NZ199795A - Ergoline derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 99795 199795 . W ^ GS Priority Date(s): Complete Specification Filed: Class: CP.Tfb M.7. L.tf. &.&!/.<*$ Pubiication Date: ?.Q. A...

P.O. Journal, No: .

J&g. ^ATBtfT QPRCE f 22 FEB 1982 Received NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION NEW ERGOLINE DERIVATIVES, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS THEREOF K/We, SANDOZ LTD., 35 Lichtstrasse, CH-4002 Basle, Switzerland; a Swiss Body Corporate hereby declare the invention for which R/ we pray that a patent may be granted to mec/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) la 199795 NEW ERGOLINE DERIVATIvES. THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS THEREOF This invention relates to ergoline derivatives, their production and pharmaceutical compositions containing them.

United Kingdom Patent No. 1,191,099 discloses a very broad class of N-acy1-N-(12-hydroxy-l,6-dimethyl ergol in-8-yl-methyl ) ami no derivatives, which are stated to be especially clinically useful in the treatment of migraine, trigeminal neuralgia, general allergies and inflammation disorders as indicated by antagonism of serotonin. A wide variety of acyl derivatives are specifically suggested. One such acyl derivative is the derivative from diethyl carbaminic acid. No other carbaminic derivatives are specifically suggested. There are only 5 characterised examples, but none of these are carbaminic acid derivatives. We have now found that the ergoline derivatives encompassed by the following formula I which are nowhere specifically mentioned or suggested by the above German Offenlegungsschrift possess especially interesting anti-hypertensive activity as indicated by e.g. potency in the tests herei nafter .

The present invention provides compounds of formula I I 1 99795 -2- 400-5 55-5- in which R-j is H, (C-j _^)al kyl/or a precursor thereof, R2 1s (ci_4)alky!» R3 and R^ independently are H, or (C^_^)alkyl or together are (C2_g)a 1ky1ene , 5 R5 is H or alkyl , and A and B each are H or both together are a bond, with the proviso that, when R, and R„ are I c each CH^, R3 and are each and A and B are each H, then R,. is alkyl, 10 hereinafter referred to as compounds of the invention.

As precursors in position 1 are meant such substituents 15 which under physiologically conditions may be converted into the other indicated significances of R-j > particularly H.

Such substituents are e.g. CH^OH, ( C.J _22)al kanoyl oxymethyl or acetyl. R,-, if alkyl, contains preferably 1-20, especially 1-4, carbon atoms. Preferred substituents in the com-20 pounds of formula I are R-j = H, (C-j _^) a 1 ky 1 , Ch^OH, or (C1 _4)al kanoyl oxymethyl , R3 = H or (C-j _4)al kyl , R^ = (C_^) alkyl and/or = H or (C-| _4) a 1 kyl .

These preferences are especially combined together; A and B preferably form together a bond.

Especially preferred substituents are, individually or combined R-j = H, R2 = CH^. R3 = ^4 = ^3 and R^ = H or CH^, especially CH^.

A group of compounds comprises the compounds of formula la 199795 H la HN in vhich is as defined above,R3a and are independently (C-j alkyl and R,-a is H or Cn3.

Another group of compounds comprises compounds of formula I wherein when R-j and R^ are each and R^ are each (C-j_^)alkyl and A and B are each h', then R- is alkvl.

