JPS5993079A - Manufacture of vincaminic acid ester - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides racemized or optically active vincamic acid esters of the general formula () (wherein R is 01-4 alkyl group) and its pharmaceutically acceptable esters. It relates to the method for producing acidic acid paste by IT et al.

It has been reported that vincamic acid esters and apovincamic acid esters of the order Apovincamic acid have useful activities as medicines. Among vincamic acid esters, %VC methyl ester (vincamine) is particularly important as a vasodilator.

It has been found that general E (II) (7) vincamic acid ester can be produced by a simple method with low yield. That is, racemized or optically active 14-oxo-15-hydroxyimino-3 (χ) of formula % lo-N C2H5.

17α-E-homoeburnan is racemized with alcohol of general formula R1-OH or optically active general formula (11)
When preparing the vincamic acid ester of
The reaction was carried out at a temperature of 0° C. for 5 to 10 minutes, and the resulting new racemized or hydroxyamino compound of the general formula (IV) 2H5 (wherein R1 is as defined above) The nanometer conductor is treated and the mixture of the racemized or optically active apovincamic acid ester of the general formula (1) and the vincamic acid ester of the general formula (■) obtained is separated and optionally the obtained The apovincamic acid Nisder of the general formula (1) or the vincamic acid ester of the general formula (11) is re-Nysderized, and then, if desired, the racemized or optically active vincamic acid of the general formula (II) is formed. The ester can be converted into an acid compound that can be used as a drug and/or can be converted into a racemized or optically active vincamic acid ester (general formula (
11) Divide ).

The racemization or optically active starting material of formula (Ill) is a compound of formula (Vl in which R2 is cl-4 argyl and X- is an acid anion) or an acid addition thereof. A pigeon,
, i, (original, and i4 et al.) j, and racemization or C optics 11j/1 T i+2 general formula of D cis and/
or trans compounds: C2-15 (where T is as defined above) or 1, optionally without separation of the acid salt, or fractional crystallization and
・／After dividing ζ・, treat with alkaline agent,
And I↓Ira no 1. Racemization or t'' of the formula (Vll)2H5 is produced by fractional crystallization and/or resolution of an optically active cis and/or trans compound optionally with a nitrosating agent, followed by reaction.

If the reaction between the compound of the formula R and the alcohol of the general formula R is carried out in a base, a new compound of the general formula ROH will be produced. Cow/jk with alcohol and alkali metals such as sodium
It is possible to use alcoholates.

If the compound of general formula (goods) can be treated with red aqueous acid, then 7
0ζ1Li=, -j vincamic acid nisful has the general formula (
1) Nisdel apovincamate is used as the main product. Compounds of general formulas (1) and (11) are separated into Jj by crystallization.

If vincamic acid ester and apovincamic acid ester having different alkyl groups must be prepared, for example, if vincamic acid ester and apovincamic acid ethyl ester have to be prepared simultaneously, the suitable ester is After crystal separation, the ester can be converted into a 4M ester by re-Nysderization. This re-esterification can be carried out by known methods, and by one such method the re-esterification (1
′ compound to the ester to be introduced into this molecule↓1・6
, heated in the presence of an acid with an alcohol. Acids may include any residual or organic acids such as sulfuric acid, P-
Toluenesulfonic acid etc. can be used.

Therefore, the intermediate product (IV) is prepared by subjecting the reaction to 1 to 20 molar equivalents of acid, preferably 6 to 10 molar equivalents, under very mild conditions at 60 to 80°C for about 5 to 1 minute. Although it can be obtained by carrying out the reaction under suitable conditions, it can be converted to the compound of general formula (1) by using a large amount of acid, applying a high sieving temperature, or reacting for a long time.

The compound of the general formula (II) can be converted into a medical compound by adding a suitable acid. Hydrochloric acid J'l'
lll, Bromine-2 Mausoleum, etc., Lin January edition; Rhodan acid place,
sulfate, I1Ife acid hydroxide J, 4A, 7M
+47. Succinate, maleate, nitrate [\outer surface, salicylic acid, ammonium 2u, rzeic acid j11, zolobimen 19) expander salt, sulfonate, etc. can be generated.

