DE2638401A1 - NEW PROSTAGLANDIN, THEIR USE AND MANUFACTURING - Google Patents

Description

2G38AQ1

SANDOZ PATENT GMBH

Loerrach Case 100-4409

New prostaglandins, their uses and manufacture

The invention relates to new compounds of the formula I in which

A is a group of the formula Al to A7 or a mirror image of a group of the formula Al to A6 means

B is -CH ₂ -CH ₂ - or (cis) _{-CH = CH-, D is -CH 2} -CH ₂ - or (trans) -CH = CH-, R is alkyl with 1-10 carbon atoms or one

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Group of the formula II denotes in which Z is alkylene having 1-5 carbon atoms, X is -CH ₂ - or -0- and

R., R ₅ and R, independently of one another, represent hydrogen, halogen with an atomic number from 9 'to 35 or trifluoromethyl,

R ₂ denotes hydrogen or alkyl having 1-7 carbon atoms and

R- hydrogen, alkyl with 1-10 carbon atoms, by phenyl mono- or disubstituted alkyl with 1-10 carbon atoms or by biphenyl means mono- or disubstituted alkyl with 1-10 carbon atoms,

with the restriction that,

B for (CiS) -CH = CH- and

D stand for (trans) -CH = CH-,

R, denotes a group of the formula III in which

R- and Rg independently of one another represent hydrogen or alkyl with 1-4 carbon atoms,

R _{2 is} hydrogen,

R ₃ denotes hydrogen, alkyl with 1-8 carbon atoms or phenyl monosubstituted alkyl with 1-6 carbon atoms,

A denotes a group of the formula A5 to A7 or a mirror image of a group of the formula A5 or A6, and their Racemates.

The compounds of the formula I can exist in optically active or in racemic form. In the

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in the 1-position carboxyl group-containing compounds of formula I may exist in free form or in salt form present \ of the latter compounds in free form can be obtained salts and vice versa, in a known manner. In this way they form salts with bases, e.g. the sodium salt.

The substituents on the cyclopropane ring are in the cis or trans position, preferably in the trans position to each other.

A preferably denotes a group A2, A3 or A4, preferably A3 or A4, in particular A4.

R preferably denotes alkyl. If R, is alkyl, it is preferably straight-chain and is, for example, 1-heptyl or 1-pentyl, or is branched in the α-position / ie on the carbon atom in the 16-position of the prostaglandin structure; if the carbon atom in the 16-position is secondary, R is, for example, 2-hexyl or 5-nonyl and, if it is additionally asymmetrically substituted, as in 2-hexyl, the configuration on the carbon atoms in the 15- and 16-positions is preferred identical to that in (15S, 16R) -16-methyl-PGE ₂ ; if the carbon atom in the 16-position is tertiary, two of the alkyl substituents are preferably identical, for example as in 2-methyl-2-hexyl. Z preferably denotes alkylene having 1-3 carbon atoms, in particular methylene or isopropylidene. X preferably represents -0-, halogen preferably represents fluorine

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or chlorine? one or in particular two of the radicals R ₄ , R ₅ and Rg are preferably hydrogen, the other or the others are preferably in the meta or para position; two of the radicals R ₄ , R and R preferably represent hydrogen, the third radical preferably represents fluorine in the p-position or trifluoromethyl in the m-position; R_ preferably denotes hydrogen} if R "denotes alkyl, it preferably denotes methyl; does R _? for alkyl having more than 2 carbon atoms, it is preferably straight-chain; R ₃ preferably denotes hydrogen or unsubstituted alkyl. If R_ stands for substituted alkyl, it preferably contains 1-4, in particular 1 carbon atom and is preferably disubstituted by phenyl, in particular on the same carbon atom, in particular on the terminal carbon atom, or monosubstituted by biphenyl. R _{3 is} , for example, benzyl, di (phenyl) methyl or biphenylmethyl. If the compounds of the formula I are in optically active form, the 15-OH group is preferably in the same configuration as in natural PGE, ie in the α configuration; P stands for a group Al to A6, preferably a mirror image of a group Al to A6.

According to the invention "one arrives at the new compounds of the formula I by converting a compound of the formula IV wherein

A ^{1 has} the meaning given above for A or for a group of the formula A8 or A9,

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where R-- denotes an acid-sensitive protective group, or a mirror image of a group of the formula A8 or A9, B, D, R ₁ and R _{2 have the} above meaning, R _{g has} the meaning given above for R ₃ or an acid-sensitive group Protecting group means and
R ₁₀ denotes hydrogen or an acid-sensitive protective group

with the proviso that at least one acid-sensitive Protective group is present, or in front of a racemate of a compound of the formula iy, d £ e Splitting off protecting groups.

The method according to the invention represents a splitting off of prostaglandin protective groups. It can be carried out analogously to known methods. You work under acidic conditions. Examples of suitable protecting groups are the tetrahydropyran-2-yl and tert-butyldimethylsilyl groups. Examples of suitable acidic reaction media are the following mixtures:

Acetic acid / tetrahydrofuran, hydrochloric acid / acetone, hydrochloric acid / methanol and sulfuric acid / methanol. If desired, it can be carried out in the presence of water. The temperature is about -10 ⁰ C to +50 ⁰ C, preferably about +10 ⁰ C to +30 ⁰ C.

