EP0415294A2
Expired / Lapsed
EP
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Cyclohexanol derivatives, production and use thereof
Assignee: Takeda Pharmaceutical Co Ltd
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Filing: 1990-08-25
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Granted: —
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Expires: 2010-08-25
Abstract
Abstract The present invention relates to a compound of the formula: wherein A is halogen, N(O)mR¹R², N ⊕ R¹R²R³·X ⊖ , S(O)nR¹ or S ⊕ (O)mR¹R²·X ⊖ where R¹,R² and R³ are each optionally substituted hydrocarbon or heterocyclic group, X ⊖ is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R¹ and R² may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR⁴ where R⁴ is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group; provided that, when A is chlorine, E is an optionally substituted hydrocarbon or acyl excepting dinitrobenzoyl, a salt thereof, production and use thereof. The novel cyclohexanol derivatives of the present invention have angiogenesis inhibiting activity and anti-tumor activity, and they are used as anti-rheumatic agents, therapeutic agents of psoriasis, therapeutic agents of diabetic retinopathy and anti-tumor agents.
Inventors
- 👤 Shoji Kishimoto
- 👤 Shogo Marui
- 👤 Takeshi Fujita
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-24 03:00
CPC Classifications
C; C07; C07D; C07D303/00; C07D303/02; C07D303/12; C07D303/18; C07D303/20; C07D303/22; C07D303/23; C07D303/34; C07D303/36; C07D405/00; C07D405/02; C07D405/12; C07D405/14; C07D409/00; C07D409/02; C07D409/12; C07D417/00; C07D417/02; C07D417/12
Claims Analysis
Total Claims: 24
Claim 1
Independent Claim
152 words
A compound of the general formula: wherein A is halogen, N(O)mR¹R², N ⊕ R¹R²R³·X ⊖ , S(O)nR¹ or S ⊕ (O)mR¹R²·X ⊖ where R¹,R² and R³ are each optionally substituted hydrocarbon or heterocyclic group; X ⊖ is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R¹ and R¹ may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR⁴ where R⁴ is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group; provided that, when A is chlorine, E is an optionally substituted hydrocarbon or acyl excepting dinitrobenzoyl, or a salt thereof.
Claim 2
Dependent Claim
152 words
A compound of the general formula: wherein A is halogen, N(O)mR¹R², N ⊕ R¹R²R³·X ⊖ , S(O)nR¹ or S ⊕ (O)mR¹R²·X ⊖ where R¹,R² and R³ are each optionally substituted hydrocarbon or heterocyclic group; X ⊖ is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R¹ and R¹ may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR⁴ where R⁴ is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group; provided that, when A is chlorine, E is an optionally substituted hydrocarbon or acyl excepting dinitrobenzoyl, or a salt thereof.
Claim 3
Dependent Claim
40 words
The compound according to claim 1, wherein A is N(O)mR¹R², N ⊕ R¹R²R³·X ⊖ , S(O)nR¹ or S ⊕ (O)mR¹R²·X ⊖ where R¹, R², R³, X ⊖ , m and n are the same as defined above in claim 1.
Claim 4
Dependent Claim
86 words
The compound according to claim 2, wherein R¹, R² and R³ are each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₇₋₁₃aralkyl, 5- or 6-membered heterocyclic group containing nitrogen, oxygen or/and sulfur atom or bicyclic condensed heterocyclic ring of 5- or 6-membered heterocyclic ring containing nitrogen, oxygen or/and sulfur atom with a 5- or 6-membered ring, which may be substituted, or R¹ and R² form a 4- to 7-membered nitrogen or sulfur-containing ring or bicyclic condensed heterocyclic ring with a 5- or 6-membered cyclic group, which may be substituted.
Claim 5
Dependent Claim
38 words
The compound according to claim 1, wherein A is N(O)mR¹R² in which R¹ and R² are each C₁₋₆alkyl, or together with the adjacent nitrogen atom form a pyrrolidine, piperidine, morpholine or 4-methylpiperazine, and m is 0 or 1.
