CS204594B1 - Analogs of prostaglandin f2 alpha - Google Patents

Description

The invention relates to prostaglandin analogues

Prostaglandins are a group of naturally occurring hydroxylated fatty acids with a characteristic potent and diverse biological activity that primarily regulate the endocrine, reproductive, nervous, digestive, hemostatic, respiratory, cardiovascular and renal systems. The prior art prostaglandin F 1 analogues exhibit activity in controlling the reproductive cycle (DOS No. 2,034,671, South African Pat. No. 69/6089) and have luteolytic effects (Nature 230,528 / 1971). Research has shown that 15-methylanalogs show enhanced efficacy as abortives in hamsters, monkeys and humans (J.Pharmacol.-Expth.Therap 186,67 / 1973); Adv.Biosci 9, 125 (1973); Prostaglandins 1, 319 (1972); J. Obsted.Gynekol.Brit.Commonw.

79, 737 (1972)], whereas the methyl ester of C-15 methyl PGE ₂ shows the inhibitory effect of gastric Slav in both dog and human when administered orally (Adv.Biosci 9, 247 (1973); Brit.Med. J. 1,143 (1973); Life Sci 14,533 (1974)] The methyl ester C-15 of methyl ether PGF _{2 <6} has significant smooth muscle activity and is 2 to 3 times more potent than the parent compound as an abortive (Prostaglandins 6, 207 (1974)). and disubstituted alkyl- and fluoro-analogues of PGF _2a ^{have been} found to be highly potent derivatives inhibiting gastric juice secretion (J. Org. Chem. 40,521 (1975)); Adv, Prostaglandin Thromboxane Res. 1, 195 (1976); Chem. Lett 211 (1976) 16-Fluoro-13-dehydro-PGF ₂ , α-bis-homo-PGF 2 derivative and their oxa-analogue (Prostaglandin 2,

375 (1972); Adv. Prostaglandin Throboxane Res. 1, 183 (1976); Prostagladins 9,391 (1975);

DOS No. 2,327,813) and 16- (substituted phenoxy) -tetranor-PGF- _{(µgA pat <QQ8 325)} stimulating effect on smooth uterine muscle (Prostaglandis 10, _5/1975 ); 6, 87 (1974); especially 16- (m-trifluoromethylphenoxy) -; and 16- (m-chlorophenoxy) -omega-tetranor PGF ₂ are an extremely effective luteolytic agent for cattle (Prostaglandins II, 155 (1976));

204 594 suppression of infertility in cows and horses. Recently also in the management of sows birth rate

The known prostaglandin analogues have broad, but often specific, effects. It is therefore expedient to synthesize such derivatives, which would have the disadvantages of the previously prepared analogues F 1. eliminated and in particular increased and specificity and at the same time protracted their effect.

This problem is solved by the invention. The present invention provides prostaglandin analogs of the formula wherein n is 0-6,

A is hydroxyl or hydrogen,

B is hydrogen or hydroxyl, wherein when A is hydroxyl, B is hydrogen or when A is hydrogen, B is hydroxyl, and wherein if

X represents a hydroxyl group

Y is an alkenyl group having 2 to 6 carbon atoms or a cycloalkyl group having 5 to 10 carbon atoms, optionally an alkyl group having 1 to 6 carbon atoms substituted with 1 to 3 substituents from the group of halogens, trihalomethyl, nitro, hydroxy, mercapto- , or alkoxy-, dialkylamino groups containing 1 to 3 carbon atoms in the aliphatic chain, or o

Y is OH where

R is an alkyl or alkenyl group having 3 to 6 carbon atoms, optionally substituted with 1 to 3 substituents from the group of halogen-, hydroxy-, mercapto-, or alkoxy groups having 1 to 4 carbon atoms in the aliphatic chain.

or if:

X denotes an OR ¹ group, wherein r ¹ is R ¹ ; is alkyl or alkenyl of 1 to 8 carbon atoms containing, in the chain of 1 to β hydroxyl groups, free or partially or wholly protected in the form of esters, ethers or acetes (a) or containing 1 to 2 substituents from the halogen group, or

204,594 r! denotes cycloalkyl, bicycloalkyl, tricycloalkyl of 5 to 10 carbon atoms, optionally substituted with 1 to 3 substituents from the halogen group,

Y is hydrogen or (C1-C6) alkyl or (C6-C6) cycloalkyl, or (C2-C6) alkenyl or alkynyl, or (C6-C6) cycloalkenyl, optionally substituted with 1 to 6 carbon atoms; 3 substituents from the group of halogen, hydroxy, nitro, trihalomethyl, mercapto, alkoxy, dialkylamino and 1 to 3 carbon atoms in the aliphatic chain, or by 2

OR is a group wherein R is a (C 6 -C 10) aryl group optionally substituted with 1 to 2 carbon atoms or trihalomethyl, hydroxy, nitro, mercapto, alkyl, alkoxy, (C 1 -C 3) dialkylamino carbon in the aliphatic chain or o

R is C 3 -C 6 alkyl or alkenyl optionally substituted with 1 to 2 halogen atoms or hydroxy, mercapto, or C 1 -C 3 alkoxy in the aliphatic chain.