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The compounds of the formula IV can be obtained, for example, by analogously to known methods, a compound of the formula V in which

R ₁ , R ₂ , R ₁ and D have the above meaning and E is a group of the formula E1 to E3, in which R _{12 is} hydrogen or an acid-sensitive group

Protective group means, or a mirror image of a group El to E3 means,

under Wittig conditions with a compound of the formula VI, in which R _{g has the} above meaning, and, if necessary, subsequently in the compounds of the formula VII thus obtained , in which

D, R, _# R ", Rg and R ₁₀ have the above meaning and F Fl to F3, wherein R. _ the above meaning, or a mirror image of a group Fl represents a group of the formula to F3 performs one or more of the following reactions :

a) Oxidation of a group Fl to a group Al}

b) Oxidation of a group F2 to a group A2

and, if desired, then isomerization of the group A2 obtained in this way under alkaline conditions

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Conditions for a group A7;

c) Oxidation of a group F3 to a group A4 or A9 and, if desired, subsequent reduction with sodium borohydride

ca) a group A4 thus obtained to the groups A3 and A5 or

cb) a group A9 obtained in this way to the two groups A8 with the 9-hydroxyl: in the α or β position

and subsequent chromatographic separation of the compounds formed with the 9-hydroxyl in the α-position of the compounds formed with the 9-hydroxyl in the ß-position;

d) Oxidation of a group F3, in which R _{12 is} hydrogen, to a group A6 and subsequent separation of the resulting compounds which contain a group A6 from any compounds which may have arisen which contain a group A4;

e) Catalytic hydrogenation of a compound of the formula VII to give a compound in which the 5,6 double bond is saturated, ie B stands for -CH ₂ -CH ₂ -, and / or

f) Protection of existing hydroxyl and / or carboxyl groups by an acid-sensitive protective group .

Steps a) to f) can also be carried out with compounds of the formula VII in which F is a mirror image of a group F1 to F3 means carried out for the preparation of the corresponding compounds of the formula IV will.

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For the preparation of the compounds of the formula IV in optically active form, one can use optically active Run out of compounds of formula V? for the preparation of the compounds of the formula IV in racemic form one can start from compounds of the formula V in racemic form.

Stages a) to f) can be carried out analogously to known methods. One works in general under mild conditions. For example, step e) in the presence of palladium at a Temperature from about -40 ° C to -10 ° C for the selective hydrogenation of the 5,6 double bond in compounds of formula VII, which still has a 13,14 double bond included.

So much for the production of the required raw materials is not described, these are known or can be carried out by methods known per se or analogous to the here, e.g. described in the examples or analogously to those known per se Process to be manufactured and cleaned.

The compounds of the formula I in optically active or racemic form and, if appropriate, their pharmacologically acceptable salts, hereinafter referred to as substances according to the invention for short, show interesting pharmacodynamic effects in animal experiments. They can therefore be used as a remedy be used.

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In particular, they show prostaglandin-like effects. Some of these effects are uterine stimulating Effect, a bronchospasmolytic effect, an inhibition of gastric secretion, a Decrease in arterial blood pressure and inhibition of platelet aggregation.

Because of these effects, they can be used, among other things as uterotonics, bronchospasmolytics, gastric acid secretion inhibitors, Antihypertensive drugs and platelet aggregation inhibitors suitable.

The (Ha, 13E, 15S, 16R) -11,15-dihydroxy-16-methyl-9-OXO-2,3 - (-) - trans-methylene-prost-13-enoic acid and their physiologically compatible salts have a particularly interesting bronchospasmolytic Effect on.

The invention also relates to medicinal products which contain a substance according to the invention. These medicinal products, for example a solution, a tablet or a nebulizer can according to known Methods, using the usual auxiliary or Carriers, are produced.

The substances according to the invention can be administered as medicaments alone or in a suitable pharmaceutical form will.

In the following examples, which explain the invention in more detail, all temperature

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given in degrees Celsius and are uncorrected. IR refers to the characteristic bands of the infrared spectrum (in methylene chloride solution). The naming of the connections is natural Prostanoic acid based, with the 5-membered ring on the left and the two side chains on the right. That Prefix "epi" means the specified carbon atom has the configuration that of the configuration of prostanoic acid at this carbon atom is opposite. "(+)" or "(-) - trans-methylene" refers to the one used as the starting product (+) - or (-) - trans-2- (2'-Bromoethyl) cycloprop-1-ylcarboxylic acid or their esters.

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Example 1; ÜiSxl ^ i ^

2z3- J -) _-

mg (11α, 13EzISSjIeR) -IIfIS-BiS (tetrahydropyran-2'-yloxy) -16-niethyl-9 ~ oxo-2,3 - (-) - trans-methyleneprosta-13-enoic acid are dissolved in 18 ml of a 1: 1 : 1 mixture of acetic acid / tetrahydrofuran / water dissolved. After 36 hours at room temperature, the solution is concentrated and the residue is chromatographed on silica gel with chloroform / 1% methanol. The title compound is obtained (IR 3650, 3500-3400, 1745-1740, 1700-1690 cm "" ¹ ).