O * The present invention in another aspect provides a process 5 for the production of a compound of the invention, which includes the step of a) oxidizing a compound of formula II wherein R-| to and A and B are as defined above, and Rg is hydrogen or hydroxy!, lOor a precursor thereof, to produce a compound of formula I wherein R^ is .-hydrogen, or H II 1 9 97 9 5 -4- 100-5555' b) alkylating a compound of formula I wherein at least one of R-j,- R^, R^ and Rj- is hydrogen/or a precursor to produce the corresponding compound wherein at least 5 R-| is (C i ) al ky 1 , CH^OH of' (C^ al kanoyl oxymethyl and/or at least R^R^ and Rj. is alkyl and' if desired converting a resultant formula I compound into another formula I'compound . The oxidation according to process a) may be effected in conventional manner for the introduction of a double bond into the 2,3 position, and when Rg is hydrogen for the lOintroduction of a hydroxy! group in the 12 position of the ergoline nucleus. When Rg is hydrogen if desired the oxidation may be effected simultaneously or in two stages, one stage being the introduction of the hydroxyl group and the other stage being the introduction of the double bond. 15The introduction of the 2,3 double bond may be effected in conventional manner for the conversion of indolines into the corresponding indoles, e.g. by passing a stream of air through a solution of the compound. The reaction may be effected at room temperature.. 20The introduction of the hydroxy! group may be effected with an appropriate oxidizing agent such as a nitrosodisulphonate, e.g.in the form of the potassium salt. Generally such reactions also lead to the introduction of the double bond in the 2,3 position (see Helv.Chim.Acta, 756-769,1964). 25The reaction is preferably effected with the. nitrosodisulphonate in an aqueous .medium at a pH about 3 to about 9,preferably at pH of about 7. The ergoline may be dissolved in an organic sol vent ,e . g . chl oro-form, and the system stirred rigorously. The reaction tem-peraturermay be for example from about 0°C to about 50°C. 199795 If there is a group present e.g. Cf^OH in the 1 position of the ergoline nucleus, then Rg is-preferably hydroxy. Preferably such groups are introduced after the oxidation . reacti on.

The alkylation process b) may be effected in conventional 5 manner,using appropriate alkylating agents to alkylate the appropriate group. The term alkylation includes not only the introduction of unsubstituted alkyl radical but also the introduction of CH^OH and al kanoy1oxymethyl . Where selective alkylation is required, it may be desirable to 10 block temporarily other reactive groups present.

Etherification of the hydroxy radical may be effected with a diazoalkane , e . g . diazomethane. Introduction 'of the CH^OH radical in position 1 may be effected with formaldehyde.The CH^OH radical may be subsequently acylated with for example 15 an acid ha 1i de .

The compounds of formula II wherein Rg is hydrogen are known or may be prepared i n . conventi orial manner .Some compounds of formula II hereinafter referred to as compounds of formula III are in general new and may be prepared e.g. as described in the 20 following reaction scheme and exemplified for compounds III in which is hydrogen.

Reaction scheme Acylation ii ' /R3 ch9-n-c-nC 3 ^ 11 D 0 R 4 • hn- ^r Acyl* H ■ R, I /'No h9-n-c-n\ j II \ D 0 4 L> 2 H Nitration *h Acyl, 111 a H \/ ■r.

N — R, warming in acid medi un qh9-n-c-n' j " 0 4 11 lb Reduction • /R3 ch?-n-c-n\ j c 11 0 4 <T warming in acid medium III e * Acyl radical, e.g. acetyl. 11 Id 111 c I CT> CO <£> <1 CO U\ 199795 -7- 400-555 5" In the reaction scheme to are as defined above.The several reaction steps are described in extenso in example 1 for the production of a 9,10-didehydro-ergoline compound of the invention.

The compounds of formula I in which R^ is hydrogen may be converted into other compounds of formula I in conventional manner,e.g . they may be alkylated or, for the production of the above mentioned precursor groups ,acetylated or formy-lated in position 1 and the formylated products preferably 10 acylated. The compounds may be optionally alkylated in the ureamethyl radical and hydrogenated in position 9,10.

The etherification of the 12-hydroxylated product may be effected in conventional manner for the synthesis of analogous phenol-ethers .

The alkylation may be effected in conventional manner.The acetylation and the formylation v/hich may be carried out conventionally by reaction with ketene, and with formaldehyde and an acid respectively.

The acylation of a CH^OH radical in position 1 formed by 20 formylation may also be effected by known methods,e.g. with an acid halide. Other precursor groups in position 1 may be produced in conventional manner.

The hydrogenation may be carried out in conventional manner, particularly by catalytic hydrogenation , e.g .with Pd-C as a 25 catalyst.

The compounds of formula I may be recovered in,for example, „/ free base form or acid addition salt form.