Claim 6
Dependent Claim
50 words
The compound according to claim 1, wherein A is N ⊕ R¹R²R³·X ⊖ in which R¹, R² and R³ are each C₁₋₆alkyl, or R¹ and R² together with the adjacent nitrogen atom form a pyrrolidine, piperidine, morpholine or 4-methylpiperazine and R³ is C₁₋₆alkyl, and X ⊖ is inorganic counter anion.
Claim 7
Dependent Claim
46 words
The compound according to claim 1, wherein A is S(O)nR¹ in which R¹ is C₁₋₆alkyl which may be substituted with hydroxyl, mesyloxy or phenyl which may be further substituted with halogen, hydroxymethyl or mesyloxymethyl, C₂₋₆alkenyl, phenyl, naphthyl, pyridyl or quinolyl, and n is 0 or 1.
Claim 8
Dependent Claim
72 words
The compound according to claim 1, wherein A is S ⊕ (O)mR¹R²·X ⊖ in which R¹ is C₁₋₆alkyl and R² is C₁₋₆alkyl which may be substituted with phenyl, C₂₋₆alkenyl, C₂₋₆alkynyl or phenyl which may be substituted with halogen or C₁₋₆alkyl, or R¹ and R² together with the adjacent sulfur atom form tetrahydrothiophene, thioxane, dihydrobenzo[c]thiophene, hexahydrobenzo[c]thiophene, perhydrobenzo[c]thiophene, tetrahydrobenzo[c]thiophene, dihydrothieno[3,4-c]pyridine, dihydrothieno[3,4-b]piradine, dihydrothieno[3,4-d]piridazine, m is 0 and X ⊖ is organic or inorganic counter anion.
Claim 9
Dependent Claim
12 words
The compound according to claim 1, wherein B is O or NH.
Claim 10
Dependent Claim
10 words
The compound according to claim 1, wherein D is 2-methyl-1-propenyl.
Claim 11
Dependent Claim
12 words
The compound according to claim 1, wherein E is hydrogen or C₁₋₆alkyl.
Claim 12
Dependent Claim
38 words
The compound according to claim 1, wherein E is C₁₋₆alkanoyl, C₇₋₁₁aroyl, 5- or 6-membered heterocyclic carbonyl containing 1 to 4 of nitrogen, oxygen or/and sulfur atoms, carbamoyl, thiocarbamoyl, C₆₋₁₁arylsulfonyl, C₇₋₁₃alkylsulfonyl, sulfamoyl, C₂₋₇alkoxycarbonyl or C₇₋₁₁aryloxycarbonyl, which may be substituted.
Claim 13
Dependent Claim
38 words
The compound according to claim 1, wherein E is benzoyl; carbamoyl; C₁₋₆alkylcarbamoyl which may be substituted with halogen; C₁₋₆alkanoylcarbamoyl which may be substituted with halogen, C₁₋₆alkylthio, C₆₋₁₁arylthio, C₇₋₁₃aralkylthio, quinolylthio or benzothiazolylthio; Ψ₂₋₆alkenylcarbamoyl; C₆₋₁₁arylcarbamoyl; morpholyl; C₆₋₁₁arylsulfonyl; C₁₋₆alkylsulfonyl or C₇₋₁₁aryloxycarbonyl.
Claim 14
Dependent Claim
65 words
The compound according to claim 1, wherein A is S ⊕ R¹R²·X ⊖ wherein R¹ is C₁₋₆alkyl and R² is C₁₋₆alkyl which may be substituted with phenyl, or R¹ and R² together with the adjacent sulfur atom form dihydrobenzo[c]thiophene and X ⊖ is halogen anion; B is O or NH; D is 2-methyl-1-propenyl; and E is hydrogen or C₁₋₆alkanoyl which may be substituted with halogen.
Claim 15
Dependent Claim
10 words
The compound according to claim 1, which is 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3,3a,4,7,7a-hexahydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride.
Claim 16
Dependent Claim
10 words
The compound according to claim 1, which is 4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride.
Claim 17
Dependent Claim
10 words
The compound according to claim 1, which is 4-(N′-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride.
Claim 18
Dependent Claim
60 words
A method of producing the compound according to claim 1 which comprises reacting a compound of the formula: wherein B, D and E are the same as defined above in claim 1, with halogenated hydrocarbon or a compound of the formula HNR¹R² or HSR¹, and if desired, by subjecting the reaction product to oxidation, N- or S-alkylation, hydrocarbonation or acylation.