The starting product is obtained as follows: a) 600 mg of sodium borohydride are suspended in 6 ml of absolute dimethyl sulfoxide, and the suspension is ^{kept at 75 °} C. for 55 minutes under nitrogen. After cooling, 4.5 ml of this solution are slowly added dropwise to a prepared solution of 4.08 g of triphenylphosphonium salt of (-) - trans-2- (2'-bromoethyl) cycloprop-1-y! Carboxylic acid in 10 ml of dimethyl sulfoxide and added dropwise Nitrogen stirred for 45 minutes. 8 ml of the ylid solution obtained are slowly added to a solution of 2.0 g of 2ß- (4'R-methyl-3'S-tetrahydropyran-2-yloxy-trans-l'-octenyl) -5ahydroxy-3a-tetrahydropyran-2 ' -yloxvcvclopent-la-y1-acetic acid ~ V-lactal in 6 ml of absolute tetrahydrofuran and 6 ml of dimethyl sulfoxide were added. That

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React Ionsgemis ch is held for 60 minutes at 5 NC ^D C. After adding a further 8 ml of the ylid solution, the mixture is again held at 50 ° C. for 1 hour. The cooled reaction mixture is poured onto 100 g of ice, the aqueous phase is adjusted to pH 3-4, extracted 3 times with methylene chloride and chromatographed on silica gel with chloroform / 2% methanol, the (5Z, 9cc, IIIa, 13E, 15S , 16R) -Il, 15-bis (tetrahydropyran-2'-yloxy) -9-hydroxy-16-methy1-2,3 - (-) - trans-methylenprosta-5,13-dienoic acid is obtained (IR 3600, 3550, 1730-1690 cm " ¹ ).

b) 1.6 g of (5Z, 9a, lla, 13E, 15S, 16R) -Il, 15-bis (tetrahydropyran-2'-yloxy) -9-hydroxy-16 ~ methyl - 2, 3 - (- ) -trans-methylenprosta-5,13-dienoic acid in ml of acetone are at -15 ° C according to Jones using appropriate amounts of a mixture of 13.34 g of chromium (VI) trioxide, 10.7 ml of sulfuric acid and 35 ml of water, which is added dropwise, reacted. After 25 minutes, methanol is added and, after a further 10 minutes, the mixture is poured onto 300 ml of ice water and extracted several times with methylene chloride. The (5Z, 11a, 13E, 15S, 16R) -Il, 15-bis (tetrahydropyran-2'-yloxy) -16-methyl-9-oxo-2, 3- (-) - transmethylene prosta-5,13 are obtained dienoic acid (TR: 3500, 1740-1730, 1690 cm " ¹ ).

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c) 460 mg of (5Z, 11α, 13E, 15S, 16R) -U, I ₅ -Bi ₅ (tetrahydropyran-2'-yloxy) -lG-methyl-g-oxo ^, 3- (-) - trans- methylenprosta-5,13-dienoic acid in 40 ml of absolute methanol are hydrogenated for 3 hours at -IS ⁰ C to -10 ⁰ C in the presence of 100 mg palladium / carbon 10% ± g, the (11a, 13E, 15S, 16R) -11,15-bis (tetrahydropyran-2'-yloxy) -16-methyl-9-oxo-2,3 - (-) - trans-methylenoprost-13-enoic acid is obtained.

Analogously to Example 1, the following compounds of the formula i are obtained, starting from the corresponding 15-tetrahydropyran-2-yl ethers of the formula IV, in which R _{9 has} the meaning of R ₃ , or if the end product contains an 11-hydroxy group of the corresponding 11,15-bis (tetrahydropyran-2-yl) ethers of the formula IV, in which R _{g has} the meaning of R ₃ :

Example 2: (5Z, 9a _f 11a, 13E, 15R) -15-Methy1-9,11,15 -

trihy droxy-2, 3 -. (-) - trans-meth y len -prosta -

5,13-dienoic acid methyl ester

IR: 3600-3400, 1710-1700 cm " ¹

Example 3; (5Z, 9a , 11a, 13E, 15S) -15-methyl-9,11,15 -

-tri hydroxy-2,3 - (-) - trans-methylene -prosta-

5,13-dienoic acid ethy! ester

M.p. 76-77 ° C

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Example 4: (5Z, 9α, 11α, 13Ε, 15R) -15-Μ et h y1-9, 11.15 -

trihy droxy-2 , 3- (+) - tän s-tnetliy lon -prosta -5 , 13-d ien säureroe thy lester_

IR: 3550, 1710 cm " ¹

Example 5; (5 Z, 9α, 1] α _f 13Ε, 155) ~ 15-Heth yl-9 _r II, 15

trihydroxy-2,3 - (+) - trans-me tl ylene -prosta 5, 13-diene äuremeth y ester
M.p. 68-70 ° C.

Example 6: (5Z, 9α, 11α , 13Ε, 15S) -15-Het hy1-9,11 , 15

trihydroxy-2 , 3- (· -) -Irans- methylen.-p rosta 5 , 13-diene sä

^IR: 3500-3300, 1700cm " ¹

Example 7; · · (5Z , 9rx _f 11a, 13 B, 15R) -15-methyl-9 , 11.15 - trihydrqxy-2 _t 3 - (-) - trans-methylene-prostate- 5,13- dienoic acid

IR 3500-3300, 1700 cia " ¹

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Beisnjel 8: (57., 9q, 11α, 13Ε, 15R) -15-Mct: hy.1.-9, 11, 15 -

trihydroxy- 2,3 (+) -tr a ns-methylene-prosta - 5,13-dienoic acid

IR 3550-3300, 1720-1680 cm " ¹

Example 9: (ΰΖ ^ α , ΙΙα, Ρ ^ Ε, Ιΰε) -15-meth yl-9, 11.15 - tr.i hydroxy-2, 3- (+) -trans-methylene -prosta- 5 f 13 dienoic acid

IR "3600-3300, 1720-1680 era" ¹

Example 10; (5z, 1 1α, 13π, 15R) -Il, lS-Dihyclroxy-lS-Neth yl-

9 '~ oxo-2, 3- (-) -trans-methylene -prosba-5, 13 - diensäureroethylester IR 3600, 1740-1710 cm * ^"1