The acid addition salt forms of a compound of formula I may be produced in conventional manner from the free base forms 30 and v i ce versa. Suitable acids include fumaric acid and hydrochloric acid. 1 99795 -8- 44^ "trtrtrtr If compounds of formula I are to be prepared in which one or more of the substituents are (C-j_^)alkyl or A and B are H, the required alkylation or hydrogenation in position 9,10 may occur either before or after the formation of the 12-hydroxy radical. Precursors of R-j are preferably introduced after the introduction of the hydroxyl group. 1997 -3- W-SS5S- E x a mpl e 1; -1;51 -di;methyl -3-^.(12 thydroxy-6 -^methy 1 -9, ] 0r-d t - " dehydro-ergol in-'3;Vy1 -nethyl )urea a) IaI-- I1?? ttlYl 1^-11 1 lU| t tlZl I? i 3 & i h yd r o - 9^, 10 - d i_ - dehvdro^erQol in-8S=vlniethyl )urea 14 ml of triethylamine are added to a suspension of 13 g (35,8 mM) of 1,1-dimethyl-3-(6^methyl-2,3p>-dihydro-9,l0-didehydro-ergolin-8p>-ylmethyl)urea-hydrochloride in ' 300 ml of absolute methylene chloride. When the substrate has dissolved,a solution of 3.6 ml (50.7 mM) of acetyl chloride in 20 ml of absolute methylene chloride is added in drops at 10 - 15°, and the solution is stirred for 1 hour at room temperature. It is subsequently poured onto water/ice, then 20 ml of saturated KHC03 solution are added, and the solution is extracted twice with methylene chloride which contains 5% isopropanol, The combined organic phases are dried with sodium sulphate, filtered and evaporated on a rotary evaporator. After drying in a high vacuum,the title compound'in free base form is obtained in the form of a yellow-brown foam.The hydrogen fumarate of the title compound is obtained and crystallised from 2-butanone/water/methanol (5:3:2).M.p.: decomposition from 135°,[a]^ = + 36° [c = 0.355 in ethanol/water (1:1)]. 19979 40OD00D- b) 1,1 -^dimethyl -=3—Y1 -acetyl -5-methyl ^12tnitro-^2,3|i~di hydro--2ilQ:^i^hvdro:erQo1^n:8§:yliriethyl]urea 1,45 ml (35 mM) of nitric acid (100%) are added in drops at 10° over the course of 3 minutes to a solution of 13 g 5 (35 mM) of the crude base obtained under a) in 80 ml of sulphuric acid (100%), the solution being maintained in an argon atmosphere. After stirring for 20 minutes at room temperature, the solution is poured onto ice, set to a p!-! of 8 with 10 N sodium hydroxide at a temperature of 5 - 10°, 10 and extracted with methylene chloride which contains 10% isopropanol. The organic phases are combined, dried with sodium sulphate, filtered and dried on a rotary evaporator.

After drying in a high vacuum, the title compound is obtained, and this can be reduced further without purification. c) lili^i^etbYlzSzllrScetYl-^-ami no-6-methyl_-2,3§-di hydro- A solution of 13.5 g (32.7 mM) of 1,1-dimethyl-3-(l-acetyl-6-methyl -12-ni tro-2,3{i-di hydro-9,10 -didehydroergol in-8^-ylmethyl)urea in 300 ml of ethyl acetate and 100 ml 20 of methanol is hydrogenated under normal conditions in the presence of 1.5 g of palladium on carbon (10%) until the calculated amount of hydrogen has been absorbed.

