acetamidobenzoyloxy) phenyl ester and p-hydroxybenicarbazone dehyde.

Examples of new prostacyclin amides (ie Xi = COL4) according to the invention are as follows:

(1) Examples of amides with alkylamido groups of the formula —NR21R22 are methylamide, ethylamide, n-propylamide, ■ n-butylamide, n-pentylamide, n-hexylamide, n-heptylamide, n-octylamide, n-nonylamide, n-decylamide , n-undecylamide and n-dodecylamide and their isomeric forms.

Further examples are dimethylamide, diethylamide, di-n-propylamide, di-n-butylamide, methylethylamide, methyl

propylamide, methylbutylamide, ethylpropylamide, ethylbutylamide and propylbutylamide. Examples of amides with cycloalkylamino groups are cyclopropylamide, cyclobutylamide, cyclopentylamide, 2,3-dimethylcyclopentylamide, 2,2-dimethylcy-5 clopentylamide, 2-methylcyclopentylamide, 3-tert-butylcy-clopentylamide, cyclohexylamide, 4- tert-Butylcyclohexylamide, 3-isopropylcyclohexylamide, 2,2-dimethylcyclohexylamide, cycloheptylamide, cyclooctylamide, cyclononylamide, cyclode-cyclamide, N-methyl-N-cyclobutylamide, N-methyl-N-cyclopen-lotylamide, N-methyl-N-cyclohexylamide , N-ethyl-N-cyclopentyl-amide, N-ethyl-N-cyclohexylamide, dicyclopentylamide and dicyclohexylamide.

Examples of amides with aralkylamino groups are benzylamide, 2-phenylmethylamide, 2-phenylethylamide, N-Me-15-methyl-N-benzylamide and dibenzylamide.

Examples of amides with substituted phenylamino groups are p-chloroanilide, m-chloroanilide, 2,4-dichloroanilide, 2,4,6-trichloroanilide, m-nitroanilide, p-nitroanilide, p-methoxyanilide, 3,4-dimethoxyanilide, 3, 4,5-trimethoxyanilide, p-hydroxyme-iothylanilide, p-methylanilide, m-methylanilide, p-ethylanilide, t-butyl anilide, p-carboxyanilide, p-methoxycarbonylanilide, o-carboxyanilide, o-hydroxyanilide.

Examples of amides with carboxyalkylamino groups are carboxyethylamide, carboxypropylamide and carboxybutyl-25 amide.

Examples of amides with carbamoylalkylamino groups are carbamoylmethylamide, carbamoylethylamide, carbamoylpropylamide and carbamoylbutylamide.

Examples of amides with cyanoalkylamino groups are 3o cyanomethylamide, cyanoethylamide, cyanopropylamide and cyano-butylamide.

Examples of amides with acetylalkylamino groups are acetylmethylamide, acetylethylamide, acetylpropylamide and acetylbutylamide.

35 Examples of amides with benzoylalkylamino groups are benzoylmethylamide, benzoylethylamide, benzoylpropylamide and benzoylbutylamide.

Examples of amides with substituted benzoylalkylamino groups are p-chlorobenzoylmethylamide, m-chlorobenzoyl-40 methylamide, 2,4-dichlorobenzoyimethylamide, 2,4,6-trichlorobenzoylmethylamide, m-nitrobenzoylmethylamide, p-nitrobenzoylmethylamide, p-methoxyamidzoyl , 4-dimeth-oxybenzoylmethylamide, 3,4,5-trimethoxybenzoylmethylamide, p-hydroxymethylbenzoylmethylamide, p-methoxybenzoylme-45 thylamide, m-methylbenzoylmethylamide, p-ethylbenzoylme-thylamide, t-butylbenzoyloxybenzoylmethylyloylmethylamide, p- o-carboxy-benzoylmethylamide, o-hydroxybenzoylmethylamide, p-chloro-benzoylethylamide, m-chlorobenzoylethylamide, 2,4-dichlorobenz-50 zoylethylamide, 2,4,6-trichlorobenzoylethylamide, m-nitrobenzoylethylamide, p-nitrobenzoylethylamide, p-methoxy -ethylamide, p-methoxybenzoylethylamide, 2,4-dimethoxybenzoylethylamide, 3,4,5-trimethoxybenzoylethylamide, p-hydroxy-methylbenzoylethylamide, p-methylbenzoylethylamide, 55 m-methylbenzoylethylamide, p-ethylbenzoy methylamide, t-butylbenzoylethylamide, p-carboxybenzoylethylamide, m-methoxycarbonylbenzoylethylamide, o-carboxybenzoylethylamide, o-hydroxybenzoylethylamide, p-chlorobenzoylpropylamide, m-chlorobenzoylpropylamide, 2,4-dichlorobenzoylpropylloylpropylamide, 2,4-dichlorobenzoylpropoylpropylamide , p-nitrobenzoylpropylamide, p-methoxybenzoylpropylamide, 2,4-dimethoxybenzoylpropylamide, 3,4,5-trimethoxybenzoylpropylamide, p-hydroxymethylbenzoylpropylamide, p-methoxybenzoylpropylamide, m-methylbenzoylpropylamide, p-hydroxylamide, p- Carboxybenzoyl-propylamide, m-methoxycarbonylbenzoylpropylamide, o-carb-oxybenzoylpropylamide, o-hydroxybenzoylpropylamide, p-chlorobenzoylbutylamide, m-chlorobenzoylbutylamide, 2,4-

635 836

Dichlorobenzoylbutylamide, 2,4,6-trichlorobenzoylbutylamide, m-nitrobenzoylmethylamide, p-nitrobenzoylbutylamide, p-methoxybenzoylbutylamide, 2,4-dimethoxybenzoylbutyl amide, 3,4,5-trimethoxybenzoylbutylamide, p-nitrobenzylbutylamide, p- Methylbenzoylbutylamide, p-ethylbenzoylbutylamide, t-butylbenzoylbutylamide, p-carboxybenzoylbutylamide, m-methoxycarbonylbenzoylbutylamide, o-carboxybenzoylbutylamide, o-hydroxybenzoylmethylamide.

Examples of amides with pyridylamino groups are a-pyridylamide, β-pyridylamide and y-pyridylamide. Examples of amides with substituted pyridylamino groups are 4-methyl-a-pyridylamide, 4-methyl-ß-pyridylamide, 4-chloro-a-pyridylamide and 4-chloro-ß-pyridylamide.

Examples of amides with pyridylalkylamino groups are a-pyridylmethylamide, ß-pyridylmethylamide, y-pyridylmethylamide, a-pyridylethylamide, ß-pyridylethylamide, y-pyridylethylamide, a-pyridylpropylamide, ß-pyridylpropylamide, y-pyamid, y-pyrid -Pyridylbutylamide, ß-pyridylbutylamide and y-pyridylbutylamide.

Examples of amides with substituted pyridylalkylamino groups are 4-methyl-a-pyridylmethylamide, 4-methyl-ß-pyridylmethylamide, 4-chloropyridylmethylamide, 4-chloro-ß-pyridylmethylamide, 4-methyl-a-pyridylethylamide, 4-methyl-ß- pyridylethylamide, 4-chloropyridylethylamide, 4-chloro-ß-py-ridylethylamide, 4-methyl-a-pyridylpropylamide, 4-methyl-ß-pyridylpropylamide, 4-chloro-a-pyridylpropylamide, 4-chloro-ß-pyridylpropylamide, 4- Methyl-ß-pyridylbutylamide, 4-methyl-a-pyridylbutylamide, 4-chloro-a-pyridylbutylamide, 4-chloro-ß-pyridylbutylamide, 4-methyl-ß-pyridylbutylamide.

Examples of amides with hydroxyalkylamino groups are hydroxymethylamide, a-hydroxyethylamide, ß-hydroxyethylamide, a-hydroxypropylamide, ß-hydroxypropylamide, y-hydroxypropylamide, l- (hydroxymethyl) ethylamide, 1 - (hydroxymethyl) propylamide, (2-hydroxymethyl) propylamide and a, a-dimethyl-β-hydroxyethylamide.

Examples of amides with dihydroxyalkylamino groups are dihydroxymethylamide, a, a-dihydroxyethylamide, a, β-dihydroxyethylamide, β, β-dihydroxyethylamide, a, a-dihydroxypropylamide, a, β-dihydroxypropylamide, <x, y-dihydr-oxypropylamide, β, β-dihydroxypropylamide, β, y-dihydroxy-propylamide, y, y-dihydroxypropylamide, l- (hydroxymethyl) 2-hydroxyethylamide, l- (hydroxymethyl) -l-hydroxyethylamide, a, a-dihydroxybutylamide, a, β-dihydroxybutylamide , a, y-Dihydroxybutylamid, a, ô-Dihydroxybutylamid, ß, ß-Dihydr-oxybutylamid, ß, y-DihydroxybutyIamid, ß, ö-Dihydroxybu-tylamid, y, y-Dihydroxybutylamid, y, ô-Dihydroxybutylamid, ô -Dihydroxybutylamide and l, l-bis (hydroxymethyl) ethyl amide.

Examples of amides with trihydroxyalkylamino groups are tris (hydroxymethyl) methylamide and 1,3-dihydroxy-2-hydroxymethylpropylamide.

(2) Examples of amides with cycloamino groups of the above type are pyrrolidylamide, piperidylamide, morpholinylamide, hexamethyleneiminylamide, piperazinylamide, pyrrolinylamide and 3,4-didehydropiperidinylamide.

(3) Examples of amides with carbonylamino groups of the formula -NR23COR21 are methylcarbonylamide, ethylcarbonylamide, phenylcarbonylamide and benzylcarbonylamide. Examples of amides with sulfonylamino groups of the formula -NR23SO2R21 are methylsulfonylamide, ethylsulfonylamide, phenylsulfonylamide, p-tolylsulfonylamide and benzylsulfonylamide.

(4) Examples of hydrazides having the above hydrazino groups are hydrazine, N-aminopiperidine, benzoylhydrazine, phenylhydrazine, N-aminomorpholine, 2-hydroxyethylhydrazine, methylhydrazine, 2,2,2-hydroxyethylhydrazine and p-carboxyphenylhydrazine.

A pharmacologically acceptable acid addition salt is understood to mean known acid addition salts of compounds containing amino groups which are relatively little toxic and well tolerated.

5 Preferred are acid addition salts which facilitate a pharmaceutical formulation (for example, crystallize better) or are conveniently available for use. Examples of acids from which salts can be prepared are, in particular, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and other acids such as tartaric acid, fumaric acid, maleic acid, methanesulfonic acid and p-toluenesulfonic acid.

A pharmacologically permissible cation is understood to mean the pharmacologically permissible salts of prostacyclin-like 15 carboxylic acids (Xx = -COOH) which are usually used for prostaglandins. The pharmacologically permissible salts include, in particular, the salts of permissible metal cations, amine cations and quaternary ammonium cations. Basic amino acids such as arginine and 20 lysine are also used. Furthermore, certain amine cations such as THAM [tris (hydroxymethyl) aminomethyl] are particularly suitable for the present purposes. US Pat. No. 3,016,184 describes salts which can also be prepared for the present purposes.