Example 11:. ^^ J ^ ÄjIsIjI ^ r - ^15R ) " ⁹ r 15-Dihydroxy-15- ' Inethyl-II-oxo-2,3 (-) -trans-methylene - • prosta-5,13-dienoic acid ethyl ester 3600 , 1740-1710 cm "

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Example 12:. (3Z, H «, 13K, 15R) -II, 15-D! Hydroxy-15-

jnol: h yl-9-oxo- 2 , 3- (■ <-) -trans-methyl ion -presto-

IR 3600, 1740-1710 cm " ¹

(5z, 9σ, 13Ε, 15R) -9.15-0ihydrpxy-15- methyl-13-oxo-2,3 - (+) - tra ns-mcthyücn prosta ~ 5, 3- dicaurenethylester
IR 3600, 1740-1710 cm " ¹

Example x 14; (5Z, 3 3 α, 13Ε, 3.5S) -11,3.5-Dihydroxy-15- ynethyl-9-ox o-2 f 3- (-) -tra ns-methylene prosta-5,13-dioneSciuremethy! ester

IR 3600, 1740-1700 cm " ¹

• example 15; (5Z _f 9α, 13Ι5,15S) -9,15-DU) ydroxy-15-

1.-11 - ο>: ο -2, 3- (-) -trans-inethyl en_ -

prosta-5,13- dionic acid methyl ester

" ¹

IR 3600, 1740-1700 cm

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Example 16: (5R, 11α, 13F, 15S) -Ll, 15-Ο .ihydroxy-15 - methyl-9-oxo- 2, 3- (4-) -tr a ns-me th hy l on. pros ta-5,13-dl cn3 acid ethyl ester IR 3600, 1740-1700 cm " ¹

Example 17: (5Z, 9a, 13E, 15S) -? , IS-pihydroxy-IS- methyl-II-oxo-2,3- (H -) - trans- methylene prosta-5 , 1.3-cl. ren'3a acid methyl ester IR 3600, 1740-1700 cm " ¹

Example 18-: (5Z, lla _f 13E, 15P) -11,15-D'ihy droxy-15 niet hy 1-9-oxo-2 _f 3- (-) -trans-meth yl_en_- prosta-5, 13-dienoic acid

IR 3600, 3400, 1735, 1695 cm

Example. 19.:.- '(5Z, 1.1a, 13K, 15R) -11,15-Dihydroxv-15- ^ Gthy l-9-oxo-2, 3- (H-) -tr ans -methylene st a- 5 -, 13-d io ns Mure

IR 3600, 3500-3400, 1735, 16 95 cm " ¹

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Example 20: (5Z , 9α, 13E , 15R) -9 , 1 5-nJh ydroxy-15 ~ nu? Thy l · - ll ~ oxo-2 _f 3- (-) - tran s-methylene-"prosta-5 , 13 - dlen-sSure
IR '3600, 3500-3400, 1740-1730, 1700-1690 cm " ¹

Example 21: (5Z, 9 α, 13 Ε, 15R) -9,15-Dih yd roxy-15-methy3 ll-oxo-2, 3- ( t) -l-ra ns-mothylen -pror, fca-5 , 13 -dienoic acid

IR 3600, 3500-3400, 1740-1730, 1700-1690 cm " ¹

Example 22: (5Z , Her, 13E _f 15S ) -11, IS-Pi hydroxy-IS-

mGthyl-9-oxo-2 , 3 - (-) - trans-methylene -pro sta - 5,13-diene acid

IR 3600-3300, 1740-1760 cm " ¹

Example 23: f5Z , Uη, 13E, 155) -1.1 _f 15-P ihydroxy I 5- methyl-9-oxo-2,3 - (+) - brans-methylene prosta-5,13-diacid

IR 3550, 3450, 1735, 1690 era " ¹

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Example 24; (5Z, 9ct, 13K, ISS) - 9, 15-Dih ydroxy -15-

niethyl- .1 l- oxo-2, 3- (-) -trans-methylenprostn-5,13-dio] -ic acid

IH 3600, 3500-3400, 1740-1730, 1695 cm "" ¹

Example 25; (57 ,, 9a, 13E , 15 S) -.9 , 15-dihydroxy-15-ynethyl-II-oxo-2 , 3 - (H-) -trans-iuGthylen - prosta-5,13-diene acid

IR 3600, 35OO-34OO _r 1740-1730, 1700-1690 at " ¹

Example 26; (5Z, 9a, 11a, 15S) -16,16-D-imethyl-9 , 11,15 -trihydx-oxy -2, 3- (-) -trans-methylene-prost-5-ensMure

IR 3600, 3500, 1690 cm " ¹

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r7j_ '''(5Z, 9π, 1.1σ, 155) -16, IG-D irnethyl ~ 9, 11,15-'Izrihydroxy -?., 3 ~ (I) -brans-methylen -pror.t-5 -enic acid
IR "36OO _f 3500-3400, 1700-1690" cm " ¹

Example 28; (5'Z, 11α, 15P) - 11,15- dihydroxy-16, 16-dimeth yl-9-oxo -2 , 3- (-) - trans-methy lrn pro ^^ tS-enoic acid