According to the method of the present invention 1. :l, both racemized and optically active compounds of general formula (II) can be prepared. In the process of synthesis! (If the compound of the general formula (VD) is optically active, then the target Dy product of the general formula (11) is also optically active.On the other hand, if the compound of the general formula (VD) is racemic, then r1-μm: The compound is also racemic. If desired, the racemic compound of general formula (n) can be resolved.

The undiscovered, undiscovered manufacturing method can be explained using examples i and V below. However, these examples do not limit the scope of the invention.

Diameter i; II l a) 1-(2'-methoxycarbonylethyl)-1
-ethyl-1,2,3,4,6,7-hexahy10-1
2■]-in'dro[2,3-a]-quinolinonium-
Chloride 27. Og (72,0 mmol) was dissolved in methanol 300 rn13 and mixed with charcoal]~palladium l (1,!i') in water under 111 stones. The consumption of the theoretical amount of hydrogen was completed in 5 hours. .This catalyst-(,
- Then filter, wash with methanol, and then evaporate this P solution in the same air. This residue was dissolved in water at 20°m, and an aqueous solution of sodium carbonate was added to bring the solution to +1
It was made alkaline to 8-9 and extracted several times with dichloromethane. The dichloromethane extract was dried over magnesium sulfate and the solution was evaporated off in JLζυ. This residue (250,9) was mixed with 3 od of methanol.
], 9.0, V(775) to precipitate a mixture of aqueous isomers.

In this way, IL was recrystallized from 9.0 g of Ise (mixture of the two in methanol J707) + l.

,7. (1 g (285%) of 1β-(2'-me[ginecarbonyl-ethyl)-1α-ethyl-1,2,3,4
,6,7,12,121>α-mectahide+1 indolo[2,3-a) quino-11-sine precipitated uk. ＃＋! I!
A: 142-143°C Evaporate this solution and obtain a mixture of nnu-trans isomers containing many cis-isomers9. og(367) may be crystallized and this mixture may also be subsequently ring-closed.

h) As shown in Reference Example 18, H1■ (~1β-
(2'-methoxycarbonyl-ethyl)-1α-ethyl-7,2,3,4,6,7,12,12bα-octahydro-471 (2,3-a) quinolino 77, (l g
(20 mmol) of 50% hydrogen, suspension 1
The mixture was boiled in 360 ml of anhydrous toluene for 12 hours with constant bubbling in the presence of nitrogen atmosphere. After cooling, the mixture with
Extracted with yd three times. The acid layer was diluted with ice ('::-1・(S>Ammonium hydroxide 4-?# was added to P11=
9 and extracted the alkaline solution several times with dichloromethane. The combined bath liquors were dried over magnesium fiffiate, filtered, and the liquors were evaporated to dryness in vacuo. This residue is crystallized under methanol and thus has a melting point of 165-1 (i
The target compound was obtained at 7° C. in the form of white crystals (literature melting point: 164° C., recrystallized from ether, see Hungarian Patent No. 14163769).

Yield": 5.0 g (79 parts) IR spectrum (KBr): 1690 (M'amide-CO) C) Introductory Example 1 a) Ic Therefore, a mixture of cis-trans esters of 9.0 I Anhydrous toluene 46 (l m
1 in accordance with Example 1b). (I) By processing the 116 compound obtained, 14-Kagiso 3α, 1F α-E
- Homoieburnan and 14-oxo-3β, 17α-E
- the isomer mixture with Pomoieburnan, beef h′y, l
,, then convert this into nochloromethanezome and cony-
Full 3 Q N crystals were prepared from a mixture of m and l. Thus 45 g (55%) of 14-oxo-3α,j7(χ-
Obtain E-homoe burnan.

Overall yield relative to starting immonium salt is 42.8%
Met. The total weight of 14-oxo-3α, 17α-E-homoepurnan was 95 I/0 iiVli point: 105-167°C (circular crystals from methanol) Reference example 2 l-(2'-meth)gicicarbonyl ethyl )-1-ethyl-1,2,3,4,6,7-hexhydride l-1-12
H-yne Fo[2,3-a:]quinolidinium chloride 42 g (11.2 mmol) with total charcoal? Hydrogenation was carried out in 400 ml of water in the presence of 20 g of radium catalyst. Theoretically, the consumption of hydrogen at Tsuge was 311 photons between 〒. Is this catalyst filtered and washed twice with water? The resulting furnace solution was made alkaline (pH=9) by adding a 5% aqueous solution of 11% sodium carbonate, and extracted three times with dichloromethane. The monolayer was dried, the solvent was removed, and 39 g of di-14-oxo-3α, 17α
-E-homoeburnan and de-14-oxo-3β
The residual mixture consisting of +17a-E-homoeburnan was dissolved in anhydrous toluene 2 (l Oml) as described in Example 1b).
The mixture was heated in the presence of a suspension of 06 g of IJium.

