CA2425164C

CA2425164C - (4-acylaminopiperidin-1-yl)acetamides as neurokinin antagonists

Info

Publication number: CA2425164C
Application number: CA002425164A
Authority: CA
Inventors: Horst Dollinger; Franz Esser; Birgit Jung; Gerd Schnorrenberg; Kurt Schromm; Georg Speck
Original assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2000-10-17
Filing date: 2001-10-16
Publication date: 2009-02-03
Anticipated expiration: 2021-10-16
Also published as: DE10051321A1; ATE364594T1; AU2002210537A1; ES2289000T3; EP1337512B1; JP2004513096A; UY26971A1; JP4173363B2; WO2002032866A1; DE50112633D1; CA2425164A1; EP1337512A1; MXPA03003335A

Abstract

The invention relates to new compounds of formula I
(see formula I) or the pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, X and Ar1 have the meanings given in the specification, as well as the preparation and use thereof. The new compounds are valuable neurokinin (tachykinin) antagonists.

Description

(4-ACYLAMINOPIPERIDIN-1-YL) ACETAMIDES
AS NEUROKININ ANTAGONISTS

The invention relates to new compounds of formula I, ~
R. N N R.4 (I) RZ H Ar wherein the groups Ar, R', R2, R3 , R4 and X have the meanings given in the claims and 1o specification, processes for preparing them as well as their use as pharmaceutical compositions, and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing thege compounds. The compounds are valuable neurokinin (tachykinin) antagonists.

15 Background to the invention The compounds of formula I are partly covered by the broad general formula of International Patent Application W096/32386 . Hovi~ever, this does not disclose any compounds in which the amide group is substituted with a 2-phenyl-ethyl group and the piperidyl group in the 4 position is substituted with a substituted urethane or urea group. The compounds described in 20 this international patent application are neurokinin antagonists with a broad spectrum of activity.

The problem of the present invention is to provide new neurokinin antagonists with an enhanced activity. This problem is now solved according to the invention by the preparation 25 of the new compounds of formula I. .

1l1155-ff Boehringer Ingelheim Pharma KG

Detailed description of the invention Surprisingly it has been found that the activity of the new NK, receptor antagonists of formula I is dramatically increased compared with the known compounds.

{ The invention therefore relates to new compounds of formula I
O O~ R3 N
Ri N -C - N \R4 (I) R2 H Arl or the pharmaceutically acceptable salts thereof, wherein R' denotes Ci-C6-alkyl or Ar2, R2 denotes hydrogen, Ci-C6-alkyl or Cs-C6-cycloalkylmethyl, or R' and RZ taken together denote a C2-C3-alkylenediyl group optionally substituted by one or two oxo groups (=O), X denotes 0 or NRS, Ar' and A? independently of one another denote unsubstituted phenyl or phenyl which is I-to 5-substituted by halogen, hydroxy, Ci-C4-alkyl, Ci-Ca-alkoxy, Ci-C4-fluoroalkyl, Ci-Ca-fluoroalkoxy or -OCH2O-;

R3 denotes 2-phenyl-ethyl, wherein the phenyl group may be substituted by 1 to substituents, while the substituents, independently of one another, are selected from among halogen, hydroxy, Ci-Ca-alkyl, Ci-Ca-alkoxy, Ci-C4-fluoroalkyl, C i-Ca-fluoroalkoxy;
R4 denotes hydrogen, CI-Ca-alkyl, C3-Cs-cycloalkyl, CH2COOH, -CH2C(O)NH2, -OH or phenyl-Ci-Ca-alkyl ; and R5 denotes hydrogen or Ci-Cs-aHyl.
In the foregoing and in what is to follow, the terms "alkyl" and " alkoxy" as used with reference to the groups R', R2, R3, R4 or the substituents of Arl or A? denote straight-chain or branched, saturated hydrocarbon groups with up to 6 carbon atoms, preferably 1 to 4 carbon atoms, particularly methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy or i-propoxy.

1/1155-ff Boebringer Ingelheim Pharma KG

In the foregoing and in what is to follow, the terms " fluoroalkyl" and "fluoroalkoxy" as used with reference to the group R3 or the substituents of Ar denote straight-chain or branched, fluorine-substituted hydrocarbon groups with up to 4 carbon atoms and up to 9 fluorine atoms, preferably 1 or 2 carbon atoms and up to 5 fluorine atoms, particularly trifluoroethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy or 2-fluoroethoxy.

