NL8000345A - NEW TRIFLUORMETHYL OLIGOPEPTIDES, PROCESS FOR THEIR PREPARATION AND USE IN MEDICINES. - Google Patents

Description

803001 / vdVeken 35

Applicant j DELALANDE S0A., In COURBEVOIE, France.

BRIEF DESCRIPTION: Novel trifluoromethyl oligopeptides, method for their preparation and their use in medicines. The invention relates to new trifluoromethyl oligopeptides, a method for their preparation and their use in medicines.

More specifically, these new compounds have the general formula 1 of the formula sheet, wherein -Y- or the group 10 -L-Ala-, in which case (R, n) has one of the following meanings: (isobutyl, 0 ), (cyclohexyl, 0), (fluoro, 0), (N, N-diethyl-amino, 0), (H, 1), or one of the groups -L-Pro-, -L-Phe-, -L-Val-, or -L-Leu-, in which case π = 0 and E represents the isopropyl group.

For the sake of simplification, the following groups are referred to in the following as follows: -Ala-; -Pro- $ -Phe-; -Fall-; -Leu-, wherein the groups -Lys-, -Ala-, -Pro-, -Phe-, -Yal- and -Leu- have the L configuration.

Finally, it is noted that the symbol -Ala- the group of formula la of the formula sheet, the symbol -Lys- the group of formula lb of the formula sheet, the symbol -Pro- the group of formula lc of the formula sheet, the symbol -Phe- represents the group of formula ld of the formula sheet, the symbol -Yal- represents the group of formula le of the formula sheet and the symbol -Leu- represents the group of formula lf 25 of the formula sheet.

The invention also relates to the addition salts of the compounds of the formula I with acids and in particular inorganic acids such as hydrochloric acid.

Of the compounds of formula 1 and their salts, the preferred compounds are those in which -Y- represents the group -Ala- and in particular those in which (R, n) means (isobutyl, 0) and (fluoro, 0) possession.

As already noted, the invention also relates to a process for the preparation of the compounds of formula 35 1 * According to this process, compounds of formula 2 of the formula sheet, wherein Z represents the benzyloxycarbonyl group and the whole (Y, n, R), are subjected one of the meanings (Ala, 0, isobutyl), (Ala, 0, cyclohexyl), (Ala, 0, fluorine), (Ala, 0, Ν, Ν-diethylamino), 39 (Ala, 1, H), ( Pro, 0, isopropyl), (Phe, 0, isopropyl), 8000345 * x 2 (Yal, 0, isopropyl), and (leu, 0, isopropyl) "property, on hydrolysis. The hydrogenolysis reaction is carried out in particular in the presence of 10 foos palladium on carbon and hydrochloric acid, in methanolic solution, the hydrochloric acid preferably being in the form of a 1 N aqueous solution.

The compounds of formula 2 are new compounds and can be prepared in two different ways.

According to a first preparation method, the compounds of formula 2 are obtained by condensation of the compound of formula 3 of the formula sheet, wherein Z has the same meaning as in formula 2, with compounds of formula 4 of the formula sheet, in which the whole (Y , n, R) has the same meaning as in formula 2, this condensation preferably being carried out in tetrahydro-! furan in the presence of tetramethylguanidine and in particular 15 | at a temperature around 0 ° C.

The compound of formula III, which is itself obtained by condensation, for example in the presence of pyridine, in a mixture of water and ethyl acetate and adjusting the pH of the solution to 4-5 using a 3R hydrochloric acid solution, of 20 '7-hydroxy-N-ethylbenzisoxazolinium tetrafluoroborate of formula 5 of: the formula sheet with the compound of formula 6 of the formula sheet, wherein Z still has the same meaning as in formula 2 «The: compound of formula 6 obtained by condensation of Ν-ε-! benzyloxycarbonyl-lysine of formula 6 "of the formula sheet, wherein Z has the same meaning as in formula 2, with thioethyl trifluoroacetate of formula 6", preferably at room temperature and in a 1N aqueous sodium hydroxide solution.

The compounds of formula 4 are in turn obtained by removing the protecting group from compounds of formula 7 of the formula sheet, in which the whole (Y, n, R) has the same meanings as in formula 2 and BOC de tert , butyloxycarbonyl group, preferably using a solution of hydrochloric acid in acetic acid,! ; Finally, the compounds of formula 7 are obtained! by condensation of the compound of formula 8 of the formula sheet 8000345-3 - with compounds of formula $ of the formula sheet, in which the whole (R *, n) means (isobutyl, O), (cyclohexyl, 0), (fluorine, O), (η, N-diethylamino, 0) or (H, 1), and by condensation of the compound of formula 10 of the formula sheet with compounds of formula 11 of the formula sheet, wherein Y 'represents the groups Pro , Phe, Yal and Leu may propose, these reactions preferably being carried out by the mixed anhydrides method.