IR ■ ". 3GOO ₇ 3450, 1735, 1690 era" ¹

ggAspiel 29ji (SZ, 11α, 155) -11,15-Ρ ihydroxy-16, 16-

diethyl g-ox o- ?. , 3- (+) -trans-methylene - f. Pros-b-5-.enic acid

IR - .. 3600, 3500-3400, 1740-1730, 1690 cm "" ¹

Example 30j ^ (5Z, 15S) -IG , le-pimethyl-lS-hydroxy-g-oxo-2_ _/ 3 -_ (- ) -trans-methylene - prosta-5 , 10-diene acid

IR - 3500, -1730, 1690 cm " ¹

Beispiel_ 31: (57 ', 15S) -1 6, 16-Ditriethyl-15-hydroxy-9 -

oxo-2,3 - (+) - trans-methylene -prosta-5, 10-

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diengic acid
^IR . 3GOO, 3500, 1735-1730, 1695-1690 cm " ¹

Example 32: (9a, 11a, 13E, 15R) -16,16-dimethyl 1-9,11,15

trihydroxy-2,3 (- <·) -trans-niethylcn -pro.st - 13-enoic acid

IR '... '3600-3400, 1695 cm * " ¹

Example 33; (9a, 11a, 13E, 15 S ) -16-n-Butyl-9,11,15 -

trihydroxy-2 , 3 - (-) - trans-methylene -prost-

IR 3600, 3500-3400, 1700-1690 '"" ¹

Example 34; (9α, 11π, 13E, 15S) -16-n - butyl-9 , 11.15 -

trihydroxy-2,3 - (+) - trans-methylene -prost-13-

enoic acid
IR '3600, 3500-3400, 1700-1690 cm "" ¹

Example 35; (lla, 13E, 15R) -11,15-dihydroxy-16,16-

• dimethyl-9-oxo-2 , 3 - (+) - trans-methylene -

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prpst-13-enoic acid
IR .. 3400, 1735, 1690 cm " ¹

Example 36; (n _af 13E, 15S) -16-n-butyl-ll, 15-dihydroxy-

9-OXO-2,3 - (-) - trans -niethylen -prost-13-enoic acid

IR - '3600, 3400, 1740-1730, 1690 cm " ¹

Example 37: (IIIa, 13E, 15S) -16-n-Butyl-II, 15-dihydroxy- 9-OXO-2,3 (4) -trans-methyl n -prost-13-enoic acid

IR. 3600, 3500-3400, 1735, 1700-1690 cm " ¹

- Example 38: (13E, 15R) -16 _f lG-Di

oxo-2,3 - (+) - trans-methylene.-prosta-10,13-diene acid

IR 3600, 1695 cm " ¹

Example 39: (13E, 15S) -le-n-

7-j ³ ~ (.-) -trans-methylene-prosta-10, 13-diene acid

IR. ^ 600, 3500-3400, 1700-1690 cm " ¹

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Example 40; (13E, 15S) -16-n-Butyl-15-hydroxy-9-oxo -

2,3- (H) -trnns- methylene- prosta-10,13-dienoic acid

IR 3600, 1695 cm " ¹

Example 41; (9a , 1 3 et, .15R) -16, 3 6- pLmethyl-9, 11.15-

trlhydroxy-2, 3- (· <■) trans-methylene prostcin säyre

IR 3600-3400, 1695 cm " ¹

Example 42; (9a, 3 Ip , 15R) -16, lG-pimethy l-9, 11.15-

trihydroxy-2, 3- (-) -trans-niethylen prosban.acid '

IR · .- 3600, 3500-3400, 1700-1690 cm " ¹

Example 43; (9a , lla , 15R) -16-n-butyl-9, 11.15 -

trihydroxy-2,3- (-) - trans-methylene. -prostanoic acid

IR 3600, 3500-3400, 16 95 cm " ¹

Example 44: (9a, lla, 15R) -16-nB _u tyl-9,11,15-

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trihydroxy-2,3 - (+) - trans-methylene, - prostanoic acid

-1

IR - "3600-3400, 1695 cm

Example 4 5 : (Ha, 15S) -.11,15-pihy droxy-9-oxo-2, 3- (-) -

trans-methylene -.prostanoic acid

IR. 3600, 3400, 1735, 1690 cnf ¹

Example 46 : (11α, 155) -11.15- Dihydroxy-9 ~ oxo-2,3 - (+ )

trans-methyj.en -prostanoic acid IR 3600, 3400, 1740-1730, 1690 cm " ¹

Example 47 : (11α, 15S) -11,15-dihydroxy -16,16 - dimethyl-9-oxo-2,3 - (-) - trans-methylene prostanoic acid
IR-. X 3600, 3500-3400, 1735, 1700-1690 cm " ¹

Example 48 : '(11α, 15R) -11,15-dihydroxy-16,16-dimethyl-9-oxo-2,3 - (+) - trans -methylene prostanoic acid

IR 36OO _f 3500-3400, 1740-1730, 1700-1690 cm " ¹

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Example 49: (11α, 15R) -16-n-Butyl ~ ll, 15-dihydroxy- 9-OXO-2, 3- (-) -trans-riethylene-prostanoic acid
3600, 3500-3400, 1740-1730, 1695 cm " ¹

Example 50; (Ha, 15R) -16 ~ n-Batyl-II, 15-dihydroxy - 9-OXO-2,3 - (- fr) -trans-methylene-propane acid

IR: '3600, 3500-3300, 1740-1730, 1695 cm

Example 51; (15S) -IS-Hydroxy-D-oxo-Z, 3 - (-) - transmethylene -prost-10-enoic acid IR 3600-3400, 1730-1680 cm " ¹