The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which io have substance P-antagonistic properties. They are useful for treating and preventing neurokinin-mediated illnesses and additionally have a dramatically increased effect.

Compounds of general formula I may have acid groups, mainly carboxyl groups, and/or basic groups such as, for example, amino functions. Compounds of general formula I
may therefore be in the form of internal salts, salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or salts with pharmaceutically useable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as, for example, diethylamine, triethylamine, triethanolamine etc.

The compounds according to the invention may occur as racemates, or they may be obtained as pure enantiomers, i.e. in the (R)- or (S)-form. Compounds which occur as racemates or as the (S)-forrn are preferred.

The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have substance P-antagonistic properties. They are useful for treating and preventing neurokinin-mediated illnesses:

Treatment or prevention of inflammatory and allergic complaints of the airways, such as asthma, chronic bronchitis, hyperreactive airways, emphysema, rhinitis, COPD, pulmonary hypertension, cystic fibrosis, coughs;
of the eyes, such as conjunctivitis and iritis, 111155-ff Boehringer Ingelheim Pharma KG
..~ .

of the skin, such as dermatitis in contact eczema, neurodermatitis, pruritus, urticaria,.psoriasis, sunburn, burns, insect bites, rosacea, itching, sensitive or hypersensitive skin, of the gastro-intestinal tract, such as gastric and duodenal ulcers, ulcerative colitis, Crohn's disease, inflammatory bowel disease, initable colon, Hirschsprung's disease, motility problems;
of the joints or bones, such as rheumatoid arthritis, reactive arthritis, arthrosis, osteoporosis and Reiter's syndrome;
of the bladder, such as irritable bladder, incontinence, urinary urgency, urethritis, colic and cystitis.

Also for the treatment of diseases of the central nervous system such as dementia, Alzheimer's disease, schizophrenia, psychoses, anxiety states, alcohol or drug dependency, sexual dysfunctions, eating disorders, depression, headaches (e.g. migraine or tension headaches), epilepsy; Parkinson's disease, stroke, treatment of Herpes zoster as well as postherpetic pain, tumours, collagenoses, a dysfunction of the deferent urinary tracts, haemorrhoid, nausea and vomiting, triggered for example by radiation or cytostatic therapy or motion, and painful conditions of all kinds.

2o The invention therefore also relates to the use of the compounds of formula I as curative agents and pharniaceutical preparations which contain these compounds. They are preferably used on humans. The compounds according to the invention may be given intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation, transdermally, optionally assisted by iontophoresis or enhancers known from the literature, and by oral route.

For parenteral administration the compounds of formula I or their physiologically acceptable salts, may be put into solution, suspension or emulsion, possibly with substances conventionally used for this purpose such as solubilisers, emulsifiers or other adjuvants.
Suitable solvents include, for example: water, physiological saline solutions or alcohols, e.g.
ethanol, propanediol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of various solvents.

1/1155-ff Boehringer Ingelheim Pharma KG
In addition, the compounds may be administered by the use of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations.

Compounds of formula I, wherein R4 denotes Cl-C4-alkyl, particularly methyl, are preferred.

Also preferred are compounds of formula I wherein Ar is unsubstituted phenyl or 2,3-methylenedioxyphenyl, particularly unsubstituted phenyl.

Preferred compounds of formula I are those wherein R3 denotes 2-phenylethyl, wherein the phenyl 1o group may be substituted by 1 to 3 substituents, wherein the substituents are selected independently of one another from among halogen, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, particularly wherein R3 is 2-(3,5-bis-trifluoromethylphenyl)-ethyl.

Particularly preferred compounds of formula I are those wherein the group -NR3R4 is In a preferred aspect the invention relates to compounds of formula I, wherein R' denotes a CI-C3-alkyl, particularly methyl, phenyl or Cl-C3-alkoxyphenyl group, particularly 4-methoxyphenyl, X denotes NH, and R2 denotes a hydrogen atom.

In another preferred aspect the invention relates to compounds of formula I, wherein R' and R2 taken together denote an ethylene-l,2-diyl, 1-oxoethylene-l,2-diyl, propylene-1,3-diyl, 1-oxopropylene-1,3-diyl or 1-oxobutylene-1,3-diyl group, and X denotes 0, NH or NCH3.