25 The new prostacyclin analogs according to the invention stimulate the smooth muscles.

These new prostacyclin analogs can therefore be used to study, prevent, control and cure diseases and other undesirable physiological conditions 30 in mammals, particularly humans, valuable farm animals, domestic animals, zoological species and laboratory animals (e.g. mice, rats, rabbits and monkeys) .

The novel prostacyclin analogs according to the invention are 35 extremely effective stimulators of the smooth musculature, and they are also highly active in enhancing other known stimulants of the smooth musculature, for example oxytocin agents such as oxytocin and the various ergot alkaloids, including their derivatives and analogs. They are therefore, for example, usable instead of or together with less than the usual amounts of the known stimulators, for example to relieve the symptoms of paralytic ileus or to combat or to prevent atonic uterine bleeding after miscarriage or delivery, for 45 rejection of the placenta, as well as during the puerperium. For the latter purpose, the compound can be administered by intravenous infusion immediately after the miscarriage or childbirth in a dose of about 0.01 to about 50 [xg / kg body weight / minute until the desired effect is achieved. After-50 subsequent doses are usually injected or infused intravenously, subcutaneously or intramuscularly in an amount of 0.01 to 2 mg / kg body weight / day during the puerperium, the exact dose depending on the age, weight and condition of the patient.

The new prostacyclin analogs according to the invention are therefore surprisingly useful for pharmacological purposes, so that these compounds are both pharmacologically and structurally analogs of prostacyclin. Furthermore, the present prostacyclin analogues show an increased chemical resistance, which facilitates the formulation and use in pharmacological preparations.

The novel prostacyclin analogs according to the invention, in which Xj denotes the radical -COORx or -COL4 and the one

/ \

6515a hydroxyl group (that is Mj = R5 OH)

are useful as anti-thrombotic and anti-asthmatic, anti-ulcer and dermatotic agents, as explained below:

635 836 10

(a) Inhibition of Platelet Aggregation, Reduction of Undesirable Gastrointestinal Effects, The New Prostaglandin Analogs are useful for inherently resulting from systemic administration of anti-inflammatory platelet aggregation, reducing prostaglandin synthetase inhibitors, and they will

Platelets have a tendency to stick and to eliminate or prevent them by simultaneously administering prostate

of thrombi in mammals and humans. For example, 5 glandin derivative and anti-inflammatory prostaglandin syn-

the compounds are useful for the treatment and contraceptive inhibitor. U.S. Patent No. 3,781,429 discloses

treatment of myocardial infarctions, for the treatment and prevention of the ulcerogenic effects of certain non-postoperative thromboses and for the treatment of steroids in rats due to conditions such as atherosclerosis, arteriosclerosis, blood co-oral oral administration of certain prostaglandins by rats Lipemia, as well as in other clinical conditions, 10 is inhibited. The new prostacyclin analogs are therefore useful in those with the underlying etiology with a lipid, for example to reduce the undesired

Imbalance or related to hyperlipidemia. gastrointestinal effects resulting from systemic administration

Other areas of application in vivo are in the treatment of indomethacin, phenylbutazone or aspirin.

geriatric patients for the prevention of cerebral ischemia. These substances are mentioned in US Pat. No. 3,781,429 as no severe attacks and anti-inflammatory agents which are steroids in long-term prophylaxis after myocardium-15. you are

Heart attacks and strokes. For the purposes mentioned, prostaglandin synthetase inhibitors are also known,

which the compounds are administered systemically, for example in- The anti-inflammatory synthetase inhibitor, for example in travenous, subcutaneous, intramuscularly or in the form of sterile implant game indomethacin, aspirin or phenylbutazone, is described in

prolonged action. For rapid uptake, known to administer an inflammatory condition, particularly in emergency situations, intravenous administration 20 will facilitate, for example, in any known dosage.

prefers. Doses ranging from about 0.01 to the regimen are used for systemic administration.

about 10 mg / kg body weight / day, the exact amount (d) bronchodilation (anti-asthmatic effect)

of the age, weight and condition of the patient or animal and the new prostacyclin analogues are also dependent on the treatment frequency and route of administration. suitable for asthma. These connections are suitable for

The preferred dosage form is directed to the oral example for use as bronchodilators or inhibitors.

Administration, although other non-parenteral administration of mediators such as SRS-A and histamine, the routes of delivery (e.g. buccal, rectal or sublingual) consist of cells activated by an antigen / antibody complex.

can preferably be released for parenteral administration. The compounds therefore fight. Oral dosage forms become formulas in the usual way and facilitate breathing in conditions such as bronchial

(tablets, capsules and the like) and two to four times 30 chial asthma, bronchitis, bronchiectasis, pneumonia and em-

given daily. Doses in the range of approximately 0.05 physem are effective. For these purposes, the connections are

up to 100 mg / kg body weight / day. administered different dosage forms, for example orally in

The addition of these compounds provides an in vitro form of tablets, capsules or liquids, rectally in the form of use, for example storage of whole blood for the heart / of suppositories, parenterally, subcutaneously or intramuscularly,

Lung machines. The blood 35 containing these compounds, with intravenous administration preferred in emergency situations, can also be circulated through organs, for example heart, by inhalation in the form of aerosols or solutions and kidneys, which are donated to a nebulizer prior to the transplant or by sniffing in the form from Pul-

were taken. The compounds are also suitable for hearts. Doses of approximately 0.01 to 5 mg / kg body weight will be used

Placement of platelet-enriched concentrates, used one to four times a day, using the exact amount used to treat thrombocytopenia, in chemotherapy 40 age, weight and condition of the patient and frequency and and radiation therapy. When in vitro depends on the mode of administration. For the above purposes, the

Phrases from 0.001 to 1.0 (xg / ml total prostacyclin analogs are advantageously used with other antiasthmatics blood. Can be combined, for example with sympathomimetics (iso-

(b) Reduced gastric secretion proterenol, phenylephrine, ephedrine, etc.), xanthine derivatives The new prostacyclin analogues are in mammals and 45 (theophylline and aminophylline) and corticosteroids (ACTH

Humans, for example certain farm animals such as dogs and prednisolone).

and pigs, useful for abatement and control. The compounds are effective in administering excessive gastric secretion to astmatics, causing the formation of masses by oral inhalation or aerosol inhalation. genes / intestinal ulcers can be reduced or avoided and for administration by oral inhalation with conventional ulcers the healing of already existing ulcers can be accelerated or by oxygen aerosol formation. For this purpose, the compounds are intravenously injected or infused with the active ingredient in dilute solution, in a diluted solution, subcutaneously or intramuscularly, preferably at concentrations of about 1 part of medication — an infusion dose in the range from about 0.1 to about 20 µg / kg ment to about 100 to 200 parts by weight of solution. Conventional additives, for example body weight, can be added to stabilize body weight / minute, or with a total dose per day of these solutions or to prepare isotonic media by injection or infusion from about 0.01 to about 10 mg / kg 55 exact amount of age, sodium chloride, sodium citrate, citric acid, sodium bisulfite weight and condition of the patient or animal and the common and the like. The route of administration of the active ingredient depends on the aerosolity and route of administration. For inhalation, the formulation can contain the active ingredient. Preferably, the new prostacyclin analogs are suspended in an inert propellant (for example a mixture of dichlorodifluoromethane and difluorotetrafluoroethane administered orally or by another non-parenteral route). When administered orally, 1 to 6 daily and with a co-solvent such as ethanol, flavorings are administered at doses of approximately 1.0 to 100 mg / kg of body weight and / or stabilizers. Instead of a co-lion day. Once the ulcers have healed, a dispersant such as oleyl alcohol, the maintenance dose required to prevent relapse, can also be used. Suitable devices for the application of the set down until the patient or the animal 65 aerosol therapy are for example in US Pat. No. 2,868,691 without symptoms. wrote.

(c) inhibition of NOSAC-induced damage (e) averting dermatoses

The new prostacyclin analogs are also useful for the The new prostacyclin analogs are useful for the

11

635 836

treatment of spreading skin diseases in humans and pets, for example psoriasis, atopic dermatitis, non-specific dermatitis, itchy contact dermatitis, allergic contact dermatitis, basal cell carcinoma, squamous cell carcinoma, lamellar ichthyosis, epidermolytic hyperke-ratiosis, by non-malignant, pre-malignant, pre-malignant, pre-malignant, pre-malignant, pre-malignant, pre-malignant, pre-malignant, pre-malignant, malignant, pre-malignant, caused by non-malignant skin cancer - Malignant keratosis, acne and seborrhoeic dermatitis in humans and atopic dermatitis and mange in pets. The compounds relieve the symptoms of these skin diseases: psoriasis, for example, is relieved as soon as dandruff-free psoriasis damage has noticeably decreased in thickness or has become noticeable, but still incomplete or completely pure.

For the above purposes, the compounds are applied topically in preparations which contain a suitable pharmaceutical carrier, for example as ointments, lotions, pastes, gels, sprays or aerosols, using topically applicable bases such as petrolatum, lanolin, polyethylene glycols and alcohols. The active ingredient makes up about 0.1 to about 15% by weight, and preferably about 0.5 to about 2%, of the preparations. In addition to topical administration, an intradermal, intra- or peri-lesional or subcutaneous injection with correspondingly sterile saline solutions can also be carried out.

In the context of the new prostacyclin analogs according to the invention, certain compounds are preferred which have increased potency or selectivity or which have otherwise proven to be particularly convenient and useful agents.

Compounds in which p and q are 0 are preferred. Also preferred are compounds in which Zj is - (CH2) g-CH2-CH2-. g is preferably 0 or 2, and in particular 0. With regard to the radical Yj, preferred compounds are those in which Y! the remainder is trans-CH = CH-or -CH2CH2-, where compounds with Yt =

trans-CH = CH- are particularly preferred. With regard to the grouping Mj, preference is given to those compounds in which Mi

R5 OH or R5 OH

5 means.

R5 is preferably hydrogen, methyl or ethyl, and in particular hydrogen or methyl.

With regard to the grouping Lj, compounds are preferred in which R3 and R4 are identical. Furthermore, 10 compounds are preferred in which at least one of the radicals R3, R4 and R5 consists of hydrogen. If Y1; Y2 or Y3 mean cis-CH = CH- or -C = C-, compounds are preferred in which all the radicals R3, R4 and R5 consist of hydrogen.

With regard to the numbers m, h and s, the following applies: m preferably denotes the number 3, h 0 or 1 and s 0 or 1. The symbol T preferably corresponds to chlorine, fluorine or the trifluoromethyl radical.

Also preferred are the carboxylic acids or their derivatives, that is to say esters, in particular the p-substituted phenyl esters, and the amides. With regard to the amides, preferred compounds are those in which R21 and R22, which may be the same or different, are preferably hydrogen or alkyl radicals having 1 to 8 carbon atoms, the

25th

total number of carbon atoms in R21 and R22 is preferably equal to or less than 8. More preferred are amides in which R21 and R22, which may be the same or different, denote hydrogen or alkyl radicals having 1 to 4 carbon atoms, the total number of carbon atoms in R21 and

30th

R22 is 4 or less. Furthermore, R23 is preferably a hydrogen atom.