Example 52; (15S) -15-Hydroxy-9-oxo-2,3 - (+) - transmethylene -prost-10-enoic acid IR 3600, 3500-3400, 1730-1680 cm

Example 53; (15R) -le-n-butyl-lS-hydroxy-g-oxo ^, 3 (-) - trans-methylene-prost-10-enoic acid

IR 3600-3400, 1730-1680 cm-1

7 0 9 8 11/1110

- 26 - 100-4409

Example 54; (15R) -16- nB utyl-15-hydroxy-9-oxo-

2,3 - (+) -trans-methylene. -prost-10-enoic acid e

3600-3400, 1725-1685 cm " ¹

Example 55 t (15 S) -16, lG-diiriethyl-lS-hydroxy-g-oxo -

2 _f 3 - (-) - trans-methylene-prost-10-enoic acid e IR · 3600-3400, 1730-1680 cm " ¹

Example 56; (15R) -16,16-dimeth yl-15-hydroxy-9 ~ oxo -

2, 3- (-) -) - tra ns-methylene-prost-10-enoic acid IR * ■ 3600-3400, 17 25-16 80 cm "" ¹

Example 57 :; (9 «, lla _f 15Γ») -9 _r 11 , 15-Trihy droxy-2 , 3- (-) -

trans- methylene-propanic acid IR 3600-3400, 1710-1680 cm " ¹

Example 58; (9α, 11α, 155) -9.11 , 15-trihydroxy-2,3 - (+)

trans-methylene-prostanoic acid IR 3600, 3500-3400, 1700-1690 cm " ¹

Example 59; (9a, 11a, 13Ε, 15R) -16,16-DJmethyl-9,11,15 trihydroxy-2 , 3 - (-) - trans-methylene -prost-

7 0 9 8 11/1110

- 27 - 100-4409

13-enoic acid
IR 3600-3400, 1695 era " ¹

Example 60 ; (11 α, 13Ε, .15R) -11 _f 15-dihydroxy-16, 16-dimethyl-9-oxo ~ 2 , 3 - (-) - trans-methylene prost-13-enoic acid

IR 3600-3400, 1735, 1690 cm " ¹

Example 61; (13E, 15R) -1 6 , 16-Dimethyl -15- hydroxy-9 - OXO- 2, 3- (-) -tra ns-methylene n -prosta-10, 13- ~

dienic acid

IR. ■ 3600, 1695 cm " ¹

Example 62; _{(9a> lloCy 13π> 15S} ) _ _{9 f} n _r i5-trihydroxy-2 _f 3 - (-) - trans-methylene-prost-13-enoic acid IR. . 3600-3400, 1695 cm " ¹

Example 63 ; (9σ, 11α, 13E, 15S) -9,11,15-trihydroxy-2,3 - (+) - trans-methylene -prost-13-enoic acid IR "3600, 3500-3400, 1700-1690 cm"" ¹

Example 64; (llg _f 13E, 15S) -11,15-dihydroxy-9-oxo-2,3-

70981 1/1110

- 28 - 100-4409

(· -) -tran β-inethylene -p rost -1 3 -enoic acid IR '3600-3400, 1735, 1690 cm " ¹

Example 65: (lla _f , 13E, 15S ) -11,15-dihydroxy-9-oxo-

2, 3 (+) t rans-methyll en - prost-3.3- ensäu re IR 3600, 3500-3400, 1735, 1700-1690 cm ^"1

Example 66: (13E, 15S) -15- Hydroxy ~ 9-oxo-2,3 - (-) -

tr an s -me t hy 1 e η -pros ta-10 , 13- diacid. IR. "3600, 1720, 1695 cm" ¹

Bei Piel 6 7_: (13E, 15 S) -1 5-hydroxy-9-oxo-2, 3- (+) -

trans-methy ^ leiie-j ^ roata-10, 13-dienoic acid IR. 3600-3400, 17 25-1710, 1700-16 90 cm " ¹

Example 68: (5Z, 1I g, 13E, 15R) -1 1, 15-dihydroxy-9-oxo 16 - (3 ^f -tri fluoromethy! Phenox y) -17,18,19,20 - tetranor-2, 3 - (+) - trans-methylene-prostate - 5, 13-dlenoic acid

IR 3600-3400, 1740, 1690, 1590 cm " ¹

Example 69: (5Z, 9a, 11a, 13E, 15R) -16- (3 ^! -Trifluoro-

70981 1/1110

- 29 - 100-4409

me thy! phenoxy) -9, 11,15-trihydroxy - 17,18,19,20 ~ tetranor ~ 2,3 ~ (+) - trans-methylene prosta-5,13- dienoic acid
IR 3600-3300, 1690, 1590 cm "" ¹

Example 70 ; (5Z, 9σ, 11α, 13Ε, 15R) -16- (3'-Trifluoromgthylphenox y) -9,11 , 15-trihydroxy -3.7, 18, 19 , 20-tetranor - 2, 3- (-) - trans-methylene prosta-5,13-dienic acid

IR::. 3600-3300, 1G90, 1590 cm " ¹

Example 71; (11σ, 15R) -11,15-P.ihydroxy-15-meth yl ~ 9 ~

οχο-2,3- (·! ■) -trans-methylene-prostanoic acid IR. 3600, 1740-1680 cm "

