N-substituted 4-aminopteridines, synthesis and use thereof as pharmaceutical agent

• US 6,844,343 B1
• Filed: 09/11/2000
• Issued: 01/18/2005
• Est. Priority Date: 09/17/1999
• Status: Expired due to Term

• Current Assignee: Vasopharm Biotech GmbH
• Original Assignee: Vasopharm Biotech GmbH
• Inventors: Taghavi-Moghadam, Shahriyar, Kotsonis, Peter, Schmidt, Harald, Pfleiderer, Wolfgang, Fröhlich, Lothar
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US10/070,976
• Time in Patent Office: 1,590 Days
• Field of Search: 544/260, 514/249
• US Class Current: 514/249
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 239/46 Two or more oxygen, sulphur or nitrogen atoms
• CPC Class Codes: C07D 475/08 with a nitrogen atom directly attached in position 2

Abstract

Compounds of formula (I), where preferably: A=a bridge of partial formula (II) or (III), R¹ and R²=independently (substituted) alkyl, aryl or aralkyl, or together form a heterocycle, R³=H, —CO-Alkyl, or —CO-Aryl, R⁴=Aryl, —CO—O-Aryl or —CO-Aryl and R⁵=H, are potent inhibitors of NO-synthase and are suitable as pharmaceutical agents of prophylaxis and treatment of disease states associates with a disturbed NO metabolism.

Claims

1. A compound of the formula (Ia), (Ib) or (Ic),

R¹ is hydrogen, C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl, wherein R¹ is unsubstituted or substituted with at least one substituent chosen from R⁶,

R² is C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂C₂₀-alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, or heteroaryalkyl wherein R² is unsubstituted or substituted with at least one substituent chosen from R⁶,

R^2′

is C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, or heteroaryalkyl wherein R^2′

is unsubstituted or substituted with at least one substituent chosen from R⁶,

or R¹ and R², together with the nitrogen atom bearing them, form a 3-8-membered ring which may optionally comprises 0, 1 or 2 further heteroatoms chosen from N, O, and S, and wherein said 3-8-membered ring is unsubstituted or substituted by at least one substituent chosen from R⁶,

R³ is hydrogen, —

CO-alkyl, —

CO-alkylaryl, —

CO-alkylheteroaryl, —

CO-aryl, or —

CO-heteroaryl,

R⁴ is C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl, —

CO—

O-alkyl, —

CO—

O-aryl, —

CO—

O-heteroaryl, —

CO-alkyl, —

CO-aryl or —

CO-heteroaryl wherein R⁴ is unsubstituted or substituted with at least one substituent chosen from R⁷,

R⁴′

is C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, heteroaryl, alkylheteroaryl, heteroarylalkyl, —

CO—

O-alkyl, —

CO—

O-aryl, —

CO—

O-heteroaryl, —

CO—

O-aryl or —

CO—

O-heteroaryl wherein R^4′

is unsubstituted or substituted with at least one substituent chosen from R⁷,

R⁵ is hydrogen, —

CO-alkyl, —

CO-alkylaryl, —

CO-alkylheteroaryl, —

CO-aryl, or CO-heteroaryl,

R⁶ is —

F, —

OH, —

O—

(C₁-C₁₀)alkyl, —

O-phenyl, —

O—

CO—

(C₁-C₁₀)alkyl, —

O—

CO-aryl, —

O—

CO-heteroaryl, —

NR⁸R⁹, oxo, phenyl, —

CO—

(C₁-C₅)-alkyl, —

CF₃, —

CN, —

CONR⁸R⁹, —

COOH, —

CO—

O—

(C₁-C₅)-alkyl, —

CO—

O-aryl, —

CO—

O-heteroaryl, —

S(O)_n—

(C₁-C₅)-alkyl, —

SO₂NR⁸R⁹,

R⁷ is —

F, —

OH, —

O—

(C₁-C₁₀)-alkyl, —

O-phenyl, —

O—

CO—

(C₁-C₁₀)-alkyl, O—

CO—

O-aryl, O—

CO—

O-heteroaryl, —

NR⁸R⁹, oxo, phenyl, —

CO—

(C₁-C₅)-alkyl, —

CF₃, —

CN, —

CONR⁸R⁹, —

COOH, —

CO—

O—

(C₁-C₅)alkyl, —

CO—

O-aryl, —

S(O)_n—

(C₁-C₅)alkyl, —

SO₂—

NR⁸R⁹,

R⁸ is hydrogen or C₁-C₂₀-alkyl, and

R⁹ is hydrogen, C₁-C₂₀-alkyl, aryl, or heteroaryl,

wherein aryl groups are carbocyclic aryl groups,

wherein heteroaryl groups are 5- to 7-membered unsaturated heterocycles comprising 1-4 heteroatoms chosen from O, N, and S,

or a physiologically acceptable salt, hydrate, or ester thereof, in any stereoisomeric or tautomeric form.