According to a second method of preparation, the compounds of formula 2 are obtained by condensation of the compound of formula 12 of the formula sheet, wherein Z represents the benzyloxycarbonyl group, with compounds of formula $ of the formula sheet, and by condensation of the compound of formula 10 of the formula sheet with compounds of formula 13 of the formula sheet, wherein Z has the same meanings as in formula 12 and Y 'represents a group Pro, 15 Phe, Yal or Leu, these two condensation reactions preferably being carried out under the same operating conditions as | for the preparation of the compounds of formula 2 by condensation: of the compound of formula 3 and the compounds of formula 4e. The compound of formula 12 and the compounds of formula 20; mule 13 are obtained by condensation of compounds of formula; mule 14 of the formula sheet, wherein Z has the same meanings as in formula 2 and Y represents a group Ala, Pro, Phe, Yal or Leu; with the compound of formula 5 under the same operating conditions: as in the preparation of the compounds of formula 30 25! Finally, the compounds of formula 14 are obtained. by condensation of compounds of formula 15 of the formula sheet, wherein Z and Y have the same meanings as in formula 14, with; the compound of formula 6 "under the same operating conditions as in the preparation of the compound of formula 6". The invention will be further illustrated by the examples below.

Example I. Trifluoroethyl-lysyl-prolyl-para-isopropyl-anilide-I chlorohydrate (formula 1) I Code number: 60, 35 I A solution of 0.257 g of Na-trifluoro-i-acetyl-carbobenzoxy-lysyl-prolyl is subjected -p-isopropylanilide (formula 2) 8000345 s - 4 - β (code number 69, prepared in example II) in 20 ml methanol and 0.5 ml 1N hydrochloric acid under hydrogenolysis under atmospheric pressure and at room temperature in the presence of 0.05 g 10 The palladium on carbon is filtered, the solvent is evaporated, the residue is taken up in benzene and evaporated again. The residue is taken up in tetrahydrofuran, diluted with ethyl ether and the precipitate formed is filtered. 0.2 g are obtained. of the desired product.

Yield: 90fo

Melting point: 15 ° C

10 ec 25: - 54 ° 4 (C-1, MP) | J 546

Rough formula: σ22¾2 ° 3, ïï2 °

Molecular weight: 510.99 'Basic analysis! 5 i r ----------------------- r --------- t ---- --T ------- 1

y 0 Η N

Calculated (fo) 51.71 6.71 10.97 'Found (fo) 51.45 6.36 11.21. In the same manner, but starting from the corresponding reagents, the compounds listed in Table A below are obtained. with formula le 5 jf! "10 0 0 3 4 5 - 5 - ....... - = -: ---- 1 --- 1 ---- f- Η CM VO O K \ rt ^

ON CM A O COr-t A

fcs; · »« · »· * **** - +

OrHOO 952S

H r-i Η H

S _j FOR rM CO CM O H ^

£ M C— A A CO H VO A CO

^ vo VO VO A C— VO f-VO

• --- H - A - 3 - M = - M-- £ - £ --E--

Yy P *. -5J- tA fA CJNOOOO C-

WU ο ·. "*« * * "_T

Lj ° _i _i tn OO H H

g * SStnnAAAAA

a___________ S. · * · »·« I * g m «S a o wow & <^

a B 'Z

vo Ph o § Ö m ^,. S ^ g w a O - »i-i CL <2 £ £

H 'd- A C— VO

O O O O.

I I VO H A

1-1 in rH A A

i + I i la i? Q o c - cm cm I § W σν 00 σν os

ft U

o a_____ h ^ a ^ a S § £

3 a 3 O H H H H

g 01 Pi w μ - + ------- W + D VO t> -

J ^ 5xi CO A O A

** +, a o <n ο ο o

h ® ® -H o * ^ <n A

Se ol S "? H a

"§53 SiJO .A in. A A

EH g> --------

5D

5 m a A a

See O O O O.

».S * - _-i a a a w

Ö d A A A _ A

I I a a a ° c a ° cv! > ° ° CM ^. * ° VO "φ p ° c * P" tiP \ P \ te CM Μ VO N M · W vi ·

5 CM CM CM CM

£ 0 + 0 0 + 0 + rt + O + Ο + o

§ —4 CO iH rH CV | H "CM

o Ö a ο o a o a g ana a -vma a ^ ia £ £ 4. £ P O 5 = __ “_

A A

aw «8 0 0 0 3 4 S —r - * ----- a> ο

ο I ο H CM A

g 1 S VO VO VO

.i-s ----- L - * - 6 - in 00 NO Η in in ΟΝ Η f2; VO KN CO Η NO CM in m «* k« I * Λ Λ ft Λ

Η Η Ο Η,> 04 CM CM CM

ι — j I — I I — i r — liH i! iH H

H ----------

£ 2 HCTn- ^ · -3- KN m CM

ft M £ - m CO O CM ON NO ’q * ΛΛΛΛΛΛΛ ··

g VO VO NO t- tn 'ί VO VO

<< --------______

ni g · NN m "Sf · H NO CM CM

-G-VOmNOHtnmCM

<- <O>. K · «** ·« * ·> «

p4 CM O m NN VO rt * in UN

ö in in in in -Φ 'tg * o «« · β ο β 1-3 -tS φ © φ Φ Φ Φ © a) h ^ ft ο ft ο m <a _ ft oi = c ^ S So § § CM _

ft Hi O

* m «I

VO -> LTV * S

in g · Η o n ft - cm in ·> "* · *

--1 Η Η Ο H

·] J w v__ '^ v _-> a for rcm oo o o o o ι I H O ON l> -' · »· m m t— cm ι ι i r -qp ----- ©

^ ^ -S in H CM O

1¾¾¾. oo on oo on ft U ^ O 42 -3 ----- * <} Η -P ^ *} o 00 ® e o cm H oo m

h S3o 1-1 w H H

© co ft w 43 -1 -----

_p 'j 4J ON in H NO

w Λ m o ^ in.

