Substituted amino alcohol compounds

• US 5,641,783 A
• Filed: 09/08/1994
• Issued: 06/24/1997
• Est. Priority Date: 11/12/1993
• Status: Expired due to Term

• Current Assignee: Cell Therapeutics, Inc.
• Original Assignee: Cell Therapeutics, Inc.
• Inventors: Klein, J. Peter, Kumar, Anil M., Underiner, Gail E.
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Cebulak, Mary C.
• Application Number:
  US08/303,842
• Time in Patent Office: 1,020 Days
• Field of Search: 544/272, 514/263
• US Class Current: 514/263.35
• CPC Class Codes: A61K 31/45 having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: C07C 215/08 with only one hydroxy group and one amino group bound to the carbon skeleton
• CPC Class Codes: C07C 215/56 with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
• CPC Class Codes: C07C 217/62 linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 217/64 with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 229/22 the carbon skeleton being further substituted by oxygen atoms
• CPC Class Codes: C07C 233/36 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/78 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 233/91 with carbon atoms of the carboxamide groups bound to acyclic carbon atoms
• CPC Class Codes: C07D 207/404 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 211/76 attached in position 2 or 6
• CPC Class Codes: C07D 211/88 attached in positions 2 and 6, e.g. glutarimide
• CPC Class Codes: C07D 217/24 Oxygen atoms
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 239/90 with acyclic radicals attached in position 2 or 3
• CPC Class Codes: C07D 239/96 : Two oxygen atoms
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 473/10 : with methyl radicals in positions 3 and 7, e.g. theobromine

Abstract

Disclosed are compounds having a straight or branched aliphatic hydrocarbon structure of formula I: ##STR1## In formula I, n is an integer from one to four and m is an integer from four to twenty. Independently, R₁ and R₂ are hydrogen, a straight or branched chain alkyl, alkenyl or alkynyl of up to twenty carbon atoms in length or --(CH₂)_w R₅. If R₁ or R₂ is --(CH₂)_w R₅, w may be an integer from one to twenty and R₅ may be an hydroxyl, halo, C_1-8 alkoxyl group or a substituted or unsubstituted carbocycle or heterocycle. Alternatively, R₁ and R₂ may jointly form a substituted or unsubstituted, saturated or unsaturated heterocycle having from four to eight carbon atoms, N being a hetero atom of the resulting heterocycle. R₃ may be either hydrogen or C_1-3. In the compounds, a total sum of carbon atoms comprising R₁ or R₂, (CH₂)_n and (CH₂)_m does not exceed forty. R₄ is a terminal moiety comprising a substituted or unsubstituted, oxidized or reduced ring system, the ring system having a single ring or two to three fused rings, a ring comprising from three to seven ring atoms. The disclosed compounds are effective agents to inhibit undesirable responses to cell stimuli.

Claims

1. A compound comprising a straight or branched aliphatic hydrocarbon structure of formula I:

##STR108## wherein;

n is an integer from one to four;

m is an integer from seven to twenty;

independently, R₁ and R₂ are hydrogen, a straight or branched chain alkyl, alkenyl or alkynyl of up to twenty carbon atoms in length or --(CH₂)_w R₅, w being an integer from one to twenty and R₅ being an hydroxyl, halo, C_1-8 alkoxyl group or a substituted or unsubstituted carbocycle or heterocycle;

or

jointly R₁ and R₂ form a substituted or unsubstituted, saturated or unsaturated heterocycle having from four to eight carbon atoms, N being a hereto atom;

R₃ is hydrogen or C_1-3 ;

or

jointly one of R₁ or R₂ and R₃ form a substituted or unsubstituted linking carbon chain, having from one to four carbon atoms, joining the O and N in a cyclic structure, an integer sum equal to n+ a number of carbon atoms in the linking carbon chain being less than six;

a total sum of carbon atoms comprising R₁ or R₂, (CH₂)_n and (CH₂)_m does not exceed forty; and

R₄ is a substituted or unsubstituted terminal, heterocyclic moiety having one five-to-six-membered ring or two five- to six-membered rings, (CH₂)_m being attached to a nitrogen atom of the heterocyclic moiety, the compound including resolved enantiomers and/or diastereomers, hydrates, salts, solvates and mixtures thereof.

2. The compound of claim 1, wherein n is one or two.

3. The compound of claim 1, wherein m is an integer from ten to fourteen.

4. The compound of claim 1, wherein R₅ substituents are selected from the group consisting of hydroxyl, chloro, fluoro, bromo, or C_1-6 alkoxyl, or a mono-, di- or tri-substituted carbocycle or heterocycle having from four to seven carbon atoms.

5. The compound of claim 1, wherein (CH₂)_m is substituted by a halogen atom, an hydroxyl group, or substituted or unsubstituted C.sub.(1-10) alkoxyl, C.sub.(1-10) alkyl, C.sub.(2-10) alkenyl or C.sub.(1-10) alkynyl group.

6. The compound of claim 1, wherein heterocyclic moiety substituents are selected from the group consisting of C.sub.(1-4) alkyl, C.sub.(2-4) alkenyl, C.sub.(1-4) alkynyl, hydroxy, carbonyl, amino, thio, thiol, thiocarbonyl and imino group and a single atom.

