Claims
- 1. A substituted 2-pyridine cyclohexane-1,4-diamine compound corresponding to formula I
- 2. A compound according to claim 1, wherein R1 and R2 are independently selected from the group consisting of H and C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or R1 and R2 together form a ring and denote CH2CH2OCH2CH2, CH2CH2NR6CH2CH2 or (CH2)3-6, where R6 is selected from the group consisting of H and C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted.
- 3. A compound according to claim 2, wherein R1 and R2 are independently selected from the group consisting of H and C1-4 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, or R1 and R2 together form a ring and denote (CH2)4-5.
- 4. A compound according to claim 3, wherein R1 and R2 are independently selected from methyl and ethyl, or R1 and R2 together form a ring and denote (CH2)5.
- 5. A compound according to claim 1, wherein R3 is selected from the group consisting of H; C1-8 alkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C3-8 cycloalkyl, saturated or unsaturated, mono-or polysubstituted or unsubstituted; aryl or heteroaryl, each being mono- or polysubstituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkylene, each being mono- or polysubstituted or unsubstituted; SH, OH, F, Cl, I, Br, CN, NO2, NH2, and OR2, where R26 is C1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted.
- 6. A compound according to claim 1, wherein R3 is selected from the group consisting of H; C1-6 alkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; SH, OH, F, Cl, I, Br, CN, NO2, NH2, and OR26, where R26 is selected from C1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted.
- 7. A compound according to claim 6, wherein R3 is H.
- 8. A compound according to claim 1, wherein R4 is selected from the group consisting of H, C(X)R7, C(X) NR7R8, C(X)OR9, C(X)SR9 and S(O2)R9, where X═O or S.
- 9. A compound according to claim 8, wherein R4 is selected from the group consisting of H, C(X)R7, C(X)NR7R8 and C(X)OR9, where X=O.
- 10. A compound according to claim 9, wherein R4 is H or C(O)R7, where R7 is H or C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted.
- 11. A compound according to claim 10, where R7 is H or C1-3 alkyl, saturated, unsubstituted, branched or unbranched.
- 12. A compound according to claim 12, wherein R7 is CH3.
- 13. A compound according to claim 1, wherein R4 and R5 together form an N-containing heterocyclic ring containing from 3 to 8 atoms, saturated or unsaturated; mono- or polysubstituted or unsubstituted.
- 14. A compound according to claim 13, wherein said N-containing heterocyclic ring contains from 5 to 7 atoms, including in addition to said N, zero or 1 other heteroatom selected from the group consisting of N, S and O.
- 15. A compound according to claim 13, wherein the heterocyclic ring formed by R4 and R5 together is condensed with at least one other ring.
- 16. A compound according to claim 15, wherein said at least one other ring comprises an aromatic or heteroaromatic ring.
- 17. A compound according to claim 16, wherein the aromatic or heteroaromatic ring is condensed at least one further aromatic or heteroaromatic ring.
- 18. A compound according to claim 15, wherein the heterocyclic ring formed by R4 and R5 together is condensed with one or two other rings.
- 19. A compound according to claim 15, wherein the heterocyclic ring formed by R4 and R5 together is condensed with two other rings such that R4 and R5 together denote
- 20. A compound according to claim 1, wherein R4 is H or C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted.
- 21. A compound according to claim 20, wherein R4 is H or C1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted.
- 22. A compound according to claim 21, wherein R4 is H or saturated, unbranched and unsubstituted C1-3 alkyl.
- 23. A compound according to claims 1, wherein R5 is selected from the group consisting of C3-8 cycloalkyl, aryl and heteroaryl, each being unsubstituted or mono- or polysubstituted.
- 24. A compound according to claim 23, wherein R5 is selected from the group consisting of cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl, benzo[1,2,5]thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, and quinazolinyl, each being unsubstituted or mono- or polysubstituted.
- 25. A compound according to claim 24, wherein RS is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl, each being unsubstituted or mono- or polysubstituted.
- 26. A compound according to claim 1, wherein R5 is selected from the group consisting of —CHR11R12, —CHR1—CH2R12, —CHR11—CH2—CH2R12, —CHR11—CH2—CH2—CH2R12, —C(Y)R1, C(Y)—CH2R12, —C(Y)—CH2—CH2R12, and —C(Y)—CH2—CH2—CH2R12, where Y═O, S or H2.
- 27. A compound according to claim 26, wherein R5 is selected from the group consisting of —CHR11R12, —CHR11—CH2R12, —CHR11—CH2—CH2R12, —C(Y)R12, —C(Y)—CH2R12, and —C(Y)—CH2—CH2R12, where Y═O or S.