The mixture is filtered and evaporated.The resultant crude product is subjected to chromatography on 300 g of 25 silicagel with methylene chloride containing 15% methanol and 0.5% aqueous ammonia,obtaining the .title compound. 1 9 97 9 5 -11- 400=5555- d) 1 il-di methyl i3-Q2-hydroxy;;63methyl-9 »IQ:didehYdro- §!222llQ:§&:Yll5§^t!Yllyn§5 A solution of 4.5 g (11.7 mM) of the- product obtained under c) in 100 ml of 1 N HC1 is heated with stirring 5 for 17 hours to 95°. With cooling by ice, the solution is subsequently adjusted to at a pH of 7 with concentrated ammonia solution, and is extracted 4 times with methylene chloride which contains 10% isopropanol. The combined organic phase are dried with sodium sulphate, 10 filtered and evaporated in a rotary evaporator. The residue of evaporation, 1,1-dimethyl-3-(12-hydroxy-6-methyl -2,3^>-di hydro-9,10-didehydro-ergol in-8fS-ylmethyl) urea, is dissolved in 10 ml of ethanol. After adding 1 ml of concentrated ammonia solution, air is blown 15 through the solution for 1 hour. After evaporation, the crude product is subjected to chromatography on 100 g of silicagel, with methylene chloride containing 10% methanol and 0,2% anmonia.solution. The title compound in free base form is obtained as a beige residue. 20 In order to produce the hydrochloride, the base obtained is dissolved in methylene chloride/methanol (1:1)s then 2.94 ml (5.9 mM) of 2 N HC1 are added, and concentration follows in a rotary evaporator until crystallisation commences. The hydrochloride of the title compound is obtained as beige crystals. ?n M.p.: decomposition from 220°C, [oc3p = + 126.2° [c = 0.435 in ethanol/water (1:1)]. 199795 -12- l-QO 5555~ EXAMPLE 2: 1 >lidimethyl 13^(12-methoxy-6-methyT2^2lQ:dldehYdro I? 1222110 :§& :Y 1 y !2§§ 200 ml (about 71.5 mM) of an approximately 1.5% ethereal diazo-methane solution kept in an argon atmosphere are carefully poured 5 into a solution which is cooled to -15° of 5 ml of 0.08 N methanolic tetrafluoroboric acid in 150 ml of methanol, and 2.55 g (7.5 mM) of the base obtained under Id). Stirring is subsequently effected for 20 hours at room temperature and in an argon atmosphere. The process is finished by concentrating the mixture to about 20% of the 10 original volume under a water-jet vacuum, arid concentrating further in a rotary evaporator. After the addition of 50 ml of ethanol and 1 ml of concentrated;ammonia solution, concentration is again effected, and the residue is subjected to chromatography on 120 g of silicage! with methylene chloride, containing 10% methanol and 15 0.2% concentrated ammonia solution. The title compound is obtained as in free base form, which crystallises from acetone. M.p.: p o decomposition from 180°; [a]Q = + 85° [c = 0.450 in methanol].

EXAMPLE 3: 1 > lidi methyl-^[l 2-h^droxy-^-methyl -9,1.0-dideh\/dro; A solution of 3.0 g (9.2 mM) of 1,1 -dimethyl-3-(6-methyl-23L3^-dihydro-9,10-didehydro-ergol in-8p>-ylmethyl)urea in 45 ml of isopropanol and 165 ml of chloroform is added at room temperature, while stirring, to a solution of 10.1 g (37.7 mM) of potassium nitrosodisulphonate in water, buffered with phosphate at pH 7.0.

The reaction mixture is stirred further at room temperature for 5 min., the organic phase is separated and the aqueous phase is extracted with isopropanol. chloroform (5:18).

The collected organic phases are dried over sodium sulphate, filtrated and evaporated to dryness. 19 97 9 5 -13- 100-5555 The residue is chromatographed on silicagel with a mixture of methylene chloride, methanol and ammonia (85:15:o.5), obtaining the pure title compound.

The following compounds of formula I are produced wherein:- Formula 7 1 r - ■ — : Ex.