2. The compound of the formula (Ia) as claimed in claim 1, in which

R¹ is hydrogen, (C₁-C₁₀)-alkyl, (C₃-C₈)cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, (C₁-C₃)alkylaryl, (C₁-C₃)alkylheteroaryl, arylalkyl, or heteroarylalkyl, wherein R¹ is unsubstituted or the alkyl radicals are substituted with at least one substituent chosen from R⁶,

R² is (C₁-C₁₀)alkyl, (C₃-C₈)cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, (C₁-C₃)-alkylaryl, or (C₁-C₃)alkylheteroaryl wherein R² is unsubstituted or the alkyl radicals are substituted with at least one substituent chosen from R⁶,

or R¹ and R² may, together with the nitrogen atom bearing them, form a 3-8-membered ring, wherein said 3-8-membered ring optionally comprises 0, 1 or 2 further heteroatoms chosen from N, O, and S and wherein said 3-8-membered ring is unsubstituted or substituted by at least one substituent chosen from R⁶,

R³ is hydrogen, —

CO—

(C₁-C₇)-alkyl, —

CO—

(C₁-C₃)alkylaryl, —

CO—

(C₁-C₃)-alkylheteroaryl, —

CO-aryl, or —

CO-heteroaryl,

R⁴ is (C₁-C₁₀)alkyl, aryl, heteroaryl, (C₁-C₃)-alkylaryl, (C₁-C₃)-alkylheteroaryl —

CO—

O—

(C₁-C₅)-alkyl, —

CO—

O-aryl, —

CO—

O-heteroaryl, —

CO—

(C₁-C₅)alkyl, —

CO-aryl or —

CO-heteroaryl, wherein R⁴ is unsubstituted or the alkyl radicals are substituted with at least one substituent chosen from R⁷,

R⁵ is hydrogen, CO—

(C₁-C₇)-alkyl, —

CO—

(C₁-C₃)-alkylaryl, —

CO—

(C₁-C₃)alkylheteroaryl, —

CO-aryl, or —

CO-heteroaryl,

R⁶ is —

F, —

OH, —

O—

(C₁-C₁₀)-alkyl, —

O-phenyl, —

O—

CO-(C₁-C₁₀)alkyl, —

O—

CO-aryl, —

O—

CO-heteroaryl, —

NR⁸R⁹, oxo, phenyl, —

CO—

(C₁-C₅)-alkyl, —

CF₃, —

CN, —

CONR⁸R⁹, —

COOH, —

CO—

O—

(C₁-C₅)-alkyl, —

CO—

O-aryl, —

CO—

O-heteroaryl, —

S(O)_n—

(C₁-C₅)-alkyl, —

SO₂NR⁸R⁹,

R⁷ is —

F, —

OH, —

O—

(C₁-C₁₀)-alkyl, —

O-phenyl, —

O—

CO—

(C₁-C₁₀)-alkyl, —

O—

CO-aryl, —

O—

CO-heteroaryl, —

NR⁸R⁹, oxo, phenyl, —

CO—

(C₁-C₅)-alkyl, —

CF₃, —

CN, —

CONR⁸R⁹, —

COOH, —

CO—

O—

(C₁-C₅)-alkyl, —

CO—

O-aryl, —

CO—

O-heteroaryl, —

S(O)_n—

(C₁-C₅)-alkyl, —

SO₂—

NR⁸R⁹,

R⁸ is hydrogen or (C₁-C₅)alkyl, and

R⁹ is hydrogen, (C₁-C₅)-alkyl or phenyl,

wherein each aryl group is phenyl or naphthyl, and

wherein said heteroaryl groups are 5- to 7-membered unsaturated heterocycles comprising 14 heteroatoms chosen from O, N, and S,

wherein said phenyl, naphthyl and heteroaryl groups are substituted groups which are substituted by at least one substituent chosen from halogen, (C₁-C₅)-alkyl or phenyl, —

OH, —

O—

(C₁-C₅)-alkyl, (C₁-C₂)-alkylenedioxy, —

N⁸R⁹, —

NO₂, —

CO—

(C₁-C₅)alkyl, —

CF₃, —

CN, —

CONR⁸R⁹, —

COOH, —

CO—

O—

(C₁-C₅)alkyl, —

S(O)—

_n—

(C₁-C₅)-alkyl, —

SO₂—

NR⁸R⁹,

wherein n is 0, 1 or 2,

or a physiologically acceptable salt, hydrate, or ester thereof, in any stereoisomeric or tautomeric form.