- 28. A compound according to claim 27, wherein R5 is selected from the group consisting of —CHR11R12, —CHR11—CH2R12, —CHR11—CH2—CH2R12, —C(Y)R12, and —C(Y)—CH2R12, where Y═O.
- 29. A compound according to claim 26, wherein R11 is selected from the group consisting of H; C1-4 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; and C(O)O—C1-4 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted.
- 30. A compound according to claim 29, wherein R11 is selected from the group consisting of H; C1-4 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; and C(O)O—C1-2 alkyl, saturated, unbranched, mono- or polysubstituted or unsubstituted.
- 31. A compound according to claim 30, wherein R11 is selected from the group consisting of H, CH3, C2H5, and C(O)O—CH3.
- 32. A compound according to claim 26, wherein R12 is selected from the group consisting of C3-8 cycloalkyl, aryl and heteroaryl, each being unsubstituted or mono- or polysubstituted.
- 33. A compound according to claim 32, wherein R12 is selected from the group consisting of cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl, benzo[1,2,5]thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, and quinazolinyl, each being unsubstituted or mono- or polysubstituted.
- 34. A compound according to claim 33, wherein R12 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, and pyrimidyl, each being unsubstituted or mono- or polysubstituted.
- 35. A compound according to claim 1, selected from the group consisting of:
N-(4-dimethylamino-4-pyridin-2-yl cyclohexyl)-N-[2-(1H-indol-3-yl)ethyl] acetamide dihydrochloride, non-polar diastereoisomer; N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-yl cyclohexane-1,4-diamine trihydrochloride, non-polar diastereoisomer; N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-yl cyclohexane-1,4-diamine trihydrochloride, polar diastereoisomer; (S)-2-(4-dimethylamino-4-pyridin-2-yl cyclohexylamino)-3-(1H-indol-3-yl) methyl propionate trihydrochloride, non-polar diastereoisomer; (S)-2-(4-dimethylamino-4-pyridin-2-yl cyclohexylamino)-3-(1H-indol-3-yl) methyl propionate trihydrochloride, polar diastereoisomer; and (S)-2-(4-dimethylamino-4-pyridin-2-yl cyclohexylamino)-3-(1H-indol-3-yl) propionic acid dihydrochloride, non-polar diastereoisomer in the form of a racemate, a pure stereoisomer, a mixture of stereoisomers in any desired mixing ratio, a free base, a salt or a solvate.
- 36. A compound according to claim 1, wherein said compound is in the form of a pure enantiomer or diastereoisomer.
- 37. A compound according to claim 1, wherein said compound is in the form of a mixture of enantiomers or diastereoisomers.
- 38. A compound according to claim 1, wherein said compound is in the form of a salt with a physiologically compatible acid.
- 39. A compound according to claim 1, wherein said compound is in the form of a hydrate.
- 40. A pharmaceutical composition comprising at least one compound according to claim 1 and at least one carrier, adjuvant or another active substance.
- 41. A pharmaceutical composition according to claim 40, comprising said compound and an opioid or an anaesthetic.
- 42. A pharmaceutical composition according to claim 41, comprising said compound and morphine or an anaesthetic selected from the group consisting of hexobarbital and halothane.
- 43. A method of treating pain in a patient, said method comprising administering to said patient an effective pain treating amount of at least one compound according to claim 1.
- 44. A method according to claim 43, wherein said pain is acute pain, neuropathic pain, or chronic pain.
- 45. A method of treating a patient for a condition selected from the group consisting of anxiety, stress, stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, general cognitive disfunctions, learning and memory difficulties, withdrawal symptoms, alcohol dependency or abuse, drug dependency or abuse, medication dependency or abuse, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraines, hearing difficulties, deficient intestinal motility, eating disorders, anorexia, obesity, locomotive disorders, diarrhea, cachexia, and urinary incontinence, or for providing muscle relaxant, anticonvulsive, anaesthetic, diuretic, anti-natriuretic, or anxiolytic treatment, said method comprising administering to said patient a pharmaceutically effective amount of at least one compound according to claim 1.
- 46. A method according to claim 45, wherein said compound is co-administered with an opioid analgesic or with an anaesthetic.