Particularly preferred are NK1 receptor antagonists of formula I, wherein the group I 1/1155-ff Boebringer Ingeiheim Phazma KG

RI-X-CO-NRz-is a group selected from the formulae A-1 to A-8:
~
H H
,,N
I~C y OyN

p CH

{ O i N O
N\ ~

C"3 O NyO
H
N.I-I N O
~
CH 'N

N Y N~ yN,, I I N
O H3C~' O

The following compounds are particularly preferred:

N
N

~ N O
N CF

\ CH3 = CA 02425164 2003-04-07 111155-ff BOehringer Ingellieim Phazma KG

OyN
O
O N-'YAN

O

O \
N N I
~ /
i I CF 3 lVTT
/ 1.t13 O N

N
o N
O
,, -lyAN
CF

, KT
~1~

O N
~3 N
OII
CH3 N\ ~

~3 1/1155-ff Boelninger Ingelheim Pharma KG

H
N O

N

N

H H CFs NyN 0 N~

~ lj CF

\ NyN
~ O
O / O --"A

CH3 L+H3 0~0 CN,,,o O

CF

<

1/1155-ff Boebringer Ingelheim Phanna KG

H

N O
H f ~.
NN CF

O
The compounds may be prepared in a manner known per se.
Advantageous methods are illustrated and described in the following diagram The compounds of general formula I may be prepared by reacting an amide of formula II

" NJ
x- R4 (II) H Ar wherein X denotes a suitable leaving group, preferably halogen, alkylsulphonyloxy, particularly methylsulphonyloxy, or arylsulphonyloxy, particularly p-tolylsulphonyloxy, with a piperidine of general formula III
O
X1NN-H Rl ( ~ ) RZ
in an inert solvent in the presence of abase.

This process is illustrated by means of the following Diagram 1 for compounds wherein Ar is phenyl, R3 is bis-(trifluoromethyl)-phenylethyl and R4 is methyl. However, the process can be used analogously for all compounds of formula I. The compounds of fonnula III are known or may be prepared analogously to methods known per se.

1/1155-ff Boehringer Ingelheim Phazma KG
Diagram I

HO QH CH3SOZC1 ~CSO2OOH

~ \
HN ~ CF3 CI-i3 CF'3 R1~X~0 RziN TEA
H
t~

R'~X~/ O CF3 R2/N ` O
N V `N \' CF

The reactant for this piperazine derivative is obtained as shown in Diagraazn 1, on the right.
(R)-Mandelic acid is reacted with methanesulphonic acid halide to obtain (R)-2-(methanesulphonyloxy)-acetic acid. This is then reacted with a coupling reagent and the 5 correspondingly substituted phenethylamine to obtain the corresponding amide, or it is converted into the corresponding acid halide (e.g. with SOC12/S02C12) and then converted with the suitably substituted phenethylamine into the corresponding amide. In the last step the amide thus obtained is reacted with the piperidine derivative described above, while during the substitution of inethanesulphonate C-N-linking takes place with simultaneous reversal of 1/1155-ff Baehringer Ingelheim Pharma KG

the chiral centre. The reaction is carried out in an inert solvent, preferably a polar aprotic solvent such as, for example, DMF, dimethyl acetamide, ethylmethylketone or acetonitrile in the presence of a base, preferably an inorganic base such as, for example, K2C03, NaHCO3 or CaCO3, or organic bases such as, for example, tertiary amines, preferably triethylamine, Hiinig base, pyridine or N-methylmorpholine, at between 0 C and 120 C, typically between C and 80 C. The reaction time is generally between 0.5 h and 48 h.

The compounds and compositions according to the invention will now be illustrated by the Examples which follow. The skilled person is aware that the Examples serve only as an 1o illustration and are not to be regarded as limiting.