Example 72 : (15R) '• 15 -hydroxy -15-methyl-9-ox o-2,3 C +

trans-meth yl en-prost-10-ensaire IR 1740-1640 cm " ¹

Example 73; (11α, 155) -11, 15-P-hydroxy-15-methyl-2,3

(H) -trans-methylene -9-oxo -prostanoic acid IR 3600-3300, 1760-1660 cm " ¹

709811/1110

- ³⁰ - 100-4409

Example 74: (15R) -IS-Hydroxy-Q-oxo-IG- (3'-trifluoromethy! Phenoxy) -17,18,19,20-tetranor-2,3- {+) - trans-methylene-prost-10- ^e n acid-

methyl ester IR - "3600, 1735, 1710, 1595 cm" ¹

Example 75_; (lice, 13E, 15R) -11, IS-dihydroxy-g-oxo-ie- (3 '-trifluorometh y! phenox y) -17.18 , 19.20-tetranor - 2,3 - (+) - trans -methylene -prost-13- enoic acid-

me thy ! ester IR 3600-3300, 1740, 1720, 1590 cm "" ¹

Example 76 ; (11a, 1.5R) -11,1 5-_Dihydroxy-9-oxo-l _6 _-_ (j '-tri ff luoro iae thy! Phenox y) -17,18,19,20-tetranor - 2, 3- (+) - tr ans- methylen _ι - prostansäxire-

methyl ester IR. 3600-3400, 1740, 1720, 1590 cm * " ¹

Example 77; (5z _f 13E, 15R) -lS-hydroxy-g-oxo-ie- (3 ' ~ trifluoromethylphenoxy) -17,18,19,20 - tetranor-2,3- { +) -trans-methylene -p r ost -5 f 10, 13- trien s; acid

IE 3600, 1700, 1590 cm " ¹

7 0 9 8 11/1110

- 31 - 100-4409

Example 78: (5Z, 9β, IIcc, 13E, 15R) -16, 16-niroethyl-16- (3'-trifluoromethyl- phenoxy) -9,11,15-trihydroxy-17,18,19,2 0-tetranor -2,3 - (+) - transmethylene-prosta-5,13-dienoic acid IR ■; 3600-3300, 1700-16 80 cm " ¹

Example 79; (5Z, 9σ, llcx, 13E _f 15R) -16, 16-Dime i-h yl-16- (3'-trifluoromethylphenoxy) -9,11,15-tri- ■ hydrox y-17,18,19,2 0- tetranor-2,3 - (+) - transmethylene- prosta -5,13-dienoic acid

IR. 3600, 3350, 1690 cm

Example 80 : (5Z, 9cc _f l lcc, 13E ₇ 15 R) -16, 16-pimethyl-16- (3'- trifluoromethyl phenoxy) -9,11,15-trihydroxy-17,18,19,20 -tetranor-2,3 - (-) - transmethylene -prosta-5,13-dienoic acid

IR- 3500-3300, 1700-16 80 cm " ¹

Example 81 t (9a, lla, 13E, 15S, 16R) -16-methyl-9,11,15-trihydroxy-2,3 - (-) - trans-methylene-prost-13-enexires

IR. 3400, 1720-1695 cm " ¹

70981 1/1110

^"32 - 100-4409

Example 82: (11α, 15R, IGR) -11 _f 15-dihydroxy-16-methyl

9-OXO-2,3 - (-) - trans-methylene -prostane acid

IR. 360073300, 1740-1690 cm " ¹

Example 83: (15R, 16R) -15-Hydroxy-16-methyl-9-oxo -

2, 3 - (-) - trans-methylene-prost-10-enoic acid IR: 3600, 3500-3400, 1710-1695 cm " ¹

Example 84: (13E, 15S _f 16R) -

oxo-2,3 - (-) - trans-methylen.-prosta-10,13 dienoic acid

IR 3600, 3500, 1730-1695 cm " ¹

Example 85 ; (5Z, 11a, 15R, 16R) -11,15-pihydroxy-16 methyl-9-oxo-2,3 - (-) - trans-methyl n prost-5-enoic acid

IR 3600-3350, 1735-1685 cm "" ¹

Example 86: (52,11a, 15R, 16R) -11,15-Dihydroxy-16 methyl-9-oxo-2,3 - (-) - trans-methylenoprost-5-acid methyl ester IR 3600-3450, 1750 -1700 cm " ¹

70981 1/1110

- 33 - 100-4409

Example 87: (5Z, 1 3E, 15R) -16,16-Dimothyl-15-hyaroxy - 9-OXO-16- (3'-trifluoromethylphenoxy) -17,16,19,20-tetranor-2,3 - (+) - trans-methylene prosta-5, 10,13-trienoic acid

IR 3600-3500, 1720-1680 cm "" ¹

Example 88: (5Z _f -lla, 13E, 15R) -11,15-dihydroxy-16, 16 - dimethyl-9-oxo-16- (3'-trlfluoromethylphenoxy) -17, 18, 19, 20-tetranor-2 , 3- (>>) -transmethylene-prosta-5,13-dienoic acid

IR; 3700-3500, 1760-1720, 1720-1680 cm " ¹

Example 89: (5Z, 15R _f 16R) -15-Hydroxy-16-methyl-9-oxo - 2 / 3- (-) -trans-methyle'n- -prosta-5 ·, 10-dienoic acid

IR 3600-3400, 1740-1670 cm "" ¹

Example 90: (5Z, Ρα, 1Ί.α, 13 ^, 15R) -lfi _y -lf: -r »iniQthvl-9, 11,15-trihydroxy-2,3 (■» ·) -trans-methylene . -prosta-5,13-dienoic acid diphenyl methyl ester

