DE1443060A1 - Process for the preparation of derivatives of tetrahydronaphthylamine acylated with amino acids or peptides - Google Patents

Description

EICHTSR GEDEOH VegySszeti Gyar HT. Budapest X. Oserkesz utca 65

pJ.704413-8.USV ^HoTember1961

Yerfahren for the production of amino acids or
Peptides aqylated derivatives of 5? Etrah.ydronaphthylaEain3

It is known that 1,2,3,4-tetrahydronaphthyl oxide and some derivatives of this compound are physio-
logical effectiveness show «Bovet and coworkers (Rend. Ist» Sup * SaiL * Boiaa _t 1952). have produced various amino acid-like 'derivatives of 1,2,3,4-tetrahydronaphthylaiains' in such a way that they amidated halogenated aliphatic acid chlorides or tetrahydronephthylamine and then the halogejaatoÄ of the eMialten halogenated aliphatic
CarboxHaatiretetrahydronaphthy! Amide have exchanged with a dfealkylanabstitaerteii amino group;

- Alk - Hal

HH-C- Alk - Hal + HH It

^ Alky. 1 ^s Alkil

Alky 1

Bovet and his staff in this way, besides the dialkyl glycinamide derivative mainly! Etrahydronaphthy! Amides of β-amino acids produced dialkyl they} found "that these _f Y onnectivity as ζ · Β · E-IIethyl-E- tetrahydronaphthyl-1 ^ -r.thyl - / ^ - -alaninaniid show considerable oxytocic and sympathetic effects.

vTir have now found that the preferably ίΚ-amino acids "* s with optically active o ^ ~ amino acids with or composed of such amino acid peptide acylated derivatives of _2,5,4-t l Tetrahydronaphthylamins which correspond to the general j? I Ormel

H-O-CH-E O

Cl)

-. where E is hydrogen or a lower alkyl group, R ^ Eg and E ^ for identical or different substituents * and indeed for hydrogen atoms or for optionally substituted alkyl, aryl or aralkyl groups or heterocyclic groups Best stand "- but if R ^ is a hydrogen

- 3-809806 / 0 ^ 93

ORfG / N _AL

denotes atom, then one of Rp and R is also a hydrogen atom, where any of the substituents B · ,, R ₂ , R, can also form a heterocyclic ring together with the nitrogen atom; R «or R can also mean the acyl residue of a further, preferably optically active, amino acid or peptide - valuable pharmacological properties, and primarily have effects that excite or inhibit the central nervous system and inhibit the sympathetic nervous system Properties of the above compounds are therefore completely different from those of the compounds produced by Bqvet.

The new compounds of the general formula I can be prepared in this way for the purposes of the present invention that one can introduce the tetrahydronaphthylamine with a 'dQS amino acid acyl residue on the nitrogen atom converts suitable derivative of the desired amino acid, which does not participate in the desired reaction Amino groups of the reacting amino acid or peptide derivative temporarily through the generally customary peptide-chemical Methods are protected. This method can be carried out in various ways within the meaning of the present invention becoming

a) The tetrahydronaphthylamine is temporarily protected on the nitrogen atom with an amino acid halide implemented according to the following reaction formula:

BATH ORIGINAL

8 09806/0793

Ji ₁ Up

Γ Γ.

^ s. ^. HHj, + Hal - C - CH - II - X

ay

HH-C-CH-K-X

where X is any conventional, subsequently removable protective Group means.

b) The QJetrahydronaphthylamine is with a, am Nitrogen atom temporarily protected, optionally activated amino acid ester of the formula below

Rt Sp

, 1 _f 2

R'O 4C-CH-II-X

H ■ ■■ O

where R * is an alkyl radical Group means activated alkyl or aryl radical, brought into reaction

c) The tetrahydronaphthylamine is with one after mixed using the method of Boissonas or "Vaughan" Anhydride of the formula below

Rp R ₁ XH-CH-C

R »O - β

implemented

For the preparation of compounds of general formula I, in which the letrahyd'ronaphthylamine to the

- 4 809806/0793 - .., '. ^ - BATH "