The following schemes describe a preferred process for the preparation of the new prostacyclin analogs from known or easily synthesized starting materials.

Scheme A

\

nvch2-z1-c00r1

40

1 * -1

Hv Zi-COORi

\ /

r- ^ C = C \

/ CH H

• cho

0, _

45 (qh2) _ (ch2) (

XXI

50

/

/

r8

Y1-Ç-Ç-R7

XXIII

Wed Lj

55

Scheme B

H

60

(ch?) 0h vp oc

XXII

65

(ch2) -ch £ "

ym-c-c-r7

IN THE!

ml lx

ch2-z1-x2

xxxi

635 836

Scheme B (continued)

Shark

S 7 V

CH-CH2 ^ i-X2

CH

/ \ 0 f «2

(chj) p tch2) q

12

/

Rf v | t7

Mi Li

Shark ch-ch2-zi-x,

S

/ Ciï \

o ch2

(ch2) (ch2) q

/

R36

y ^ -c c-r7

11 il

H6 1-1

h z.-x,

c <xh

0 • CH2

(c ^ 2) n (ch2)

\ p

R36

cc-c-c-r, M5 Li

Z1-X3

z /

Lz

/ \ (ch2) (ch2) (

xxxv

XXXII15

c = c-c-c-r7 il il

Mi Li

Scheme C

20th

s.

(CH?) P0H (CH2) -CH2 (CH2) 3-C00Rn

\ X q

/

35

XXXIII

y3-c-c-r7

il ii

Hi Li

XLI

40

Shark

S

CH- (CH2) 3-C00Rn

CH

/ \

0 ■ CH2

^ I

55 (CH2) p (CH2) q

50

XXXIV

/

Y c — c-ry ii ii

Mi Li.

65

XLII

V

13

635 836

Scheme C (continued)

Shark ch- (ch2) 3-c00r11 CHv

0 ch2

1 i

(CH ^) p (CH2.)

y n ✓ Y, -C — C-R7

38 3 II Ii m7 left

Shark

5

CH- (CH2) 2-CH-C00Rn CHV SePh x \

0 (jH2

(cn2) p (ch2)

Ys-C- ^ C-R?

Ii tl

M7 Li

/

i l38

V

Shark;

CH- (CH2) 2-CH-C00R11 5 ^ CH ^ SePh

0 CH,

! i

10 (CH2) p (CH2) q /

v

XLIII R8

20th

25th

30th

r3-n-R7

Ml k

Shark \ c00rn

5 X = Cv

"H-CHo H

.CH

\

0

CH '

35 (CH2) p (CH2) q

XLIV ^ 8

45

yo-c-c-r7

ii il

Mi l-i

XLV

XL VI

55

60

635 836

Scheme C (continued)

14

z3-ch2oh

(ch2L \

vP (CH2) -

/ ^ Y, -Ç — J-R

Mi Lj h h \ ^ -coorn

\ / -c = c

^ c = c \

/ ch v h / X

\

H

XLVIII

(ch2) \ \ p (ch2)

3-col ^

> q

* 8 ys1 ftr?

Mi Li

45

50

55

'(ch2)

/ z3-ch2nl2l3 z2

\.

60

65

y c — C-R7 3 II I 7

Mi Li

LI

15

635 836

Scheme D

H

(ch2loh (ch2)

\ px / P

y

-ch2

\ /

j> c

\

H

z3-x2

yo-c-g-r7.

k f.

Shark s

CH-CH2-Z3-X2

S

/ c \

0 CH2 "" vq

(CH2). ■ (^ 7)

v'p

Y -.- C 3 ii

C-R7

l1

»1 Lx z3-x,

/ 2 \

(CH ^) p (CH2} q y

X2 denotes -COORn, -CH2OR10 or -COL4, where R] 1 represents an ester residue in the context of Rt and R10 and L4 have the meaning given above.

M6 means

R5 OR10 or R5 OR

10th

andM7

/ \ '' "n

R5 OSi (Gi) 3 or R5 OSi (G1) 3

LXI

LXII

LXIII

V

frr?

^ left

In the diagrams do p, q, Lb Mt, Xt, X2, X3, Y1? Y3, Zj, Z2, Z3, Rj, R7 and R8 have the meanings given above.

R36 denotes one of the radicals -OR10 or -CH2OR10 or hydrogen, where R10 is a protective group which is easily hydrolyzed by acid, such as the tetrahydrofuranyl or tetrahydropyranyl radical. Examples of protective groups which are suitable according to the invention can be found in US Pat. No. 4,016,184. R38 means one of the residues -OSiÇG ^ or -CH2OSi (Gi) 3 or hydrogen, wherein -Si (G1) 3 are to be understood as silyl groups, see in particular the residues described in US Pat. No. 4,016,184.

wherein R5, -Si (Gi) 3 and R10 has the meaning given above.

Y4 denotes the radical trans-CH = C (Hal), in which shark represents chlorine, 15 bromine or iodine. Ac means the acetyl radical and SePh the phenylselenyl radical.

X3 means -COORn, -CH2OH or -COL4, where Rn and L4 have the meaning given above.

Scheme A shows a process for converting a 20 PGF2a (q = 0) or cis-4,5-didehydro-PGF2a (q = ^ compound of the formula XXI into new prostacyclin analogs XXIII,

The compounds of the formula XXI used as starting materials are expediently prepared from known or easily accessible starting compounds. Formula 25 XXI comprises oxygen-free compounds on the C-11 (11-deoxy-PG-like compounds) or compounds substituted on the C-II by a hydroxymethyl group instead of the hydroxyl group (11-deoxy-ll-hydroxymethyl-PG-like compounds). These compounds can be prepared according to known Metho-30 from PGA2- or cis-4,5-didehydro-PGAi-like compounds. The PGA2- or cis-4,5-didehydro-PGAj-like compounds are expediently obtained by acid dehydration of the corresponding PGE2 or cis-4,5-di-dehydro-PGEj compounds. All compounds of formula XXI are thus either known prostaglandin analogs or compounds which can be prepared using known chemical reactions on known prostaglandin starting materials.

In a modification of the procedure from Scheme A, the PGF2a or cis-4,5-didehydro-PGFla compounds XXI can be used as mono- or bis-ether, the hydroxyl groups in question, with the exception of the C-9-hydroxyl groups group, to be converted into ether derivatives. Protective groups R10 are usually used as ether groups, which are usually used in the synthesis of prostaglandin-like products from various intermediates and can easily be split off hydrolytically from the product of the formula XXIII under acidic conditions. A residue that is particularly suitable for this purpose is the tetrahydrofuranyl-50 residue.

According to Scheme A, the PGF2a or 9-deoxy-9a-hydroxymethyl-PGF2-like compounds of the formula XXI can be converted into the bicyclic intermediates XXII by acetylpalladiocyclization, from which the product XXIII is formed by eliminating the acetylpalladio radical.

Preferred solvents for this two-stage process are lower alkanols, especially methanol, but also isopropanol and tert-butanol. The cyclization / elimination is usually complete after a few hours, the reaction 60 is conveniently carried out at 0 to 50 ° C.

The two-step cyclization / elimination can also be described in by Nicolaou, et al, J.C.S. Chem. Communications 1977: 331-332, in which phenylselenocyclization is followed by elimination in aqueous potassium carbonate solution and methonal to give product XXIII.

According to an optional and preferred procedure according to scheme A, instead of the free hydroxyl compounds

635 836 16

bindings the 11,15-bis-ether (corresponding to R10) of the formula The compound of the formula XLV is usually by XXI or XXII, whereby after etherification one obtains ether hydrolysis of the silyl groups under mildly acidic product XXIII. The R10 ether residues can then be obtained un- (for example mineral acid).

ter mild acetic acid conditions (tetrahydrofuran in aqueous The compound of formula XLV can then be hydrolyzed by dehy-acetic acid), the product XXIII ent-5-drophenylselenization in the trans-2,3-didehydro-5-halogen. PGIi intermediate of formula XL VI are transferred.

The etherified compounds of formula XXI can This intermediate XL VI can then be prepared using known methods or they are basic conditions (see above) for the compound XL VII de-

himself known, the etherified compounds are hydrohalogenated accordingly. The ester XLVII is then used

Formula XXII are e.g. formed by known methods, 10 saponified (for example with potassium hydroxide in methanol)

compare the above information regarding R10 ether. whereby the acid of the formula XLIX is obtained. This acid can

Scheme B shows a preferred process for the conversion subsequently by amide formation into prostacyclin analogs of

PGF2a-like compounds of the formula XXXI are converted into various formula L. If L4 is the amino group, then 4,5,13,14-tetradehydro-PGIj-like ones according to the invention are preferably the prostacyclin amides of the formula L with

Products XXXV. 15 lithium aluminum hydride to the corresponding 2-decarboxy

The compound of the formula XXXII is usually derived from the 2-aminomethyl compounds LI (L3 and L3 mean water

Compound XXXI reduced by halogenating cyclization). The 2-decarboxy-2-aminomethyl compound. Does shark in compound XXXII e.g. iodine, the cyclization can then be carried out according to known methods by reacting the compound XXXI with secondary and tertiary amines (L2 and / or L3 mean potassium iodide or an alkali metal carbonate or bicarbonate 20 alkyl); see the procedures of US-PS

implemented in an iodine-containing organic system. In the latter 4 028 350 regarding methods for producing the various

Usually, solvents such as methylene chloride and 2-decarboxy-2-aminomethyl analogs are used.

used. The reaction temperatures are preferably around. The compound of the formula XLVII can also be

or below room temperature, especially at about 0 ° C. methods for converting prostaglandin analogs into

Then sodium sulfate and sodium carbonate can be added to the corresponding prostanols for 2-decarboxy-2-hydroxymethane.

to give the iodine compound XXXII. Means Hai thylverbindung XLVIII be reduced. In this case,

e.g. Bromine, N-bromosuccinimide is a suitable bromine, preferably a reduction with lithium aluminum

solvents. One usually works in solvents such as niumhydride; see U.S. Patent 4,028,419 for the

Methylene chloride at 0 ° C to room temperature until the completion of the production of such C-1 alcohols from certain bicyclic

implementation. If one wishes to isolate pure prostaglandin analogues.

product of the formula XXXII, chromatographi are preferably used. Scheme D provides a further preferred method for the isolation method. A special production of the 2,3,4,5-tetradehydro-

The most suitable technique is the high-pressure liquid chromatography-PGI-like compounds, which consists in making a tography. 2,3-Didehydro-PGF2o-like compound of the formula LXI ha-

The compound of formula XXXIII can then be cyclized from 35 and then the compound compound XXXII so obtained can be formed by dehydrohalogenating all to form product LXIII. Conveyed hydroxyl groups into the R10 ether. Scheme D uses the methods described above and the methods described above. Halogenation Cyclization and Dehydrohalo

The compound of formula XXXIV can be used from the compounding.

dung XXXIII obtained by double dehydrohalogenation 40 According to the above schemes, the will be according to the invention. With this method e.g. the 5,14-dihalogenes new prostacyclin analogs are generally initially obtained as PG compound XXXIII in the 4,5,13,14-tetradehydro-PGl! primary alcohols, esters or amides. The degenerate compound XXXIV is transferred. speaking carboxylic acids, these can be used in this double dehydrohalogenation, hydrolysis of the corresponding esters in a conventional manner, in a customary basic manner. Preferably be made. For example, the hydrolysis is carried out by following the dehydrohalogenation in a mixture of one of the esterified form of the prostacyclin analog in a lower alkanol and dimethyl sulfoxide with potassium tert-buty water / alkanol mixture with base. So you use lat as a base. The compound XXXIV can then be hydrolyzed under mildly preferably sodium hydroxide and methanol for the hydrolysis of acetic acid conditions to the prostacy ester according to the invention with the formation of the corresponding sodium salt, clin-analog XXXV. The pharmacologically acceptable salts of these carboxylic acids, for example mixtures of tetrahydrofuran and aqueous, can then be used by neutralization with the corresponding base, acetic acid. be formed. The isolation and processing of the salts in Scheme C provides a preferred method of preparation follows e.g. by conventional methods, from 2,3,4,5-tetradehydro-prostacyclin analogs of the formulas If acid addition salts are desired, XLIII to LI can be used to obtain XLI from PGF2a-like compounds. 55 Implementation of the prostacyclin analogue with the corresponding

The compound of the formula XLII can obtain the desired product from the compound acid.