R1 R2 R3 R4 R5 A, B Decomposition from 4u h ch2ch2ch3 ch3 ch3 ch3 Bond 115° (Hydrogentartrate) 51' h ch3 ch3 ch3 ch2ch3 Bond 135° (Hydrogenfumarate) 61' h ch3 ch3 ch3 chg h, h 300° (Hydrochloride) 72' h ch3 H -(ch2)3ch3 h Bond 181° (Base) 81' "I \ h ch3 h -(ch2)^ch3 ch3 Bond 107° (Base) 9 ^ h ch2ch3 ch3 ch3 ch3 Bond 190° (Base) O CO ch2oh ch3 ch3 ch3 ch3 Bond 170° (Base) 11 } ch2occh3 ch3 ch3 CH3 ch3 Bond 78° (Base) 125> v . CH3 ch n o ch3 ■ CH3 Bond 185° (Hydrogenfumarate) 132> h ch2ch2ch3 ch0 ch3 h Bond 205° (Base) 14 h c»3 h h ck3 3ond 153° (Base) 1) Prepared in analogous manner to Example 2 2) Prepared in analogous manner to Example 1 or 3 3) Prepared by formylating the Example.2 title compound 4) Prepared by acetylating the Example 10 compound ) Prepared by alkylating the Example 2 title compound In an analogous manner the following compounds of formula I may be prepared Ex. r1 r2 r3 R4 r5 a + b a -c-ch, II 3 0 -ch2ch(ch3)2 -ch2ch(ch3)2 ch3 -ch2ch(ch3)2 h + h b„ -ch20c-(ch2)16ch3 0 -(ch2)3ch3 — (CH2)4— 17^3 Bond 199795 -16- >100 G550— a 1st group of compounds R-j is H " 2nd " " " R1 is CH20H " 3rd " " " R^ is alkanoylcxymethyl " 4th R1 is (C]_4)alkyl " 5th " " " R2 is (C1_4)alkyl " 6th " " " R3 is H " 7th " " " R3 is (C1_4)alkyl " 8th " " " R4 is H " " " " R4 is (C1_4)alkyl " 10th " " " R5 is H Hth R5 is alkyl " 12th " " " A and B are together a bond 11 13th " " " A and B both are H. 199795 - 17 - *100 5555- The compounds of the Invention exhibit pharmacological activity and are therefore indicated for use as pharmaceuticals.

In particular they lead to a lowering of the blood pressure as indicated in tests with the conscious spontaneously hypertensive rat upon administration of from 0,001 to 0,1 mg/kg s,c.

In addition they lower blood pressure and decrease vascular resistance in the anaesthetised,normotensive dog upon administration of a dose of from 0,001 to 10 mg/kg r.v. especially of from 0,001 to 0,2 mg/kg i.v..

The compounds are therefore indicated for use in the treatment of hypertension and cardiac insufficiency.

An indicated daily dosage is in the range from about 0.2 to about 300 mg, conveniently administered in divided doses 2 to 4 times a day or in sustained release form, and dosage forms suitable for oral administration compose from about 0.05 to about 150 mg of the compound, admixed with a solid or liquid pharmaceutical carrier or diluent. The compounds of Examples 1 and 2 are particularly interesting, especially the compound of Example 2. 199795 - 18 - 1-00 -'5555 A compound of formula r may be administered in free base or in pharmaceutical!}' acceptable acid addition salt form. Such salt forms exhibit the same order of activity as the free base forms.

The present invention also provides a pharmaceutical composition comprising a compound of the invention in association with a pharmaceutical carrier or diluent.

Such compositions may be prepared by conventional techniques to be in conventional forms, for example, capsules or tablets. 139795

Claims (38)

WHAT WE CLAIM IS:

1. A process for the production of a compound of formula I

in which R-j is H, (C-j _^)al kyl,or a precursor thereof,

R2 is (ci_4)alkj'1 »

R^ and R^ independently are H, or (C-|_d)alkyl or together are

(C2_5)alkylene,

Rg is H or alky1, and

A and B each are H or both together are a bond,

with the proviso that, when R^ and are each CH^R^

and are each C2H,- and A and B are each H, then R^ is alkyl, .

which includes the step of a) oxidizing a compound of formula II

199195

20

wherein to R^ and A and B are as defined above, and R^ is hydrogen or hydroxyl,

or a precursor thereof,

to produce a compound of formula I wherein R,- is hydrogen,

b) alkylating a compound of formula I wherein at least one of R-j, R^, R4 and R,. is hydrogen,or a precursor thereof,

to produce the corresponding compound wherein at least R-j is (C-j_4)al-kyl, CH^OH or (C-j _22)a^ kanoyloxymethyl and/or at least R3»R4 and is ana if desired,cor,verting a resultant formula I compound into another formula I compound.

2. A process for the production of a compound of formula I defined in claim 1 as hereinbefore described with reference to any one of the examples.

3. A compound of formula I whenever produced by a process of claim 1

4. A compound of formula I as defined in claim 1.

5. A compound of claim 4 wherein when R^ and are each CH^, R^ and R^ are each (C-j)a 1 kyl and A and B are each H, then R^ is alkyl.