A Example of the synthesis of compounds according to the invention Example 1 N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-N-methyl-2-[4-(3-methyl-ureido)-piperidin-l-y,l]-2-phenyl-acetamide 6.8 g of 4-(3-methylureido)-piperidine are refluxed together with 19.2 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide (prepared analogously to the method described in WO 99/62893 ) and 6.8 ml of triethylamine in 400 ml of acetone for 8 hours. Then the solution is evaporated down, combined with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate.
The extract is dried, the solvent is eliminated in vacuo and the residue is chromatographed with methylene chloride / methano19:1 over silica gel. The fractions found to be uniform by TLC are combined and the solvent is eliminated in vacuo. N-[2-(3,5-bis-tifluormethyl-phenyi)-ethyl]-N-methyl-2-[4-(3-methyl-ureido)-piperidin-l-yl]-2-phenyl-acetamide is crystallised from the residue with ethanolic hydrochloric acid and ether in the form of the hydrochloride, yielding 7.1 g of colourless crystals.
'H-NMR (250 MHz, CD3OD) S ppm = 7.93 - 7.33 (81-L m); 5.58; 5.38 (1H, 2s);
4.03 - 2.59 (5H, m); 3.05 (4H, m); 2.98; 2.90 (3H, 2s); 2.74; 2.70 (3H, 2s); NH in the solvent blind peak 4.89; 2.27 - 1.52 (4H, m). Most signals are split by amide rotation.

111155-ff Boehringer Ingelheim Phaima KG

Example 2 (S)-N-[2-(3,5-bis trifluoromethyl-phenyl)-ethyl] N-methyl-2-[4-(2-oxo-[1.3]oxazinan-3-yl)-piperidin-1-yl]-2-phenyl-acetamide 5.4 g of 4-(2-oxo -[ 1. 3 ]oxazinan-3 -yl)-piperidine are refluxed together with 12.5 g of (R)-N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy N-methyl-2-phenyl-acetamide (prepared from D-(-)-mandelic acid) and 4.5 ml of triethylamine in 250 ml of acetone for 6 hours. Then the solution is concentrated by evaporation, combined with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate.
The extract is io dried, the solvent is eliminated in vacuo and the residue is chromatographed with methylene chloride / methanol 9:1 over silica gel. The fractions found to be uniform by TLC are combined and the solvent is eliminated in vacuo. (S)-N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-N-methyl-2-[4-(2-oxo-[1,3]oxazinau-3-yl)-piperidin 1 yl]-2-phenyl-acetamide is crystallised from the residue with ethanolic hydrochloric acid and ether in the form of the hydrochloride. 7.5 g of light beige crystals are obtaine(i 'H-NMR (250 MHz, CD3OD) S ppm = 7.88 - 7.55 (8H, m); 5.47; 5.28 (iH, 2s); 4.24 (2H, t, J = 5.8 Hz); 4.13 (IH, m); 4.06 - 2.69 (6H, m); 3.04 (4H, m); 3.00; 2.89 (3H, 2s); 2.34 - 1.71 (6H, m). Most signals are split by amide rotation.

Rotational value [a]D20 = +36,7 (c=1; methanol) Examples 3 to 10 may be prepared analogously.

R1~X~0 CF

RZ~N O
"'A

RS ' CH3 1/1155-ff Boebringer Ingellheim Phatioaa KG

Example R X- R- R R

3 -O-CH2-C=O- H H
4 -N(CH3)-C=O-CH2CH2- H H
N(CH3)-C=O-CH2CH(CHs)- H H

7 phenyl-NH- H- H H
8 4-methoxy-phenyl-NH- H- H H

methyl-NH- H -O-CH2-O-5 B Results of investigations into the compound according to the invention:
The receptor affinity to the NKl-receptor (substance P-receptor) is determined on human lymphoblastoma cells (IM-9) with cloned NKl-receptors, by measuring the displacement of 12sI-labelled substance P. The Kl-values thus obtained show the efficacy of the compounds.

lo The compounds according to the invention were compared with the compounds of the following fonnulae known from International Patent Application W096/32386 :

1/1155-ff Boehringer Ingeiheim Pharma KG

N N
H3C N~ ~ \

1 \ CF3 N~
H N N
H

These compounds correspond to the compounds of Examples 6 and 7, wherein the 2-bis-trifluoromethylphenyl-ethyl group has been replaced by a bis-trifluoromethylbenzyl.