XLI by halogenating cyclization, as in Scheme B The new PG-like amides (Xt = -COL4) and p-substi-

wrote, made. tuated phenyl esters (Rj = -p-substituted phenyl) are

The compound XLII can then be produced in a known manner, preferably as follows:

Conversion to silyl ether XLIII (see, for example, 60 above. The p-substituted phenyl esters are

Notes). ren of U.S. Patent No. 3,890,372. According to the preferred, there

The compound of the formula XLIV can be derived from the method described, the p-substituted phenyl ester

XLIII are formed by a-phenylselenization. To make by first making a mixed anhydride,

The position of this phenylselenyl derivative is e.g. the connection in particular in the manner described below for producing

XLIII initially treated with lithio-N-isopropylcyclohexylamine, such anhydrides in the first stage of the preparation, the compound corresponding to compound XLIII corresponding C-2-amino and cycloamino derivatives.

Anion receives. Finally, this anion can be reacted with diphenylsele. This PG-like mixed anhydride can then be reacted with a nid to give the compound XLIV. Solution of the corresponding phenol are implemented. The

17th

635 836

Reaction is preferably carried out in the presence of a tertiary described with the mixed anhydride,

Amines such as pyridine. After the reaction has ended, the p-sub-, with about 4 equivalents of the sodium salt per equiva-

substituted phenyl esters can be isolated in a conventional manner. lent anhydride. The reaction temperatures are

From the PG-like carboxylic acids, the carboxyamides can be at or near 0 ° C.

de According to one of several known amidation methods s To produce the phenacyl or substituted ones. For example, U.S. Patent Phenacylester describes U.S. Patent 3,979,440.

3 981 868 the preparation of corresponding amino and cy- In the following examples the infrared absorbers

cloamino derivatives of prostaglandin-like free acids, ion spectra with an infrared spectrophotometer Perkin-

and U.S. Patent 3,954,741 relates to the manufacture of Carbonyl Elmer Model 421. Unless otherwise stated

Amino and sulfonylamino derivatives of prostaglandin-like free io ben, undiluted samples were used. The ultraviolet

Acids. Spectra were recorded using a Cary Model 15 spectrophotometer

The preferred method for making the invention. The nuclear magnetic resonance spectra were

According to the amino and cycloamino derivatives of free prostacyden with a spectrophotometer Varian A-60, A-60D or clinic-like acids, the acid in T-60 in deuterochloroform solution with tetramethylsilane as the in-

the mixed anhydride transferred. This procedure uses a standard (field down). The mass spec

The prostaglandin-like free acid preferably with a tren were used with a double-focusing high-resolution

Neutralized equivalent of an amine base and then using a CEG Model HOB mass spectrometer or a gas

small stoichiometric excess of the LKB model 9000 matograph / mass spectrometer to be produced

chloroformic acid corresponding to the mixed anhydride. Unless otherwise stated, trimethylsilylde-

esters implemented. 20 derivatives used.

The preferred amine base for neutralization is triethyl- The amine used in thin-layer chromatography, although other amines such as pyridine, methyldiethyl solvent system A-IX consist of ethyl acetate, acetic acid,

amine and the like can be used. One with the 2,2,4-trimethylpentane and water (90: 20: 50: 100, see

Formation of the mixed anhydride of convenient M. Hamberg and B. Samuelsson, J. Biol. Chem. 241,257

Chloroformic acid ester is chloroformic acid isobutyl-25 (1966)). Under Skellysolve B (SSB) is a mixture of isomeric esters. Hexanes understood.

The formation of the mixed anhydride can be done conventionally. Under silica gel chromatography, elution can be done in the normal manner. The PGF-like free acid is e.g. by collecting the fractions and combining those fractions of tertiary amine and chloroformic acid ester in a suitable one, which according to thin-layer chromatography mixed the riding solvent (for example aqueous tetrahydrofuran) 3 "ne product free of starting material and impurities, and the reaction is left at -10 to 20 ° C before included.

go out. The melting points were determined using a Fisher-Johns or

Then the mixed anhydride can be taken up by reaction with Thomas Hoover melting point apparatus. The special

the corresponding amine in the amino or cycloaminode-specific rotations [a] were made on solutions of a compound

be transferred privately. If the simple amide (-NH2) production is to be placed in the specified solvent at room temperature, the reaction is usually carried out using an ammo- using an automatic Perkin-Elmer niak polarimeter. The amine (or ammonia) can be determined using model 141.

mixed anhydride at or near -10 to +10 ° C

be mixed until the implementation turns out to be complete. example 1

In the case of highly volatile amines, acid addition di-40 trans-4,5-didehydro-6β-PGIi methyl ester salts (for example methylamine hydrochloride) are preferably used instead of the (IV: Xt = -COOCH3,

corresponding free bases (ie methylamine) - Zt = ~ (CH2) 2,

The carbonylamino and sulfonylamino derivatives of the present PG-like compounds can also be prepared by known methods. For example, / \

U.S. Patent 3,954,741, methods for making such de-50

derivatives. According to this known method the prostaglandin and p = 0, R8 = hydroxy, Y1 = trans-CH = CH-, R3 and R4-like free acid e.g. with a carboxyacyl or sulfonyl iso of Lt and R5 of Mj all hydrogen, R7 = n-butyl), cyanate, which corresponds to the carbonylamino or sulfo 6 a isomer to be prepared and the corresponding free acid, nylamino derivative.

According to another, more preferred method 55 Compare Scheme A.

The sulfonylamino derivatives according to the invention are produced. At room temperature, molecular oxygen is placed in by first stirring the PG-like mixed anhydride in a solution of 4.7 g of PGF2a methyl ester-11,15, using the method described above anis (a-ethoxyethyl ether), 0.206 g palladium acetate and 1.833 g. Then the sodium salt of the corresponding copper (H) acetate in 46 ml of methanol and 3.7 ml of water for 2 hours.

Sulfonamids initiated with the mixed anhydride and hexamethyl-60. Then another 0.206 g of palladium acetate added phosphoramide are reacted. Add the pure PG-like sulfonyl and after another 2½ hours the mixture is then filtered through di-amino derivative, usually in a conventional manner, atomic earth and the solids on the filter are obtained from the resulting reaction mixture. washed with methanol and ethyl acetate. The combined filtrate

The sodium salt of sulfonamide is e.g. generated by concentrating under reduced pressure and the residue, the sulfonamide is reacted with alcoholic sodium ethylate. 65 is taken up in ethyl acetate and water (100 ml each). According to a preferred procedure, methanolic is extracted. The aqueous phase is extracted with ethyl acetate, the organosodium methylate with an equimolar amount of the sulfone extract is reacted with saturated sodium chloride solution Gewa-amide. The sulfonamide can then be seen as above, dried over magnesium sulfate and concentrated using.

zj = h

The PGF-like amino or cycloamino derivative can then be isolated from the reaction mixture in a conventional manner.

635 836

18th

5.05 g of crude trans-4,5-didehydro-PGIi methyl ester-l 1,15-bis (a-ethoxyethyl ether) can be obtained in the form of a brown oil. The brown oil is chromatographed on 500 g silica gel packed with 30% ethyl acetate and Skellysolve B while eluting with the same solvent system to give 2.77 g of the 5 pure intermediate; NMR absorptions at 5.85-5.2.5.0-2.9.3.65 and 2.4 ô.

B. 3.27 g of the reaction product according to Part A in a mixture of 19 ml of tetrahydrofuran, 38 ml of water and 114 ml of ethyl acetate are heated to 40 ° C. for 4 hours. 10th

The resulting mixture is diluted with 350 ml of water and lyophilized. The residue is dissolved in diethyl ether and washed with 1N aqueous potassium bicarbonate solution and saturated sodium chloride solution. The ether extracts are then dried over magnesium sulfate and concentrated, which is obtained in the form of an oil from 2.2 g of crude trans-4,5-didehydro-PGI1 methyl ester. The oil is chromatographed on 50 g silica gel packed with 50% acetone in methylene chloride while eluting with the same solvent system to give 2.06 g of the 6a and 6β-epimer mixed title compound. 1.25 g of the epimer mixture are chromatographed on 200 g of silica gel while eluting with 30% acetone in methylene chloride.

This gives 0.46 g of a sample enriched in the less polar 6a isomer. This sample, enriched in 6a isomer, is again chromatographed on two successive columns with silica using 50% acetone in hexane. This gives 0.14 g of the pure trans-4,5-didehydro-6a-PGI1 methyl ester as a waxy solid of melting point 63 to 73 ° C .; Analysis: found: C = 68.45%; H = 9.57%. IR absorptions at 3500.3420.1735.1720, 1315.1260.1210.1080.1050.1025.970 cm "1.

The mass spectrum of the trimethylsilyl derivative shows a high-resolution peak at 510.3183 and further peaks at 495, 479.439.420.349.323.199 and 173. NMR absorptions at m 5.8-5.4.4.45-2.7.3.67 and 2, 4 ô. Rf (thin layer chromatogram on silica gel in acetone and methylene chloride (1: 1) =

0.41).

From the product of the first 4Q chromatographic separation, a sample of 0.89 g of approximately 90% pure trans-4,5-didehy-dro-öss-PGIi methyl ester is again chromatographed on two columns with silica, eluting with 50% acetone in Methylene chloride. 0.375 g of 99% pure 6ß product and 0.359 g of pure 6ß product are obtained as oils; NMR absorptions at 5.8-5.3.4.65-2.9.3.63 and 2.36 ô. The mass spectrum for the trimethylsilyl derivative shows a high-resolution peak at 510.3193 and further peaks at 495.479.439.420.354.307 and 173; Rf value in a thin layer chromatogram on silica gel in acetone 50 and methylene chloride (1: 1) = 0.36.