This reaction mixture was treated as described in Example 1h) and thus 1.5&(43.4%) of de-14-ogiso-3α
, 17 (χ-E-homeburnan).

M (point: 165 1 (37℃ (from methanol) light example 3 Charcoal Chimochi, P In the presence of radium 3μ, ethanol 360
In m1, 1-(2'-ethoxycarbonyl-
ethyl)-1-ethyl-1,2,3,4.

6.7-hegizahydro-12H-indolo[2,3-a
] Quinolinium chloride 7.0. ? (18 mmol) was hydrogenated. i￥1' of hydrogen was consumed in about 13 hours, after which the catalyst was filtered and washed with ethanol,
This p solution was evaporated to dryness in vacuo. Add this residue to 200 ml of water.
m+, l! The solution was made alkaline with a 5% ditrium carbonate water bath and extracted several times with nochloromecun. This 'M' 1811i (IiIj IV
Dry over magnesium, evaporate the solution to dryness, and dilute the isomer mixture with 10 d to 7 d of ethanol.
TJ crystallized.

3.7. ! i' (57%) de-1β-(2'-, Z
Toxic d-2-ethyl)-1α-ethyl-1,2
゜3.4. fi, 7,12,12bα-octahydro-
Indolo[2,3-a:]ginori gin was precipitated.

(;''(1 (point -136-138°C (recrystallized from ethanol) IR spectrum (KBr): 3400 (indole N+ (), 1730 (-m-' (Co2C2H,,)
NMR spectrum (cDcz3): δ=8.
12 ppm LH.

S (indole-1gH), 7.48-6.99 (4H
.

m1 Niji'j group proton, 4.00 (2IT,
J=7.3(!P!l, C00CH2CH,,),
1.27-1. (14(6H, 2t.

J-7,3cps, C00CH2CI■s and C11
Molecular weight for 2C1 (,) C22113oN202 = 354.48 words 1 calculated value: C74, 53 H8
，! '13% N7.90 coefficient Actual measurement value: C74.5 (Relationship H8.47chi N7.69 coefficient If left unattended, (1,60
& (9th) 1β-(2'-ethoxycarbonyl-ethyl)-1α-ethyl-1,2,3,4,6,7,12,
12bβ-octahytone loindro[2,3-a]-
Quinolidine precipitated from the mother liquor.

1 point: 105-107℃ (from ethanol to 111
Crystal) IR wave vector Kllr): 332 (1(indole-NH), 17], 2 crn-' (C
O2C2H5,) NMR Su-! ! Ril-Ruru (CDC73
) 'δ = 8.78 ppm: (L H, s, indole-NH), 7.46-6.90 (4H + m +
iy aromatic proton, 4.16 (21-1, d.

J-7,3cps, C00C■-1zcHs),
133 (3+1, t, J=7.3cps+CH2
C! I3), 0.66 (3H, t, J=7.3cps
, C00CI(2CH,) Analysis of C22■l3oN20 Bimolecular Kunji 543
．． 48th correction trowel value: C74, 53φ H853no N 7.
9 (Actual measurement value for l ratio: C74, 12 ratio H844 ratio N7
Section 72” - 3, 7 & (1,0,
4 mmol) of de-1β-(2'--I-toxicyl-ethyl)-1α-ethyl-1,2,3,4,
6, 7, 1, 2.

12ba~octahydro-indolo[:2,3-a]quinolizine was prepared as described in the previous flj.
The ring was closed in 70ml. This reaction produces the target product 24
F (745chi) was generated.