5 © oo on o co T- —ι © · Η “" »* '

J H JS O VO CM NO

s Ο Φ 00 Ή g · in to g iio -vim m 'M * in Φ' _______> m 'o m m m g- ο ο o Φ ft. Cf J ^ h m a a a

a Ph m ^ KN

S H ft ft 1¾

δ Ο Η Η H

O CM O O Ü <h m g ·. m m a m JP * cm m

Φ h ft w ft W

is W WN Jn, C-H

S Ο CM n ° - H CM

ft O + O o a + ο + o 54 Η H CM Η H CM, 0 O O ft U oft

j> ft ft HJCM ft ft HJKN

i | A 5 1 -f ft o = = =

Cjf j ^ N sT βΓ

a ^ rIM CM CM

ft N> ft ο o 00 0 0 3 4 5 -; - ^ --- 1—51- v j rrt o g- in VO j Γ "·

o to NO NO VO I NO I

i_w_s ___ i - f - 7 -; - -

j CM; CM

I ί (Μ I (Μ I i> Η \ Η <_ί _; _ ϊ pq! 1: ί

03 ί C— ί Η I

• η! τΗ 1 Ο! ij: μ «*; * Ί I <j U3 ι νο;

Β _; _! ______ I

I Ο Ο; ; «Ff \ CX3, (3 ο c- ¢ -: ί El 'd' ί g -——; --- · ~~ +» —.—} <S ° 5

• gj> I

j 1-3 ^. ©? I

I H W C i 5; ! s! g l

M3 R.

in -sr »| cvi in, h f i-1 w! H w l! ö, ° CM \ I l_L <m i I · i i i — rd - i I S 5 00

Pi H ^ 00; - on! . i

T - I

H -p i tn <D S3 O; O i S 3 O: CM: * ca P <'ί; <j ... .......... 1 H 'Η β -P *

«P> P I ON

xi oof oo (ö a> -H j »-P ri * I vo o Φ j in, tiD; sw> i * · ir ~ i -; -------! o;>! h: m 3 <ö io: f> H i .J5 * 1 5 ^! ia * i Ho!

<0.1 cm

ie · Μ! β i co j

Pi \ H; _j o_ i § | g; g i §; \ ί a i

: i j i I

; > i 3 ί; _ 1 ί β Η 8000345 -1 - “*” - 'ο a 00 Ο P M3 «an,. Mnii w, mm —— - I -ν ^ · - ·. · *** ·· ΙΛ Λ - 8 -

Example II * N-α-trifluoroacetyl-N-ε-carbobenzoxy-lysyl-propyl-p-isopropylanilide (formula 2).

Code number: 69 c

To a solution of 0.2 g of prolyl-p-iso-5-propylanilide chlorohydrate (formula 4) in 1.5 al tetrahydrofuran cooled to 0 ° C, 0.105 ml of triethylamine is added, then 0.405 g of 3- (Na-irifluoro-a (tyl-N-c-carbobenzoxy-lysyloxy) - 2-hydroxy-ΐί-thylbenzamide (formul 5 prepared in Example III) and finally 0.095 ml of tetramethylguanidine. Stir for 5 hours, dilute with 20 ml of water, extracted with ethyl acetate, wash the organic phase with an aqueous solution of; potassium hydrogen sulfate and then with an aqueous solution of sodium bicarbonate. Dry over sodium sulfate, evaporate the solvent, filter the product through a column of neutral aluminum oxide (eluent: ethyl acetate) and crystallize the product obtained in isopropyl ether. . 0.31 g of the desired product are obtained

[Melting point: 117 ° C

: Rough formula: C_AÏÏ2-F_1T.0K

30 37 3 4 5 20 I I25 α - -39 ° 9 (C-1, DMF) (L J546 'Molecular weight: 590.64 Elemental analysis:

25 CHN

Calculated ($) 61.01 6.31 9 »49

Found ($) 61.02 6.31 9 »67 30 In the same manner, but starting from the corresponding reagents (compounds of formulas 3 and 4), the compounds of formula 2 listed in Table B below, having the code numbers 70, are obtained , 71, 72 and 73 In the same manner, but by condensation of the compound 35 with formula 12 with compounds of formula 9 and by condensation of 8000345-9 compounds of formula 15 with the compound of formula 10, the compounds of formula 2 listed below in Table B with code numbers 74, 75, 76 and 77 # ii ί ii | j i s i i i 8000341 - 10 ** ♦ i ___ __________ __ T?! ; i ctn c—: φ, t— la j H s a, F-,

! i -φ- vo? f-vo -φ} vo = 'cm 5 CM

J · »; ·>; ·> *> *>> *! »I | σ \ on; co · oo ca | σ \. <a j σν.

ί Η - ί ______ * _________________, __-............ --- ...... I · _ί_ I co ΐ i η η; Φ ί φ · ^ i f- - η SJmS: Α (Λ; Η i σ \ νο νο 00 00 G ί W ί »~ · ί ft ·» · »: · * ·»

[SJ j: ^ νο = νο; ia vo voïvo VO

! §! : I! ΐ pci Ο Ο ί- vo CO C; Α Ο * ^ I Ψ · 9 * '9 * C * ·> * f * * ί «*} ο Γ Η Η ί A 1 Α Ο Ο; Η Η

EH J VO νο <νο 5 VO VO VO; vo C ^ J

; S; __ -) ______.