Claim 19
Dependent Claim
149 words
A pharmaceutical composition which contains a compound of the formula: wherein A is halogen, N(O)mR¹R², N ⊕ R¹R²R³·X ⊖ , S(O)nR¹ or S ⊕ (O)mR¹R²·X ⊖ where R¹, R² and R³ are each optionally substituted hydrocarbon or heterocyclic group; X ⊖ is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R¹ and R² may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR⁴ where R⁴ is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a salt thereof and a pharmaceutically acceptable carrier or excipient therefor.
Claim 20
Dependent Claim
149 words
A pharmaceutical composition which contains a compound of the formula: wherein A is halogen, N(O)mR¹R², N ⊕ R¹R²R³·X ⊖ , S(O)nR¹ or S ⊕ (O)mR¹R²·X ⊖ where R¹, R² and R³ are each optionally substituted hydrocarbon or heterocyclic group; X ⊖ is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R¹ and R² may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR⁴ where R⁴ is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a salt thereof and a pharmaceutically acceptable carrier or excipient therefor.
Claim 21
Independent Claim
164 words
A method of inhibiting angiogenesis or treating tumor which comprises administering to mammal a therapeutically effective amount of a compound of the formula: wherein A is halogen, N(O)mR¹R², N ⊕ R¹R²R³·X ⊖ , S(O)nR¹ or S ⊕ (O)mR¹R²·X ⊖ where R¹, R² and R³ are each optionally substituted hydrocarbon or heterocyclic group; X ⊖ is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R¹ and R² may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR⁴ where R⁴ is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a pharmaceutically acceptable salt, optionally with a pharmaceutically acceptable carrier or excipient therefor.
Claim 22
Independent Claim
164 words
A method of inhibiting angiogenesis or treating tumor which comprises administering to mammal a therapeutically effective amount of a compound of the formula: wherein A is halogen, N(O)mR¹R², N ⊕ R¹R²R³·X ⊖ , S(O)nR¹ or S ⊕ (O)mR¹R²·X ⊖ where R¹, R² and R³ are each optionally substituted hydrocarbon or heterocyclic group; X ⊖ is a counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R¹ and R² may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR⁴ where R⁴ is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a pharmaceutically acceptable salt, optionally with a pharmaceutically acceptable carrier or excipient therefor.
Claim 23
Dependent Claim
159 words
An use of a compound of the formula: wherein A is halogen, N(O)mR¹R², N ⊕ R¹R²R³·X ⊖ , S(O)nR¹ or S ⊕ (O)mR¹R²·X ⊖ where R¹,R² and R³ are each optionally substituted hydrocarbon or heterocyclic group; X ⊖ is counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R¹ and R² may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR⁴ where R⁴ is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a pharmaceutically acceptable salt, optionally with a pharmaceutically acceptable carrier or excipient therefor in the preparation of a composition for inhibiting angiogenesis or treating tumor.
Claim 24
Dependent Claim
159 words
An use of a compound of the formula: wherein A is halogen, N(O)mR¹R², N ⊕ R¹R²R³·X ⊖ , S(O)nR¹ or S ⊕ (O)mR¹R²·X ⊖ where R¹,R² and R³ are each optionally substituted hydrocarbon or heterocyclic group; X ⊖ is counter anion; m is an integer of 0 or 1; n is an integer of 0 to 2; R¹ and R² may form a nitrogen-containing or a sulfur-containing heterocyclic ring, which may further form a condensed ring, with the adjacent nitrogen atom or sulfur atom, and these nitrogen-containing or sulfur-containing heterocyclic rings may have substituents, B is O or NR⁴ where R⁴ is hydrogen or an optionally substituted lower alkyl or aryl group, D is 2-methyl-1-propenyl group or isobutyl group, and E is hydrogen, an optionally substituted hydrocarbon or an optionally substituted acyl group, or a pharmaceutically acceptable salt, optionally with a pharmaceutically acceptable carrier or excipient therefor in the preparation of a composition for inhibiting angiogenesis or treating tumor.
References Cited (Backward Citations)
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