Lushin point: 165-167℃ (from methanol) Reference example
4 6.0 & (15.4 mmol) of 1-(2
'Etoki/Kal,'? Nyl-ethyl)-1-ethyl-1
, 2,3,4,6,7-hekilahydro-12I(-indolo[2,3-all-sonodinium chloride 1'') was hydrogenated. A total of a state of hydrogen was consumed in about 2 hours, and then the catalyst The Fi solution was filtered to form water θ.A 5-alkali thorium carbonate aqueous solution was added to this Fi solution to obtain a monoalkali Igi (p
The phase was dried over magnesium sulfate and extracted with dichloromethane several times.
If this solvent is removed, the isomer mixture 5.5J9 is hydrogenated +1 um! 7+Th suspension 0
8! ? The ring was closed as described in the previous example in anhydrous toluene 25 Q m,l= in the presence of . The resulting isomer mixture is recrystallized from a mixture of dichloromethane and ether or methanol, and thus 2
．． 9. ! I asked 9 (person in charge 61) what he was trying to accomplish.

Melting point: 165-167°C (11 crystals from methanol) Reference example 5.8, r (18.8 mmol) of de-1,4-okino 3 (1-17α-
E-pomoie burnan was suspended. In this suspension, te
rt-7'thia + z = Potassium tert-butylene in 40 ml of anhydrous toluene with addition of 12 rnl of toluene)
A suspension of 4.0.9 (35,461.1 mol) was added to this mixture under nitrogen atmosphere and with constant stirring. This t', -; IT was continued for I n+jr at home temperature. A homogeneous solution was produced.

This reaction was analyzed by layer chromatography (KO-G-benzene:methanol=14:3, the Rf-value of the starting material, l
After the completion of this reaction, the reaction mixture obtained was
The mixture was shaken with 150 ml of water containing 12,9, and the aqueous layer was extracted twice with 30 ml of toluene. The combined toluene layer was dried over magnesium sulfate, filtered, and the solution was concentrated in air to 10 ml. The precipitated oxime was washed with filter and cold toluene.

Yield: 4.4g (69%) 1.1su (Imaginary: 258℃ (M111 point in literature ゛260
℃, Yield, Section 60 (Bunkerie Cattle R Edition No. 163769
)) I It spec # ([3r) : 32 (10(
OH).

17 (15 (lactam Co), 1640 (ML-
"(C=N)Example 40 ml of anhydrous methanol in the presence of 1..17.9 (21.6 mmol) of sodium methylate under anhydrous Φ conditions
Specifically, de-14-oxo-15-hydroxyimino-3α,17 (3,219.5 mmol of χ-E-homoeburunane) prepared as in Reference Example 5 was heated for 1 hour. After cooling, the sodium methylate was decomposed with acetic acid and the solution was evaporated to dryness in vacuo. 30 m of water (!) were added to the residue, the pl I was slowly adjusted to 8 by addition of 1=1 aqueous ammonium hydroxide solution, and the alkaline solution was extracted three times with dichloromethane. The organic phase was dried and , and the furnace liquor was evaporated, and the residue was crystallized from 20 rnl of methanol.

Yield 4i゛: Target compound 2.42.9 (69%) Ai! I
Point i: 179°C (methanol) IH7, vector: (
KBr): 3420 (Nl, OH).

1710 sure (CO2CH3) NMR spectrum (CDCl2): δ=8 (15ppm
(1 ton (, NH), 7.6-7.0 (4H, m, aromatic foton) 3.5 (3H, 9, C02CH3), 1
．． 1 (3H,t, Cr12C113) mass spectrum: m/e 70 eVM+= 3692〇21'
Analysis of 27N303 molecular weight = 369.44 Total Q, value: C68,27% N7.36chi N11.3
Actual measurement value for B ratio: C68, 58 ratio N729 ratio N11.2
The Rf-value of this starting material is equal to the Rf (1
<G-G s, benzene-methanol-1,4,3).

Example 2 dl-14-oxo- produced as described in Reference Example 5
15-hydroxyimino-3α, 17α-E-pomoieburnan 0.5. ? (1.5 mmol) of sodium methylate was heated in 20 ml of absolute ethanol under anhydrous conditions. Digested with 51ω excess of sodium ethylene 11'r[ and the solvent was removed in vacuo. 20 ml of water was added to the residue, and the mixture was then slowly added with a 1:1 dilute aqueous ammonium hydroxide solution to make it alkaline (pH=8), and the alkaline solution was extracted several times with dichloromethane. . The combined organic layers were dried over magnesium sulfate, filtered, the solution was evaporated to dryness, and the residue was recrystallized from ethanol.