- »3! ί # 0 · · · Ο '«♦ - m ί u> ί! 4> μ ►; n ► j vp I φ QJ (D φ Φ Φ Φ Φ Η. f pq 05 "W C5 PQ C5; PQ C5 -

- ί '-ν - · ->. I '-' I

\ vo I § <H Ij \ η ιη 'φ I 5 ο I * i:, _, ϊ η η r * * I ί - · - ^' Η Η

; I ν — κ ’W

ΐ · Β? σ \ - σ \ •. , I Ο Ο W 'Φ:? 1-1! σν α ο, ο ί | A CVI ΙΑ νο

j I I + + I

0J: __ | ______ „________; _____; ____ j _: ® I; ! i ö * ι g vs. O ο 3 oj e- ia g I ft S ^ f f-, ό ^ * ό ^ I ο μ I i OS 1 «H I: ·: -PI ·; 4J-H-P ^ -n! t ~ ΚΛ vo "Φ pq Φ Φ fi O * H 'o rt' g

H w ftv ^ I

φ ff "I ™" »ι I I .......... nil. MW — MWIWWHWIjlMJMW *. <. .

P Φ H i h g 1 § 2 ^ o: voi ovt ^^ OOIVO t * - 'vo. VO; rH φ · Η «* · * ** * ö'H ^ fo ® 2ί · ^! ο φ - ο \ -φ σν ι ο, α g ίο ί ιη νο ιτ \ νο mi f>! τ "" ~ —r I I ': * - ο Ι ιη · in ia; tA, η! c> \ ο ο: ο: ff ί -φ ί -φ.-φ ι 'Φ 1 § I! 35 s S; a

S | (Ai AA A

i o i ph t ph,

i «Η £ P ~ {OV ON H

I A A A "Φ I ® I w - tn Si w g * ο -φ o, 2i -

ί a 1 A A A A

I (¾ 1 0.00 f | j -. _ - ^; j I. Ii '1 ~~~ i ι ί ^; *! I Ο ϊ Φ ί Η I ff 5 I i «fu I Λ' '® I i ! · - j-1-ί ----: -— 1 ----? Yy!:;; I ojoio; ο o; j!: '1ΜΜ | ΜΜΜ Ι || Μ · ΙΜΤΙΙΙ ·· ΙΙΜ | · ΒΙΙ, Μη · ι1ΙΙΙΓΙΙΙΙΓ lïTniUMMlnilliri · ΙΙΙΜΤ · ΓΙΙΙ1 · 1Ι | - || Ι · ι | mi · II ιιιι> ΤΊΤΤ 1Ί ---------- 1 - ·· "* - · —_ * * ν I = i '=! = I __I 1!! I _ _ ί

8000345> S y “! I

fl) S I i! s X) S j 0V I O 1 H CV! OP I VO 1 A- I C-! C ~

. a g 1___1 1 ... ..1_I

V- - 11 - ----- “1 ----; ---—--: -! t— ί η co t- voʻin o co

i CM ITV VO CO A A CO. OV

<see *.! ·> <»-« «*;« * * ‘*

σ \! CT \ QV CJV O: O Η H

j Η Η Η H

tej! O! L "- A CM j * ^ ί" A "00

W I W a c—: ^ 0 CM j cm ^ ‘O

g vo vo vo vo in j ir \: vo j vo: <3 *! ......... ....... j? * Ph co co ο o - a j h _ £ - Zt (_l J IT \ CO - CM in ur \ O ^

2 H H O OV A a - co GO

g VO vo = VO; ΙΛ A A A A

Go «» ·· ο o »· i: J4 ί t> 54 i>. U> iS tea © © S; © ® ® <D ® tpq pq o WeC5 F4 ÜJ. W c5

x-N "^ ~ X; W.

1¾ ^ 9 h s s, ® § vo η o. s A ^ ^ „! ^ _ (^ rH rH; h,

a t— 'CM A. a

1 µm; 2m; * οο%

Η H: ^ H

I I I I

o sa tf \ O CM CO

p, O A VO VO j A

m o___j_,

Hi ® H f a KN O. Λ; \ o d 2S ° id 2 η h 4a 3 S o CM H H f »CQ ft w_ H f“ j

S § P t ~ - A H = A

t OO VO VO A VO

> 'H £ -4- 00 O A

• o m 0 c—; : ®v

! g tfl vo A A A

Φ A A A A

Η Ο Ο Ο O

9 ^ i »s a,: S a A„ ^ _ a 0 Ph Ph P4 P *

£ h; Ov C— 00 CO

- A Yes cm> A

© SJ w. W, M

1¾ j — j σν a; σν

1 l A CM CM CM

k j 0 0 0.0 1 «5. l - ί -; * S 9 "i;;;! ·; I i ί i 11>;:) 0 0; o; 0 i o • ΐ ί; 5;: ί i i i 'i"; i i 4 »4»! r ^ i 1 ^ ί = »\ 7: I«! W i -i I t V; §000 3 4 5 1-j - j - Γ -------------- 1 --------------------- ; I ® j;

-S 1 A ^ A I

i Ο P t— C— I

ΐ W β j -12 ~ I -; r I. : CO. I Cvl s £ 3 * f · »j 'o; o \ ui: cm c-

: ÏÏ W. 00 ON

: adl - «*

: 1¾ in UN

f <«}, -. 1,., ... 1 .....-. 11.1. II ........... I. ·· .—. II I.

I i δ o

Ph cm h H <* »,« S5 O CO 00 - EH lf \ in a .....-- .........:.