6. A compound of formula I as defined in claim 1, in which R^ is K, (C-j_4)alkyl, CH2OH,(Ci ^Jalkanoyloxymethyl or acetyl.

7. A compound of claim 4 'of formula la or

(C,4)alkyl or 2.

21

199725

in which R2 is (C^hlkyl ,

and R4a independently are (C^_4)alkyl, and Rj-q is H or CH^.

8. A compound of claim 7, in which R^a is H.

9. A compound of claim 7, in which R^a is CH^-

10. A compound of claim 4, in which R^ is H, (C^ 4)alky1, CF^OH or (C2_^)alkanoyloxymethyl.

11. A compound of claim 4, in which R^ is H or (C^ ^Jalkyl.

12. A compound of claim 4, in which R^ is H or (C-j 4)alkyl.

13. A compound of claim 4, in which R^ is H or (C-j_4)alkyl.

14. A compound of claim 4, in which A and 3 together are a bond.

15. A compound of claim 6, in which R-j is H.

16. A compound of claim 6, in which R2 is CH^.

17. A compound of claim 6, in which R^ is CH0.

18. A compound of claim 6, in which R^ is CH^.

19. A compound of claim 6, in which R^ is H or CH^.

20. 1,1 -dimethyl -3-(l 2-hydroxy-6-methyl -9,10-didehydro-ergol i n-8D-yl methyl)urea.

21 . 1,1 -dimethyl -3-(1 2-methoxy-6-methyl -9,10-didehydro-ergol i n-8£>-yl methyl)urea.

22. 1,1 -dimethyl -3-(12-methoxy-6-n-propyl-9 JO-didehydro-ergol in-8£>-ylmethyl)urea.

23. 1,1 -dimethyl -3-(12-ethoxy-6-methyl -9,10-di dehydro-ergol in-8p>-yl -methyl)urea.

24. 1,1 -dimethyl -3-(12-methoxy-6-methyl -ergo! in-8£-ylmethyl )urea .

25. 1 -n-butyl -3-(l 2-hvdroxy-6-methyl -9,10-didehydro-ergol in-8;3-yl methyl )urea.

26. 1 -n-butyl -3-( 12-methoxy-6-methyl -9,10-didehydro-ergol in-8£-ylmethyl )urea.

27 . 1,1 -dimethyl -3-(12-methoxy-6-ethyl -9,10-didehydro-ergolin-8p>-y 1 -methyl)urea.

28. 1,1 -dimethyl -3- (1 -hydroxymethyl -12-methoxy-6-methyl -9,10-didehydro-ergol in-8£>-ylmethyl )urea.

22

2 9- 1,1 -dimethyl -3-(l -acetyl oxymethyl -12-methoxy-6-methyl -9 J 0-di -dehydro-ergol i n-Sjl-yl methyl) urea .

30. 1 ,l-dimethyl-3-(12-methoxy-l ,6-dimethyl-9,10-didehydro-ergolin-8{2i-y 1 methyl) urea .

31. 1,1-dimethyl -3- (12-hydroxy-6-n-propyl -9 JO-di dehydro-ergol i n-8£>-ylmethyl)urea.

32. 12-methoxy-6-methyl - 9,10-didehydro-ergol in-8P>-ylmethyl -urea.

33. A compound of any one of claims 3 to 32 in free base form.

34. A compound of any one of claims 3 to 32 in acid addition salt form.

35. A compound according to any one of claims 3 to 32 in free base form or in pharmaceutically acceptable acid addition salt form suitable for use as a pharmaceutical.

36. A compound according to any one of claims 3 to 32 in free base form or in phannaceutically acid addition salt form suitable for use in the treatment of hypertension or cardiac insufficiency.

37. A pharmaceutical composition which comprises a compound of any one of claims 3 to 32 in free base tGrm or ir. pharmaceutical!}' acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.

38 . A compound of formula

H

CH?-N-C-N

FT £ v

/^3

III

wherein R^, Rg and R^ are as defined in claim 1. Rg is acy! and R-, is H, NO^ or or Rg is hydrogen and R? is OH or NHg.

HATED THIS 7 DAY Of

FER

AGENTS FOR THE AfrUCAMTS

A. j park A SOW

If