Yield: 0.28 g (49, 3rd grade) of dual-purpose product Melting point: 15
6-158℃ (from ethanol)
'3r): 3400 (NH,0Il).

170()(X-1(CO2C2H5) NMR exposure (cpcz5): δ=8.3 ppm (IH.

NH), 4.0 (2H, q, J = 7.3
cps, CJX)OCH2CH3).

1.18 (3H, t, J=7.3cps, C00CIT
2C1(,).

1.18 (3H, t, J=7.3 cplICo
oC■T2CI+3) Analysis of C22H29N303; Molecule ¥=31'l: 347 words [1-value: Cf18
．． 90 Chi T (7,62 Section N], 0.!+ 5
% Actual value: C68,69chi N7.45chi N10.
! Example 3 de-vincamine and de-apovincamine dg-14-methoxy-carbonyl-14-hydroxyamino-3α,16α-eburnan prepared as in Example 1 R, 14 0.44 & (1 ,,1,9 mmol) in 1.6 ml of ice f11'acid with gentle heating.
:', r7J, and add 5-thiosulfuric acid aqueous solution 16me to this solution.
was added and the solution was heated on a water bath for 2 hours.

The mixture was made alkaline by adding concentrated aqueous ammonium hydroxide solution while cooling with water, and the resulting alkaline solution was extracted three times with dichloromethane. The combined organic solutions were dried over magnesium sulfate and filtered, and the solvent was removed from the solution by evaporation in vacuo.

To the residue containing di-vincamine, de-apovincamine and starting materials were added 15 ml of anhydrous methanol and 90S of thorium methylate. This starting hydroxyamino compound remained in solution. The precipitated pure de-hynchamine was filtered off and washed with methanol.

Melting: cte-H:y-camine o, 18 g (42%) Melting point: 234°C (chlorobenzene) The mass spectra and IR spectra of the product with dl-vincamine produced according to Hanga IJ-Patent Specification No. 163143 The spectrum was identical to that of

A solution of sulfuric acid in methanol (37 ml of methanol and 1.3 ml of concentrated sulfuric acid
e) Add 11 ml and add 111 ml of this solution! ? Heat for half a minute. This mixture was then poured into ice water, made alkaline with concentrated aqueous ammonium hydroxide solution, and dichloro[
Extracted several times with 1 methane. The combined solutions were dried over magnesium sulfate, the filtrate was evaporated and the residue was crystallized from 2 ml of methanol.

Yield: 013 g (32 g) This product is d1! as described in Example 8. - with apovincamine,
All % + Science and Chemistry Q1 "In the sign -i!lL
l'c.

Reference Example 6 In the presence of 1.8 g of IJium suspension (50% hydrogen),
In 450 ml of anhydrous toluene, with constant stirring (7 J),
9.8.9 (28.8 mmol) of 2α-mectahydroindolo[2,3-a)-quinolizine was heated for 5 hours. After cooling, this solution was diluted with 120 m/! of a 25% sulfuric acid aqueous solution.
The aqueous layer was made alkaline (pH=9) under cooling by addition of concentrated aqueous ammonium hydroxide solution and the solution was extracted several times with dichloromethane.

The extract was dried with magnesium sulfate, the solution was removed from the solution, and the remaining solution was crystallized from methanol.

Yield: 5.3 & (fio), melting point 152-154℃ (
minj1ja) [α]ゎ=+32.5° (cxx2
ct2. c2135) Consideration Example 7 (1,4-oxo-15-hydroxyimino-anhydrous toluene 12me and tert-butylnitrile fiv
4.8 me (,+-)-14-oxo-3α
, 16α-E-homoeburnan 2.10. ! i'(6
, 8 mmol) and this suspension in 12 ml of anhydrous toluene! 1fti/i5 sazetapu J
Liumium tert-butyrate 1.53 g (13,1 mm I
J mol) was added under an atmosphere of distillate with constant stirring. This mixture was stirred at room temperature for 1 hour, and then 80% water
Add 4.2 g of ammonium salt in ml, then add 15
Stir for 7 minutes. The toluene layer was separated and the aqueous phase was extracted twice with toluene. The combined toluene solutions (Ilfi: dried with magnesium oxide, filtered, and this ?) were evaporated to dryness in a Makabe dish. The remaining l* 1.9! i7 was dissolved in 8 ml of methanol, and the PII of this solution was adjusted to 5 by adding hydrochloric acid in methanol. The precipitated hydrochloride salt was filtered and washed with methanol.