^ · · H v? M> ..

J 03 03

(¾ w 03 I

S 'a i VO. t * * in "Μ- ον ΐ. cm in Λ - o I I w: i 8 nn i

1-1 5 I

_! «I

fH OJ

P ^ ft ^> O.

n ~ ‘Γ i Η H * P Λ s O j

03 03 β O ON J

.ο a ο ο h - cö m ft '»-p 1 ......... · H! ID. β + », UN i H? Λ: ΙΑ, o O O * * S S 0) Ή 'VO j β rH I® 5 ο ο φ in i> a t) 0 _____ _ j, 03 * in j rH i O.

I i a: i O ft; Oh ". Hi"; 03 W:

j> VO

β CM '\ fit O; > '........... ..... +

i I

i 1 5 - 5 • * 'λ 1

j I ^ I

«; ^ s <: Ϊ! ; j i

80 0.034 5 03! "I

, ni | -inn rnhri νΠΤΤΤΤΤΓΤ · i ι · γΓ · w ‘'· *» -w * —v * * μ »* ι · - *! n t 2 ^ 03 6 C— rd S l Ο β

WC

- 13-

Example III. 3- (N-a-trifluoroacetyl-N-e-carbobenzoxy-lysyl-oxy) -2-hydroxy-n-ethylbenzamide (formula 3) «

To a solution of 1 g of N-cc-trifluoroacetyl-Ne-carboben-zoxy-lysine (formula 6) in 5> 32 ml of an aqueous 0.5 M sodium-5 bicarbonate solution and 5 ml of ethyl acetate is added. Add 3 ml of pyridine and cool the solution to 0 ° C. Then adjust the pH to 4.5-5 with 3 N hydrochloric acid and add in small quantities in 20 min * 0.73 g of benzisoxazolinium fetrafluoroborate (formula 5). add * Then dilute with ethyl acetate, wash with a solution of potassium hydrogen sulfate, then with a solution of sodium bicarbonate and finally with water * Dry over sodium sulfate, evaporate the solvent and crystallize the residue in a mixture of isopropyl ether and petroleum ether * 1.3 g of the desired product, 15 y. Yield 90% are obtained

! Melting point. * 106 ° C

Γ125 1 α - - 49 ° 5 (C-1, DMS0) | L J546 'In the same way, but starting from the corresponding 20' reagents (condensation of the compound of formula 5 and compounds of formula 14), the compounds of formulas 12 1 and 13> are used in the crude state * Example IV. Na-trifluoroacetyl-Ne-carbobenzoxy-lysyl-alanine (formula 14). 25 To a solution of 1.9 g of Ν-ε-carbobenzoxy-lysyl-alanine (formula 15) in 10 ml of sodium hydroxide solution in water is added. 1.9 ml of thioethyl trifluoroacetate (formula 6 ") and stirring at room temperature for 20 hours. It is then acidified to pH 3 with 1N hydrochloric acid, extracted with ethyl acetate, the solvent evaporated and the crude product obtained crystallized in petroleum ether The product thus obtained is used directly for the preparation of the compound of formula 12

In the same manner, the other compounds of the formula (14 * 35) are also obtained in the same manner, but starting from 8000-345-14-Ne-carbobenzoxy-lysine (formula 6 *) and thioethyl-trifluoroacetate (6M), one obtains the compound of formula 6 "

The compounds of formulas 14 and 6 are used directly for the preparation of the corresponding compounds of formulas 12 and IJ and of formula 3e, respectively.

Example M-tert-butoxycarbonyl-propyl-p-isopropylanilide (formula 7) o

To a solution of N-tert-butoxycarbonylproline (formula 11) in 20 ml of tetrahydrofuran, 0.26 g of N-methylmorpholine 10 is added and the solution is cooled to -15 ° C, then 0.31 g of isobutyl-I chloroformate is added, stirred 20 min * at -15 ° C and add 0.35 g of p-iso-1-propylaniline (formula 10). Stirring is effected for 1 hour, filtered, the filtrate is evaporated, the residue is taken up in ethyl acetate, washed with 1 ml. aqueous solution of potassium hydrogen sulfate and then with honor 15. aqueous solution of sodium bicarbonate, dries over sodium sulfur The solvent is evaporated and the residue is evaporated. The residue is recrystallized in a mixture of n-hexane and isopropyl ether. 0.55% of the desired product is thus obtained,

! Yield t JOfo 20 · Melting point: 162 ° C

i New formulas σχ ^ 28 ^ 203

Tl 25: α - -89 ° 1 (C-1, MeOH) .. 546 Ilol molecular weight: 332.38 25: Blementary analyzes G Η ff

Calculated (fo) 68.65 8.45 8.43 30 Found (y) 68.71 8.67 8.52

In the same way, but starting from the corresponding reagents, the compounds of formula 7 and in particular the compounds listed in Table C below are obtained, wherein 35 'in the groups Phe, Val, Leu or Ala represents new connections0 "80 0 0 3 4 5 - 15 - tsj-.t ~> 7. v *%> η * νκ • WM'Mqiirw ^ 'uMWM'Hnwonp *' -» - « n — ymi inmin n <ιΐι · η m »* - μι» <h »» n. ι · ι · »ί> 11 1 - WN 'CM CM I m II» \) o I .'sfitTN. {OJ ΝΛ ; in l ts! «- ·> <* i« J *? * t; r '- 00; CO · t- 5 t- 00 · CO 1 - ® i * i! (Q ί - - y - «« ".'WWl» nj | iMiliWWirm ^ m »» W »WH · ^ ι — fWCT *. '> Ry—- -, · ν ~ κ —-« «-« »- * t- ·· =«% S \ os \ c- 0 it * -!: 5 · '1 co,;,!