Acyl residue of a dipeptide or polypeptide is bound _f those derivatives of the compounds mentioned under a), b) and c) can be used in which there are further amino acids or peptide residues in place of I} the amino acids not participating in the desired reaction or other groups must of course also in this case be protected by the usual methods, for example by the temporary Sinführong of carbobenzoxy or other suitable groups ·

Me synthesis of the new compounds of the allgeraänen formula I can each by other methods known in peptide chemistry ζ · Β · according to the well-known dicyclohexyl-earbo— diinid procedure. Äan can also proceed like this » that WUi you amino acid side chain of the compound produced of the general formula I with the use of methods customary in peptide chemistry for a dipeptide or Further builds up the polypeptide side chain

The various practical ways of performing the method according to the invention are illustrated in more detail by the following examples; but it is to be noted äass in these examples, only a few characteristic cases of application amp methods mentioned above are given, so that the charging is limited to these examples "

example 1

2.25 β (@ _t 01 M) H-carbobenzoxy-L-C +) - alanine (Sohnp · 84-85 ° ö) are ± ä 25 ml abs. Dissolved tetrahydrofuran and this solution apply at -25 ⁰ O with constant stirring

- 5 -, BATH

[ .808806 / 0793

drop by drop l, lg ζ0.01 II) irlethylanine, and then 1.9 g Co, 1 Ll) carbonic acid ethyl ester added. 27ach for 15 minutes R ^ 'iiren the resulting mixed anhydride with from 1.4 to 7 g Co »1 Ll) 2etraiiydro-2-naphth.ylaoin at -20 ⁰ G dropwise · Bas reaction mixture is 10 minutes" at -10 ° G , then 20 IHnuten at ⁰ G tind · stirred at .Zimmertemperatur 30 minutes and then the solvent is distilled off in Yakuum and the residue dissolved in 50 ml ethyl acetate, the solution in the order indicated with 30 ml of water, twice with 10 ml 5 Aqueous sodium hydrogen carbonate solution, washed twice with 10 ml of 2 H hydrochloric acid each time and finally again with 30 ml of water and then the organic solution is dried over sodium sulfate, the solvent is removed and the residue is recrystallized from aqueous ethanol or dioxane 2.80 g of 1-Cbo-L-C-fOalanyl-tetrahydronaphthylamine f5 of the theory of Gbo «cirbobenzoxy) are obtained in this way, melting point G, SU f −5t74 °.

^{Summenfonaals C} 21 ^H 24 ^H 2% ^ ¹ 552,42) j, analysis: beröciineti C TL _f & ß% H 6, ^ j M 7 »9gS found: 0 71» 6 ^ i H 6 _r 8 ^ | IT l _t & ß *

2 »0g C5.7 mß) K-Gbo-L-C +) - Alanyl-tetrahydronaphthylamine are dissolved in 5 ml of 50% bisacetic / hydrobromic acid solution at room temperature with repeated shaking over dissolved »then treated with 50 ml of absolute ether« The precipitated Hydrobromide is washed with absolute ether, then off Recrystallized alcohol / ether 1.36 g of 3fc ~ C5) - · -Alanyl · tetrahydronaphthylamine - hydrobromide

. "βΟ9.β06 / <Γ7% 3 · -.-

τ-

obtained, m.p. 183 ⁰ O. Sum nforms I: O ₁₃ H ₁₉ IT ₂ OBr (Μ: 299.2). Analysis:

calculated: G $ 52.2; H 6.4 ^} K 9 _f 3 #; 3r $ 26.7 found: 0.52.1 ^ »H 6.6 * $ E 9.2 $} Br 26.8 ~ $

Example 2

2.24 g (0.01 M) phthalyl glycyl chloride (melting point 83-85 ° ö) and 1.1 g (0.01 l) abs. Triethylamine are abs in 20 ml. Dioxane is dissolved. The solution is added ^{dropwise at −10 0} G with 1.47 g (0.01 Ii) of abs. Te trahydronaphthylamine added. The mixture is left to stand overnight at room temperature, then the triethylamine hydrochloride and the solvent are removed by shaking with water. The residue is dissolved in 100 ml of hot ethyl acetate and the solution is extracted twice with 10 ml of water each time. The solvent is then distilled off and the residue is crystallized from ethanol. 3.30 g of li-phthalyl-glycyl-tetrahydronaphthylamine (£ 99 of theory) are obtained. M.p. 228 ⁰ O.