C. A solution of 0.42 g of the reaction product according to Part B (6β-isomer) in 20 ml of 95% aqueous ethanol is flushed with nitrogen and mixed with 4 ml of 1 N aqueous sodium hydroxide solution. After 2'A hours at room temperature, the resulting mixture is concentrated under reduced pressure and the residue is dissolved in water. The aqueous solution is acidified with 0.6 g of potassium bisulfate and extracted with ethyl acetate. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a colorless oil which contains the crude title compound (free acid). When chromatographing on 50th

g of silica gel washed with acid and packed with 20% acetone in methylene chloride gives 0.33 g of the pure title acid as a 65 yellow oil while eluting with 20 to 60% acetone in methylene chloride. The mass spectrum of the trimethylsilyl derivative shows a high-resolution peak at 568.3454 and further peaks at 553.497.478.463.407.399.279.225.199.173 and 117.

The procedure of Example 1 is repeated, but using the various PGF2a, cis-4,5-didehydro-PGFla (q = 1) or 9, II-deoxy-9a-hydroxymethyl-PGF2 compounds of the formula XXI instead of the PGF2a-methyl ester, the corresponding 4,5-didehydro-6a or 6β-PGI-like products are obtained in the form of the methyl ester or the free acids.

Example 2

trans-4,5,13,14-tetradehydro-6ß-PGIi methyl ester (formula V: Xt = -COOCH3, Zï = - (CH2) 2-,

Z2 = FK

c = c;

. q-ch-cho / \

p and q = 0, Rs = hydroxy, R3 and R4 of Lj and

R5 of Mj all hydrogen, R7 = n-butyl) and its free acid.

Compare Scheme B.

A. A solution of 1.9 g of 14-bromo-PGF2a methyl ester in 30 ml of methylene chloride is added to a suspension of 2.85 g of molecular iodine, 1.80 g of potassium iodide, 0.82 g of sodium acetate and 6 ml of water. The resulting mixture is stirred for 2 hours, then mixed with 20 ml of 2N aqueous sodium sulfite solution, washed successively with 5% aqueous sodium bicarbonate solution and 5% aqueous sodium chloride solution, dried and concentrated, 2.95 g of crude 9-deoxy -6,9a-epoxy-5-iodo-14-bromo-PGFla methyl ester can be obtained. 0.13 g of this crude product is chromatographed on 13 g of silica gel washed with acid, eluting with ethyl acetate and benzene (3: 7), giving 0.088 g of pure product of the formula XXXII; NMR absorptions at 0.89.1.1-3.18.3.66.3.6-4.8, and 5.88 ô. The mass spectrum for the trimethylsilyl derivative shows a high resolution peak at 701.1183, a molecular ion at 716 and further peaks at 645, 637,589,547,529,510 and 173. IR absorptions at 3380, 1740.1655, 1230, 1170, 1080 and 1050 cm "1.

B. The reaction product according to Part A (1.0 g of crude, not chromatographed product) in 10 ml of methylene chloride is mixed with 3 ml of dihydropyran and 3 ml of methylene chloride saturated with pyridine hydrochloride. After 20 hours the resulting mixture is diluted with diethyl ether, successively with

5% aqueous sodium bicarbonate solution and 5% aqueous sodium chloride solution, dried and to a residue of 1.12 g of 9-deoxy-6.9a-epoxy-5-iodo-14-bromo-PGF10-methyl ester-11, 15-bis (tetrahydropyranyl ether) concentrated; NMR absorptions at 0.9.1.05-2.20.2.2-3.2.3.2-4.35, 3.66.4.35-4.15 and 5.7-6, 1 ô. IR absorptions at 2900, 2820, 1760, 1440, 1350, 1210, 1215, 1090, 1035, 1025, 970 and 910 cm "1.

C. A solution of 1.1 g of the reaction product according to Part B in 15 ml of dimethyl sulfoxide and 1.5 ml of methanol is reacted with 0.504 g of potassium tert-butoxide for 20 hours. The resulting dark colored solution is then diluted with 60 ml of water, cooled, acidified with 5% aqueous phosphoric acid and extracted with diethyl ether. The ether extracts are washed with saturated sodium chloride solution, dried and concentrated to 0.173 g of crude trans-4,5-13,14-tetradehydro-6ß-PGIj-11, 15-bis (tetrahydropyranyl ether) which, after esterification with excess diazomethane in ether, evaporates the product of the formula XXXIV results. This crude product of formula XXXIV shows characteristic NMR absorptions at 5.5-5.8 and 2.41 ô:

D. 0.168 g of the crude reaction product according to part C in

6 ml of acetic acid with 3 ml of water for 3 hours at 40 ° C

19th

635 836

warms. The resulting solution is extracted with 250 ml of methanol and concentrated to give 0.106 g of the crude title compound (methyl ester) as a yellow residue. Chromatography on 50 g of silica gel gives 76.1 mg of the pure methyl ester by elution with Skellysolve B and ethyl acetate (1: 1). The mass spectrum of the trimethylsilyl derivative shows a high resolution peak at 508.3025 and another peak at 421.

E. A solution of 3 g of the reaction product according to part

B in 10 ml of a mixture of dimethyl sulfoxide and methanol io (17: 3) is reacted with 1.96 g of potassium tert-butoxide in 35 ml of the same dimethyl sulfoxide / methanol mixture. After 14 hours a further 0.85 g of potassium tert-butoxide are added and the reaction is allowed to continue for a further 21 hours. The resulting mixture is then mixed with 20 ml of 2N aqueous sodium hydroxide solution and 20 ml of water. After a further 12 hours the mixture is cooled to give a semi-solid residue which is acidified at 0 ° C with phosphoric acid and extracted with ethyl acetate. The ether extracts are washed with 5% aqueous sodium chloride solution, dried and concentrated to give 2.116 g of crude trans-4,5,13,14-tetradehydro-6β-PGIril, 15-bis (tetrahydropyranyl ether). This crude title compound is then chromatographed on 170 g of silica gel washed with acid while eluting with mixtures of Skellysolve B and ethyl acetate. 25 0.3326 g of pure bis (tetrahydropyranyl ether) are obtained.

F. A solution of 0.333 g of the reaction product according to Part E in 20 ml of acetic acid is mixed with 10 ml of water for 3 hours

Kept at 40 ° C. The resulting mixture is diluted with 25 ml of water and lyophilized to a yellow residue. This residue is chromatographed on 60 g of silica gel washed with acid, eluting with mixtures of ethyl acetate and hexane. This gives 0.0925 g of the pure title compound (free acid). 35

According to the specification of Example 2, the various products of the formula XXXV are obtained as free acids or esters from the corresponding PGF-like compounds of the formula XXXI. 40

Example 3

trans-4,5,13,14-tetradehydro-15-epi-6ß-PGI1 (formula V, as in Example 2, hydroxyl group in the

Grouping Mj but in ß configuration)

Compare Scheme B.

A. Following the procedure of Example 2, Parts A and B, the 15-epi-14-bromo-PGF2cl-methyl ester is converted into the 9-deoxy-6,9a-epoxy-5-iodine, 14-bromo-15-epi -PGFla-methyl ester-11.15-bis (tetrahydropy ranyl ether) transferred.

B. 0.350 g of the reaction product according to Part A are reacted in solution according to the procedure of Example 2, Part E, to 90.5 mg of the pure title compound.

45

55

Example 4

trans, trans-2,3,4,5-tetradehydro-PGI1 methyl ester (formula VI: X! = -COOCH3, p and q = 0, Rg = hydroxy, Y3 = trans-CH = CH-, R3 and R4 from Lj and R5 of Mj all hydrogen, R7 = n-butyl) and its free acid.

Compare Scheme C. 60

A. 2 g of 9-deoxy-6,9a-epoxy-5-iodine-PGFia methyl ester (prepared from PGF2a methyl ester according to the procedure of Example 2, paragraph A) are dissolved in 26 ml of tetrahydropyran at room temperature. Then 4.6 ml of hexamethyldisilane and then 1.2 ml of trimethylsilyl chloride are added. 65 After about 10 to 15 minutes, a white precipitate forms, and after concentration under reduced pressure, filtration through diatomaceous earth and second concentration, 2.42 g are obtained

9-Deoxy-6,9a-epoxy-5-iodine-PGFla-methyl ester-II, 15-bis (trimethylsilyl ether) of the formula XLIII.

B. A mixture of N-isopropylcyclohexylamine in 30 ml of tetrahydrofuran is cooled to -28 ° C. for 15 minutes and then added to 2.4 g of the reaction product according to Part A in 20 ml of tetrahydrofuran. Then 4.6 ml of 1.6 molar n-butyl lithium solution in hexane are added and the resulting mixture is stirred for 30 minutes. Then 1.76 g of diphenylselenide in 15 ml of tetrahydrofuran are added at -78 ° C., after which the mixture is stirred for a further 1 hour at this temperature. The resulting mixture is allowed to warm to 0 ° C and poured into ammonium chloride (150 ml) in diethyl ether (150 ml). After extraction with diethyl ether, washing of the ether extracts with water and saturated sodium chloride solution, drying over sodium sulfate and concentration under reduced pressure, 4.10 g of crude 9-deoxy-6.9a-epoxy-2-phenylselenyl-5-iodine-PGFla are obtained -methyl ester-ll, 15-bis (trimethylsilyl ether).

C. 2.98 g of the crude reaction product according to Part B are then stirred with 80 ml of a 3: 1 mixture of methanol and citric acid for 30 minutes. The solution is then decanted and 50 ml of methanol are added. The resulting mixture is concentrated under reduced pressure, the residue is dissolved in methylene chloride, washed with water, dried and added to 3.81 g of crude 9-deoxy-6,9a-epoxy-2-phenylselen-nyl-5-iodine-PGFla- concentrated methyl ester of the formula XLV. This crude product is purified by chromatography on 350 g of silica gel while eluting with acetone / methylene chloride mixture; this gives 1.87 g of pure product.

D. 3.29 g of 30% aqueous hydrogen peroxide are added to the reaction product according to Part C in 65 ml of methylene chloride from room temperature. The mixture is stirred vigorously for 1 hour, then the phases are separated and the organic phase is washed with 5% aqueous sodium bicarbonate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The aqueous washing solutions are extracted with methylene chloride and the combined organic extracts are dried. This gives 1.5 g of crude 9-deoxy-6,9a-epoxy-trans-2,3-didehydro-5-iodine-PGFla-methyl ester of the formula XLVI. This crude product is chromatographed on 20 g of silica gel while eluting with acetone and diethyl ether (1: 2), 540 mg of the pure product of the formula XLVI being obtained. The high resolution mass spectrum for the trimethylsilyl derivative shows a peak at 637.1876, further peaks are observed at 652.749, 363 and 173.