{rt al ^ ¨ for ON 1 ON - O r-ι I; I

§ j OD I ¢ 0. N; ^ CT \ ΐ I

.¾ m η cm I in I m, w j rt: no t> ~ cm o c cm · fn ί «4J ΓΛ <* ·» - »* Λ f Ij a .CO co CM CM ° 2 $ ï

O, Φ NO vo c- NO NO I

,: 1 ....... v-n-7Π-ii; h *; > ·! cl 1¾ 'o) 0) ® © ® ® mirt1' KI * * i (£) es pq c5 W C5 PR? o f i ""; W: CT l j Φ “wo l I ë; ? I:! for I OHs! . 3, _ „_i_ _i ^ · * ^ i o? in j ^ l l I]: 1 “1 CH i co ί η! i

-4 I co; ^, o: J

I 1 i + 1 ι j \ 'ti4ii lltfUWiW ........................ -i ··' * »'I» M »I IH · 1 ··· «.Hl! "" "'t *; I; i 5 j; ï + »· ^ o. cm: · co! -p

^: gS r-.VO I UN S

®; j 3 Φ 3 HO P3 '& n .... }.

· »- · - **. * tm ~ t -w * I- J 11.11 jmniun. . ιιΙ. HOT ι HOT | · ιΡι ~ ηΤΙ | ιΤ ~ -1 ~ T l ...... I mim '- *> ι · ι II IÉ »I V.-, ι,! : j i H +> oco h: H !! j (£ ‘.

o cu S ps o M.

o g ra Pi ^ 1 · · ÊH fl * T ^; : C §% 00 00 Ο ιη: • S * ο ο ΙΛ Η! <Η; φ · Η »ί * ί Γ ~ Γ; C HS CM CM ι i -S- .5 λ ω tn co nn o g ft) ^ j u; ---! -—----- ^ 0) · ί ^ ι! ; j j '- ί; '', I 5 '' i ® i rH '! e

• i NN! NN 5 m I

ί U -0: 0! O. O

? S CM 'CM: CM! CM

; "'%:" Fc I Bo; "0 !! : M,: »TSa; it € 'j & f 1 ^ 1: 1 ----- J— _ · _ι_η_ιι ni — llrm“ Ί. - · --------- --------- f ιμτ.-γτπ mi-n> mi i. j.i i-J. - i; :! i j rt j j - r I =>! ι! I '.

SOOOji ^ * j I I, 3 I.

- 16 ~; "00? nn

O 1 ON

J55 j »1 co! w i * 'cn t ~ —-—- ï-> -i I 3 _ -

hi I («o 1A

<5 ί K t "O, * § i co} σ \ i: ^ j —.- j ---

* ’T * N} KN

«* Ιλ ia: & i o»

oi; ö "ON y ON

I H NO NO

* ί Ή ----— rH — i I p £ j O j β

Cl ini H>; ; pa · * £. Q) j Φ r I ö pq CS t i r t ·· »ii» mm wii.w ^ iw-nniM '.' Iiiwiiiwian ^ nH'W * iHi »w> l> winWW ♦

! I

I 1

I I »V

] n in t! no ο $

I S? S: r-T I

: \ - w:! 8 ^ <* j i ξ_ί ο: * Η. j 'CNI ί ί »

j; I J

I -t »; ! O ®; “Λ {η 3; a ^ „j z n. k 1w! δ? π3 O t Ο -Ω -P «Η _ '» «ΤΙΙ» «> Ί · <ί1 I1 * 1 öO -f» - ϊ Η α>' ε e? ^! S § 'o C o' 1 UN j f> SsD i a C O I r ~ l; C CQ ft w. j S ί — i-r - 1 C * Η; ί • Η ί 3 + »j Η ί ro 2 Λ | "Ί ·!

Li'O O I »i S <D · Η NO; t> s H £ 2 "! O 0)! ΙΛ *> 3« ® ί «* i ί; 1 1) 0) 1

! i kn I

I fi o

! O CM

i «M &

• J I O I

? Q) 1 N "S

f Is SJ 1

ί3 ί O

i ö i, ·, r- i ίii -. .. - ·, - - | j

«FN

0 8 0 0 0 3 4 5. ____________1_ «> * 5 1 ^ ****** ^" - »—--—» * "****» «.. l.ii.> .....«. Lift - “.if.ji.-j. ïrnu --- ¾ 17 -

[Example] Prolyl-p-isopropylanilide chlorohydrate (formula 4) 0 A solution of 0.45 S of the IT-1t obtained in the previous example, butoxycarbonyl-prolyl-p-isopropyl-anilide (formula 7) in 2, 5 ml of a 2H solution of chlorinated water-5 dust gas in acetic acid for 15 min # at room temperature # Then it is diluted with ether, the oil obtained is decanted and crystallized in ether. 0.25 S of the desired product is thus obtained.