7. The compound of claim 6, wherein the single atom is selected from the group consisting of chlorine, bromine, fluorine and oxygen.

8. The compound of claim 1, wherein bonds of the heterocyclic moiety are saturated or the heterocyclic moiety has at least one unsaturated carbon-carbon bond.

9. The compound of claim 1, wherein a total number of non-carbon ring atoms does not exceed a value for X, specified by the equation:

space="preserve" listing-type="equation">X=total number of ring atoms -1.

10. The compound of claim 1, wherein a non-carbon ring atom, other than the nitrogen atom of the heterocyclic moiety attached to (CH₂)_n is selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus.

11. The compound of claim 1, wherein the heterocyclic moiety is selected from the group consisting of substituted or unsubstituted adeninyl;

alloxanyl;

azapurinyl;

barbituric acid;

biotinyl;

cinnolinyl;

guaninyl;

hydroquinolinyl;

imidazolethionyl;

imidazolinyl;

imidazolonyl;

imidazolyl;

indolizidinyl;

indolizinyl;

indolonyl;

indolyl;

isatinyl;

isoindolinyl;

isoquinolinyl;

isothiazolyl;

isoxazolyl;

lactamyl;

lumazinyl;

oroticyl;

oxadiazinyl;

oxadiazolyl;

oxathiazinonyl;

oxatriazolyl;

oxazinonyl;

oxazolidinonyl;

oxazolidinyl;

oxazolinonyl;

oxazolinyl;

oxazolonyl;

oxazolyl;

pentazinyl;

pentazolyl;

phthalimidyl;

piperazinodionyl;

piperazinyl;

piperidinyl;

piperidonyl;

prolinyl;

pteridinyl;

purinyl;

pyrazinyl;

pyrazolidinyl;

pyrazolidonyl;

pyrazolinonyl;

pyrazolinyl;

pyrazolonyl;

pyrazolyl;

pyridazinyl;

pyridazonyl;

pyridinyl;

pyrimidinyl;

pyrimidionyl;

pyrrolidinyl;

pyrrolyl;

quinazolidinyl;

quinazolinonyl;

quinazolinyl;

quinolinyl;

quinolizinyl;

quinoxalinyl;

succinimidyl;

tetrazinyl;

tetrazolyl;

thiazinyl;

thiazolyl;

thyminyl;

triazinyl;

triazolinyl;

triazolyl;

uracilyl; and

xanthinyl.

12. The compound of claim 1, wherein at least one ring of the heterocyclic moiety has one hetero atom and the heterocyclic moiety is selected from the group consisting of:

acridinyl;

alkylpyridinyl;

azaindolyl;

biotinyl;

decahydroquinolinyl;

decahydroquinolonyl;

dihydroisoquinolinyl;

dihydropyridinyl;

dihydropyridonyl;

hydroindolyl;

hydropyridinyl;

hydropyrrolyl;

hydroquinolinyl;

indolonyl;

isatinyl;

isoindolinyl;

isoindolyl;

isoquinolinyl;

maleimidyl;

oxindolyl;

perhydroazolopyridinyl;

perhydroindolyl;

phthalimidyl;

piperidinyl;

piperidonyl;

prolinyl;

pyranopyridinyl;

pyrazolopyridinyl;

pyridinethionyl;

pyridinopyridinyl;

pyridinyl;

pyridopyridinyl;

pyridopyrimidinyl;

pyridopyrrolyl;

pyrrolidinyl;

pyrrolizidinyl;

pyrrolodiazinyl;

pyrrolonyl;

pyrrolopyrimidinyl;

pyrrolyl;

quinolinyl;

quinolizidinyl;

quinolizinyl;

quinolonyl;

succinimidyl;

tetrahydroisoquinolinyl;

tetrahydropyridinyl;

thiazolopyridinyl;

thienopryidinyl;

thienopyrrolyl; and

triazolopyridinyl.

13. The compound of claim 1, wherein at least one ring of the heterocyclic moiety has two hetero atoms and the heterocyclic moiety is selected from the group consisting of:

adeninyl;

azapurinyl;

barbituric acid;

benzimidazolethionyl;

benzimidazolonyl;

benzimidazolyl;

benzisothiazolyl;

benzisoxazolyl;

benzopyridazinyl;

benzothiazinyl;

benzothiazolyl;

benzoxazinyl;

benzoxazolinonyl;

benzoxazolyl;

cinnolinyl;

diazinyl;

dihydrobenzimidazolyl;

dihydrobenzothiazinyl;

dihydrooxazolyl;

dihydropyridazinyl;

dihydropyrimidinyl;

dihydrothiazinyl;

dioxopiperazinyl;

furopyrimidinyl;

guaninyl;

hexahydropyridazinyl;

hydantoinyl;

hydroimidazolyl;

hydropyrazinyl;

hydropyrazolyl;

hydropyridazinyl;

hydropyrimidinyl;

imidazolinyl;

imidazolyl;