Aphrodisiac: L] Lolate 1.4Q, ? (55%) in the state.

Melting point: 254-257°C (from methanol) IR spectrum (Kllr): 1730 (CO).

16357B-" (C=N), the hydrochloride of the target compound was dissolved in an aqueous solution of 1% sodium carbonate, and this solution was extracted with dichloromethane. The extract was dried. It was filtered, and the furnace liquid was evaporated to dryness.

[(Y].= + 61° (C= 1, C112C
t2) 14th revision applicant Ritter
L, day.

11, r ;'e'l Application Attorney ± 9 Ki Roben 3111 Toshiyuki Nishidate Patent Attorney Akira Yamaguchi Continued from page 1 @ Inventor Ienone Farkas Budapest, Hungary XXI Magyar Utsza 11 0 shots Author: András Nemes Budapest, Hungary II Hankosy Utzza 11 0 Inventor: Hedwig Bersky Budapest, Hungary Utsutua 7 Procedural amendment (method) % formula % 1988 1.11 Revision application to '5120150 No. 2
, Name of the invention Process for producing vinca ζ' acid ester 3, Supplement II--Relationship between the name and l=f'l Patent applicant 4, representative J11!
Person 5 Date of amendment order: January 29, 1980 (shipping date) 6. Document #1 to be amended 7. Engraving of the detailed description of the amendment (no change in content) 8. Attached engraving of catalog of kites 1 statement

Claims (1)

[Claims] 1) A racemized or) chemically active vincamic acid ester represented by the general formula (n) 2H5 (wherein nj is a cl-4 alkyl group) and a pharmaceutically acceptable vincamic acid ester. In producing those fβ Irikabou to obtain, a racemized or optically active hydroxyamino-eburnane derivative represented by the general formula ≦ C2I (5 (wherein R is as defined above)) is acidified. Then, if desired, the racemized or optically active vincamic acid ester represented by the general formula (It) can be used as a medicinal product.
The racemized vincamic acid nitride salt represented by the general formula (11) is converted into a salt that can be converted into a salt that can be converted into a salt thereof, and/or the obtained racemized Nisder vincamate is resolved. A method for producing acid esters or their acid salts which can be used as pharmaceuticals. 2 In producing racemized or optically active vincamic acid esters represented by the general formula (It) 2115 (wherein R is a C1-4 alkyl group) and pharmaceutically acceptable acid addition salts thereof, Racemized or optically active 14-oxo-15-hydroxyimino-3α represented by the formula (IID)
, 17α-E-pomoieburnan or its racemic form is reacted with an alcohol of the general formula n OII (wherein R is as defined above) in the presence of an acid, and then, if desired, For example, racemic or optically active Nisder vincamate represented by the general formula (n) can be used as a pharmaceutical to convert racemic Nisder vincamic acid into a compound that can be tolerated and/or to obtain racemic vincamine. Racemized or optically active vincamic acid esters, which are represented by the above general formula (1) whose plane image is splitting the acid ester, are still acceptable as pharmaceuticals! ↓Rusono]-ra's method of producing acidic salt. 3. Racemized or optically active pincamic acid disprue represented by the general formula (II) C2■I5 (wherein R is an 01-4 alkyl group) and pharmaceutically acceptable compounds thereof. In order to prepare and report the acid compound, racemized or optically active 14-oxo-15-hydroxyimino-3α,17α-E-homoeburunane represented by the formula (II+)2H5 was converted into a compound of the general formula Rorm (formula (middle, Rlt is as defined above) and J, +t
A racemized or optically active hydro-1-cyamino-eburnan represented by the general formula (5) (wherein R is as in the above formula) invitation)! treatment with dicarboxylic acid, and then, if desired, racemization or t,1 of the resulting general formula (11).
πF as a pharmaceutical with optical activity and vincamic acid ester
If the racemization represented by the general formula (n) is 7
, a method for producing Nisder camate having optical activity or an acid addition salt thereof having a tYr volume iLq<4 as a pharmaceutical.