The results are listed in Table I:

Example No. K; [nM]
1 0.7 2 1.7 3 0.7 4 0.6 5 0.6 6 3.5 B-6 165.0 7 0.8 B-7 432.0 1/1155ff Boeluinger Ingelheim Pharma KG
C Formulations of compounds according to the Invention Injectable solution 200 mg active substance *
5 1.2 mg monopotassium dihydrogen phosphate = KH2PO4 ) 0.2 mg disodium hydrogen phosphate = ) (buffer) NaH2PO4.2H20 ) 94 mg sodium chloride ) (isotonic agent) or ) lo 520 mg glucose ) 4 mg albumin (protease protection) q.s. sodium hydroxide solution ) q.s. hydrochloric acid ) ad pH 6 ad 10 ml water for injections Znjectable solution 200 mg active substance*
94 mg sodium chloride or 2o 520 mg glucose 4 mg albumin q.s. sodium hydroxide solution ) q.s. hydrochloric acid ) ad pH 9 ad 10 ml water for injections 1/1155-ff Boehringer Ingeiheim Pharnia KG

Lyophilisate 200 mg active substance*
520 mg mannitol (isotonic agent/bulking agent) 4 mg albumin solvent 1 for lyophilisate ml water for injections solvent 2 for lyophilisate mg Polysorbat 80 = Tween 80 10 (surfactant) .-, 10 ml water for injections * active substance: compound according to the invention, e.g. one of Examples 1 to 8 dose for humans weighing 67 kg: 1 to 500 mg

Claims

CLAIMS:

1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein R1 denotes C1-C6-alkyl or Ar2, R2 denotes hydrogen, C1-C6-alkyl or C3-C6-cycloalkylmethyl, or R1 and R2 taken together denote a C2-C3-alkylenediyl group optionally substituted by one or two oxo groups (=O), X denotes O or NR5, Ar1 and Ar2 independently of one another denote unsubstituted phenyl or phenyl which is 1- to 5-substituted by halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy or -OCH2O-;

R3 denotes 2-phenyl-ethyl, wherein the phenyl group is unsubstituted or substituted by 1 to 3 substituents, wherein the substituents, independently of one another, are selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-fluoroalkyl, and C1-C4-fluoroalkoxy;

R4 denotes hydrogen, C1-C4-alkyl, C3-C8-cycloalkyl, CH2COOH, -CH2C(O)NH2, -OH or phenyl-C1-C4-alkyl; and R5 denotes hydrogen or C1-C6-alkyl.

2. A compound or salt according to claim 1, wherein Ar1 is unsubstituted phenyl or 2,3-methylenedioxyphenyl.

3. A compound or salt according to claim 1 or 2, wherein R4 is C1-C4-alkyl.

4. A compound or salt according to any one of claims 1 to 3, wherein R3 denotes 2-phenylethyl, in which the phenyl group is substituted by 1 to 3 substituents, wherein the substituents independently of one another are selected from the group consisting of halogen, hydroxy, methyl, methoxy, trifluoromethyl and trifluoromethoxy.

5. A compound or salt according to any one of claims 1 to 3, wherein R3 is 2-(3,5-bis-trifluoromethylphenyl)-ethyl.

6. A compound or salt according to claim 1 or 2, wherein the group -NR3R4 is

7. A compound or salt according to any one of claims 1 to 6, wherein R1 denotes a C1-C3-alkyl, phenyl or C1-C3-alkoxyphenyl group, X denotes NH, and R2 denotes a hydrogen atom.

8. A compound or salt according to any one of claims 1 to 6, wherein R1 and R2 taken together denote an ethylene-1,2-diyl, 1-oxoethylene-1,2-diyl, propylene-1,3-diyl or 1-oxopropylene-1,3-diyl group, and X denotes O, NH or NCH3.

9. A compound of the formula:
or a pharmaceutically acceptable salt thereof.

10. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

11. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

12. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

13. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

14. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

15. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

16. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

17. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

18. A process for preparing a compound of formula I as defined in any one of claims 1 to 8, wherein an amide of formula II

wherein Ar1, R3 and R 4 are as defined in any one of claims 1 to 8, and Y denotes a suitable leaving group, is reacted with a piperidine of general formula III
wherein R1, R2 and X are as defined in any one of claims 1 to 8, in an inert solvent, optionally in the presence of a base.

19. A pharmaceutical composition comprising a compound or salt as defined in any one of claims 1 to 17 and a pharmaceutically acceptable carrier or excipient.

20. Use of a compound or salt as defined in any one of claims 1 to 17 in preparing a pharmaceutical composition for treatment or prevention of a neurokinin-mediated illness.

21. Use of a compound or salt as defined in any one of claims 1 to 17 for treatment or prevention of a neurokinin-mediated illness.

22. A compound or salt as defined in any one of claims 1 to 17 for treatment or prevention of a neurokinin-mediated illness.

23. A pharmaceutical composition according to claim 19 for treatment or prevention of a neurokinin-mediated illness.