3. A compound of the formula (Ia) as claimed in claim 1, in which

R¹ is hydrogen, unsubstituted (C₂-C₄)alkyl, substituted (C_2-C4)alkyl which is substituted by at least one R⁶, or (C₁-C₂)alkyl aryl or (C₁-C₂)-alkylheteroaryl,

R² is unsubstituted (C_2-C4)-alkyl, substituted (C_2-C4)-alkyl which is substituted by at least one R⁶, or cyclohexylmethyl or (C₁-C₂)-alkylaryl or (C₁-C₂)alkylheteroaryl,

or R¹ and R², together with the nitrogen atom bearing them, form a 5-7-membered ring wherein said 5-7-membered ring optionally comprises an additional heteroatom chosen from N, O, and S,

R³ is hydrogen, —

CO—

(C₁-C₃)-alkyl, —

CO-aryl or —

CO-heteroaryl,

R⁴ is aryl, heteroaryl, (C₁-C₅)alkyl, —

CO—

O-aryl or —

CO-heteroaryl, wherein R⁴ is unsubstituted or substituted with at least one substituent chosen from R⁷,

R⁵ is hydrogen,

R⁶ is —

OH, —

O—

(C₁-C₃)-alkyl, —

NR⁸R⁹ or —

COOH, and

R⁷ is —

OH, (C₁-C₁₀)-alkyloxy, phenoxy or oxo,

wherein each aryl group is phenyl,

wherein said heteroaryl groups are chosen from thiophenyl, furyl and pyridyl,

wherein said phenyl, thiophenyl, furyl or pyridyl groups are unsubstituted groups or substituted groups which are substituted by at least one substituent chosen from (C_1-C3)-alkyl, halogen, (C₁-C₃)alkyloxy and (C₁-C₂)-alkylenedioxy, and

or a physiologically acceptable salt, hydrate, or ester thereof, in any stereoisomeric or tautomeric form.

4. A compound of the formula (Ia) as claimed in claim 1, in which

R¹ is arylmethyl,

R² is arylmethyl or cyclohexylmethyl,

or R¹ and R², together with the nitrogen atom bearing them, form a pyrrolidine, piperidine, morpholine, dimethylmorpholine, thiomorpholine, or N-(C₁-C₂) alkylpiperazine ring,

R³ is hydrogen,

R⁴ is aryl or 1,2-dihydroxypropyl,

R⁵ is hydrogen,

R⁶ is —

OH, —

O—

(C₁-C₃)-alkyl, —

NR⁸R⁹ or —

COOH, and

R⁷ is —

OH, decyloxy or phenoxy,

wherein each aryl group is chosen from unsubstituted phenyl or substituted phenyl, which is substituted by at least one substituent chosen from (C₁-C₃)-alkyl, halogen and (C₁-C₃)alkyloxy and (C₁-C₂)alkylenedioxy,

or a physiologically acceptable salt, hydrate, or ester thereof, in any stereoisomeric or tautomeric form.

5. The compound of formula (Ia) as claimed in claim 1, which is a tetrahydropteridine wherein R⁴ is aryl, heteroaryl, (C₁-C₅)-alkyl —

CO—

O-aryl or —

CO—

O-(heteroaryl), and wherein said R⁴ is unsubstituted or substituted with at least one substituent chosen from R⁷.

6. The compound of formula (Ia) as claimed in claim 1, wherein

R¹ and R² are each, independently alkyl aryl, or heteroaryl, or

R¹ is hydrogen and R² is cycloalkyl or cycloalkylalkyl, and

wherein R⁴ is aryl, (C₁-C₅)alkyl —

CO—

O-aryl or —

CO—

O-(heteroaryl), wherein said R⁴ is unsubstituted or substituted with at least one substituent chosen from R⁷.

7. A process for preparing a compound of formula (Ia), (Ib), or (Ic) as claimed in claim 1 comprising reacting a compound of the formula II

with a compound of the formula III

HNR¹R² 

 

(III)

which results in a compound of the formula IV

wherein the compound of formula IV is converted to a compound of formula V by catalytic hydrogenation

and wherein a compound of formula V is reacted with a compound of the formula VI

to give a compound of formula (Ia), (Ib), or (Ic).

8. A pharmaceutical comprising a compound of formula (Ia), (lb), or (Ic) as claimed in claim 1 and an additional ingredient chosen from conventional excipients and additives.

9. A method of treating or preventing strokes comprising administration of at least one pharmaceutical of claim 8 to a patient in need thereof.