- 47. A process for producing a compound according to claim 1 wherein R3═H, said process comprising the steps of:
a) reacting a cyclohexane-1,4-dione protected with groups S1 and S2 according to formula II with a cyanide in the presence of a compound having the formula HNR01R02 to produce a protected N-substituted 1-amino-4-oxocyclohexane carbonitrile compound corresponding to formula III 19and then optionally acylating, alkylating or sulfonating at least once in any sequence, or if at least one of R01, R02, and R06=H protected by a protective group, eliminating at least one protective group and then optionally acylating, alkylating or sulfonating, or if at least one of R01, R02, and R06=H, introducing at least one H-protective group and then optionally acylating, alkylating or sulfonating, b) contacting the aminonitrile of formula III with cyclopentadienyl cycloocta-1,5-diene cobalt (I) [cpCo(cod)] and irradiating under acetylene to produce a compound corresponding to formula IVa 20and then optionally acylating, alkylating or sulfonating at least once in any sequence, or if at least one of R01, R02, and R06=H protected by a protective group, eliminating at least one protective group and then optionally acylating, alkylating or sulfonating, or if at least one of R01, R02, and R06=H, introducing at least one H-protective group and then optionally acylating, alkylating or sulfonating, c) eliminating the protective groups S1 and S2 from the compound of formula IVa to produce a tetrasubstituted 4-aminocyclohexanone compound corresponding to formula IV 21and then optionally acylating, alkylating or sulfonating at least once in any sequence, or if at least one of R01, R02, and R06=H protected by a protective group, eliminating at least one protective group and then optionally acylating, alkylating or sulfonating, or if at least one of R01, R02, and R06=H, introducing at least one H-protective group and then optionally acylating, alkylating or sulfonating, d) reductively aminating the tetrasubstituted 4-aminocyclohexanone compound of formula IVa with a compound having the formula HNR04R05 to produce a 2-pyridine cyclohexane-1,4-diamine compound corresponding to formula V 22and then optionally acylating, alkylating or sulfonating in any sequence, or if at least one of R01, R02, R04, R05, and R06=H protected by a protective group, eliminating at least one protective group and then optionally acylating, alkylating or sulfonating, or if at least one of R01 R O2, R04, R05, and R06=H, introducing at least one H-protective group and then optionally acylating, alkylating or sulfonating to produce a compound corresponding to formula I, wherein R01 and R02 are independently selected from the group consisting of H; H provided with a protective group; C1-8 alkyl and C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl and heteroaryl, each being mono- or polysubstituted or unsubstituted; and aryl, C3-8 cycloalkyl and heteroaryl, each bonded via C1-3 alkylene and each being mono- or polysubstituted or unsubstituted; or R01 and R02 together form a ring and denote CH2CH2OCH2CH2, CH2CH2NR06CH2CH2 or (CH2)3-6, where
R06 is selected from the group consisting of H; H provided with a protective group; C1-8 alkyl and C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl and heteroaryl, each being mono- or polysubstituted or unsubstituted; and aryl, C3-8 cycloalkyl and heteroaryl, each bonded via C1-3 alkylene and each being mono- or polysubstituted or unsubstituted; R04 is selected from from the group consisting of H; H provided with a protective group; and C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; R05 is selected from the group consisting of H; H provided with a protective group; C3-8 cycloalkyl, aryl and heteroaryl, each being unsubstituted or mono- or polysubstituted; —CHR11; —CHR11—CH2R; —CHR11—CH2—CH2R; —CHR11—CH2—CH2—CH2R; —C(Y)R12; —C(Y)—CH2R12; —C(Y)—CH2—CH2R12 and —C(Y)—CH2—CH2—CH2R12, where
Y═H2, R11 is selected from the group consisting of H and C1-7 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; and R12 is selected from the group consisting of H, and C3-8 cycloalkyl, aryl and heteroaryl, each being unsubstituted or mono- or polysubstituted; or R04 and R05 together form a heterocyclic ring containing form 3 to 8 atoms, saturated or unsaturated and mono- or polysubstituted or unsubstituted; and S1 and S2 are independently selected from protective groups or together denote a protective group.
- 48. A process according to claim 47, wherein the protective groups at H in at least one of R01, R02, R04, R05 and R06 are selected from the group consisting of alkyl, benzyl and carbamates.
- 49. A process according to claim 47, wherein the reductive amination in step d) takes place in the presence of ammonium formate, ammonium acetate or NaCNBH3.
- 50. A process according to claim 47, wherein instead of the reductive amination with HNR04R05 in step d), compound IV is reacted with hydroxylamine and reduced after oxime formation.
- 51. A process according to claim 47, wherein the irradiation in step b) lasts between 5 and 7 hours.
- 52. A process according to claim 47, wherein the irradiation in step b) takes place at room temperature.
- 53. A process according to claim 47, wherein the irradiation in step b) takes place in a saturated acetylene atmosphere.
- 54. A process according to claim 47, wherein the irradiation in step b takes place under a protective gas.