IR 3600, 3400, 1720-1715 cm " ¹

7 0 9 8 11/1110

³⁴ 100-4409

Example 91: (Hg, 13e, 15S, 16R) -11, 15-dihydroxy-16-

n \ ethyl - 9-oxo ~ 2, 3- (-) -trans-methylcn -prost- 13 -enoic acid decany! es ter

IR 3600, 1745, 1725, 1695 cm * " ¹

Example 92: (IIß, 13E, 15S) -11,15-pihydroxy-9-oxo-

2,3- (- Q-trans- mefchylen ~ 8, 12 ~ ep l-pro5t-l3-enoic acid

IR 3600, 3500-2600, 1740, 1695 cm " ¹

Example 93: (13E, 15S) -15-Hydroxy-9-oxo-2, 3- (H -) -

trans-methylone r- 8,12-epi-prost-10,13-dienoic acid

IR 3600, 3500-2600, 1700 cm

Example 94: (15S) -15-Hydroxy-9-oxo-2,3 - (+) - trans-

methylene - ■ 8,12-epl- prosanoic acid

IR 3600, 3500-2600, 1735 cm "" ¹

Example 95: d, 1- (5Z _f 9a, 1Ip, 13E, 15R) -16-Q'-trifluoroniethylphenoxy) -9, 11-15-trihydroxy-17,18,19,20-tetranor-2,3- ( +) - trans-methylene-prosta-5, 13- dienoic acid

IR 3600-3300, 1690, 1590 cm "

70981 1/1110

26384Q1

100-4409

-COOR-3 2 ³

Al

Α2

HO

/ A4

HO

HO

ΗΟχ

Α7

HO

/ Λ8 Λ9

70981 1/1110

100-4409

HO H

El

HO

Fl

HO

F2 HQ

12 _F3

-Z-X

II

^R 7/8

III

70981 1/1110

100-4409

-COOR

Λ,

9

OR

10 IV

(C ₆ H ₅ ) 3 4-

XCOR,

VI

.COOR,

OR

^l 2

10 VII

0 9 8 11/1110

Claims (5)

100-4409 claims 1. Process for the production of new compounds of the formula / COOR ₀ 2 ³ wherein A is a group of the formula Al to A7 Al Λ2 HO, Λ3 70981 1/1110 100-4409 UOv Λ7 or is a mirror image of a group of the formula Al to A6, B is -CH ₂ -CH ₂ - or (cis) -CH = CH-, D is -CH ₂ -CH ₂ - or (trans) -CH = CH- , R, alkyl with 1-10 carbon atoms or a Group of formula II -Z-X R, ^ ₁ II 70981 1/1110 - 40 - 100-4409 means in which Z for alkylene with 1-5 carbon atoms, X for -CH ₂ - or -0- and ^R 4 ^'R 5 ^{un (^ R} 6 ^una, halogen <stand khängig represent hydrogen with an atomic number of 9 to 35 ■ or trifluoromethyl, R ₂ signifies hydrogen or alkyl with 1-7 carbon atoms and R is hydrogen, alkyl having 1-10 carbon atoms, phenyl mono- or disubstituted by alkyl having 1-10 carbon atoms or mono- or disubstituted by Blphenyl alkyl having 1-10 carbon atoms, with the restriction that, B for (CiS) -CH = CH- and D stand for (trans) -CH = CH-, R _{1 is} a group of the formula III III means in which R- and R ₀ independently of one another for water-ο substance or alkyl with 1-4 carbon atoms 70981 1/1 1 1 Q 263840Ί - 41 - 100-4409 stand, R- means hydrogen
R- hydrogen, alkyl with 1-8 carbon atoms or alkyl monosubstituted by phenyl with 1-6 carbon atoms means then
A is a group of the formula A5 to A7 or a mirror image of a group of the formula A5 or A6 means, their racemates and, if R _{3 is} hydrogen, their salts, characterized in that one of a compound of the formula IV, COOR ₉ * IV wherein A has the meaning given above for A or for a group of the formula A8 or A9, 70981 1/1110 - 42 - 100-4409 wherein R., is an acid-sensitive protecting group, or a mirror image of a group of the formula A8 or A9, is,
B, D, R, and R- have the above meaning, Rg has the _{meaning given above for R 3} or means an acid-sensitive protective group and
RQ means hydrogen or an acid-sensitive protective group with the proviso that at least one acid-sensitive protective group is present, eliminates the protective groups and the compounds of formula I thus obtained in optically active or wins racemic and optionally in salt form. 2. The method according to claim 1 for the preparation of (11a, 13E, 15S, 16R) -11,15-dihydroxy-16-methyl-9-oxo-2,3 - (-) - trans-methyleneprostic acid, characterized in that one is in the 1-, 11- and / or 15-position substituted by one or more acid-sensitive protective groups (Ila, 13E, 15S, 16R) -11,15-dihydroxy-16-methy1-9-OXO-2,3 - (-) - transmethylene prostate acid splits off the protecting groups. 70981 1/1110 Germany-West 100-4409 3. Compounds of the formula I in which A ₁ BjDfR ₁ , R ₂ and R_ have the meaning given in claim 1, their racemates and, if R is hydrogen, their salts. 4. (Ha, 13E, 15S, 16R) -Il, lS- oxo-2,3 - (-) - trans-methyleneprosta-13-enoic acid, their racemates and their salts. 5. Medicinal products, characterized in that they contain compounds of the formula I or their racemates or contain their physiologically acceptable salts. 3700 / VA / DK 70981 1/1110