E. 33 ml of dry benzene and 1.2 ml of dry room temperature DBN are combined with 590 mg of the reaction product from Part D at 40 ° C for 30 min. The reaction mixture is then washed with water, dried and concentrated to 497 mg of the crude title compound (methyl ester). This crude product is chromatographed on 60 g of silica gel while eluting with acetone and methylene chloride. In doing so

427 mg of crude methyl ester obtained as a yellow oil. The mass spectrum shows a high resolution peak for this trimethylsilyl derivative at 508.3040 and further peaks at 493.437.418, 403.347 and 328.; specific optical rotation + 51 ° at 5.1 mg / ml in chloroform.

F. 100 mg of the reaction product according to Part E in 3 ml of room temperature methanol are combined with 0.95 ml of 3N aqueous potassium hydroxide solution with stirring. After 1 V2 hours at room temperature and a further hour at 50 ° C, 67 mg of potassium t-butoxide in methanol are added and the reaction is continued at room temperature.

A mixture of 75 ml of ethanol and 5 ml of 2N aqueous potassium bisulfate solution is then added, adjusting the pH to about 3. After addition of 20 ml of water, organic and aqueous phases are separated, and the aqueous phase is saturated with sodium chloride and with Extracted ethyl acetate. The combined organic extracts are dried

635 836

20th

and concentrated to give 44 mg of the title compound (free acid). The high resolution mass spectrum for the trimethylsilyl derivative shows a peak at 566.3282 and further peaks at 551.495.426.405 and 356.

According to the instructions in Example 4, the various compounds of the formula XLI are converted into the corresponding esters XLVII and acids XLIX.

Furthermore, the esters XLVII are reduced with lithium aluminum hydride to the corresponding primary alcohols XLVIII, and the acids XLIX are converted to the amides L by the amidation process described above. Finally, the amides L are reduced with lithium aluminum hydride to the primary amines LI, which can then be mono- or dialkylated using known methods.

Analogously, the acids and esters described in and following Examples 1 to 3 are converted into the corresponding amides, primary alcohols or amines.

Example 5

trans ^ S-didehydro-öss-PGIpp-phenylphenacylester and its 6a isomer

A. trans-4,5-didehydro-6a-PGI 1.25 ml methyl cyanide, 1.5 gp-phenylphenacyl bromide and 1 ml diisopropylethylamine are reacted at room temperature for 1 hour and then diluted with potassium bisulfate solution and ethyl acetate. The ethyl acetate extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to 0.44 g of an oil which crystallizes on standing. When recrystallizing from methyl acetate, 0.26 g of pure trans-4,5-didehydro-6a-PGIj-p-phenylphenacylester of mp 92 to

96 ° C. The mass spectrum 2 shows a high resolution peak for the trimethylsilyl derivative at 690.3749, IR absorption at 3450.1735.1710.1610, 1460.1375, 1235, 1170.1050, 965.890.835 and 765 cm "1.

B. According to Part A, trans-4,5-Didehy-dro-öß-PGl! transferred to 0.65 g of crystalline 6β-title compound. When recrystallizing from ethyl acetate and hexane, 0.38 g of the pure 6β-isomer of mp 105 to 107 ° C. is obtained, NMR absorptions at 7.2-8.1.5.4-5.75.5.3, 3.5-4.7 and 0.9 Ô, IR absorptions at 3450.1740.1715.1615.1460, 1375.1240, 1170.790.840.765.725 and 690 cm "-

If the procedures of the above examples are repeated, but using the corresponding PGF2a, cis-4,5-dide-hydro-PGF2a or 9-deoxy-9-hydroxymethyl-PGF2-like starting material, trans-4,5 is obtained -Didehydro-6a-PGIx-,

trans-4,5-didehydro-6ß-PGIj-,

trans, trans-2,3,4,5-tetradehydro-6 -PGIr,

trans, trans-2,3,4,5-tetradehydro-6ß-PGIx-, 7a-homo-trans-4,5-didehydro-6cc-PGIi-, 7a-homo-trans-4,5-didehydro-6ß- PGI1-, 7a-homo-trans, trans-2,3,4,5-tetradehydro-6a-PGI1-, 7a-homo-trans, trans-2,3,4,5-tetradehydro-6ß -PGIr, or ( 6R) - or (6S) -trans-4,5-didehydro-9-deoxy-6,9a-epoxymethylene-PGFr or

(6R) - or (6S) -trans, trans-2,3,4,5-tetradehydro-9-deoxy-6,9a-epoxymethylene-PGF-like compounds as free acids, amides or esters with the following side chain substituents:

15-methyl,

16-methyl,

15,16-dimethyl,

16,16-dimethyl,

16-fluorine,

15-methyl, 16-fluorine,

16,16-difluoro,

15-methyl, 16,16-difluoro,

17-phenyl, 18,19,20-trinor, 17- (m-trifluoromethylphenyl) -18,19,20-trinor-, 17- (m-chlorophenyl) -18,19,20-trinor-, 17- (p -Fluorophenyl) -18,19,20-trinor-, 515-methyl-17-phenyl-18,19,20-trinor-, 16-methyl-17-phenyl-18,19,20-trinor-, 16,16 -Dimethyl-17-phenyl-18,19,20-trinor-,

16-fluoro-17-phenyl-18,19,20-trinor-,

16,16-difluoro-17-phenyl-18,19,20-trinor-, io 16-phenyl-17,18,19,20-tetranor-,

15-methyl-16-phenyl-17,18,19,20-tetranor-,

16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-, 16- (m-chlorophenyl) -17,18,19,20-tetranor-, 16- (p-fluorophenyl) -17,18, 19.20-tetranor-,

15 16-phenyl-18,19,20-trinor-,

15-methyl-16-phenyl-18,19,20-trinor-,

16-methyl-16-phenyl-l 8,19,20-trinor-, 15,16-dimethyl-16-phenyl-18,19,20-trinor-,

16-phenoxy-l 7,18,19,20-tetranor-,

2015-methyl-16-phenoxy-17,18,19,20-tetranor-,

16- (m-trifluoromethylphenoxy) -l 7,18,19,20-tetranor-, 16- (m-chlorophenoxy) -17,18,19,20-tetranor-, 16- (p-fluorophenoxy) -17, 18,19,20-tetranor-, 16-phenoxy-18,19,20-trinor-, 25 15-methyl-16-phenoxy-18,19,20-trinor-, 16-methyl-16-phenoxy-18, 19,20-trinor-, 15,16-dimethyl-16-phenoxy-18,19,20-trinor-, 13,14-didehydro-,

16-methyl-13,14-didehydro-, 30 16,16-dimethyl-13,14-didehydro-,

16-fluoro-13,14-didehydro-,

16,16-difluoro-13,14-didehydro-,

17-phenyl-18,19,20-trinor-l 3,14-didehydro-,

17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-didehydro-, 35 17- (m-chlorophenyl) -18,19,20-trinor-13,14-didehydro-,

17- (p-flurophenyl) -18,19,20-trinor-13,14-didehydro-, 16-methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-, 16,16- Dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-, 16-fluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-, 40 16,16-difluoro -17-phenyl-18,19,20-trinor-13,14-didehydro-, 16-phenyl-17,18,19,20-tetranor-13,14-didehydro-, 16- (m-trifluoromethylphenyl) -17 , 18,19,20-tetranor-13,14-didehydro-,

16- (m-chlorophenyl) -17,18,19,20-tetranor-13,14-didehydro-, 45 16-phenyl-18,19,20-trinor-13,14-didehydro-,

16-methyl-16-phenyl-18,19,20-trinor-13,14-didehydro-, 16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-, 16- (m-trifluoromethylphenoxy ) -17,18,19,20-tetranor-13,14-didehydro-,

50 16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-didehydro-, 16-phenoxy-18,19,20-trino-13,14-didehydro-, 16-methyl-16 -phenoxy-18,19,20-trinor-13,14-didehydro-, 13,14-dihydro-,

16-methyl-13,14-dihydro-,

5516,16-dimethyl-l 3,14-dihydro-,

16-fluoro-l 3,14-dihydro-,

16,16-difluor-13,14-dihydro-,

17-phenyl-18,19,20 -trinor-13,14-dihydro-, 17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-dihydro-,

6017- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-, 17- (p-flurophenyl) -18,19,20-trinor-13,14-dihydro-, 16-methyl- 17-phenyl-18,19,20-trinor-13,14-dihydro-, 16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-, 16-fluoro-17- phenyl-18,19,20-trinor-13,14-dihydro-, 6516,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-, 16-phenyl-17,18, 19,20-tetranor-13,14-dihydro-, 16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13,14-dihydro-,

21st

635 836

16- (m-chlorophenyl) -17,18,19,20-tetranor-13,14-dihydro-, 16- (p-fluorophenyl) -17,18,19,20-tetranor-13,14-dihydro-, 16-phenyl-18,19,20-trinor-13,14-dihydro-, 16-methyl-16-phenyl-18,19,20-trinor-13,14-dihydro-, 16-phenoxy-17,18, 19,20-tetranor-l 3,14-dihydro-, 16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-, 16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-, 16-phenoxy-18,19,20-trinor-13,14-dihydro-, 16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-, 13-cis,

16-methyl-13-cis,

16,16-dimethyl-13-cis,

16-fluoro-13-cis,

16,16-difluoro-13-cis,

17-phenyl-18,19,20-trinor-l 3 -eis-,

17- (m-trifluoromethylphenyl) -18,19,20-trinor-13-cis, 17- (m-chlorophenyl) -18,19,20-trinor-13-cis, 17- (p-fluorophenyI) -18,19,20-trinor-13-cis, 16-methyl-17-phenyl-18,19,20-trinor-13-cis, 16,16-dimethyl-17-phenyl-18,19,20 -trinor-13-cis, 16-fluoro-17-phenyl-18,19,20-trinor-13-cis, 16,16-difluoro-17-phenyl-18,19,20-trinor-13-cis -, 16-phenyl-17,18,19,20-tetranor-13-cis, 16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13-cis, 16- (m-chlorophenyl ) -17,18,19,20-tetranor-13-cis, 16- (p-fluorophenyl) -17,18,19,20-tetranor-13-cis,

16-phenyl-l 8,19,20-trinor-l 3-cis, 16-methyl-16-phenyl-18,19,20-trinor-13-cis, 16-phenoxy-17,18,19, 20-tetranor-13-eis-, 16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-cis, 16- (m-chlorophenoxy) -17,18,19,20-tetranor- 13-cis, 16- (p-fluorophenoxy) -17,18,19,20-tetranor-13-cis, 16-phenoxy-18,19,20-trinor-13-cis, 16-methyl-16 -phenoxy-18,19,20-trinor-13-cis,

2,2-difluoro,

2,2-difluoro-15-methyl-,

2,2-difluoro-16-methyl-,

2,2-difluoro-16,16-dimethyl-,

2,2-difluoro-16-f luoro,

2,2-difluoro-16,16-difluoro, 2,2-difluoro-17-phenyl-18,19,20-trinor-, 2,2-difluoro-17- (m-trifluoromethylphenyl) -18,19, 20-trinor-, 2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-, 2,2-difluoro-17- (p-fluorophenyl) -18,19,20-trinor- , 2,2-difluoro-16-methyl-17-phenyl-18,19,20-trinor-, 2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-, 2nd , 2-difluoro-16-fluoro-17-phenyl-18,19,20-trinor-, 2,2-difluoro-16,16-difluoro-17-phenyl-18,19,20-trinor-, 2,2 -Difluoro-16-phenyl-17,18,19,20-tetranor-, 2,2-difluoro-16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-,