Yield: 62 $

10 Melting point: 220 ° C

Crude formula: C .., H_ .. ClïTo0 14 21 2 ΐΓ "2 ^ yes - - 57 ° 4 (C« 1, DMF) J__546; Molecular weight: 268.75 15 y Elemental analysis: ----— - -----—------------ ή,

! CRN

> I Calculated ($) 62.56 7.87 10.42 20 I Found ($) 62.52 7.81 10.58 1 In the same manner, but starting from the corresponding reagents, the compounds of formula IV are obtained and in particular the compounds listed in Table D below, where in Y represents the groups Phe, Val, Leu or Ala, which are new compounds # i: 8000345 ** 18

s CM CO ^ 'O N'n' O I

! in κλ vo co * o I

^ - "t1 f * I 1 · * I * *; ·» - 1¾ ooo! o σ \ · ο;! ιΗ; Μ Η H rH:. ___________________i_! i «5 1 - S i ~ t- H. vo τί; irv> vo: <1! a - oo 1 oo 'ii uv' ώ co j 00.

i S *; t «_ _ c—: co co co I oo; 5 I I,; w »m. 1 *! H VO ί CM f ON j t> -; in NO i i <} I lf \ Lf \ j Ο H CM KV: 'U ·> I «: I J Λ * · · *:. * g. CM CM CM CM KV ΝΛ 0j y g I VQ j VQ; _: VQ VQ VO VO l h! * S; o ·; *? «0 9] '' 9 0: I - j vs -. ti s! j4 i> ^ ► - U ► i σΐ! -; W ü; W t Q, B O -pq O)

1 '* ··· * »·" *** ΨΙ * »Μ> m * mm« Iimmmmmmmmamm j mbméii i », J

ί I -I / "- N * / ^ s. 1" -v i = i & 'È! "i; 9 ίο" 5: 3

{NO! ^ la * {- I

j S 2 I ΰ j £: £: i 1 y i ί (Λ t- t— • l I 1: 0] O O. o.

1-J * c ~ - CM; O fOk j I i fA] σν co vo '; ^ I; +, +. + "S; i:

Gfc full ................................. ........... "» .. ... — ......... »tf nil ............... I * 11 ji Ϊ ·;: +»> 1 i ® ra ·!, Ο j & n ί j:! ai PJ I CM CM i tn · O; g; I ® w 1 VO - ον ί OO σν i MJ ft y I: = j

ο I O j, I

-p I j i>; ί «i! , = 1; ! I 'o * ir \? Irv? ir \: ® B + »/ -N! cm i co. fc \ w i, Ο®! J S3 O CM * H CM CM; cd no i J f * ο? ? ί,: EH S "CO ft w j_j__.

^! «-. ί:: 5 * 3 -p: «λ ί g \ NO ί2 .; 3 Λ t- ί C ~ - · i ^ ® ® -η 00 ί 00: o

t> H & VO ί H C— CO

^ jo®; CM s N "\ ί CM CM, 1 S« «: '', ------------- r ------------------- ------------------ i S ί I ί!! 1 I · i -. i * 1 «:!. fs! I! * H 5 oio! ο oj I i: s. § § i S; Η H: H ri:! o - OO Ü oi Ch 'H KV S ΝΛ in: I CM CM * CM CM - {® i KW; W' wi <fe;: co ί "ή · ^ i

ί B "Hi * Η · Η H

(S. O n C3 O O I

........ r ...................! ................... i. ........ ..... I ............. “I

I. I ί I j

8 0 Ö Ö 3 4 5 -1 —--- ~ L— ~ —.—----— j - - ——I

I I Μ ί

Jo I ® H I P! i * ^ ^, 5 J ί j PM j Ph> j μ ί --— L_-J ———— i ----— X .----—--. 4 * 19 ", - -Γ I j * 'I': * I 5 3 Jsj t._ ^ * i SI ί l £!. * -Ί t -.

«U Ϊ W 1 l 5 ί:; &] -; -, <I O l 1 É4: a ί g ..... · 0 ·: O! fxj '^ J .. e *: ^ 5 ·.

si - 1-? 4-; i 1 * 1 i &;; fl i i ·· * -] VO VO; in -sj · Η ί cm in ί *>

____ H

ΓΤΊ; w j_1 I o 3 1 Ό Η ί • I + ί * 3- ----—-- i.

φ + => 1 η “1

<3 ElO '—v! S

s: s § £ r «: 54 [φ w J CO i

Pi ο ρ,? 4; : * H Ο A; ; H! i CD 4 * ------ j ---—--- * pi $ - CO g: i; +5 l; s -p i: - ίφ φ - Η · Ρ '' i 50 h «> 52 S ° 1 2 i OS S 2 o - w ί £ · Η CQ ft ^ 54 -tf. ί ·: Φ S3 * - 'i ~~~ —--- ί -------- 1 ......--> - · Η' Η 43 'fi -Ρ * 54 2 Λ OOOC ~ - | > CD a a a i h £; - w i O Φ i co * S tio CM; - - -. - ---- <i \ 't; ; * ί 1 ί ί 3 * ï ί 1 φ i ί 2 rH i Ο g 5 W> ί Ε; ; a 1; 54 Hi 0 ° j i «η ^