3.30 g (0.01 H) K-phthalyl-glycyl-tetrahdronaphthylmain are in 30 ml of abs. Suspended ethanol and mixed with 10 ml of 1 M alcoholic hydrazine hydrate solution, then the mixture is heated to boiling under reflux for one hour, then freed from the solvent in vacuo. The residue is treated with 25 ml of 2 Ii Bromhydrogensäure and heated for 10 minutes at 50 ⁰ G, then allowed to cool slowly to room temperature. The phthalylhydrazide is filtered off, the piltrate is evaporated to dryness in yakuum '""

BATH ORIGINAL

8 09806/0793

and the residue crystallized from alcohol / ether · crystallized are 2.54 g eiyeyl-Tetrahydronaphthylaöin-hydrobroraid (89 i * of theory). Sehmp. 225 ° G. Suiaiaen formula: G ₁₂ H ₁₇ H ₂ OBr (SI: 283.2). Analysis:
feerecalated: 0 50, "^} H $ 6.0; IT 9.8 ^ 5 Br 28.0ji found: 0 50.7f £? H 6, l $ y M 9.7 ^ i Br 28.2? S .

Example 5

1 * 47 g Co, Ol m) Tetr ^ hydronaphthylamine are in 20 ml abs, ethanol dissolved, then with 4.2 g (0.01 m) H-Gbo-L-phenyl-alanine-p-nitrophenyl ester (Schm 126.5 ° c) added and left to stand for one hour at room temperature. The crystalline Hasse obtained is dissolved in 50 ml

Dissolved ethyl acetate, then washed with 2χΪ0 ml of water, - 2x20 ml of 2 Ή hydrochloric acid and then several times with 30 ml of 1 HH.OH solution each time until the characteristic yellow color of the p-bitrophenol disappears from the aqueous phase. The organic phase is then washed with water to a neutral reaction, dried over sodium sulfate and the ethyl acetate is distilled off in vacuo. The residue is recrystallized from aqueous ethanol. J.07 g of K-Gbo-Ir-phenylalanyl-tetrahydronaphthylamine C95 | 6 a) are obtained. M.p. *. 120-122 ⁰ G · ^{Molecular formula: C} 27 ^H 28 ^Ji 2 ⁰ 3 (Mi 328V5), ßO | 9 «+ 7.2 ° * Analysis calculated: G 75 _f 7 ^} H 6.6 # f H 6
found: C 75.6 ^} H 6.7 ^ 1 H 6

Removal of the protective group *

a) 1.15 g (2.7 mlO of the above protected compound ■ . - 8th ** - . -

809806/0793 BAD original

are in 20 ml of abs. Dissolve ethanol, decompose with 0.32 ml of concentrated hydrochloric acid and then, after adding 1 g of 10% palladium-active-pole catalyst, hydrogen is passed through the solution for one hour. After filtering off the Kstalisators the solvent in vacuo at 50 ° C is distilled off $ ea is a white crystalline product obtained * The amount of the after recrystallization from AlkohoVAether also containing L-phenylalanyl-tetrahydronaphthyl ^ Aeaea hydrochloride is 0.85 g (95.5 ^ d.Th.) mp, 131 ° C.

b) The protective group can also be removed with the aid of bromohydrogenic acid dissolved in glacial acetic acid, as described in Example 1. In this way the L-phenylalaryl-tetrahydronaphthylamine-hydrobromide is obtained with a yield of 80 %. M.p. 155 ° E , λ7 | ° »+ 62.0 °.