2,2-difluoro-16- (m-chlorophenyl) -17,18,19,20-tetranor-, 2,2-difluoro-16- (p-fluorophenyl) -17,18,19,20-tetranor-, 2,2-difluoro-16-phenyl-18,19,20-trinor-, 2,2-difluoro-16-methyl-16-phenyl-18,19,20-trinor-, 2,2-difluoro-16- phenoxy-17,18,19,20-tetranor-, 2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-,

2,2-difluoro-l 6- (m-chlorophenoxy) -17,18,19,20-tetranor-, 2,2-difluoro-16- (p-fluorophenoxy) -17,18,19,20-tetranor- , 2,2-difluoro-l 6-phenoxy-18,19,20-trinor-, 2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-, 2,2-difIuor- 16-methyl-13,14-didehydro-, 2,2-difluoro-16,16-dimethyl-13,14-didehydro-, 2,2-difluoro-16-fluoro-13,14-didehydro-, 2,2 -Difluoro-16,16-difluoro-13,14-didehydro-,

2,2-difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-, 2,2-difluoro-17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14 -didehydro-,

2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dide-5 hydro-,

2,2-difluoro-17- (p-fluorophenyl) -18,19,20-trinor-13,14-didehydro-,

2,2-difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14-dide-hydro-,

io 2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-,

2,2,16-trifluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-, 2,2,16,16-tetrafluoro-17-phenyl-18,19,20-trinor-13 14-didehydro

15 2,2-difluoro-16-phenyl-17,18,19,20-tetranor-13,14-didehydro-,

2,2-difluoro-16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13, 14-didehydro-,

2,2-difIuor-16- (m-chlorophenyl) -17,18,19,20-tetranor-13,14-20 didehydro-,

2,2-difluoro-16-phenyl-18,19,20-trinor-13,14-didehydro-, 2,2-difluoro-16-methyl-16-phenyl-18,19,20-trinor-13,14 -didehydro-,

2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-didehy-25 dro-,

2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetra-nor-13,14-didehydro-,

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-didehydro-,

30 2,2-difluoro-16-phenoxy-18,19,20-trinor-13,14-didehydro-, 2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13, 14-di-dehydro-,

2,2-difluoro-13,14-dihydro-, 2,2-difluoro-16-methyl-13,14-dihydro-, 35 2,2-difluoro-16,16-dimethyl-13,14-dihydro-, 2,2,16-trifluoro-13,14-dihydro-, 2,2,16,16-tetrafluoro-13,14-dihydro-, 2,2-difluoro-17-phenyl-18,19,20-trinor- 13,14-dihydro-, 2,2-difluoro-17- (m-trif luormethylphenyl) -18,19,20-trinor-40 13,14-dihydro-, 2,2-difluoro-17- (m- chlorphenyl) -18,19,20-trinor-13,14-dihy-dro-,

2,2-difluoro-17- (p-fluorophenyl) -18,19,20-trinor-13,14-dihy-dro-,

45 2,2-difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-,

2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-,

2,2,16-trifluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-, 50 2,2,16,16-tetrafluoro-17-phenyl-18,19,20-trinor- 13,14-dihy-dro-,

2,2-difluoro-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-,

2,2-difluoro-16- (m-trifluoromethylphenyl) -l 7,18,19,20-tetra-55 nor-13,14-dihydro-, 2,2-difluoro-16- (m-chlorophenyl) -17 , 18,19,20-tetranor-l 3,14-dihydro-,

2,2-difluoro-16- (p-fluorophenyl) -17,18,19,20-tetranor-13,14-dihydro-,

60 2,2-difluoro-16-phenyl-16-phenyl-18,19,20-trinor-13,14-dihydro-,

2,2-difluoro-16-methyl-16-phenyl-18,19,20-trinor-13,14-dihydro-,

2,2-difluoro-l 6-phenoxy-l 7,18,19,20-tetranor-13,14-dihydro-,

65 2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetra-nor-13,14-dihydro-,

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

635 836

22

2,2-difhior-16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

2,2-difluoro-16-phenoxy-18,19,20-trinor-13,14-dihydro-,

2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-di-

hydro,

2,2-difluoro-13-cis,

2,2-difluoro-16-methyl-13-ice,

2,2-difluoro-l 6,16-dimethyl-l 3-cis,

2,2,16-trifluoro-13-cis,

2,2,16,16-tetrafluoro-13-ice,

2,2-difluoro-17-phenyl-18,19,20-trinor-13-cis,

2,2-difluoro-17- (m-trifluoromethylphenyl) -18,19,20-trinor-13-

cis,

2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-13-cis, 2,2-difluoro-17- (p-fluorophenyl) -18,19,20-trinor-13 -eis-, 2,2-difluoro-l 6- (methyl-17-phenyl-18-19,20-trinor-13-cis, 2,2-difluoro-16,16-dimethyl-17-phenyl-18 , 19.20-trinor-l3-ice,

2,2,16-trifluoro-17-phenyl-18,19,20-trinor-13-cis, 2,2,16,16-tetrafluoro-17-phenyl-18,19,20-trinor-13-cis -, 2,2, -difluoro-16-phenyl-17,18,19,20-tetranor-l 3-cis, 2,2-difluoro-16- (m-trifluoromethylphenyl) -17,18,19,20 -tetra-nor-13-cis-,

2,2-difluoro-16- (m-chlorophenyl) -17,18,19,20-tetranor-13-cis,

2,2-difluoro-16- (p-fluorophenyl) -17,18,19,20-tetranor-13-cis,

2,2-difluoro-16-phenyl-18,19,20-trinor-13-cis,

2,2-difluoro-16-methyl-16-phenyl-18,19,20-trinor-13-cis,

2,2-difluoro-l 6-phenoxy-17,18,19,20-tetranor-l 3-cis,

2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetra-

nor-13-cis,

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13-cis,

2,2-difluoro-16- (p-fluorophenoxy) -17,18,19,20-tetranor-13-cis,

2,2-difluoro-16-phenoxy-18,19,20-trinor-13-cis,

2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13-cis,

trans-2,3-didehydro-,

trans-2,3-didehydro-15-methyl-,

trans-2,3-didehydro-16-methyl-,

trans-2,3-didehydro-16,16-dimethyl-,

trans-2,3-didehydro-16-fluoro-,

trans-2,3-didehydro-16,16-difluoro-,

trans-2,3-didehydro-17-phenyl-18,19,20-trinor-,

trans-2,3-didehydro-17- (m-trifluoromethylphenyl) -18,19,20-

trinor,

trans-2,3-didehydro-17- (m-chlorophenyl) -18,19,20-trinor-, trans-2,3-didehydro-17- (p-fIuorphenyl) -18,19,20-trinor-, trans-2,3-didehydro-16-methyl-17-phenyl-18,19,20-trinor-, trans-2,3-didehydro-16,16-dimethyl-17-phenyl-18,19,20- tri-nor-,

trans-2,3-didehydro-l 6-fluoro-17-phenyl-18,19,20-trinor-, trans-2,3-didehydro-16,16-difluoro-17-phenyl-18,19,20- tri-nor-,

trans-2,3-didehydro-16-phenyl-17,18,19,20-tetranor-, trans-2,3-didehydro-16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-,

trans-2,3-didehydro-16- (m-chlorophenyl) -17,18,19,20-tetranor-,

trans-2,3-didehydro-16- (p-fluorophenyl) -17,18,19,20-tetranor-,

trans-2,3-didehydro-16-phenyl-18,19,20-trinor-, trans-2,3-didehydro-16-methyl-16-phenyl-18,19,20-trinor-, trans-2, 3-didehydro-16-phenoxy-17,18,19,20-tetranor-, trans-2,3-didehydro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-,

trans-2,3-didehydro-16- (m-chlorophenoxy) -17,18,19,20-tetra-nor-,

trans-2,3-didehydro-16- (p-f luorphenoxy) -17,18,19,20-tetra-nor-,

trans-2,3-didehydro-16-phenoxy-18,19,20-trinor-, trans-2,3-didehydro-16-methyl-16-phenoxy-18,19,20-trinor-, trans-2, 3-didehydro-13,14-didehydro-, trans-2,3-didehydro-16-methyl-13,14-didehydro-, s trans-2,3-didehydro-16,16-dimethyl-13,14-didehydro -, trans-2,3-didehydro-16-fluoro-13,14-didehydro-, trans-2,3-didehydro-16,16-difluoro-13,14-didehydro-, trans-2,3-didehydro- 17-phenyl-18,19,20rtrinor-13,14-didehy-dro-,

io trans-2,3-didehydro-17- (m-trifluoromethylphenyl) -18,19,20-trinor- 13,14-didehydro-,

trans-2,3-didehydro-17- (m-chlorophenyl) -18,19,20-trinor-13,14-didehydro-,

trans-2,3-didehydro-17- (p-fluorophenyl) -18,19,20-trinor-15 13,14-didehydro-, trans-2,3-didehydro-16-methyl-17-phenyl-18, 19.20-trinor-13.14-didehydro-,

trans-2,3-didehydro-16,16-dimethyl-17-phenyl-18,19,20-tri-nor-13,14-didehydro-, 20 trans-2,3-didehydro-16-fluoro-17- phenyl-18,19,20-trinor-13,14-didehydro-,

trans-2,3-didehydro-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-,

trans-2,3-didehydro-16-phenyl-17,18,19,20-tetranor-13,14-25 didehydro-,

trans-2,3-didehydro-16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13,14-didehydro-, trans-2,3-didehydro-16- (m-chlorophenyl) -17 , 18,19,20-tetra-nor-13,14-didehydro-, 30 trans-2,3-didehydro-16-phenyl-18,19,20-trinor-13,14-didehy-dro-,

trans-2,3-didehydro-16-methyl-16-phenyl-18,19,20-trinor-13,14-didehydro-,

trans-2,3-didehydro-16-phenoxy-17,18,19,20-tetranor-13,14-35 didehydro-, trans-2,3-didehydro-16- (m-trifluoromethylphenoxy) -17,18, 19,20-tetranor-13,14-didehydro-, trans-2,3-didehydro-16- (m-chlorophenoxy) -17,18,19,20-tetra-nor-13,14-didehydro-, to trans -2,3-didehydro-16-phenoxy-18,19,20-trinor-13,14-dide-hydro-,

trans-2,3-didehydro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-,

trans-2,3-didehydro-13,14-dihydro-, «trans-2,3-didehydro-16-methyl-13,14-dihydro-, trans-2,3-didehydro-16,16-dimethyl-13 , 14-dihydro,

trans-2,3-didehydro-16-fluoro-13,14-dihydro-, trans-2,3-didehydro-16,16-difluoro-13,14-dihydro-, trans-2,3-didehydro-17- phenyl-18,19,20-trinor-13,14-dihy-50 dro-,

trans-2,3-didehydro-17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-dihydro-,

trans-2,3-didehydro-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-, 55 trans-2,3-didehydro-17- (p-fluorophenyl) -18, 19,20-trinor-13,14-dihydro-,

trans-2,3-didehydro-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-,

trans-2,3-didehydrorl6,16-dimethyl-17-phenyl-18-19,20-tri-60 nor-13,14-dihydro-, trans-2,3-didehydro-16-fluoro-17-phenyl- 18,19,20-trinor-13,14-dihydro-,

trans-2,3-didehydro-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-,

65 trans-2,3-didehydro-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-,

trans-2,3-didehydro-16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13,14-dihydro-,