The prastaglandin analogs of the invention act specifically on the targeted organs and organs respectively. function, and do not show a wide range of often unwanted side effects. Furthermore, the substances according to the invention have different, more suitable duration of action for use.

Examples of selected F ₂ analogs _{and their efficacy} are further specified in the Examples below.

Example 1

The prostaglandin Fg * analog of the above formula, wherein A = OH, Β = Η, n = 0, Y = CFg, CH »and X = OH, affects gastric funnel secretion.

ch ₃

It is an oily substance whose structure has been confirmed by spectral methods.

Example 2

The prostaglandin analogue Fg ^ of the above formula wherein A = OH, Β = Η, n = 2, Y = OCgHg i

and X = OH. The proposed structure is in accordance with the interpretation of 1 H NMR-, IC-, UF- spectra. The derivative has been shown to have a 10-fold luteolytic effect than prostaglandin Fg * and oxytocin-like effects.

204 594

Example 3

The prostaglandin ^F 2 * analogue of the above formula wherein A = OH, B = Η, n = CH 4 and X = OCH 8 CH 6 OH, whose structure has been shown by spectral methods. This substance has a significant effect on the cardiovascular system, affecting the contraction of arteries.

Example 4

The prostaglandin F analog _{of the} above formula wherein A = OH, B = H, is characterized by an abortive effect when administered orally. The structure of this material by 1 H NMR and HS spectra.

n-4. Y-0-φ was confirmed

Example 5

The prostaglandin analog of the above formula wherein A = OH, Β = H, n = 1, X * OCH 3 and Y = O- is characterized by a luteolytic effect in rats, hamsters and cattle. The proposed structure was confirmed by spectral methods.

Example β

The prostaglandin F ₂ analogue of the above formula wherein A = Η, B = OH, n = 1, X = OCH 2 and Y = O-CH _{2 has a} significant luteolytic effect in cattle and affects uterine muscle contraction. Interpretation of NMR, IR, UF and mass spectra is in accordance with the proposed structure.

Example 7

The prostaglandin F2 _{< e} analogue of the above formula wherein A = OH, Β = Η, n = 1, X = OH and T = OCHgCFgC (CHg) = CHg has a significant luteolytic effect in cattle and sheep. Furthermore, it was successfully applied in the management of sows' birth rate. The product of this formula is an oily substance and NMR and mass spectra confirm the proposed structure.

Claims (2)

Analogs of prostaglandin F ^ _formula. where n is 0 to 6, A is hydroxyl or hydrogen, B is hydrogen or hydroxyl, wherein when A is hydroxyl, B is hydrogen or when A is hydrogen, B is hydroxyl, 204 594 where in case X represents a hydroxyl group Y is C 2 -C 6 alkenyl or C 5 -C 10 cycloalkyl or C 1 -C 6 alkyl optionally substituted with 1 to 3 halogen, trihalomethyl, nitro, hydroxy, mercapto, or alkoxy, dialkylamino groups containing 1 to 3 carbon atoms in the aliphatic chain, or Y is OR ² group, who about R is C 3 -C 6 alkyl or alkenyl optionally substituted with 1 to 3 substituents from the group of halogen, hydroxy, mercapto, or C 1 -C 4 alkoxy in the aliphatic chain or when: X represents a group OR 6, where R * is alkyl or alkenyl of 1 to 8 carbon atoms which contain in the chain 1 to 6 hydroxyl groups free or partially or fully protected in the form of esters, ethers or acetals and / or contain 1 to 2 halogen substituents. or R ¹ is cycloalkyl, bicycloalkyl, tricycloalkyl having 5-10 carbon atoms, optionally substituted with 1 to 3 substituents selected from halogen, Y is hydrogen or alkyl of 1 to 6 carbon atoms or cycloalkyl of 5 to 10 carbon atoms, or alkenyl or alkynyl and 2 to 6 carbon atoms or cycloalkenyl of 5 to 8 carbon atoms, optionally substituted with 1 to 3 substituents from the group of halogens, hydroxy-, nitro-, trihalomethyl-, mercapto-, alkoxy-, dialkylamino groups having 1 to 3 carbon atoms in the aliphatic chain, or 2 2 OR is a group wherein R is a C 6 -C 10 aryl group optionally substituted with 1 to 2 halogen atoms or trihalomethyl-, hydroxy-, nitro-, mercapto-, alkyl-, alkoxy-, dialkylamino groups containing 1 to 3 β 204,594 carbon atoms in the aliphatic chain, or o R is C 3 -C 6 alkyl or alkenyl optionally substituted with 1 to 2 halogen atoms or hydroxy, mercapto, or C 1 -C 3 alkoxy in the aliphatic chain.