^ ^Ki 375,3) · Analysis:

bereehnats Ö 60, ^ Sj H 6.2 ^} I 7.5 ^ 5 Br found: 0. 60.6? δ | H 6.356; H 7.7 # $ Br 21.7 ^ ·

Example 4

2.50 g (0.01 Μ) Ιϊ-Cbo-L-proline (melting point 77 ° C) are dissolved in 25 ml of fetrahydrofuran and the solution at -15 ⁰ C with 1.1 g (0.01 If) abs . Triethylamine, then with 1.09 g of Co ₉ Ol Η) chlorocarbonic acid ethyl ester dropwise, rereetzt under tubes. The mixture is stirred for a further 15 minutes, then the mixed anhydride formed is mixed with 1.59 g CO> 1 JU Äetbyl-tetrahydronaphthylamine drop entry st. Bs is then worked on as in Example 1 and eo J _t 35 β-Cibo-Ir-Prolyl-H-methyl-tetrahydronaphthyl-Äla Cs ^ 4.BiJ are obtained. Sohmp. 125 ° C. Molecular formula:

_{ßAD 0R {G} , _NAL

₅ ClI: 392, '5>. Analysis:
calculated: C 73.44 £; H 7.19f »l I 7» Η ^ ί found: G 73.54 $? H 7.16? 5j Έ 7.5O? S.

In the usual way of splitting off the protective group, L-prolyl-H-methyl-tetrahyronaph / ethyl amine hydrochloride is obtained in 90% yield; M.p. 175 ^P C; Molecular formula: C ₁₆ H ₂₃ Ii ₂ OGl (M: 294.8).

Example 5

3.15 g Co, 01 m) Ep-Gl-Gbo-L-glutamine CSchmp.114-116 ⁰ C) in 50 ml abs. Dissolved tetrahydrofuran, 1.47 g (0.01 m) (detrahydronaphthylamine) are added, the solution is then ^{cooled to 0} ° C. and 2.6 g of Co, Ol H) bicyclohexylcarbodiimide are added. The homogeneous solution begins to become cloudy after a few minutes. The solution is left to stand at room temperature over power, then after filtering off the precipitated cyclohexyl carbodiimide (2.2 g, melting point 230 c) it is mixed with 50 ml of ethyl acetate, then with 2 × 30 ml of water, 3 × 10 ml of 5% sodium hydrogen carbonate solution , 3x10 ml 2% hydrochloric acid and 2 * 10 ml water (in the order given) shaken out. The organic is then dried over sodium sulfate and that

Solvent in Takuura distilled off at 50 ⁰ C. The residue is crystallized from aqueous ethanol. 4 g of ir-p-Cl-Gbo-L-omutaminyl-tetrahydronaphthylamine of the 20th century: Analysis:

- Io -

BATH ORIGINAL

809806/0793

calculated: C 62.2 <£ | H 5.9: *} Ii 9.5 ^} Gl 8, C $ j found: O 62.2- ^} H 6, CiSj H 9 »7 ^ f 01 8.0 $.

1.0 g (2.3 μl) of the above protected compound are treated as described in Example 1 with 5 ml of 50% hydrogen bromide acid dissolved in glacial acetic acid. The product obtained is crystallized from a mixture of alcohol and ether 0.70 g of LG-lutaminyl-tetrahydronaphthylamine-hydrobromide (85 # of theory) were obtained. Sehmp. 192 ~ 194- ° C Sxunm formula: C ₁₁ -H ₂₂ ^ ⁰ P- ⁸¹ '^ ^{Ms 2} 56.5). Analysis: Calculated C 50.6fSj H 6.2 ^ j H 11.8; $} Br 22.55 ^ 5 found: C 50.8? 5j H 6.3? '} H 11 · 4 / δ} Br 22.5 $ ·