23

635 836

trans-2,3-didehydro-16- (m-chlorophenyl) -17,18,19,20-tetra-nor-13,14-dihydro-,

trans-2,3-didehydro-16- (p-fluorophenyl) -17,18,19,20-tetranor-13,14-dihydro-,

trans-2,3-didehydro-16-phenyl-18,19,20-trinor-13,14-dihy-dro-,

trans-2,3-didehydro-16-methyl-16-phenyl-l 8,19,20-trinor-13,14-dihydro-,

trans-2,3-didehydro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-,

trans-2,3-didehydro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14-dihydro-, trans-2,3-didehydro-16- (m-chlorophenoxy) -17 , 18,19,20-tetranor-13,1 4-dihydro-,

trans-2,3-didehydro-16- (p-fluorophenoxy) -17,18,19,20-tetra-nor-13,14-dihydro-,

trans-2,3-didehydro-16-phenoxy-18,19,20-trinor-13,14-dihy-dro-,

trans-2,3-didehydro-16-methyl-16-phenoxy-18,19,20-trinor-

13,14-dihydro-,

trans-2,3-didehydro-13-cis,

trans-2,3-didehydro-16-methyl-13-cis,

trans-2,3-didehydro-16,16-dimethyl-13-cis,

trans-2,3-didehydro-16-fluoro-13-cis,

trans-2,3-didehydro-16,16-difluoro-13-cis,

trans-2,3-didehydro-17-phenyl-18,19,20-trinor-13-cis,

trans-2,3-didehydro-17- (m-trifluoromethylphenyl) -18,19,20-

trinor-13-cis,

trans-2,3-didehydro-16- (m-chlorophenyl) -18,19,20-trinor-13-cis,

trans-2,3-didehydro-17- (p-fluorophenyl) -18,19,20-trinor-13-cis,

trans-2,3-didehydro-16-methyl-17-phenyl-18,19,20-trinor-13-cis,

trans-2,3-didehydro-16,16-dimethyl-17-phenyl-18,19,20-tri-nor-13-cis,

trans-2,3-didehydro-16-fluoro-17-phenyl-18,19,20-trinor-13-cis,

trans-2,3-didehydro-16,16-difluoro-17-phenyl-18,19,20-trinor-13-cis,

trans-2,3-didehydro-16-phenyl-17,18,19,20-tetranor-13-cis, trans-2,3-didehydro-16- (m-trifluoromethylphenyl) -17,18,19,20 -tetranor-13 -eis-,

trans-2,3-didehydro-16- (m-chlorophenyl) -17,18,19,20-tetra-5 nor-13-cis,

trans-2,3-didehydro-l 6- (p-fluorophenyl) -l 7,18,19,20-tetranor-13-cis,

trans-2,3-didehydro-16-phenyl-18,19,20-trinor-13-cis, trans-2,3-didehydro-16-methyl-16-phenyl-18,19,20-trinor-iol3 -cis-,

trans-2,3-didehydro-16-phenoxy-17,18,19,20-tetranor-13-cis,

trans-2,3-didehydro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-cis, 15 trans-2,3-didehydro-16- (m-chlorophenoxy) -17, 18,19,20-tetra-nor-13-cis,

trans-2,3-didehydro-16- (p-fluorophenoxy) -17,18,19,20-tetra-nor-13-cis,

trans-2,3-didehydro-16-phenoxy-18,19,20-trinor-13-cis, 20 trans-2,3-didehydro-16-methyl-16-phenoxy-18,19,20-trinor- 13-cis,

and the corresponding ll-deoxy-PGFi and 11-deoxy-ll-hydroxymethyl-PGF1 analogs.

25th

Furthermore, the corresponding 2-decarboxy-2-hydroxymethyl-like compounds are obtained by reducing the carboxylic acid esters and the corresponding 2-decarboxy-2-aminomethyl-like compounds by reducing the prostacyclin-like amides with lithium aluminum hydride by the processes described above, compare in particular US Pat. No. 4,028,350, which describes the preparation of Cl-amine and Cl-alcohol-analogs of certain bicyclic prostaglandins. The pharmacologically acceptable salts are also formed from the above carboxylic acids by neutralization with the corresponding base. In the case of the 2-decarboxy-2-aminomethyl-like compounds, the pharmacologically acceptable acid addition salts are obtained by neutralization with the corresponding acid.

C.

Claims (9)

635 836 2nd PATENT CLAIMS 1. Therapeutically effective prostacyclin analogues of the formula (1) -COORj, in which Ri is hydrogen, an alkyl radical with 1 to 12 carbon atoms, cycloalkyl radical with 3 to 10 carbon atoms, aralkyl radical with 7 to 12 carbon atoms, the phenyl radical, one with 1, 2 or 3 chlorine atoms or alkyl radicals 5 with 1 to 3 Carbon atoms substituted phenyl, one in the p-position by O io (a) -NH-CR25 (IV) O II (b) -0-C-R26 Y5-C-C-R7 (c) -Ö-C T R27 or 20th O wherein Zj the rest H. 'C = C (d) -CH = N-NHC-NH2 25 substituted phenyl radical, wherein R25 is methyl, phenyl, acetamido-dophenyl, benzamidophenyl or -NH2, R26 methyl, phenyl, -NH2 or methoxy and R27 is hydrogen or the acetamido radical, the phenacyl radical of the formula O-CH-CH, 30th O -CHo-C- or 35 (2) 40 O-CH-CH, 45 one of the symbols p and q 0 or 1 and the other 0, Z5 one of the residues (1) - (CH2) g-CH2-CH2- (2) - (CH2) g-CH2-CF2- or (3) trans- (CH2) g-CH = CH-, where g is 0.1 or 2, R8 is hydrogen, the hydroxyl group or the hydroxymethyl radical, Y5 is one of the radicals (1) trans-CH = CH-, (2) cis-CH = CH— (3) -CH2CH2— or (4) -C = C- / \, / \ Mj one of the groups R5 OH or R5 OH, where Rs is hydrogen or an alkyl radical having 1 to 4 carbon atoms, // \ Lj one of the groups R3 R4, R3 R4, / \ or a mixture of R3 R4 and R3 R4, wherein R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, provided that one of the radicals R3 or R4 only mean fluorine if the other is hydrogen or fluorine, X [one of the residues 50 55 60 is a phenacyl radical substituted in the p-position by chlorine, bromine, the phenyl or benzamido radical or a pharmacologically acceptable cation, (2) -CH2OH, (3) -CH2NL2L3, in which L2 and L3 are hydrogen or alkyl radicals having 1 to 4 carbon atoms, or (4) -COL4, where L4 (a) an amino group of the formula -NR21R22, in which R21 and R22 are hydrogen, alkyl radicals having 1 to 12 carbon atoms, cycloalkyl radicals having 3 to 10 carbon atoms, aralkyl radicals having 7 to 12 carbon atoms, the phenyl radical, by 1,2 or 3 chlorine atoms or Alkyl radicals with 1 to 3 carbon atoms, the hydroxyl group, carboxyl group, alkoxycarbonyl groups with 1 to 4 carbon atoms or the nitro group substituted phenyl radicals, carboxyalkyl radicals with 1 to 4 carbon atoms, carbamoylalkyl radicals with 1 to 4 carbon atoms, cyanoalkyl radicals with 1 to 4 carbon atoms, acetylalkyl radicals with 1 up to 4 carbon atoms, benzoylalkyl radicals with 1 to 4 carbon atoms, through 1,2 or 3 chlorine atoms or alkyl radicals with 1 to 3 carbon atoms, the hydroxyl group, alkoxy radicals with 1 to 3 carbon atoms, the carboxyl group, alkoxycarbonyl radicals with 1 to 4 carbon atoms or the nitro group substituted benzoylalkyl radicals, pyridyl radicals, by 1,2 or 3 chlorine atoms or Alkyl radicals with 1 to 3 carbon atoms or alkoxy radicals with 1 to 3 carbon atoms substituted pyridyl radicals, pyridylalkyl radicals, pyridylalkyl radicals with 1 to 4 carbon atoms, by 1,2 or 3 chlorine atoms or alkyl radicals with 1 to 3 carbon atoms, which substituted the hydroxyl group or alkoxy radicals with 1 to 3 carbon atoms Represent pyridylalkyl radicals, hydroxyalkyl radicals with 1 to 4 carbon atoms, dihydroxyalkyl radicals with 1 to 4 carbon atoms or trihydroxyalkyl radicals with 1 to 4 carbon atoms, with the further proviso that 3rd 635 836 that no more than one of the radicals R2i and R22 can be different from hydrogen or alkyl, (b) one of the following cycloamino groups < 2 1 22 ■ N NR21 r 22 Substance atoms mean, provided that no more than two radicals T are different from alkyl, and the pharmacologically acceptable acid addition salts of these compounds, in which Xx is the radical -CH2NL2L3; with the proviso that when R7 is n-butyl, R3, R4 and R5 are all hydrogen, Y 3 is trans-CH = CH-, Rs is hydroxy, p and q are both 0 and Z5 is only - (CH2 ) 2- means if X1 is not -COOH. 2. Prostacydin analogs according to claim 1, characterized in that R8 is hydroxy. 3. Prostacyclin analogs according to claim 2, characterized in that p and q are both zero. 4. Prostacyclin analogs according to claim 3, characterized in that Z2 means the following group H \ c = c: -H 22 or 22 O-CH-CH- / \ 25 5. Prostacyclin analogs according to claim 4, characterized in that Y5 -CH = CH—. 6. Prostacyclin analogues according to claim 5, characterized in that Z5 - (CH2) g-CH2-CH2-is. 7. prostacyclin analogs according to claim 6, characterized 30 records that Xj COOR! is. 8. The prostacyclin analog 15-methyl-trans-4,5-didehy-dro-6ß-PGJi according to claim 7. 9. The prostacyclin analog 16,16-difluoro-trans-4,5-di-dehydro-öss-PGJ! according to claim 8. 10. The prostacyclin analog 16,16-dimethyl-trans-4,5-didehydro-6ß-PGJj according to claim 9. wherein R2i and R22 have the meaning given above, (c) a carbonylamino group of the formula -NR23COR21, in which R23 is hydrogen or an alkyl radical having 1 to 4 carbon atoms and R21 has the meaning given above, (d) a sulfonylamino group of the formula -NR23S02R21, in which R2i and R23 have the meaning given above, or (e) a hydrazino group of the formula -NR23R24, in which R23 has the meaning described above and R24 is an amino group of the formula -NR2iR22 as defined above or cycloamino group as defined above, and R7 one of the residues 40