- 55. A process for producing a compound according to claim 1 wherein R3═H, said process comprising the steps of:
a) reductively aminating a cyclohexane-1,4-dione protected with groups S1 and S2 according to formula II with a compound having the formula HNR04R05 to produce a 4-aminocyclohexanone compound corresponding to formula VI 23and then optionally acylating, alkylating or sulfonating at least once in any sequence, or if at least one of R04 and R05=H protected by a protective group, eliminating at least one protective group and then optionally acylating, alkylating or sulfonating, or if at least one of R04 and R05=H, introducing at least one H-protective group and then optionally acylating, alkylating or sulfonating, b) reacting the 4-aminocyclohexanone compound of formula VI with cyanide in the presence of a compound having the formula HNR01R02 to produce a cyclohexanone nitrile compound corresponding to formula VII 24and then optionally acylating, alkylating or sulfonating at least once in any sequence, or if at least one of R01R02, R04, R05 and R06=H protected by a protective group, eliminating at least one protective group and then optionally acylating, alkylating or sulfonating, or if at least one of R01, R02, R04, R05 and R06═H, introducing at least one H-protective group and then optionally acylating, alkylating or sulfonating, c) contacting the cyclohexanone nitrile compound of formula VII with cyclopentadienyl cycloocta-1,5-diene cobalt (I) [cpCo(cod)] and irradiating under acetylene to produce a 2-pyridine cyclohexane-1,4-diamine compound corresponding to formula V 25optionally acylating, alkylating or sulfonating at least once in any sequence, or if at least one of R01, R02, R04, R05 and R06=H protected by a protective group, eliminating at least one protective group and then optionally acylating, alkylating or sulfonating, or if at least one of R01, R02, R04, R05 and R06=H, introducing at least one H-protective group and then optionally acylating, alkylating or sulfonating to produce the compound corresponding to formula I, wherein R01 and R02 are independently selected from the group consisting of H; H provided with a protective group; C1-8 alkyl and C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl and heteroaryl, each being mono- or polysubstituted or unsubstituted; and aryl, C3-8 cycloalkyl and heteroaryl, each bonded via C1-3 alkylene and each being mono- or polysubstituted or unsubstituted, or R01 and R02 together form a ring and denote CH2CH2OCH2CH2, CH2CH2NRO6CH2CH2 or (CH2)3-6, where
R06 is selected from the group consisting of H; H provided with a protective group; C1-8 alkyl and C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl and heteroaryl, each being mono- or polysubstituted or unsubstituted; and aryl, C3-8 cycloalkyl and heteroaryl, each bonded via C1-3 alkylene and each being mono- or polysubstituted or unsubstituted; R04 is selected from the group consisting of H; H provided with a protective group; and C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; R05 is selected from the group consisting of H provided with a protective group; C3-8 cycloalkyl, aryl and heteroaryl, each being unsubstituted or mono- or polysubstituted; —CHR11R2; —CHR11—CH2R12; —CHR11—CH2—CH2R12; —CHR11—CH2—CH2—CH2R12; —C(Y)R12; —C(Y)—CH2R12; —C(Y)—CH2—CH2R12, and —C(Y)—CH2—CH2—CH2R12, where
Y═H2; R11 is selected from the group consisting of H, C1-7 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; and R12 is selected from the group consisting of H, and C3-8 cycloalkyl, aryl and heteroaryl, each being unsubstituted or mono- or polysubstituted, or R04 and R05 together form a heterocyclic ring containing from 3 to 8 atoms, saturated or unsaturated; mono- or polysubstituted or unsubstituted, and S1 and S2 are independently selected from the group consisting of protective groups or together denote a protective group.
- 56. A process according to claim 55, wherein the protective groups at H in at least one of R01, R02, R04, R05 and R06 are selected from the group consisting of alkyl, benzyl and carbamates.
- 57. A process according to claim 55, wherein the irradiation in step c) lasts between 5 and 7 hours.
- 58. A process according to claim 55, wherein the irradiation in step c) takes place at room temperature.
- 59. A process according to claim 55, wherein the irradiation in step c) takes place in a saturated acetylene atmosphere.
- 60. A process according to claim 55, wherein the irradiation in step c) takes place under a protective gas.
Priority Claims (1)
Number |
Date |
Country |
Kind |
101 23 163.6 |
May 2001 |
DE |
|
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of international patent application no. PCT/EP02/05078, filed May 8, 2002, designating the United States of America, and published in German as WO 02/090330, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on Federal Republic of Germany patent application no. DE 101 23 163.6, filed May 9, 2001.
Continuations (1)
|
Number |
Date |
Country |
Parent |
PCT/EP02/05078 |
May 2002 |
US |
Child |
10704200 |
Nov 2003 |
US |