imidazothiazolyl;

isothiazolyl;

isoxazolidinyl;

isoxazolinonyl;

isoxazolinyl;

isoxazolonyl;

isoxazolyl;

lumazinyl;

methylthyminyl;

methyluracilyl;

morpholinyl;

oroticyl;

oxazinonyl;

oxazolidinonyl;

oxazolidinyl;

oxazolidonyl;

oxazolinonyl;

oxazolinyl;

oxazolonyl;

oxazolopyrimidinyl;

oxazolyl;

perhydrocinnolinyl;

perhydropyrrolooxazinyl;

perhydropyrrolothiazinyl;

phthalazinyl;

piperazindionyl;

piperazinodionyl;

pteridinyl;

purinyl;

pyrazinyl;

pyrazolidinyl;

pyrazolidonyl;

pyrazolinonyl;

pyrazolinyl;

pyrazolonyl;

pyrazolopyridinyl;

pyrazolopyrimidinyl;

pyrazolotriazinyl;

pyrazolyl;

pyridazinyl;

pyridazonyl;

pyridopyrazinyl;

pyridopyrimidinyl;

pyrimidinethionyl;

pyrimidinyl;

pyrimidionyl;

pyrrolopyrimidinyl;

quinazolidinyl;

quinazolinonyl;

quinazolinyl;

quinoxalinyl;

tetrahydrooxazolyl;

tetrahydropyrazinyl;

tetrahydropyridazinyl;

tetrahydroquinoxalinyl;

tetrahydrothiazolyl;

thiazinyl;

thiazolidinonyl;

thiazolidinyl;

thiazolinonyl;

thiazolinyl;

thiazolyl;

thienopyrimidinyl;

thyminyl;

triazolopyrimidinyl;

uracilyl; and

xanthinyl.

14. The compound of claim 1, wherein at least one ring of the heterocyclic moiety has at least three hetero atoms and the heterocyclic moiety is selected from the group consisting of:

benzoxadiazinyl;

dithiadazolyl;

dithiazolyl;

hydrotriazolyl;

hydroxytriazinyl;

oxadiazinyl;

oxadiazolyl;

oxathiazinonyl;

oxatriazolyl;

pentazinyl;

pentazolyl;

sydnonyl;

tetraoxanyl;

tetrazinyl;

thiadiazinyl;

thiadiazolinyl;

thiadiazolyl;

thiadioxazinyl;

thiatriazinyl;

thiatriazolyl;

thiatriazolyl;

triazinoindolyl;

triazinyl;

triazolinedionyl;

triazolinyl;

triazolyl;

triphenodioxazinyl;

triphenodithiazinyl;

trioxanyl and trioxanyl.

15. The compound of claim 1, wherein the heterocyclic moiety is selected from the group consisting of:

dimethylxanthinyl, methylxanthinyl, phthalimidyl, homophthalimidyl, methylbenzoyleneureayl, quinazolinonyl, octylcarboxamidobenzenyl, methylbenzamidyl, methyldioxotetrahydropteridinyl, glutarimidyl, piperidonyl, succinimidyl, dimethoxybenzenyl, methyldihydrouracilyl, methyluracilyl, methylthyminyl, piperidinyl, dihydroxybenzenyl, and methylpurinyl.

16. The compound of claim 1, wherein the heterocyclic moiety has at least one substituent bonded to a ring carbon atom being by an sp² bond said ring carbon atom adjacent to a ring heteroatom.

18. The compound of claim 1, wherein the compound is selected from the group consisting of:

##STR110##

21. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient, the pharmaceutical composition being formulated for oral, parenteral, ex vivo or topical administration to a patient.

22. The composition of claim 21, wherein an oral dose of compound is from about 50 mg to about 1500 mg, twice or three times daily, a parenteral dose is from about 1.0 g to about 5.0 g administered (i.v., i.p., i.m., or s.c.) over a course of 24 hours, a topical formulation is from about 1% to about 4% concentration by weight, and the ex vivo culture concentration is from about 10 mM to about 500 mM.

17. A compound selected from the group consisting of:

##STR109##

19. A compound comprising a straight or branched aliphatic hydrocarbon structure of formula III:

##STR111## wherein;

n is an integer from one to four;

m is an integer from four to twenty;

R₄ is a substituted or unsubstituted terminal, heterocyclic moiety having one five- to six-membered ring or two five- to six-membered rings, (CH₂)_m being attached to a nitrogen atom of the heterocyclic moiety;

independently, R₆ and R₇ are hydrogen, a straight or branched chain alkane, alkene or alkyne of up to twenty carbon atoms in length, --(CH₂)_x R₈, at least one of R₆ or R₇ being --(CH₂)_x R₈, x being an integer from zero to fourteen and R₈ being a moiety having a general structure as provided in formula III;

##STR112## Z is N or CH;

R₃, R₄ and in of formula III are as defined above;

p is an integer from zero to four; and

R₉ is H or a straight or branched chain alkane, alkene or alkyne of up to twenty carbon atoms in length.

20. The compound of claim 19, wherein the compound is selected from the group consisting of:

##STR113##