Example 6

3.06 g (θ, 01 M) K-Gbo ~ L-prolyl ~ glyein are in 25 ml abs. Of tetrahydrofuran! And the solution at -2O ⁰ G under Eührent ropfenweise with 1.01 g (o, Ol IU abs. Triethylamine, then 1.09 g Co, Ol m) sets Chlorkohlensäureäthylester comparable. The mixture is stirred for a further 15 minutes and then the mixed anhydride formed is added dropwise to the mixed anhydride, also with stirring at -20 ° C., with 1.47 g of Co, Ol M> letrahyaronaphthylamine. In the following, the procedure is as described in Example 1, after recrystallization of the crude product obtained from aqueous methanol, 3.0 g of li-Cbo-Ir-prolyl-glycil-tetrahydronaphthylamine (69 $ of theory) are obtained. Mp · 128-130 ⁰ C. Suomen formula: C _ot -H _on &, 0- (Ms 435 »5) · Analysis:

Calculated: C $ 68.9} H $ 6.7} Ii
found: C 68.8 #} H 6.8? S} H 9.7 ^ ·

"* ^{1: L} -. BAD ORIGINAL

S09806 / 0793

The protective group is split off as described in Example 3 under a). From 1.75 g (4 ιπμ) protected compound is isolated after recrystallization from a mixture of alcohol and ether, 1.30 g of L-prolyl-glycil tetrahydronaphthylamin ~ hydrobroinid (96.5 $ »d.Tiu) · Sehmp obtained. 143-146 ⁰ C, empirical formula: C

i 337.8). Analyzes
calculated: 0 60.4 ^ j H 7.2 ^; H 12.4 # | Cl 10.5? Sj found: C 60.2 ^ j H 7.2? Sj H 12 * 2 ^} 01 10.6 $ ·

BATH. ORiQfNAL

- 12 -

809806/0793

Claims (1)

PATBlil CLAIMS: 1 · Process for the production of new derivatives of tetrahydro acylated with amino acids or * peptides naphthylamines of the formula I. ? 1? 2 Cl) where S is hydrogen or a lower alkyl group, Β · «, Βλι Ε« iur identical or different substituents, namely for hydrogen atoms or for optionally substituted alkyl, aryl or aryl groups or heterocyclic groups, but if B ^ means a hydrogen atom, then one of B « " onä. B _{5 is} also a hydrogen atom, where any two of the subs tu tue nt en B ^, Bu and B, together bits of the nitrogen atom can also form a heterocyclic ring, Bg or B ^ can also mean the acyl residue of a further, preferably optically active, amino acid or a peptide, characterized in that 1,2,3,4- ethrahydro-2-naphthylamine is combined with an amino acid -acyl radical reacts to the nitrogen atom suitable compound, with the usual temporary header protection of the Aiaino or other groups not participating in the reaction, 2 · Terfahren according to claim 1, characterized in, that sen tetrahydronaphthylamine with one, on the amino group Protected ABinosurehalogenid of Pormel II - 13 809806/0793 A R ₁ R ₂ ■ Hal -C-CH-H-X Cll) where R-j and R «have the above meanings, Hal is a halogen atom and X either one of the above definition of R, corresponding Group or (if R ^ = H) one which can be split off afterwards protecting group, e.g. a carbobenzoxy group, means, implements 5. The method according to claim 1, characterized in that that 2etrahydronaphthylamine with one on the amino group «Protected amino acid esters of the formula III S ₁ Ro
J ¹ I ² r »o -σ- CH -H-x Cm) Ii where R ^, R «and X have the above meaning and R 'is a Alkyl group or one through an electron withdrawing group Group activated remainder means, implements. 4. The method according to claim 1, characterized in that that you can letrahydronaphthylamine with a mixed anhydride the! Formula IV R ₉ R ₁ O
I ² I ¹ J- X-U-CH-C ^ o civ) R'O - C " wherein R ^, Rg, R 'and X have the above meaning, converts. 5. The method according to claim 1, for the preparation of a dipeptide or polypeptide side chain containing -U- BATH ORIGINAL 809806/0793 45 Compounds of the formula I _f, characterized in that the amino acid side chain of the compounds of the formula I obtained is extended with further amino acid groups by using methods customary in peptide chemistry. ~ · '- ■ {> V ferries according to claim 1 to 5 »characterized in that one reactive derivatives of optically
applies active amino acids or peptides to the reactions » Vl- -. -15 BAD OFUGiN ^AL 809806/0793