; J CM J

Φ j κ

Is ί ιη: ι pi: Η i ί # j ο j! j ~~ j 8ΟΟΟ345 cö> * r}

wrH

, “20 - - .. η .... ...--- .... - - - _ ______ ____

The compounds of formula 1 have been tested in vitro and have been shown to have properties as reversible inhibitors of porcine pancreatic elas and human white blood cells. The latter elastase was purified by the method of TRAVIS (BAUGH R * J TRAVIS Je, (1976, Biochemistry *, 15, 4, 836) 0 The research method used is the well-known method of DIXON (M. DIXON (1953) »Biochemical Journal, 55, 1970) for the determination of the inhibition constants K4 of the compounds of the invention with respect to hydrolysis reactions of succinyl-tri-L-10-alanine paranitroanilide, which are catalyzed by the two above-mentioned elastases (J0 BIETH, Be SPIESS, CeG0 WERMUTH, 1974, Biochemical Medecine, 11, 350) All determinations were made at 25 ° C in a 0.2 M buffer solution of tri-hydroxymethylaminomethane 1 with a pH of 80. Table E shows the results obtained with the compounds of formula 1 as well as with comparative compound '(A), acetyl-L-prolyl ~ L-alanyl ~ L ~ propyl-L-alaninal for elastase from! The pancreas (R »C« THOMPSON, Biochemistry, 1973 »12, 1, 47) and comparison compound (b), oleic acid, for elastase from white blood-20: bodies (B» M0 ASHE and M »ZIMMERMAN, 1977 »Bioch0 Biophys * Hes,: Comm0 75, 1974)«! i i j i 8000345

- 21-Table E

Research (a) (a) compound pancreatic elastase leucocytic elastase 5 (Μ) (M) 60 2.2, 10 "7 2. 10 ~ 6 61 4.5. 10" 7 2 «10'6 62 3 , 6, 10 "7 3.8 ♦ Hf6 10 63 3.5. 10 ~ 7 3 * 10 ~ 7 I 64 7 · ΙΟ" 8 1. 10 “6 I 65 1. 10 ~ 7 5. 10 ~ 7 «66 4.5 o 10" 8 1.8 β 10 ~ 5 • 67 1.5. 10 "7 4.5. 10-7 i5 ---------------------------------------------- ----------------------- A 8 10 ”7: B - $ * 10 ~ 6 '(a) Values obtained in the absence of any solvent i Furthermore, the toxicity of the compounds of the invention has been studied in mice by intravenous administration. More specifically, the compounds have been tested in the form of a solution in physiological serum with 10 DMF,

For example, no deaths have been observed when administering 20, 40 and 80 mg per kg of the compound, with code number 63,

Due to their pharmacological properties, the compounds according to the invention can be used in medicines, for example for the treatment of emphysema.

i 8000345

Claims (3)

Trifluoromethyl oligopeptides of the general formula 1 of the formula sheet, wherein Y is the group -L-Ala-, in which case (R, n) one of the meanings (isobutyl, 0), (cyclohexyl, 0), (fluorine, 0), 5 (1, R-diethylamino, 0) or (H, 1), or represents one of the groups -L-Pro - L-Phe-, -L-Val- or -L-Leu, in which case n * 0 and R represents the isopropyl group. 2. Trifluoromethyl oligopeptides of formula 1, wherein Y represented the group -Ala- 3 * Trifluoromethyl oligopeptide of formula 1, wherein Y represents the group -Ala- and (R, n) has the meaning (isobutyl, 0) 40 Trifluoromethyl-oligopeptide of formula 1, wherein Y represents the group -Ala- and (R, n) has the meaning (fluoro, 0), 5th Pharmacological composition, characterized in that it contains at least one compound as active ingredient one or more of claims 1-4. ; 6. A process for the preparation of compounds of the formula I, characterized in that compounds of the formula II of the formula sheet, in which Z represents the benzyloxycarbonyl group and the whole (Y, n, R), are one of the meanings ( Ala, 0, isobutyl), (Ala, 0,; cyclohexyl), (Ala-y 0, fluoro), (Ala, 0, ï, N ~ diethylamino), (Ala, 1, Η),: (pro, 0 , isopropyl), (Phe, 0, isopropyl), (Val, 0, isopropyl) or (Leu, 0, isopropyl), subject to hydrogenolysis. 7. Process for the preparation of compounds of formula 2 used in the process according to claim 6, characterized in that the compound of formula 3 of the formula sheet, in which Z has the same meaning as in formula 2, is condensed with compounds of formula 4 of the formula sheet, in which the whole (Y, n, R) has the same meanings as in formula 2. 8 Process for the preparation of compounds of the formula 4 used in the process according to claim 7, characterized in that the protecting group is removes from compounds of formula 7 wherein the whole (Y, n, R) has the same meaning as in formula 2 and B0C represents the t-butyloxycarbonyl group. 1000345 - 23- "· 9. Process for the preparation of compounds of formula II, characterized in that the compound of formula III of the formula sheet, in which Z represents the benzyloxycarbonyl group, is condensed with compounds of formula III of the formula sheet, in which (Sf, 5n) the has meanings (isobutyl, 0), (cyclohexyl, 0), (fluoro, 0), (1i, W * -diethylamino, 0) or (H, 1), and the compound of formula 10 of the formula sheet condenses with compounds of formula 13 of the formula sheet, wherein Z has the same meanings as in formula 12 and Y1 represents one of the groups Pro, Phe, Tal and Leu »10 10 * Process for the preparation of compounds of formulas 12 used in the process according to claim 9 and 13, characterized in that compounds of formula 14 of the formula sheet, wherein Z has the same meaning as in formula 2 and y represents one of the groups Ala, Pro, Phe, Tal or Leu, are condensed together. compound of formula 5 of the formula sheet »! 11o As an intermediate and produce the compounds of formulas 2, 4, 7, 12, 13 and 14 * i! J i i i 8000345